摘要:

Recent Advances in the Use of Enzyme-catalysed Reactions in Organic Synthesis N. J. Turner Department of Chemistry University of Exeter Exeter EX4 400 Reviewing the literature published between July 1988 and December 1992 (Continuing the coverage of the literature in Natural Product Reports 1989 Vol. 6 p. 625) 1 Introduction 2 Hydrolytic Enzymes 2.1 Esterases and Lipases 2.2 Proteases and Acylases 2.3 Lipases and Esterases in Organic Solvents 2.4 Nitrile Hydrolysis 3 Reduction 3.1 Reduction of Ketones and Aldehydes 3.2 Reduction of 1,2 and 1,3-Dicarbonyl Compounds 4 Oxidation 4.1 Hydroxylation of Aromatic Rings 4.2 Hydroxylation at Non-aromatic Positions 4.3 Miscellaneous Oxidations 5 Other Biotransformations 5.1 Aldolases for Carbon-Carbon Bond Formation 5.2 Enzymes other than Aldolases for Carbon-Carbon Bond Formation 6 Enzymes Involved in Carbohydrate/Oligosaccharide Synthesis 6.I Glycosyl Transferases 6.2 Glycosidases 7 Novel Biocatalysts 7.1 Catalytic Antibodies 7.2 Modification of Existing Enzymes 8 References 1 Introduction During the period since the last review in Natural Product Reports of enzyme catalysis as applied to organic synthesis there has been a steady expansion of published literature. In addition there has been a shift in the emphasis of the work. Five years ago the idea of using enzymes to catalyse specific synthetic steps was still largely confined to laboratories with the necessary expertise.Nowadays the use of certain types of enzymes e.g. lipases and esterases can be considered to be a reliable and routine step in a synthetic sequence. Many groups both in academe and industry have successfully employed biocatalysis in the stereoselective synthesis of complex natural products. Apprehension regarding the inclusion of an enzymic transformation is receding as more biocatalytic processes are successfully taken to the plant stage. However despite this development many questions both general and specific remain unanswered is it better to use whole cells or an isolated enzyme?; can nicotinamide co-factors be recycled effectively?; what are the advantages of using lipases and esterases in organic solvents? Importantly the range of reactions being examined is increasing.Areas such as oxidation (e.g. remote hydroxylation) carbon-carbon bond formation and oligosaccharide synthesis are receiving increased attention. Five years ago a review of the literature of the synthetic application of nitrile hydrolysing enzymes would have revealed only a few isolated papers. Recently a series of papers has begun to emerge revealing the potential for using these enzymes to effect the hydrolysis of a wide range of nitriles under mild conditions. The aim of this review is two fold. First to highlight those biocatalytic methods (e.g. hydrolysis reduction) that can be confidently and reliably used to prepare target molecules in optically active form and second to drawn attention to emerging reactions (e.g.hydroxylation C-C bond synthesis) that may soon be in a form suitable for more widespread use. During the period of review a number of general reviews on enzyme-catalysed organic synthesis have appeared.l-' 2 Hydrolytic Enzymes 2.1 Esterases and Lipases A useful review on esterolytic and lipolytic enzymes has appeareda together with an overview of the applications of pig liver esterase (PLE) in asymmetric synthesi~.~ Sih's group have reported an elegant approach to the synthesis of optically active dihydropyridines. Since the chiral centre in the product is relatively hindered then conventional approaches to hydro- lysing the corresponding ester have been unsuccessful.Sih's approach has been to remove the electrophilic carbonyl group from the potential chiral centre by the use of a spacer group. After careful experimentation they were able to find a set of conditions that converted the diester (1) to the optically active dihydropyridine (2) with an enantiomeric excess (e.e.) up to 97 %.lo Complementary results have been obtained by another e.e.= 3547% yield = 834% 1 NATURAL PRODUCT REPORTS 1994 SCH2CH2C02Me Pseudomonaslipase - ,SCH2CH2C02Me steps- ArCH Ar*H \SCH2CH2C02Me SCH2CH2CO2H CI SCH$2H$2ONMe2 (3) (4) (5) 0oAo-o OAc I op0:- 2-o3p0."OQOH 0po:- (13) 0 Pseudomonas lipase 0 R= OMe K-10 R' OMe Rw OH group.ll A useful intermediate for the synthesis of potent agonists of leukotriene LTD has been prepared by Pseudomonas lipase catalysed hydrolysis.Hydrolysis of the prochiral dithioacetal (3) gave the corresponding half-ester (4) in 92 Yo yield with an enantiomeric excess of 98 YO,which was then elaborated further into both the (R)and (S)-isomers of MK-0571 (5)." A useful model for rationalizing the Candida cylindracea catalysed hydrolysis of esters of bicyclic alcohols has been reported. For alcohols containing bicyclo[2.2.llheptane and bicyclo[2.2.2]octane units the enantioselectivity has been compared and rationalized on the basis of the proposed m0de1.l~ The ring opening of a-substituted cyclic anhydrides (6) has been achieved using lipase Amano P (from Pseudomonas juorescens). Preferential attack occurs at the less hindered carbonyl group to give monoesters with high regioselectivity.l4 A potentially useful C chiral building block (7) has been prepared by porcine pancreatic lipase (PPL) catalysed hy-drolysis.The half-ester (7) obtained in 63YOyield and 96 YOe.e. via PPL catalysed hydrolysis of the corresponding prochiral diacetate can be converted to a synthetic equivalent of (8).15 The optically active bicycloalcohol (9) was prepared by lipase catalysed hydrolysis of the corresponding racemic acetate. Alcohol (9) was then converted into the enone (10) and further elaborated into (+ )-cuparenone (1 1).l6 D-myo-Inositol 1,4,5-triphosphate (1 3) plays an important role in secondary messenger functions being derived by breakdown of phosphatidylinositol 4,5-trisphosphate.Syn-thetic approaches to (13) need to address the problems of enantiomeric resolution during synthesis and the preparation of differentially protected intermediates. By the use of chol-esterol esterase (-)-(12) can be prepared by hydrolysis of the racemic diacetate (+)-(12) in 34% yield and 86 % e.e. Alkaline hydrolysis of (-)-(12) gave the (+)-diol which was re-crystallized from ether-hexane (1:3)to give the diol with > 98 YOe.e. The diol was then converted into (-)-(13) in seven steps and an overall yield of 45%.17 A useful method for preparing optically pure sulfoxides has been reported by Burgess et al. Racemic methyl sulfinyl acetates (&)-(14) are hydrolysed by Pseudomonas lipase K-10 to give optically active carboxylic acid products (15).The lipase was tolerant of a wide range of substituents (R =p-N02C6H4 p-ClC,H, Ph p-MeOC,H, Bun cyclohexyl) in all cases the recovered ester (14)having > 98 YOe.e.18The hydrolysis of enol esters to the corresponding a-substituted ketones has been reported to give optically active products via enantioface differentiation. By using cycloalkanone enol esters (16) in the presence of the microorganism Pichia miso at pH 6.5 optically active products (17) were derived.lg PLE has been widely used as a versatile catalyst for carrying out enantioselective hydrolyses of ester-containing sub-strates.20. 21 However its applications in asymmetric synthesis have been somewhat hampered by the uncertainty concerning NATURAL PRODUCT REPORTS 1994-N.J. TURNER the absolute configuration of the product obtained. To overcome this problem Jones and his group have developed a simple active site model of the enzyme.22 The model which is based on simple cubic space descriptors accounts for the structural selectivity and stereospecificity of PLE-catalysed hydrolyses so far documented. Most importantly it can be used in a predictive way for new substrates. Indeed the paper gives guidelines for construction of the model on a desk-top scale. A review detailing the range of PLE-catalysed reactions has appeared.23 An active-site model for PPL-catalysed hydrolyses has been reported based on the known transformations of primary acetate esters. The authors note the problems associated with contaminant enzymes (e.8.cholesterol esterase) in PPL preparations but predict that when these are overcome it should be possible to provide a model for PPL which is as accurate as that for PLE in predicting the stereoselectivity of new reactionsz4 The preparation of chiral derivatives of tris(hydroxymethy1)- methane has been studied by Seebach’s Using a range of diacylated derivatives of ethyl 3-hydroxy(hydroxymethyl) propionate the best results were obtained with the dihexanoate (1 8) which was converted into the monohexanoate (1 9) using PPL (85% e.e.); (19) could then be converted into the desired asymmetric tris(hydroxymethy1)methane derivatives.Crude pig liver acetone powder (PLAP) has been found to hydrolyse trans-1-acetoxy-2-aryloxycyclohexanols(20) in 90-99 % e.e.26 Optically active (R)-(21) obtained by lipase-catalysed hydrolysis of the corresponding racemate has been converted into (R)-mevalonolactone (22) in seven steps and an overall yield of 21.5 %.27 The lipase-catalysed resolution provides an interesting example of the hydrolysis of an ester having a hindered a-centre.The employment of hydrolases to provide useful quantities of optically active material for multi-step natural product synthesis is well illustrated by a number of recent reports. Sih’s group have used four separate enzyme-catalysed reactions to provide building blocks for the C-10-C-34 fragment of FK-506.28,29 PPL-catalysed hydrolysis of (*)-(23) gave (+)-(23) with > 99% e.e.thus providing the C-10-C-13 portion. The C-14-C-18 fragment was derived from (25) which was in turn obtained from the asymmetric reduction of optically pure (24) using baker’s yeast. Similarly the C-2042-34 fragment (3 1) was obtained from the chiral intermediates (27) and (28). Analogous approaches have been adopted for the enantiospecific synthesis of venturicidin30 and the C-244-34 segment of FK-506.31 P S OTBDMS 0 PPh2 Me OMe bMe Me Me AcO.. Psedomonas HOa lipase (AK) JO2.. * baker‘syeast &02Et -Me0 C02Me Me0 C02Me OH 0 Me0 CHO (311 MeO*C$N;c; Me02C N-Chloro-2,2-bis(methoxycarbonyl)aziridine(32) has been obtained with high enantiomeric purity by enzymic hydrolysis using either a-chymotrypsin or a lipase from Rhizopus dele~zar.~~ The first-order rate constant and the activation parameters for pyramidal inversion at nitrogen were de-termined.2.2 Proteases and Acylases Roberts and co-workers have reported an interesting and commercially useful biotransformation namely the enantio- selective hydrolysis of the racemic bicyclic lactam ( & )-(33). Using a Rhodococcus species they were able to obtain a highly selective hydrolysis resulting in both the recovered lactam (33) and amino acid (34) being nearly optically pure. The amino acid was subsequently elaborated to the anti-viral carbocyclic nucleoside carbovir (35).33 Whiteside and co-workers have reported a detailed and comprehensive study of acylase I (EC 3.5.1.14) from both porcine kidney and the fungus Aspergillus.The enzyme catalyses the hydrolysis of a wide range of N-acyl-L-amino acids (both natural and unnatural) producing homochiral products from racemic mixtures. 34 Using L-aspartate diesters as substrates chymotrypsin can catalyse regioselectively the hydrolysis of either the a-or p-ester. For the dimethyl isopropyl and benzyl esters the enzyme almost exclusively attacks the westers whereas for the dicyclopentyl and dicyclohexyl esters the hydrolysis occurs preferentially at the The enzymic synthesis of peptides has been reviewed.36 Topics covered include thermodynamically controlled peptide synthesis use of organic solvents kinetically controlled peptide (33) 98% e.e. Dorcine Dancreatic ’ tipase dry ether NATURAL PRODUCT REPORTS 1994 synthesis use OfD amino acids and immobilization of enzymes.In order to identify the factors influencing the selectivity between aminolysis and hydrolysis in enzyme-catalysed peptide synthesis a systematic study was carried out for kinetically controlled peptide ~ynthesis.~’ The reaction temperature the type of C-terminal protecting group and different organic co- solvents all showed little influence on the selectivity. The enzyme excess nucleophile pH N-terminal protecting group and ionic strength of the solution were identified as major factors controlling the selectivity and therefore the yield of the dipeptide synthesis. Under optimized conditions the selectivity of the a-chymotrypsin-catalysed synthesis of Phe-Ser could be increased from 35 to 100%.The effect of selectively modifying an amino acid residue in a-chymotrypsin with respect to peptide synthesis has been in~estigated.~~ The mutant [Met- 192 sulfoxidel-a-chymotrypsin was examined for its ability to carry out these reactions and deductions were made about active-si te conditions. 2.3 Lipases and Esterases in Organic Solvents Lactonization of (f)-4-hydroxypentanoic acid (36) in dry ether in the presence of porcine pancreatic lipase leads to a 36% yield of the butyrolactone (37) with 94% e.e.39940 An ingenious method for preparing optically active cyanohydrin acetates has been rep~rted.~’ The initial reaction involves formation of a racemic cyanohydrin (40) via the reaction of an aldehyde (38) with acetone cyanohydrin (39).Subsequent lipase catalysed acetylation using isopropenyl acetate as the acetyl donor results in a kinetic resolution leading to (41) with concomitant in situ racemization of the unreacted cyanohydrin via the prochiral aldehyde. The application of lipases in organic solvents has been reviewed by two group^^^,^^ together with a discussion on enzyme-catalysed irreversible acyl The racemic ferrocene derivative (42) has been enantio- selectively esterified to give (43) using Pseudomonas JEuorescens lipase and the corresponding acyl Racemic (1,l’-binaphthyl)-2,2’-diol (44) has been acylated stereoselectively 0 (34) > 98% e.e. Me anion-exc hange resin (OH-form) L OH Pseudomonas sp.lipase OAC 10 mol % RACN % R*CN (38) HO CNA (40) AcO e.e. 70-91% (39) yield 68-96% Me Me &H I OH Pseudomonas fluorescens -+ I OCOR lipase NATURAL PRODUCT REPORTS 1994-N. J. TURNER &OR Scheme 1 (46) R = Pr" c'6H330v OH (45) OH (47) R = Pr" 0 Reagents i "'>roL lipase c' CI n with enol esters in diisopropyl ether-acetone (9 1)to give solely (R)-2-acyloxy-2'-hydroxyl- 1,l'-binaphthyl with 9&95 YOe.e. and unreacted (S)-binaphthol (69-89 % e.e.). Alternatively, simple hydrolysis of racemic binaphthylmonochloroacetyl ester gave (R)-binaphth~l.~~ PPL and Chromobacterium viscosum lipase catalyse trans- esterification reactions between ethyl esters of carboxylic acids and tri-n-butyltin ethers of primary and secondary Crown ethers have been found to enhance the rate of the a-chymotrypsin catalysed transesterification of Ac-Phe-OEt with propanol in n-octane and to a lesser degree when subtilisin is Oxime acetates and acrylates have been used effectively as irreversible acyl transfer agents for lipase-catalysed trans- esterifications in organic media.49 Various lipases were screened in order to find a system that was capable of regioselectively acylating either of the two hydroxyl groups present in the tetrahydrofuran derivative (45).Out of 20 lipases examined a number gave useful selectivities producing the corresponding acylated products (46) and (47) using trichloroethyl butyrate (5 equivalents) as the acylating agent and benzene as the solvent.For example with Humicola lanuginosa the ratio of (46) (47) was 3 :97 (71 YOconversion) whereas the use of Rhizopus juponicus gave a corresponding ratio of 86 14 (96% conversion). The reactions could be carried out on a scale of up to 400 mg5' Two independent studies have been made of the factors r! Rhodococcus sp. -A NC CN NC C02H (52) (53) controlling sequential biocatalytic kinetic resolutions especially those involving lipases and e~terases.~~.~~ In the first quantitative expressions have been developed that govern these kinetic resolutions in order to calculate relative kinetic constants and hence allow the optimization of chemical and optical yields. In this way enantiomerically pure (2R,4R)-and (2S,4S)-pentane-2,4-diols have been prepared by sequential enantioselective esterifications in anhydrous isooctane.In the second a lipase-catalysed inter-esterification procedure has been developed for the preparation of esters of chiral secondary alcohols in high enantiomeric purity ;e.g. stirring the immobilized lipase with the racemic ester (48) in hexane containing cyclohexanecarboxylic acid gave after 66 h a 27 % yield of the optically active ester (-)-(49). Guidelines for solvent selection for hydrolase-catalysed reactions in mainly organic systems have been put These predictions are based on data for the liquid-liquid distribution of the reactants. The effective equilibrium constant for esterification reactions is predicted to alter by more than four orders of magnitude on changing between different water- immiscible solvent systems.Castanospermine (50) and I-deoxynojirimycin (51) are both potent glycosidase inhibitors and have been found to have anti- HIV properties. In an attempt to modify their effects several biologically active esters have been prepared using subtilisin- catalysed acylation in ~yridine.~~-~~ Under these conditions subtilisin possesses a high regioselectivity and at the same time a broad substrate specificity and enantioselectivity. It is possible to regulate the hydrophobicity of the acylating group (acetyl butyryl octanoyl) or to incorporate an aromatic moiety (phenylacetyl) or L-or D-amino acids (phenylalanyl L-and D-alanyl). 2.4 Nitrile Hydrolysis The ability of enzymes to hydrolyse nitriles to amides and carboxylic acids has been long known to biochemists but vastly under exploited by organic chemists.It is generally recognized that there are two enzymic pathways available (Scheme 1). In path (a) the nitrile is hydrolysed via a two-step process involving initially a hydratase that converts the nitrile to an amide followed by an amidase that transforms the amide to a carboxylic acid. The alternative pathway (b) involves direct conversion of a nitrile to a carboxylic acid under the influence of a nitrilase. The enzymes are widely distributed in micro- organisms and indeed a number of groups have reported that a broad range of nitrile and amide containing substrates can be hydr~lysed.~~-~' Recent work in this area has been directed towards the preparation of optically active compounds.Thus two groups have independently shown that a Rhodococcus sp. is effective for the kinetic resolution of racemic a-aryl-propionitriles61 and for the hydrolysis of prochiral P-substituted glutaronitriles (52) yielding the corresponding optically active nitrile-acids (53).62 Bianchi et al. have carried out the enantioselective hydrolysis of racemic aryloxynitriles using Brevibacterium irn~eriale.~~ NATURAL PRODUCT REPORTS 1994 I I + I Mn Mn Mn OC’ A ‘CO OC’ A ‘CO OC’ A ‘CO co co co (*I4541 (55) (54) 35% yield 30% yield >99% e.e. > 99% e.e Br Thermoana erobium brockii Br 0 3 Reduction 3.1 Reduction of Ketones and Aldehydes The manganese tricarbonyl derivative (54) has been successfully reduced by horse liver alcohol dehydrogenase (HLADH) with concomitant kinetic resolution to yield (55).64 Both enantiomers of phorocantholide 1 (58) a defensive secretion of the eucarypt longicorn (Phoracantha synonyma) have been prepared using baker’s yeast mediated reduction of a ketone as the key step.Thus diethyl 3-oxoglutarate was converted into the keto acid (56) and then reduced with immobilized baker’s yeast to give (57) which was subsequently converted into (58).65 The alcohol dehydrogenase from Thermoanaerobium brockii reduces the keto group of the isoxazole (59) to give the (S)-isomer of (60) in > 98 % ex. Bromide (60) was then converted through to (S)-(61) a potent and selective b,-adrenergic stimulant.The corresponding (R)-(61) was prepared via a highly enantioselective (97 % e.e.) transesterification of the racemic bromohydrin (60) with trifluoroethyl octanoate to give (62) (catalysed by lipase P from P. JEuorescens).66 Baker’s yeast reduction of methyl 3-oxopentanoate normal:j gives the corresponding methyl 3-hydroxypentanoate having the D-configuration. However if the yeast is initially im- mobilized in magnesium alginate and the reaction is run under a high concentration of magnesium ion then the selectivity is reversed to give the isomer.^' A review has been published covering the synthetic use of amino acid dehydrogenases hydroxy acid dehydrogenases and alcohol dehydrogenases.In addition methods for co-factor regeneration are discussed.68 A new NAD-dependent alcohol dehydrogenase isolated from a Pseudomonas species catalyses the reduction of several acyclic ketones to the corresponding optically active alcohols with very high enantioselectivity (90 to > 98% e.e.).69 The stereochemical course of the reduction was detected to be the transfer of the pro-R hydrogen from NADH to the Si face of the carbonyl group a process different from that known for II :A (57) 0 Me H HO H (67) 80% yield > 99% e.e. (68) (R)-(69) (S)-(69) baker’s yeast 62% yield 43% e.e. immobilized 50% yield baker’s yeast 64% e.e. other dehydrogenases. Baker’s yeast promotes moderately enantioselective but diastereorandom reduction of the diketone (63) via preferential hydrogen transfer to the exo-Si and endo-Re faces of one of the two carbonyl groups to give the keto alcohols (64) and (65)’ respe~tively.’~ Reduction of the symmetrical irontricarbonyl dialdehyde (66) with baker’s yeast NATURAL PRODUCT REPORTS 1994-N.J. TURNER Geotrichurncandidurn 0glycerol dehydrogenase hexane AC02Bu f\ (72) NADH + H+ NAD+ t I OH ~\CO~BU (73) >99%e.e. ?H A,"+ ?H @x -(J; Pseudornonas OH I '02 Amano P-30 steps p utida 11. lipase 0 0 * ao" I (75) OH OAc NH2 (77) (78) 95% e.e. (+)-conduritol C CI 0 5 OH . .. I II -(79) HO p3 O Reagents i (MeO),CMe,; ii 0,;iii NaBH,; iv DIBAL; v Ph,P=CH,; vi LiAIH leads to a highly efficient synthesis of the optically pure hydroxyaldehyde product (67).71 3.2 Reduction of 1,2-and 1,3-Dicarbonyl Compounds The stereoselectivity of baker's yeast mediated reductions of p-keto esters [e.g.(68) to (69)] can be modulated by immobilization of the cells within a calcium or magnesium alginate gel. Thus when using the immobilized yeast the addition of 3.0 M MgCl to the solution causes an inversion of the stereoselectivity of the ketone reduction.72 Baker's yeast entrapped in calcium alginate beads provides a readily reusable catalyst for stereoselective reductions and has been used to prepare (5Z 13S)-tetradec-5-en- 13-0lide an aggregation pheromone of the Crytolesters grain beetle.73 The octyl ester (70) was obtained in 82% e.e.and 77% chemical yield via reduction of the corresponding p-keto ester with baker's yeast. The nature of the ester group had a profound effect on the stereoselectivity of the reduction since with the ethyl ester the enantiomeric excess was 56% and with the t-butyl ester it was 46%. In all cases the absolute configuration of the product was S. The alcohol (70) was subsequently converted into (I?)-( +)-a-lipoic acid (71) in five 3-Fluoropyruvate has been converted into 3-fluoro-L-alanine on a large scale (space-time yield of 76 g litre-l day-l) with average conversion of 73 YO.The reactor contained in addition to the substrate alanine dehydrogenase poly(ethy1ene glycol)- modified NADH (catalytic) and formate dehydrogenase to regenerate the NADH.75 Attempts to control the stereochemical course of baker's yeast-mediated reductions are constantly being sought.By adding ethyl chloroacetate to the reaction L-p-hydroxyesters could be obtained from the corresponding P-keto esters with high enantiomeric excesses (80-94 %).76 Bio-reduction with immobilized baker's yeast proceeded smoothly in hexane by using alcohols (e.g. methanol ethanol propan-2-01) as energy sources instead of glucose.77 Ethyl 3-oxobutanoate and ethyl benzoylformate were each reduced to the corresponding chiral hydroxy esters with a high enantiomeric purity. Rapid enantioselective reduction of butyl pyruvate (72) to the hydroxyester (73) in a non-polar organic solvent has been carried out using immobilized glycerol dehydrogenase from Geotrichum candidum.Both the enzyme and the co-factor were immobilized in a water-adsorbent polymer the simultaneous oxidation of cyclopentanol to cyclopentanone was used to recycle the co-factor in situ leading to an efficient overall process.78 A range of p-substituted nitroalkenes has been reduced with high enantiomeric excess (66-98 YO)using baker's yeast.79 4 Oxidation 4.1 Hydroxylation of Aromatic Rings The conversion of benzene (74) to cyclohexadiene diol (75) by mutants of Pseudomonas putida has provided organic chemists with a unique starting material for natural product synthesis. Moreover the organism P.putida is able to transform certain simple derivatives of benzene (toluene chlorobenzene fluoro- benzene) leading to the corresponding cyclohexadiene diol derivatives which are now chiral.Johnson et al. have devised an elegant method for converting the benzene derived product (75) into a homochiral synthon.80 Thus the rneso-diol (76) is converted to the optically active half-ester (77) by lipase catalysed acetylation. The chiral synthon is a precursor to (+)-and (-)-conduramine C-1 (78).81 Hudlicky's group have used the diol(79) derived from chlorobenzene to prepare a range of natural products including protected L and D-erythrose (81) and (82).82 Metabolism of 1,2-dihydronaphthalene indene and 1,2- NATURAL PRODUCT REPORTS 1994 Pseudornonas putida * 0II (86) Aspergillus niger Aspergillus hOCONHPh niger (92) -0 .,** ,s: ROCH2CH2 Ph (93) 0 H&Cl Br N3 (94) (95) benzocyclohepta- 1,3-diene bv a mutant strain of Pseudomonas putida has been shown to yield benzylic monoalcohols containing the R configuration (along with some vicinal diols as minor products with the S configuration at the benzylic positions).For example 1,2-dihydronaphthalene (83) gave a 3 :1 mixture of dihydronaphthalenol(84) and dihydroxytetralin (85).83 Other examples of the use of benzene cis-glycol products include the preparation of 6-deoxycyclitol analogues of rnyo-inositol 1,4,5-tripho~phate.~~ Using a UV4 mutant of Pseudornonas putida benzothiophene (86) has been hydroxylated to give cis-diol products. The novel cis-diol (87) is the major product together with the cyclo- hexadiene diol (88).85 4.2 Hydroxylation at Non-aromatic Positions Aspergillus niger has been shown previously to be an effective catalyst for oxidation and hydroxylation reactions.Furstoss has shown that N-phenylcarbamate derivatives of both geraniol (89) and nerol (90) undergo highly stereoselective bis-S 0 -baker'syeast R-XKN-Rl R-XKN-R' H H (96) X =O (97) X = NH (98) X= 0 (99) X = NH hydroxylations to give the diols (91) and (92) respectively. The conversions are 49 % and 40 YO, respectively with > 90 YOe.e in both cases.86 Optically active epoxides can be prepared via microbial epoxidation of the precursor alkene~.~' Epoxides can subsequently act as substrates for enantioselective ring opening catalysed by a microsomal epoxide hydrolase.88 Oxidations in particular hydroxylations and oxygenations are an emerging class of enzyme-catalysed reactions with enormous potential.To examine the selectivity of a group of fungi able to hydroxylate steroids a series of racemic substituted cyclopentanones with alkyl groups corresponding to the upper prostanoid side chain and/or the lower prostanoid side chain without the C-15 alcohol have been synthesized. The pre- dominant products were hydroxylated at the prostanoid C-18 and C-19 positions. In addition the hydroxylations were enantioselective with excesses in the range 10-60 YOand in most cases the predominant configuration corresponded to that of the natural pr~stanoids.~~ Catalytic oxygenation of linoleic acid to (92,ll E,13s)- 12- hydroperoxyoctadeca-9,11-dienoic acid has been achieved using soya bean lipoxygenase.The reaction was carried out at 4 atm. and concentrations of 100 mM; the yield of the product was 80 % (95 YOe.e.) on a 250 mg scale.9o 4.3 Miscellaneous Oxidations Homochiral sulfoxides (93; R = CH,OMe Me) have been obtained in > 99% e.e. via oxidation of the corresponding sulfides using Rhodococcus equi IF0 3730.'l Kinetic resolution of the racemic ketone (i-)-(94) has been achieved using Acineto- bacter NCIB 9871. This organism carries out enantiospecific Baeyer-Villiger reactions and in this case leaves behind the unreacted ketone isomer (-)-(94) of high optical purity; (-)-(94) was then converted into the carbocyclic nucleoside (95).' The chloroperoxidase-catalysedand horse radish peroxidase- catalysed oxidation of sulfides using t-butyl peroxide as the co- oxidant have been investigated.The former enzyme afforded the corresponding sulfoxides having the R absolute con-figuration in up to 92 % enantiomeric excess whereas the latter gave racemic products. The various factors that control the enantioselectivity of the oxygenation were also examined.93 It has been found that the enzymic conversion of thiocarbamates (96) and thioureas (97) into their 0x0 counterparts carbamates (98) and ureas (99) respectively can be carried out by baker's yeast. The yields range from 78 to 96Y0." Incubation of aryl alkyl ethers (100) with growing cells of Pseudomonas oleovorans results in epoxidation of the terminal alkene giving epoxides (101) with high optical activity (98-99 % e.e.).The enzyme catalysing this reaction is believed to be a non-haem NAD(P)H/O,-dependent mono-oxygenase that contains an active site iron.95 NATURAL PRODUCT REPORTS 1994-N. J. TURNER AcNH 0 AcNH OH 0 + OH Me02CuH &opi OH Me02C+OPi -HOAS~*-RI-OA~O:-R-OH c R-OASO:-enzyme ROH Scheme 2 OH OH OP; OH 0 OH 0 -0Pi Fru Ald Rha Ald H3C+OPi (3S 4R) (3R 45) OH OH OH OH OPi OH 0 OH 0 -09 (3sTag Ald4s) (3R,Fuc Ald 4R) H3C+OPi OH OH OH OH Scheme 3 0 Sialic acid R3sC02H aldolase HO OH + A02H R' HO paring dihydroxyacetone phosphate for use in the aldolase 5 Other Biotransformations reaction Wong and co-workers have investigated the in situ 5.1 Aldolases for Carbowcarbon Bond Formation formation of the corresponding vanadate and arsenate esters The use of aldolases for stereoselective C-C bond synthesis has (Scheme 2).lo1 They found that for several enzyme reac-expanded noticeably in recent years.Whitesides and co-workers tions that use organophosphates (including RAMA) arsenate have published an extensive and detailed paper summarizing and vanadate esters act as good mimics of phosphate esters. ' their work with rabbit muscle aldolase (RAMA).96This aldolase Fessner has pointed out that all four possible vicinal-diol con- accepts a broad range of aldehydes (102) but is highly specific figurations are possible by selection of the appropriate aldolase for dihydroxyacetone phosphate (103) leading to diols (104).(Scheme 3). The substrate specificities of all but the fructose RAMA has been used to catalyse the key C-C bond forming diphosphate aldolase are not well known and are currently step in the synthesis of a range of natural products including being investigated. lo' acid 7-phosphate (107) [via Much work has also been carried out on N-acetylneuraminic 3-deoxy-~-arabino-heptulosonic condensation of the aldehyde (105) with the phosphate (103) to acid (sialic acid) aldolase. The enzyme is highly specific for give the key intermediate diol (106)],97 (+)-(IS,SR,7S)-exo- pyruvate (108) but will utilize a range of analogues of N- brevi~omin,~~ Fructose- 1,6-diphosphate acetylmannosamine (109) as the electrophilic component and amino-sugar~.~~ lo4 aldolase is now available in large quantities as a result of over- yielding the corresponding sialic acid derivatives (1 10).lo3* expression of the gene in Escherichia coli.lo0 To avoid pre- Deoxyribose-5-phosphate aldolase catalyses the reaction NATURAL PRODUCT REPORTS 1994 OP.OH 0 OPi OH I -OH iA lJYH OH 0 OH OH C02H Pi bopi (116) Reagents i transketolase ; ii DAHP synthase 0 HO H oxynitrilase RKH [ENZ-HCNI-RxCN / HO CN 0 Mex Me MeK Me (39) Scheme 4 0 OH OH Reagents i Alcaligenes bronchisepticus; ii CH,N between acetaldehyde (1 12) and ~-glyceraldehyde-3-phosphate (1 11) to yield deoxyribose-5-phosphate (1 13). As with other aldolases there is high specificity for the nucleophile (acet- aldehyde) although this can be replaced by acetone fluoroacetone and propionaldehyde.Glyceraldehyde-3-phos- phate can be replaced by a range of other aldehydes.lo5 The gene encoding production of the enzyme has been over-expressed in E. coli enabling large quantities to be obtained (3.1 x lo4 units from a six litre culture). Transketolase although not strictly an aldolase is a related enzyme that catalyses stereoselective C-C bond synthesis. The enzyme is commercially available from yeast and recently has been produced in E. coli106 using an over-expressing organism. Studies have shown that it can use a variety of a-hydroxy aldehydeslo7 and also simpler a-unsubstituted aldehydes have been coupled.lo6- lo8 By localizing in a single plasmid the genes encoding the enzymes transketolase and 3-deoxy-~-arabinoheptulosonate synthase biocatalysis previously exploited in the multi-step immobilized enzyme synthesis of DAHP (107) is reconstructed in an intact microbial cell.In this reaction sequence fructose- 6-phosphate (1 14) is converted into erythrose-4-phosphate (1 15) under the action of transketolase followed by coupling of (115) with phosphoenol pyruvate (116) in the presence of DAHP synthase to yield DAHP (107). This plasmid biocatalysis takes advantage of the long overlooked impact of transketolase activity on the flow of carbon into aromatic amino acid biosynthesis. The result is an E. coli strain that produces substantially elevated levels of DAHP without the need for enzyme purification enzyme immobilization and co-factor regeneration required by multi-step immobilized enzyme synthesis.log 5.2 Enzymes other than Aldolases for Carbowcarbon Bond Formation Oxynitrilases catalyse the enantiospecific addition of cyanide ion to aldehydes yielding the corresponding cyanohydrins.(R)-Cyanohydrins can be obtained by using the enzyme from almonds (mandelonitrile lyase),'lo' ll1 whereas a recent report describes the use of an (S)-specific enzyme.112.113 Kyler et al. have reported the use of acetone cyanohydrin (39) as a more convenient source of cyanide The enzyme uses this substrate to form the cyanohydrin (40) in the usual way (Scheme 4). It is worth noting that complementary methods for the synthesis of optically active cyanohydrins have been explored namely the lipase catalysed hydrolysis of racemic cyanohydrin acetates1l5-l1' and the lipase catalysed irreversible transesterification of cyanohydrins using enol esters as acyl 118 A novel carbon+arbon bond forming reaction has been described in the baker's yeast-mediated reduction of cyanoacetone (1 16).When ethanol was added to the reaction instead of obtaining the expected 3-hydroxy compound the diastereoisomers (1 17) and (1 18) were obtained in a combined yield of 88 YO[ratio (I 17) (1 18) = 66 341. Separation of (1 17) and (1 18) followed by conversion into their Mosher's esters revealed that each had been formed in > 99% e.e. Although the authors offer no explanation for the mechanism one possible clue is that if the reaction is stopped after 4 h then the 2-ethyl-3-0x0 compound is isolated in 58 YOyield indicating that a-ethylation is the first step in the sequence followed by reduction.119 Asymmetric enzyme-mediated decarboxylation of di-carboxylic acids (1 19) in the presence of Alcaligenes bronchi- septicus followed by esterification with diazomethane gave optically active methyl esters (120) with high enantiomeric excesses. A wide range of R groups could be tolerated by the organisn (e.g. R = Ph 4-MeOC,H4 6-methoxynaphthyl 4-C1C,H4 and 2-thienyl). For the example where R = Ph it was found that the corresponding ester (120; R = Ph) could be obtained in 87% yield and 91 YOe.e.120 Baker's yeast has been shown to catalyse the regioselective NATURAL PRODUCT REPORTS 1994-N.J. TURNER R’oC.h-.o-+ bakets yeast c OH HO.. A..OH OH HO.,&(ILoHY AcN HO HO R R HO OH OH HO . ._ HO X (127) + HoJ t3-galactosidase from E. coli HO HO (128) yield = 46% (R) :(S) = 1.00 0.86 Scheme 5 cycloaddition of nitrile oxides [121; R = 2,6-C1, 2,4,6-Me3 2,4,6-(Me0),] to cinnamic esters (122; R’ = H Me; R3 = Et But) to give the corresponding isoxazoline products (123). A reversal of regioselectivity in these cycloadditions was observed by using P-cyclodextrin as an artificial enzyme along with the baker’s yeast.’, 6 Enzymes Involved in Carbohydrate/Oligosaccharide Synthesis 6.1 Glycosyl Transferases Two excellent reviews covering the application of enzymes (especially glycosyl transferases glycosidases and alcolases) to carbohydrate synthesis have appeared.122.lZ3 Glycosyl transferases have been used to prepare oligo-saccharides via a combination of an activated sugar nucleotide (e.g. UDP-glucose) with the appropriate glycosyl transferase (e.g. glucosyl transferase). The groups of Whitesides and Wong in particular have explored the possibility of using multi-enzyme systems with co-factor recycling for the synthesis of complex sugars.124-126 A recently isolated strain of Bacillus subtilis (NCIB 11871) has been found to produce a new fructosyl transferase (EC 2.4.1.161). This transferase can catalyse formation of a wide range of a,,,-linked disaccharides; for example it is able to transfer 1,6-dichlorofructose from 1’,6-dichlorosucrose to glucose.Most importantly this transferase has a preferred tendency to transfer only a single fructose moiety thereby forming sugars only one residue longer.’,’ Glycosylated derivatives of 1-deoxynojirimycin (124) have been prepared using a combination of cyclodextrin glycosyltransferase and glycoamylase.12* Sialyl lactosamine structures (125) [R = OH N, NHCOCH,CH(NHR’)COR” ; R’= CH,=CHCH,O,C-Phe R”= Ser-Thr-Ile,OH; R’ = H-Gly-Gly R”= Gly-Gly-OH] have been synthesized in high yield from carbohydrates and glycopeptides containing a terminal N-acetyl glucosamine residue by a two-step enzymic glycosylation in a one-pot reaction.A key improvement in the procedure was the use of alkaline phosphatase to destroy nucleotide phosphate inhibitors generated in the glycosyltransferase ~eacti0n.l~~ The cell-free enzymic synthesis of sucrose and trehalose using partially purified preparations of sucrose synthetases and trehalose synthetase have been described. The coupling of the regeneration of UDP-glucose with the synthesis of the disaccharide offers a practical route to millimolar quantities of these carbohydrates. The syntheses used pyruvate kinase UDP-glucose pyrophosphorylase and inorganic pyro-phosphatase and the regenerated UDP-glucose was recycled approximately 10 times.130 A report from the same group describes a method for preparing a mixture of nucleoside triphosphates suitable for use in the synthesis of nucleotide phosphate sugars from ribonucleic acid.The enzymes employed are nuclease P, a mixture of nucleoside monophosphokinases and acetate kinase. The nucleoside monophosphokinases were extracted from brewer’s yeast in a four-step procedure. The specific activity of the yeast enzyme preparation after gel permeation chromatography was sufficientlyhigh that the yeast kinases could be immobilized in volumes that were practicable for laboratory syntheses. Conversions from nucleoside mono-phosphates into triphosphates in a mixture containing 0.34 mol nucleoside phosphates were :ATP 90 YO,GTP 90 YO,CTP 60 YO and UTP 40Y0.l~~ 6.2 Glycosidases P-Galactosidase from E. coli shows very high anomeric specificity (i.e.P versus a) but low diastereoselectivity in the synthesis of the P-galactoside (128) from the galactosyl donor (126) and the racemic diol(l27). The preference for reaction at the primary hydroxyl group rather than the secondary in propane-l,2-diol is as expected (Scheme 5).132 Sialidase from NATURAL PRODUCT REPORTS 1994 OH HO OH HOW:*$Me (130) ACN -L7\/ Sialidase from AcN Vibrio cholerae H HO H HO HO OH (1 29) OH 1 <OH HO (75) spacer Vibrio cholerae has been used to catalyse the stereospecific synthesis of sialyl-containing oligosaccharides. Using p-nitro- phenylsialic acid (129) as the donor and methyl-/3-D-galactopyranoside (1 30) as the acceptor two products were obtained namely the 2,3 (1 3 1) and 2,6 (1 32) regioisomers (ratio 2.9 1 combined yield = 20 %).133 Attempts to convert meso-cyclohexadienediol (75) to an optically active product via stereoselective glycosidation of one of the secondary hydroxyl groups using /3-galactosidase resulted in only partial success.Early on in the reaction the diastereoselectivity is fairly high (-9 :1) resulting mainly in (1 33) but as the conversion increases the selectivity decreases. It is interesting to note that the authors also tried the more conventional approach based on lipase catalysed hydrolysis of (134) although this was unsuccessful owing to rapid aromatization of the intermediate (135).134 By employing an enzyme system containing N-acetyl-P-D- hexosaminidase from the mollusc Chamelea gallina a range of N-acetylhexosamine-containingdisaccharides have been OH HOWJT& AcN H HO HO OMe HO HO ?H (133) major diastereoisorner (9 1) (1 37) + OH hm,,=620nrn E =29700 'N NO2 HO indigo (139) obtained.The regioselectivity of the enzyme was found to depend on the anomeric configuration of the glycoside acceptor. 135 7 Novel Biocatalysts 7.1 Catalytic Antibodies Schultz and co-workers have devised an elegant method for screening large antibody libraries to select those antibodies with high catalytic activity (Scheme 6).136 Using the chromo- genic substrate (136) antibodies that are able to catalyse hydrolysis of the p-nitrophenyl carbonate group will release the ester of 3-hydroxyindole (1 37) which spontaneously loses butyrolactone to yield 3-hydroxyindole (138).The latter dimerizes to yield the highly visible-active dye indigo (1 39) which precipitates at the site of the reaction thus increasing the sensitivity of the method. This approach should be particularly useful for the screening of large bacterial colonies producing antibodies. NATURAL PRODUCT REPORTS 1994-N. J. TURNER ACO~OAC AcOwOH antibody (140) 0 e.e./% 86 98 98 (141) i. couple to carrier protein ii. immunize mice iii. 33 antibodies produced * octane the corresponding kinetic parameters were 3.89 min-' and 569 m~.'~~ Electrostatic interactions between a hapten and the comp- lementary antibody have been exploited to generate catalytic amino acid side-chains in an antibody-combining site.Mono- clonal antibodies generated to hapten (143) were capable of catalysing HF elimination from the fluorinated substrate (144). This was rationalized on the basis that the positively charged alkylammonium ion in (143) should induce a carboxylate ion at the active site of the antibody that would then facilitate deprotonation and hence HF elimination from (144).139 Catalytic antibodies have been shown to catalyse redox reactions by raising antibodies to a fluorescyl hapten and then using them to accelerate the ratio of reduction of resazurin by ~u1fite.l~~ Antibody catalysis of a Diels-Alder reaction has been achieved by Hilvert and co-workers. They reasoned that in a Diels-Alder cycloaddition the transition state is highly ordered and resembles the product more than it does the starting material.However the reaction product cannot be used as a suitable hapten for generating antibodies since severe product inhibition of the catalyst would be expected. Thus they concentrated on the reaction between N-ethylmaleimide (1 46) and tetrachlorothiophene dioxide (149 which proceeds via the unstable bicyclic intermediate (147) that extrudes SO to give a dihydrophthalimide (148) as product. Now the final product no longer resembles the transition state and hence product inhibition should be minimized. Five high-affinity monoclonal antibodies were elicited against the hapten (149) a stable analogue of (147). When the antibodies were presented with (145) and (146) in aqueous buffer at pH 6.0 they were found to accelerate the rate of the Diels-Alder reaction significantly.14' Table 1 Catalyst M k,,,/min-' antibody I77 0.007 acetylcholinesterase but yrylcholinesterase 620 830 250 7 F L d CI "CI 0 (149) A catalytic antibody has been produced that is capable of stereoselectively hydrolysing the meso-diacetate (140) to the chiral half-ester (141). The transition state analogue (142) was prepared in optically pure form and used to elicit the antibody response. The best catalytic antibody obtained gave an e.e. of 86% in the product (Table l).13' Catalytic antibodies have been demonstrated to carry out hydrolysis of ester substrates both in aqueous media and also in reverse micelles.Thus an antibody generated against the transition-state analogue phenylphosphonate was shown to catalyse the hydrolysis of phenyl acetate in aqueous solution with k,, and K values of 18.8 min-' and 157 mM respectively. When the antibody was solubilized in reverse micelles formed from 50 mM bis-(2-ethylhexyl)sodium sulfosuccinate in iso- 7.2 Modification of Existing Enzymes An artificial selenoenzyme selenosubtilisin has been prepared by chemical conversion of the active site nucleophile (serine- \ CI CI 0 221) in the protease subtilisin into a selenocysteine. The effect of XGNEt this change of Se for 0 was that the intermediate acylenzyme was considerably more reactive towards amines than water (up to 14000-fold compared with native subtilisin) thereby effectively converting the protease into an acyltransferase.14 Staphyllococcal nuclease (DNAse) is a relatively non-specific phosphodiesterase that cleaves DNA. By attaching sequence- specific oligonucleotides to a unique site on the enzyme the new hybrid nucleases were shown to hydrolyse single-stranded DNA in a catalytic fashion at specific sequences. One such hybrid nuclease was able to site-selectively cleave single- stranded M13 mp 7 DNA (1214 nucleotides) primarily at one phosphodiester Mosbach and co-workers have developed a procedure termed 'bio-imprinting' in which the specificity of an enzyme can be altered by precipitating the enzyme from a solution containing a substrate that differs from the natural substrate of the enzyme.For example a solution containing a-chymotrypsin and 20m~ N-acetyl-D-tryptophan was cooled to 0 "C and equilibrated for 30 min. Addition of propanol at -20 "C caused the protein to precipitate. The enzyme was collected and dried and found to contain 3.5 mole of amino acid per mole of Table 2 Relative rates of conversion of (150) to (151) using ‘bio-imprinted ’ enzymes N-acylated ligand present during bio-imprinting Substrate L-Trp L-Phe L-Tyr no ligand N-Ac-L-Trp 72 0 0 24 N-Ac-L-Phe 0 398 0 131 N-Ac-L-Tyr 0 0 306 I83 D-Trp D-Phe D-Tyr no ligand N-Ac-D-Trp 1.9 0 0 0 N-Ac-D-Phe 0 1.7 0 N/D N-Ac-D-Tyr 0 0 0.8 N/D protein. When this ‘bio-imprinted’ enzyme was then used as a catalyst for the conversion of an N-acetylated amino acid (I 50) to the corresponding ethyl ester (151) then the enzyme was found to have a high specificity for the imprinting substrate (Scheme 6; Table 2).144 8 References 1 C-H.Wong Science 1989 244 1145. 2 S. M. Roberts Phil. Trans. R. Soc. London B 1989 324 577. 3 S. M. Roberts Prog. Heterocycl. Chem. 1989 1 65. 4 D. H. G. Crout and M. Christen Mod. Synth. Methods 1989 5 1. 5 ‘ Biotransformations in Preparative Organic Chemistry ’ ed. H. G. Davies R. H. 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Dalmas Tetrahedron Lett. 1991 32 5085. 109 K. M. Draths and J. W. Frost J. Am. Chem. Soc. 1990 112 1657. 110 T. Ziegler B. Hoersch and F. Effenberger Synthesis 1990 575. 1 1 1 J. Brussec T. Loos C.G. Kruse and A. van der Gen Tetrahedron 1990 46 979. 112 U. Niedermeyer and M. R. Kula Angew. Chem. 1990 102,423. 113 F. Effenberger B. Hoersch S. Foerster and T. Ziegler Tetrahedron Lett. 1990 31 1249. 114 V. Ognyanov V. K. Datcheva and K. S. Kyler J. Am. Chem. Soc. 1991 113 6992. 115 H. Ohta S. Hiraga K. Miyamato and G. Tsuchihashi Agric. Biol. Chem. 1988 52 3023. 116 H. Ohta Y. Miyamae and G. Tsuchihashi Agric. Biol. Chem. 1986 50 3181. 117 A. van Almsick J. Buddrus P. Honicke-Schmidt K. Laumen and M. P. Schnieder J. Chem. SOC.,Chem. Commun. 1989 1391. 118 Y.-F. Wang S.-T. Chen K. K.-C. Liu and C.-H. Wong Tetra-hedron Lett. 1989 30 1917. 119 R. P. Short R. M. Kennedy and S. Masamune J. Org. Chem. 1989 54 1802. 120 K. Miyamato and H.Ohta J. Am. Chem. SOC. 1990 112 4077. 121 K. R. Rao N. Bhanumathi T. N. Srinivasan and P. B. Sattur Tetrahedron Lett. 1990 31 899. 122 D. G. Drueckhammer W. J. Hennen R. L. Pederson C. F. Barbas 111 C. M. Gautheron T. Krach and C.-H. Wong Synthesis 1991 499. 123 E. J. Toone E. S. Simon M. D. Bednarski and G. M. Whitesides Tetrahedron 1989 45 5365. 124 E. S. Simon M. D. Bednarski and G. M. Whitesides Tetrahedron Lett. 1988 29 1123. 125 E. S. Simon M. D. Bednarski and G. M. Whitesides J. Am. Chem. Sac. 1988 110 7159. 126 Y. Ichikawa C.-H. Wong and G.-J. Shen J. Am. Chem. SOC. 1991 113 4698. 127 P. S. J. Cheetham A. J. Hacking and M. Vlitos Enzyme Microb. Technol. 1989 11,212. 128 Y. Ezure S. Marno N. Ojima K. Komo H.Yamashita K. Miyazaki T. Seto N. Yamada and M. Sugiyama Agric. Biol. Chem. 1989 53 61. 129 C. Unverzagt H. Kunz and J. C. Paulson J. Am. Chem. SOC. 1990 112 9308. 130 S. L. Haynie and G. M. Whitesides Appl. Biochem. Biotechnol. 1990 23 155. 131 S. L. Haynie and G. M. Whitesides Appl. Biochem. Biotechnol. 1990 23 205. 132 D. H. G. Crout D. A. Macmanus and P. Critchley J. Chem. SOC. Perkin Trans. 1 1990 1865. 133 J. Thiem and B. Sauerbrei Angew. Chem. Int. Ed. Engl. 1991,30 1503; 555. 134 D. H. G. Crout D. MacManus and P. Critchley J. Chem. Soc. Chem. Commun. 1991 376. 135 K. G. I. Nilsson Carbohydr. Res. 1990 204 79. 136 B. Gong S. A. Lesley and P. G. Schultz J. Am. Chem. Soc. 1992 114 1486. 137 S. Ikeda M. I. Weinhouse K.D. Janda R. A. Lerner and S. J. Danishefsky J. Am. Chem. Soc. 1991 113 7763. 138 C. N. Durfor R. J. Bolin R. J. Sugasawara R. J. Massey J. Jacobs and P. G. Schultz J. Am. Chem. Soc. 1988 110 8713. 139 K. M. Shokat C. J. Leumann R. Sugasawara and P. G. Schultz Nature (London) 1989 338 269. 140 N. Janji and A. Tramontdno J. Am. Chem. Soc. 1989,111,9109. 141 D. Hilvert K. W. Hill K. D. Nared and M.-T. Auditor J. Am. Chem. Soc. 1989 111 9261. 142 Z. P. Wu and D. Hilvert J. Am. Chem. Soc. 1989 111,4513. 143 D. R. Corey D. Pei and P. G. Shultz Biochemistry 1989 28 8277. 144 M. Stahl U. Jeppson-Wistrand M-U. Mansson and K. Mosbach J. Am. Chem. Soc. 1991 113 9366. NPR 11

ISSN:0265-0568    

DOI:10.1039/NP9941100001

出版商:RSC    

年代:1994

数据来源: RSC

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Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann University of Reading Dr D. A. Whiting University of Notting ha m Natural Product Reports is a bimonthly journal of critical reviews. It aims to foster progress in the study of bioorganic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis and chemistry of the major groups of natural products -alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds. Many reviews provide a details of biological activity and wider aspects of bioorganic chemistry including developments in enzymology genetics and structural spectroscopic and chromatographic methods of general interest to all workers in the area.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England. 1995 Annual Subscription Price EEA f295.00 Overseas f310.00 USA $542.50. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. SG6 1 HN England.Air Freight and mailing in the US by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. Second-Class postage paid at Jamaica NY 11431-9998. All other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0 The Royal Society of Chemistry 1995 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1995 EEA f295.00 Overseas f310.00 USA US $542.50 Subscription rates for back issues are (1990) (1991) (1992) (1993) (1994) EEA f177.00 f198.00 f222.00 f242.00 f266.00 Overseas f204.00 f228.00 f250.00 f266.00 f286.00 USA $398.00 $467.00 $474.00 $532.00 $500.00 Members of the Royal Society of Chemistry should ord r the journal fr m The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF England

ISSN:0265-0568    

DOI:10.1039/NP99411FX005

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年代:1994

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99411BX007

出版商:RSC    

年代:1994

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lndol izidine and Quinolizidine Alkaloids J. P. Michael Centre for Molecular Design Department of Chemistry University of the Witwatersrand Wits 2050 South Africa Reviewing the literature published between July 1991 and June 1992 (Continuing the coverage of literature in Natural Product Reports 1993 Vol. 10 p. 51) 1 Slaframine Reference 3a). Shortly after the appearance of Pearson's 2 Hydroxylated Indolizidine Alkaloids original communication Cha and co-workers revealed the 2.1 Swainsonine and Related Compounds enantioselective synthesis of (-)-slaframine shown in Scheme 2.2 Castanospermine and Related Compounds I. Both the oxazoline (2) and the lactol (3) were derived from 3 Monomorine I optically active precursors. The key step is an intramolecular 4 Piclavines dipolar cycloaddition of the azide formed in situ from tosylate 5 Alkaloids from Amphibians (4)and sodium azide.The synthesis proceeded with complete 5.1 Identification and Biological Activity stereocontrol apart from a little epimerization at C-1 during the 5.2 Synthesis conversion of (5) into (6); the 1,8a-di-epi-analogue of (6) (ca. 6 Elueocurpus Alkaloids 10%) was easily removed by column chromatography. An 7 Phenanthroindolizidine Alkaloids and Seco Analogues alternative approach to (-)-slaframine was abandoned after 8 Nuphar Alkaloids intermediate (7) failed to undergo tandem ene reaction/[2,3]- 9 Myrtine and Epimyrtine sigmatropic rearrangement with TsN=X=NTs (X = S Se). 10 Alkaloids of the Lupinine-Cytisine-Sparteine-Matrine-Slaframine increases the concentrations of circulating Orrnosia Group hormones and blood metabolites when administered to sheep 10.1 Occurrence Detection and Chemical Ecology and Angora goats over a period of time.5 Other effects on 10.2 Structural Spectroscopic and Biological Studies livestock have recently been summarized in a succinct review 10.3 Synthesis that also described the natural sources of the alkaloid.6 11 9b-Azaphenalene Alkaloids 12 References 2 Hyd roxy Ia ted IndoIi zi d ine AlkaI o ids The chemistry biochemistry and biological effects of several polyhydroxylated indolizidine alkaloids amongst them lentiginosine 2-epi-lentiginosine swainsonine castano-1 Slaframine spermine and 6-epi-castanospermine have been reviewed.6 A Full experimental details of the synthesis of (-)-slaframine (I) general review on glycosidase inhibitors of N-linked oligo- and two related indolizidines (-)-1,8a-di-epi-slaframine and saccharide processing highlights the utility of swainsonine and (-)-8a-epi-desaceto~yslaframine,~ have now followed the com- castanospermine as tools for probing the mode of action of munication by Pearson et al.2discussed in last year's review (cf.these enzymes.' PMP\ PMP Ts ,N PMB iii,iv OSi(Pr') 67% (2) PMP = prnethoxyphenylPMB = prnethoxybenzyl (3) 89% (4) I TsO v vi 93% ix-xiii c-- (7) (1) (-)-Slaframine ~MB PMB OH (6) (5) Reagents :i PPh, MeCN reflux; ii KN(SiMe,), -78 "C then (3) -78 "C; iii p-TsC1 NEt, cat. DMAP CH,Cl ;iv DIBAL (5 eq.) THF 0 "C; v N-tosyl-N-methylpyrrolidineperchlorate CH,Cl, 0 "C; vi NaN (5 eq.) DMF 60 "C then toluene reflux; vii MsCl NEt, CH,CI, 0 "C; viii NaBH, EtOH 0 "C then K,CO, reflux; ix CAN H,C&MeCN; x Bu,NF THF; xi Na NH,-THF; xii HCI HOAc; xiii Ac,O pyridine Scheme 1 17 NATURAL PRODUCT REPORTS 1994 8 Hw $0 Ho&..OH HO BnO' H " Oa H oH OH HO'* HO (12) (+)-Castanosperrnine 2.1 Swainsonine and Related Compounds Aspects of the chemistry and biology of swainsonine (8) have been surveyed in two noteworthy reviews.In the first livestock toxicosis caused by Australian Swainsona species provides the starting point for a general discussion of the isolation occurrence synthesis and biological properties of the alkaloid.8 The Swainsona species now known to produce swainsonine include S.canescens S. galegfoliu and S. greyana (the richest source); other toxic species that probably contain the alkaloid are S.luteola S.procumbens and S.swainsonioides. The second re vie^,^ which covers similar ground in relation to the North American locoweeds contains the following updated list of locoweed and related sources of swainsonine Astragalus species; A. asymmetricus A. bicristatus A. bisulcatus A. didymocarpus A. emoryunus A. flavus (var. argillosus and flaws) A. lentiginosus (var. diphysus lentiginosus micans nigricalysis and wahweapensis) A. mollissimus A. oocarpus A. oxyphysus A. praelongus A. pycnostachyus A. succumbens A. trichopodus and A. wootoni Oxytropis species; 0.kansunsis 0.lambertii 0.ochrocephala and 0.sericea. Swainsonine N- oxide has been detected in most of these species and varieties.'O The production of swainsonine in tyrosine-fed batch cultures of the fungus Metarrhizium anisopliae has also been reviewed. " For the first time in several years no new syntheses of swainsonine have been published during the review period. However a short survey of some published strategies for the synthesis of the alkaloid has been presented in a book dealing with organic synthesis.' Also an efficient new preparation of (9) in 15 steps from manno nos el^ completes a formal synthesis of (-)-swainsonine (cf. Reference 14). The two swainsonine analogues (10) and (ll) made from D-arabinose and L-arabinose respectively proved to be inhibitors of glycosidases.l5 A review by Olden et al. presents a state-of-the-art synopsis of the potential importance of swainsonine as a therapeutic agent in controlling metastasis and tumour growth promoting proliferation of bone marrow cells and augmenting immuno- modulatory activity. l6 The alkaloid has been found to confer some protection against cytotoxic anticancer agents in mice the increased survival rate correlating with stimulation of bone marrow cell proliferation.'i Swainsonine's ability to inhibit the mannosidases implicated in glycoprotein processing has been exploited in studies dealing with the substrate specificity of rat liver cytosolic a-D-mannosidase la glycoprotein expression in mouse ~erebellum,'~ T cell proliferation and the expression and function of the T cell receptor complex,2o N-glycan trimming in HT-29 cells from a human colonic adenocarcinoma,21 and the function and biosynthesis of the vasopressin V receptor site in renal epithelial cells.22 The alkaloid did not inhibit platelet aggregation in H-ras-transformed fibroblasts and thus failed to reduce metastasis in this tumour cell line.23 It also had little effect in inhibiting tyrosinase activity in certain human melanoma cells.24 HO-OoH OH OH a 5 HOwN 2.2 Castanospermine and Related Compounds Castanospermum austrule that prolific source of poly-hydroxylated alkaloids has yielded yet another epimer of castanospermine (I ( +)-6,7-Di-epi-castanospermine(13) a minor component of the seeds was isolated from mother liquors of an extract from which castanospermine had been removed by fractional crystallization.The new metabolite was purified by a combination of ion-exchange thin-layer and radial chromatography after which MS 13C and 'H NMR were used to confirm its gross structure and the relative stereochemistry of substituents. The absolute configuration shown in (13) is favoured on biosynthetic grounds. Another new alkaloid in the extracts the pyrrolidine (14) is of interest as a putative biosynthetic precursor of both the polyhydroxy- indolizidine and polyhydroxypyrrolizidine alkaloids found in the species. 6,7-Di-epi-castanospermine proved to be about ten times less effective than castanospermine as a competitive inhibitor of amyloglucosidase.It showed slight inhibitory activity towards /I-glucosidase but unremarkable activity towards other glycosidases tested. It should be noted that (+)-6,7-di-epi-castanospermine has recently been synthesized in an enzyme-mediated process26 (cf. Reference 3b). Interest in the synthesis of castanospermine and its analogues remains undiminished. The situation to date has been placed in perspective by Burgess and Henderson who have reviewed the published synthetic approaches to the alkaloid and some of its analogues.2i Twelve of the thirty-two possible stereoisomers of 1,6,7,8-tetrahydroxyindoIizidinehad been prepared when the review was written and several more have subsequently been made (see below).The only new synthesis of (+)-castano- spermine itself in the period covered by the present review started with a chiral allylic alcohol (15) instead of the customary carbohydrate precursors (Scheme 2).,* Two stereogenic centres present in (1 5) were augmented to the requisite five by Sharpless epoxidation and diastereoselective enolate condensation. The mixture of products from the latter process (16) was converted into the separable mixture of alcohols (17a) and (17b) the major of which had the undesired /I-OH configuration. However Mitsunobu inversion via the a-acetate yielded product (17b) with the correct configuration for the desired alkaloid. The synthesis was completed as shown in Scheme 2. The first synthesis of the unnatural (-) enantiomer of castanospermine (1 8) in 1 3 steps and cu.1&I 2 YOoverall yield from the D-xylose derivative (19) has been devised by Mulzer and co-workers (Scheme 3).29Diastereofacially selective ad- dition to carbonyl groups was exploited to good effect in realizing the synthesis. Thus addition of vinylmagnesium bromide to (19) according to the Cram chelate model produced diastereoisomeric alcohols (20a) and (20b) the ratio depending on the solvent used. In a later step allylation of the chain- extended aldehyde (21) required the Felkin-Anh mode of addition. The Hiyama-Nozaki conditions (Cr" ally1 bromide) NATURAL PRODUCT REPORTS 1994-5. P. MICHAEL 111-VI QTOH 5501~ Bu'Me2Si0 B u'Me2Si0 qLoH Bu'Me,SiO 0 OH 0 OMOM 0 (15) ~ x XI (17b) ButMe2sio~!OSiMe2But TsoQ+oTs 0 OH 60% from 0 OH Bu'Me2Si0qficCW OMOM OMOM OMOM (17a) P-OH 68% (16) a-OH:P-OH = 11 :89 xii 1 78% (17b) a-OH 5% ix v (12) (+)-Castanosperrnine Reagents i Sharpless epoxidation; ii Et,AlNBn, CH,Cl, r.t.; iii AcCl NEt, CH,Cl, 0 "C; iv MeOCH,Cl PriNEt CHCl, reflux; v LiAlH, Et,O r.t,; vi (COCI), DMSO NEt, CH,Cl, -78 "C to r.t.; vii CH,CO,Et LiN(SiMe,), THF -78 "C; viii Bu'Me,SiCl imidazole DMF r.t.;ix AcOH PPh, DEAD C,H, reflux; x Bu,NF THF r.t. ;xi p-TsC1 pyridine r.t.; xii H, Pd(OH), MeOH then NEt, MeOH reflux; xiii HCl MeOH reflux then Dowex I-X8 Scheme 2 OBn OBn OBn OBn OBn OBn 820/o OBn OH MoMo+CHo OBn OMOM HO* OBn OH + HOJkk\\ OBn (204 (211 (19) iv 55% (85:15) Of V 76% I (5:95) OBn OBn OBn OBn OBn OBn OBn OBn OH BUtph2si0~Np/,t -ix-xi vi iii vii viii MoMo+ MOMO+ NPht 39~~ from (22a) OBn OMes OBn OMOM OBn OMOM (22a) a-OH xii xiii (22b) P-OH "';vi-xv 70% i 24% t O Ho+n ~~o&~ xv HOH S xiv 91Yo BnO HN 7 8% En0 HO HO (18) (-)-Castanospermine (23) (-)-1-epi-Castanospermine Reagents i H,C=CHMgBr THF 0 "C to r.t.; ii MOM-Cl CH,CI, PriNEt 0 "C then HPLC separation; iii 0,,CH,CI, -78 "C then PPh,; iv CrCl, LiAIH, THF 0 "C then H,C=CHCH,Br (21) THF -65 "C then preparative HPLC; v H,C=CHCH,SnBu, MgCl, CH,Cl, then preparative HPLC; vi NaH BnBr DMF 0 "C to r.t.; vii LiAIH, Et,O 0 "C to r,t.; viii phthalimide DEAD PPh, THF 0 "C to r.t.; ix HC1 MeOH 5&60 "C; x ButPh,SiCl imidazole DMF 0 "C to r.t.; xi MsCl DMAP pyridine 0 "C to r.t.; xii N,H;H,O EtOH reflux; xiii Bu,NF THF r.t.; xiv PPh, CCl, NEt MeCN 0 "C to r.t.; xv H 10% Pd-C H, HC1 MeOH Scheme 3 produced a good ratio (85 :15) of the separable alcohols (22a) and (22b) whereas the combination of allylstannane and magnesium bromide swung the selectivity towards chelation- controlled addition (5 :95).Both products were taken through steps involving successive cyclizations by S,2 displacement and were converted into tetrahydroxyindolizidine targets (22a) afforded ( -)-castanospermine (18) [aID-8 1.1 (c 2.0 H,O) and (22b) gave 1-epi-castanospermine (23) the optical rotation of which was pH-dependent. This observation may well explain discrepancies in the literature for the optical rotation of ent-(23).Other synthetic stereoisomers of castanospermine reported NATURAL PRODUCT REPORTS 1994 R3 HO’* Hof5R1 R2B (24) R’ = a-OH R2 = R3 = P-OH (25) R’ = R2 = R3 = a-OH (26) R’ = R2 = a-OH R3 = P-OH (27) R’ = R2 = P-OH R3 = a-OH oH OAc OH OH (35) (36) during the period covered by this review include (-)-1,6,8-tri-epi-castanospermine (24) 1,7,8-tri-epi-castanospermine(25) and ( -)- l76,7,8-tetra-epi-castanospemine (26) made from various pentoses ;3” and (+)-8-epi-castanospermine (27) and ( -)-1,8,8a-tri-epi-castanospermine (28) prepared from pyrrolidin-3-one dianions and a tartrate-derived aldehyde.31 All were poor inhibitors of glycosidase enzymes but (24) and (26) showed weak anti-HIV activity.New synthetic analogues of castanospermine include four stereoisomers of 1-deoxy-castanospermine (29)-(32) all made from proline-derived aldehydes.32 Synthetic castanospermine-inspired compounds even more remote in structure from the alkaloid include the indolizidine (33) and quinolizidine (34) both showing about the same activity as (+)-castanospermine towards ol-gluco- sidase I ;33 the isosteric quinolizidine homologue (+)-(35) an efficient inhibitor of P-glucosidases ;34 and most bizarre of all imidazole (36) which showed moderate anti-HIV A recent drive to make new 6-O-acyl derivatives of castano- spermine spearheaded by the discovery of enhanced anti-HIV potency of castanospermine monoesters (cf. Reference 3c) needs rethinking in view of the finding that 6-O-acyl esters equilibrate to a mixture of 6- 7- and 8-O-acyl esters at physiological pH and temperature.36 Attempts to functionalize castanospermine tetraacetate by adding nucleophiles to iminium ions formed in situ were frustrated by competing ar~matization.~’ Polonovski reaction of the tetraacetate N-oxide with acetic anhydride triggered a series of eliminations at the end of which the dihydro-indolizinium salt (37) (90 YO)was isolated and characterized. Conversion into the racemic dihydroxy derivative (38) (54 YO) with methanolic hydrochloric acid provided further con-firmation of the structure. With N-bromosuccinimide and ultraviolet irradiation the tetraacetate underwent partial conversion into the pyrrole (39) (4%).Castanospermine’s ability to inhibit glucosidases involved in glycoprotein processing underlies many biological and bio- medical investigations. For example it has been a useful tool in correlating glycoprotein composition with cell development in mouse cerebell~m,’~ in probing T cell receptor function and proliferation,20 and in determining the function and bio-synthesis of vasopressin V receptors in renal epithelial cells.22 The alkaloid’s anti-cancer potential has been explored in studies dealing with inhibition of platelet aggregation in metastatic H-ras-transformed fibroblast^,^^ inhibition of tyro-sinase activity in human melanoma cells,24 and biosynthesis maturation and transport of a,-antitrypsin in the human hepatoma cell line H~PG~.~~ Castanospermine was included in a line-up of antiviral agents used to evaluate an enzyme-linked immunosorbent assay (ELISA) for the Rauscher murine leukaemia virus.3g It was also one of 18 compounds tested in a comparative study of the efficacy of six different anti-HIV assays routinely performed at four British and European antiviral testing centres4” Its anti-HIV activity has been shown to depend on both the viral strain and cell type.41 Castanospermine N-oxide made by the action of hydrogen peroxide on castanospermine and thoroughly characterized for the first time was one of many compounds included in a study that established a structure-& relationship for glucosidase inhibitors of the azasugar group.42 3 Monomorine I A new synthesis of (+)-monomorine I (40) employs a novel titanium-mediated reaction to form the pyrrolidine ring (Scheme 4).43 On exposure to triethylamine and a catalytic quantity of cyclopentadienyltitanium trichloride y-amino- alkyne (41) was converted into A1-pyrroline (42) in 93% isolated yield via the transient imidotitanium complex (43) and its ensuing [2 +21 cycloaddition product (44).Stereoselective reduction of the pyrroline to the 2,5-cis-disubstituted pyr-rolidine (45) was efficiently accomplished with diisobutyl- aluminium hydride after which the synthesis was completed as shown according to established methodology. The overall yield of (40) from (41) is a noteworthy 64%. A synthesis of (-t)-monomorine I from the cyano-oxazine (46) by Zeller and Griers~n~~ (Scheme 5) makes use of the ‘dissolving metal’ strategy that they recently devised for making the frog indolizidine 167B45 (discussed in last year’s review cf.Reference 34. Of interest in this route is the stereoselective cyclization of phosphate (47) with lithium diisopropylamide to give (48) and thence the target alkaloid after reductive decyanation. Cyclization of (47) with potassium and a crown ether on the other hand preferentially gave a stereoisomer 8a-epi-monomorine I (49). Scheme 6 which also demonstrates established methodology (the Meldrum’s acid approach of Lhommet et al.) shows a new asymmetric synthesis of (+)-monomorine I (+)-(40) in which (S)-pyroglutamic acid is the source of ~hirality.~~ Finally the previously described synthesis of (+)-monomorine I by Ito and Kibayashi4’ (cf.Reference 3e) has now been published with full experimental details.48 4 Piclavines Clavelina picta a tunicate (sea-squirt) previously shown to contain unusual quinolizidine alkaloids (cf. Reference 3fi7 has now yielded three series of indolizidines substituted with long hydrocarbon chains at position 5.49These compounds named piclavines appear to be the most powerful antimicrobial agents in the tunicate extracts. The (+)-piclavine A group of alkaloids contains four members Al-A4 in the ratio 1:3:6:6 as determined by GC. While NMR analysis on the mixture NATURAL PRODUCT REPORTS 1996-5. P. MICHAEL 21 n C4H (41) (43) H (40) Monornorine-l Reagents i cat.CpTiCl, NEt, THF 25 "C; ii DIBAL THF -78 "C to 0 "C; iii HC1 H,(TTHF then K,CO,; iv NaBH,CN THF-MeOH 5% aq. HC1 Scheme 4 R = C4H9 (49) (40) Monornorine-l (48) Reagents i BusLi THF-HMPA -78 "C then Mel; ii cat. ZnBr, CH,Cl, reflux; iii Na NH,; iv (EtO),POCN cat. ZnBr,; v LDA THF -20 "C; vi K 18-crown-6 THF Scheme 5 i ii-v HN OHQ ck:trans)-Meo2cq OY? -----+ -&-& OHQ (96:476% C02H C H~OTS C4H9 C4H9 (S)-Pyroglutarnic acid VHX78% 1 H (+)-(40) (+)-Monomorine-l Reagents i Pr,CuLi Et20-CH,Cl, -30 "C; ii Me,SO,; iii Meldrum's acid cat. Ni(acac), CHCl,; iv NaOMe MeOH; v H (100 bar) Raney Ni HCI MeOH; vi LiAIH, Et,O; vii PhCH,OCOCl; viii Py.HCI.CrO, CH,Cl,; ix CH,COCH=PPh, THF reflux; x H (1 atm) PtO, MeOH; xi H,(1 atm) 10% Pd-C MeOH Scheme 6 NATURAL PRODUCT REPORTS 1994 (50) Piclavine A1 5-a-H j3-R (51) Piclavine A2 5-a-H P-R (52) Piclavine A3 5-P-H a-R (53) Piclavine A4 5-j3-H a-R * R’ R2’ (57) Alkaloid 251F R’ = H R2 = OH (58) Alkaloid 235H R‘ = R2 = H (64) Alkaloid 2658 R’ = Me R2 = OH (65) Alkaloid 2798 R’ = Et R2 = OH *OH (62) Alkaloid 251 F‘ revealed gross structural features individual compounds were characterized by GC-MS analysis and GC-IR.The latter technique provided evidence for the cis stereochemical re-lationship of hydrogen on the bridgehead and C-5 carbon atoms and for the geometry of the olefinic bonds. The structures of piclavines A 1-A4 (relative configurations only) are shown in (50),(51) (52) and (53).(+)-Piclavines B and C also consisting of mixtures of diastereoisomers were not analysed in the same depth and only the gross structures are shown in (54) and (559 respectively. 5 Alkaloids from Amphibians 5.1 Identification and Biological Activity Structural elucidation of an entirely new class of alkaloids isolated from the skins of the Colombian dendrobatid frog Minyobates b~mbetes,~~ is undoubtedly the most significant development in this area during the review period. The presence of these alkaloids in the species was recognized well over a decade However identification of the principal alkaloid coded as 25 1 F required isolation of the metabolite in sufficient quantity for the thorough spectroscopic characterization that has only now been reported.This alkaloid and by inference at least nine congeners occurring with it in trace amounts possesses an unprecedented cyclopenta[b]quinolizidine skeleton with carbon substituents that suggest the isoprenoid origin shown in (56). Extremely comprehensive lH and 13C NMR experiments in conjunction with GC-FTIR (which showeu Bohlmann bands for a trans-fused quinolizidine) and detailed MS studies (including high resolution analysis of most fragment ions and a thorough elucidation of fragmentation patterns by MS-MS techniques) seem to leave no doubt that the gross structure and relative configuration of 251F are as shown in (57). Structures for the nine congeners coded as 235H (58) 245 (59) 247 (60) 249B (61) 25 1 F’ (62) 25 1 J (63) 265B (64) 279B (65) and 279C (66) have been tentatively assigned based on MS comparisons with 251F.The growing number of 5-substituted 8-methylindolizidines confirmed as metabolites of dendrobatid frogs has been augmented by indolizidine 203A isolated from Dendrobates pumilio.52 Comprehensive spectroscopic evidence was presented for the gross structure shown in (67). The stereochemistry was deduced from NMR and FT-IR spectra which for the first (54) Piclavines B (55) Piclavines C (59) Alkaloid 245 R = CHO (61) Alkaloid 2498 (60) Alkaloid 247 R = CH20H OH (63) Alkaloid 251 J R = H (66) Alkaloid 279C R = Et time have been interpreted as supporting a trans disposition of the hydrogen atoms at C-5 and the bridgehead position C-8a and the equatorial disposition of the substituents at C-5 and C- 8.The spectroscopic data for 203A and related natural products apparently tally with those for the growing number of stereochemically unambiguous synthetic 5,8-disubstituted indolizidines (cf. References 3d g). In consequence two minor alkaloids from Dendrobates pumilio indolizidines 233D and 251B have been assigned the structures and relative con-figurations shown in (68) and (69); and a trace alkaloid of certain dendrobatid frogs 209B is almost certainly (70).52 The following indolizidine alkaloids of the pumiliotoxin and allopumiliotoxin classes have now been confirmed in skin extracts from Dendrobates auratus pumiliotoxins 307A (71) as a mixture of epimers and 323A (72) ; allopumiliotoxins 253A (73) (tentative assignment) 267A (74) 323B (75)as a mixture of epimers 339A (76) and 339B (77); and the 0-methyl ether of 323B (78).52 Related alkaloids from D.pumilio whose structures have been elucidated with comparative certainty for the first time (mainly with the help of extensive 13C NMR data) are pumiliotoxins 209F (79) and 225F (80) and allopumiliotoxins 225E (81) 309D (82) and 325A’/325A” (83).53 The structure of another alkaloid pumiliotoxin 307F has been revised to (84) from (85) on the basis of NMR magnetization transfer techniques.Compounds previously described as natural products but now considered to be artefacts include pumiliotoxin 307B (86) and the 0-methyl ethers of 307A [‘pumiliotoxin 321’ (87)] and 323B (78) the first perhaps resulting from allylic rearrangement of the OH group in pumiliotoxins 307A’ or 307A” [(71) 15-P-OH and 15-a-OH respectively].Pumiliotoxin 307A” itself is formed from 307A’ by epimerization of the allylic hydroxy group at C-15 during isolation and this sort of epimerization may in fact be more widespread than has hitherto been recognized. Pumiliotoxin 251D (88) has recently been confirmed as the major alkaloid in skins of the Ecuadoran dendrobatid frog Epipedobates tricolor.54 The first comprehensive study of the biological activity of 5,8-disubstituted indolizidine alkaloids has shown that they are atypical but nonetheless potent non-competitive blockers of sodium ion influx through nicotinic receptor channels both in muscle (electroplax membranes from the electric eel Torpedo) and in ganglia (pheochromocytoma PC12 cells)55 -atypical NATURAL PRODUCT REPORTS 1994-J.P. MICHAEL R (67) lndolizidine 203A R = CH2CH=CHCzH (Z) (68) lndolizidine 233D R = (CH2),CH=CHCH=CH2 (Z) (69) lndolizidine 251 B R = (CH2)3CH=CHCH(OH)CH3(Z) (70) lndolizidine 2098 R = (CH2)&H3 (89) lndolizidine 205A R = (CH2)3C-CH (90) lndolizidine 207A R = (CH2)3CH=CH2 R%H H Purniliotoxins Allopurniliotoxins (73) allo-253A R = (CH2).$H3 307A R= +t (74) allo-267A R = (CH2)3CH3 OH (75) allo-323B R = 323A R= /ol-"$.-, OH OH 209F R=CH3 225F R = CH20H (76) allo-339A R= *t OH (77) allo-339B = C-7 epimer or alb339A 307F R=&t 0 (78) R = +.OMe R=&. 0 (81) alle225E R=CH3 307B R=&{ (82) alb309D R= &. OH CH3 R=&# (83) aIb325A'J325A" R =*# OH OMe 251 D R = (CH2)2CH3 (91) (-)-lndolizidine 1678 Reagents i LiAlH, THF; ii BnOCOCl K,CO, acetone; iii pyridine.SO, DMSO; iv Ph,P=CHCOC,H, THF reflux; v H, PtO, MeOH; vi H, Pd-C MeOH Scheme 7 because their potencies are reduced rather than increased in the bioelectric activity in the excitable tissue from mouse dia-presence of the agonist carbamoylcholine. The extent of phragm perhaps by mechanisms involving dual actions with unsaturation in the side chains of the otherwise similar alkaloids both calcium and sodium ion channel^.^^ In the rabbit a 205A (89) 207A (go) and 209B (70) produces remarkable fleeting hypotensive effect after administration of Pseudophryne effects; 205A for instance is unique in enhancing binding of 'coriacea extracts was succeeded by an intense long-lasting rise tritiated perhydrohistrionicotoxin a well-studied blocking in blood pressure and disturbances in cardiac rhythm.59 The agent.reversibility of the response suggests that pumiliotoxin B could Pumiliotoxin B (72) (= pumiliotoxin 323A) has been shown be of pharmacological value in the study of antiarrhythmic to induce epilepsy-like electric activity in guinea pig hippo- drugs. campal slices by increasing the rate at which sodium ion channels open and close.56 Epileptogenic effects have been noted when skin extracts of the Australian frog Pseudophryne 5.2 Synthesis coriacea a known source of pumiliotoxin B were injected into A short and easy enantioselective synthesis of ( -)-indolizidine areas of the rat brain particularly the dorsal hippo~ampus.~' 167B(91) from the (S)-pyroglutamic derivative (92) is shown in Extracts from the same source potentiated and prolonged Scheme 7.'j0 The dihydropyridone methodology of Comins has NATURAL PRODUCT REPORTS 1994 i-iii MeoQN 60% CI C02Bn (94) (93) (97) cs 1 (CH2)4c H3 (CH2)4CH3 (CH2)4CH3 (70) (f)-lndolizidine 2098 (96) Reagents i ClMgO(CH,),MgCl; ii BnOCOCl; iii NCS PPh, CH,CI,; iv NaN(SiMe,), MeI THF -78 "C; v BF,-Et,O CuBr; vi CH,(CH,),MgBr ;vii H, Pd-C Li,CO, MeOH; viii H, Pt-C MeOH ; ix N,N'-thiocarbonyldiimidazole,cat.DMAP CH,Cl,; x Bu,SnH AIBN toluene reflux; xi H, Pd-C HCl EtOH Scheme 8 (100) [+ epirner at (7:3)] vi-ix 74% I (-)-(89) (-)-lndolizidine 205A (yJ -XV &J cic @ @ PO'O 96% (~HZ)~CHZCHCH~CH~ (bH2)3CHfCHCH2CH3 (CH&C=CH (kH&CECH (CH2)&ZH (-)-(98) (-)-lndolizidine 235B (102) (103) (104) Reagents i LiEt,BH THF -78 "C; ii p-MeC,H,SO,H CH,Cl, r.t. ;iii (a-crotylmagnesium chloride ZnBr, THF 0 "C; iv Sia,BH THF 0 "C then H,O,/H,O NaOH; v flash chromatography SiO,; vi (COCI), DMSO NEt, CH,Cl, -78 "C; vii Ph,PCH,OCHi Cl-/Bu'Li; viii camphorsulfonic acid MeOH r.t.; ix LiAlH, THF reflux; x NH,OCOH 10% Pd-C MeOH r.t.; xi KCN H,O-CH,Cl, pH 34 r.t.; xii LDA THF -78 "C to 0 "C; xiii 5-trimethylsilylpent-4-ynyl chloride (for (89)) or (Z)-l-chloro-4-heptene [for (98)] THF -78 "C to 0 "C; xiv KF DMF H,O 0 "C to r.t.; xv NaBH, EtOH 0 "C to r.t.Scheme 9 been used to prepare racemic indolizidine 209B (70) which previous syntheses of 5-alkylindolizidine alkaloids6 (cJ Ref-continues to gain popularity as a synthetic target (Scheme 8).61 erence 39. Highlights of the present report include the In this work the requisite stereochemistry for the alkaloid moderately diastereoselective addition of (E)-crotylmagnesium established in intermediate (93) appears to result from chloride to the chiral acyliminium ion precursor (99) which conformational control during alkylation of the enolate of (94) produced the desired diastereoisomer (100) and the unwanted and cuprate addition to (95).An alternative approach to (&)-methyl epimer in a ratio of 7:3; and the use of a late 209B was deemed unsatisfactory because of the low-yielding intermediate the a-aminonitrile (101) to form both target (20%) reductive cyclization of acetal (96) to (97).61 compounds. Alkaloids (89) and (98) were produced in fifteen The lengthier syntheses of (-)-indolizidines 205A (89) and and fourteen steps respectively from succinic anhydride in an 235B (98) by Polniaszek and Belmont,62 illustrated in Scheme 9 average yield of 17YO.Three diastereomers of 205A (102) are the first asymmetric syntheses of these alkaloids. This work (103) and (104) were also prepared for comparison ;indeed develops methodology based on addition of organometallic the wealth of spectroscopic data included could constitute a reagents to chiral acyliminium ions introduced during their benchmark for others working in the field.The measured NATURAL PRODUCT REPORTS 1994-5. P. MICHAEL (106) (R)-Citronellol -vi vii 56% (105) (107) [+ epirner at(l+l:l)] 96%lii -v cf- -iii iv @65%90% HO N-O (CH,),C-CH (kH2)3CXSiMe3 (CH,) 3C32 S i Me3 0 (-)-(89) (-)-lndolizidine 205A (109) (108) Reagents i Pr,N+IO, CHCl, 0 "C then chromatography ; ii H (1 atm) 10Oh Pd-C MeOH r.t. ; iii 5-trimethylsilylpent-4-ynylmagnesium bromide Et,O 0 "C to r.t.; iv NaBH, AcOH r.t.; v Zn AcOH-THF-H,O (3 1:l) 60 "C; vi CBr, CHCl, PPh, 0 "C then NEt,; vii 10% KOH in MeOH r.t. Scheme 10 (112a) X= H,Y = OH 68% (112b) X= OH Y =H 17% (76) (+)-Allopurniliotoxin339A (115) (114) Reagents i THF -78 "C; ii AgOSO,CF, THF 23 "C; iii,p-TsOH NaI (CH,O), acetone-H,O 1 10,100 "C;iv Bu"Li THF -78 "C to 23 "C then MeOH; v Li NH, -78 "C Scheme 11 optical rotations of the synthetic alkaloids ([aID-83.5" (c 0.30 stereochemistry of reduction is consistent with the well-known MeOH) for (5R,8R 8aS)-205A and [aID-73.4" (c 0.5 MeOH) axial delivery of hydride ci la Stevens,66to a cyclic iminium ion for (5R,8R,8aS)-235B) differed in magnitude and in the intermediate.The synthesis of (-)-205A was completed by second case sign from the natural alkaloids. The values cited in means of the standard transformations shown in the Scheme. the present work are almost certainly more reliable in view of Addition of other appropriate Grignard reagents to (l08), the likelihood of contaminants in the products obtained from followed where necessary by manipulations of the degree of natural sources.unsaturation in the side chain yielded the remaining target At much the same time as the preceding research was alkaloids. Optical rotations measured for (-)-205A and (-)-published Shishido and Kibayashi reported their synthesis of 235B agreed with those reported by Polniaszek and Belmont ;6z the same two alkaloids (-)-(89) and (-)-(98) in a com-in addition measured [a],values for (-)-207A and (-)-209B munication6 that was soon followed by a full paper also were -86.5" (c 0.95 CHCl,) and -91.3 "C (c 0.58 MeOH) containing syntheses of (-)-indolizidines 207A (90) and 209B respectively.(70).65 Routes to these four alkaloids exploited a general The first reported total synthesis of ( +)-allopumiliotoxin protocol based on the authors' well-known use of the 339A (76) by Overman et al.,67used a nucleophile-promoted intramolecular Diels-Alder reaction of an N-acylnitroso iminium ion-alkyne cyclization for constructing the regio-and substrate in this case the chiral intermediate (105) itself stereospecifically functionalized indolizidine nucleus of the derived from (R)-citronellol(lO6) (Scheme 10). The moderately alkaloid (Scheme 11). Reaction of proline-derived aldehyde diastereoselective cycloaddition gave (107) and its bridgehead (110) previously used by these workers in model StudieP (cf. epimer in a ratio of 1.8:1 the former serving as a versatile Reference 3g) with the lithiated derivative of side chain common intermediate for the synthesis of the alkaloids precursor (11l) made in eight steps from (R)-2-methyl-4-exemplified by (-)-205A in the Scheme.Addition of 5-pentenol gave a separable mixture of (1 12a) and (112b) (4 1). trimethylsilylprop-4-ynylmagnesiumbromide to the reduced The cyclopentaoxazine (113) formed from the former on compound (108) followed by borohydride reduction yielded a treatment with silver triflate is the precursor of intermediate single stereoisomer (109) having the requisite relative iminium ion (1 14) iodide-promoted cyclization of which configuration for the target alkaloid system. The induced the pivotal cyclization to (115) in 81 YOyield. Overman NATURAL PRODUCT REPORTS 1994 Gephyrotoxin R' = (-)-8-(4-phenoxyphenyl)menthyl (120)(+)-Elaeokanine A (1 19) (+)-Elaeokanine C (+ OH epimer (95:5)] [+ ck-isomer (97:3)] Reagents i EtOCH,CH,O(CH,),MgBr THF-toluene -78 "C; ii PPh, NCS; iii NaOMe MeOH reflux; iv LDA THF -78 "C then Me,NCOCl; v (CO,H), MeOH; vi H, washed PtO,; vii PrMgC1 CeCl, 0 "C; viii NaOH MeOH Scheme 12 i-iii ___t vi vii ~ 0 00% 65% H' 0 OH OH OH (122) (1211 viii 91% (120)(+)-ElaeokanineA (1 19) (+)-ElaeokanineC [+ bridgehead isomer (3:l)l Reagents:i m-CPBA 0 "C ;ii cyclopentadiene ZnCl, -80 "C; iii chromatography SO,; iv 2-(2-bromoethyl)- 1,3-dioxolane NaH DMF 0 "C to r.t.; v NaBH, EtOH reflux; vi SmI, HMPA ButOH THF; vii pyridinium tosylate MeOH r.t.; viii 2-trimethylsilyloxy- l-pentene BF;Et,O CH,Cl, 0 "C to r.t.;ix cone. HCI r.t.; x flash vacuum pyrolysis 435 "C 0.5 Pa then recrystallization; xi H, 5 YOPt-Al,O, ButOH r.t.; xii HOCH,CH,OH (EtO),CH p-TsOH reflux; xiii LiAlH, THF reflux then 10% H,SO, r.t.; xiv NaOH EtOH reflux Scheme 13 and co-workers have also published full details of the syntheses of allopumiliotoxin A alkaloids (+)-267A (74) and (+)-339B (77) from the common (-)-indolizidinone intermediate (1 16);69 the essential features of this work were previously published as a communication70 (cf. Reference 71). Studies on the intramolecular dipolar cycloaddition of N-alkenyl nitrones [(117) R = OSiPh2But OBn CH=CH,] have been reported with a view to a projected total synthesis of gephyrotoxin (1 18).72 6 Haeocarpus Alkaloids Two quite different routes to (+)-elaeokanine C [(119) the unnatural enantiomer ; absolute stereochemistry shown] and natural (+)-elaeokanine A (120) have been reported during the period under consideration.Comins has provided yet another example of his generalized dihydropyridone strategy this time in an asymmetric variant with (-)-8-(4-phenoxyphenyl)-menthol as a chiral auxiliary (Scheme 12).73The sulfenyl- maleimide (121) is the chiral educt in the approach of Koizumi et ~l.,~~ which exploits diastereoselective addition of an enolate equivalent to a latent acyliminium ion from (122) as well as a clever use of a Diels-Alder/retro-Diels-Alder sequence both for protection and for stereochemical control (Scheme 13).Although the optical rotations measured for synthetic (+)-(119) and (+)-(120) differed slightly in the two studies their magnitudes were considerably greater than those originally determined for the naturally occurring alkaloid^.'^ The present studies also imply that natural (-)-elaeokanine C and (+)-elaeokanine A must have the opposite absolute configurations at the bridgehead carbon. 7 Phenanthroindolizidine Alkaloids and Seco Analogues Another five minor alkaloids belonging to this group have been isolated from Tylophora indica along with the major alkaloid tylophorine (123).76 (-)-Tyloindicines F (124) G (125) H NATURAL PRODUCT REPORTS 1996-5.P. MICHAEL ?Me R' Me0 Me0 Me0 6Me (123)Tyiophorine R' = OMe R2 = H R3 = -(1 24) Tyloindicine F (125)Tyloindicine G R' = OMe R2 = H R3 = OH (1 30) Antofine R' = R2 = H R3 = -(126)TyloindicineH R' = R3 = H R2 = OH (131)R' =H R~=OH,R~=O OMe OMe OMe (1 27) Tyloindicine I R' = R3 = Me R' = OH (1 29) Tyloindane (128)Tyloindicine J R' = R2 = H R3 = Ac vii-ix x.xi A:m Tfom M e ~i-vi oN 43% -\N 72% Ar OH 62% Ar CO2Ph Ar = 3,4-(Me0)'C6H3 48% 69% Br A (133) Me0 Me0 XIV OMe OMe 87% (1 32) Septicine (1 23) Tylophorine vii xiii v xii vi 83% PrhSi OH C02Ph Reagents i mesityllithium THF -23 "C; ii 12; iii 3,4-(MeO),C6H$nBr (Ph,P),Pd THF r.t.; iv BnOCOC1 THF -23 "C; v EtOCH,CH,O(CH,),MgBr; vi 10% HCl; vii PPh, NCS CH,C12 r.t.; viii H, Pd-C EtOAc; ix Bu"Li THF -78 "C to r.t.; x L-Selectride THF -23 "C; xi PhN(Tfj, -23 "C to r.t.; xii PhOCOCl THF -23 "C; xiii NaOMe MeOH reflux; xiv Py.HBr, CH,Cl, Li,CO, 23 "C; xv 3,4-(MeO),C6H,ZnBr (Ph,P),Pd THF reflux; xvi VOF, TFA CH,Cl, r.t. Scheme 14 (126) I (127) and J (128) isolated from aerial parts of the alkaloid 14-hydroxyantofine N-oxide (1 3 l) have been isolated The absolute configurations of plant were identified on the basis of comprehensive spec- from Cynanchum kornaro~ii.~~ troscopic studies on the native metabolites and on a number of five alkaloids of the tylophorine type have been assigned with acetylated and methylated derivatives. Tyloindicines F I and the aid of circular dichroism measurements. 78 J are new examples of the rather uncommon secophenanthro- New syntheses of (+)-septicine (132) and (+_)-tylophorine indolizidine alkaloids while F and G possess a rare feature (1 23) by Comins and Morgan initially follow routes similar to bridgehead hydroxylation.All the alkaloids are unusual in those already presented in Section 6 for the elae~kanines.~~ Key possessing unsaturation in the indolizidine ring between steps are illustrated in Scheme 14. Palladium-catalysed coupling positions other than the customary As,7position. It is intriguing of an arylzinc reagent to vinyl systems bearing leaving groups that T. indica has also yielded the new hydrocarbon tyloindane is a noteworthy feature of the syntheses. Especially attractive in (129) which is effectively the carbocyclic analogue of the second route is the spectacularly successful (97% yield) tylophorine.introduction of both aryl rings simultaneously into the 1-Two articles in the hard-to-come-by Chinese literature appear bromo-2-triflyloxyalkene (133). to be relevant to this discussion. Antofine (130) and a new NATURAL PRODUCT REPORTS 1994 FCH3 I\ O-0 (134) 7-Epinupharidine (135) Nupharidine 06Jh-I ii _T 72% 83% (137) (139) (136) Reagents i ZnCl, THF r.t.; ii Ph,SnH C,H, AIBN reflux; iii NaBH, EtOH 0 "C; iv PhSeCN Bu,P THF reflux Scheme 15 ii,iii iv v (+J> rGWH2 0 CH3 OH 0 CH3 (73) (143) (145) Myrtine ii,iii iv v 0 CH3 0 CH3 CH3 (144) (146) Epimyrtine Reagents i TFA CH,Cl, 0 "C; ii 0, Me$; iii 2-ethyl-2-methyl-l,3-dioxolane, p-TsOH; iv LiAlH, THF reflux; v 10% HCI Scheme 16 Radical cyclization is the central feature of a short synthesis 8 Nuphar Alkaloids of the diastereoisomer of Nuphar indolizidine shown in (1 36) Mass spectrometric studies have traditionally played a major (Scheme 15).83 Imine (137) readily made by condensing the role in facilitating the stereochemical elucidation of C, and appropriate amine with 3-furaldehyde underwent a smooth thio-C, Nuphar alkaloids.The data obtained during the past Diels-Alder reaction with the oxygenated diene (138) to give two decades have now been summarized in a short review that the dihydropyridone (1 39) after which radical-initiated ring deals both with individual alkaloids and with general frag- closure gave ketone (140) as a chromatographically homo-mentation patterns.8o Further studies on C, alkaloids and their geneous product.The stereochemistry of (140) was not N-oxides have made use of mass-analysed ion kinetic energy determined but reduction with borohydride gave a single (MIKE) spectrometry for analysis of metastable ion decompo- alcohol (141) the structure of which was confirmed by X-ray sition ;the technique showed that 7-epinupharidine exists in the crystallographic analysis. The synthesis completed as shown in trans-fused configuration (1 34) in contrast to the cis-fused the Scheme yielded the target alkaloid (136) in an overall yield nupharidine (1 35).81 of 32 O/O based on imine (137). The crystallographically determined structures of two iso- meric methiodide salts of thiobinupharidine (N,N'-dimethyl- thiobinupharidine diiodide dihydrate acetone solvate and the 9 Myrtine and Epimyrtine methanol solvate) show a trans,trans arrangement of the ring 1,3-A11ylic strain between the carbonyl and methyl groups has junctions in the first and a cis,trans arrangement in the been invoked to explain the 7 3 diastereoselectivity in the acid- second.82 promoted cyclization of hydroxylactam (142) to quinolizidines NATURAL PRODUCT REPORTS 1996-5.P.MICHAEL 0 (147) (-)-Cytisine (1 48) (-)-Sparteine R = H (149) R=OH (143) and (144).84 These products were converted by the simple reactions shown in Scheme 16 into (+)-myrtine (145) and (&)-epimyrtine (146) in overall yields of about 20% based on glutarimide. 10 Alkaloids of the Lupinine-Cytisine-Sparteine-Matrine-Ormosia Group The biochemistry physiology and chemical ecology of lupin quinolizidine alkaloids have been surveyed in a concise review that also gives insights into the expression of genes responsible for alkaloid biosynthesis and transport.85 More specific reviews deal with the isolation biosynthesis analysis and chemical modification of the pharmacologically useful alkaloid cytisine (147),8s the alkaloids of Sophora JZave~cens,~’ and the phar- macology of alkaloids isolated from Sophora alopecuroides.’* 10.1 Occurrence Detection and Chemical Ecology Several new alkaloids belonging to this group are listed in Table 1 (vide infra) which also includes new sources of known alkaloid^.^^-^^^ The large number of alkaloids (many apparently new or only tentatively identified) recently detected in trace amounts in many species bears witness to the sensitivity of modern GC and GC-MS instrumentation ;all compounds that have been identified unambiguously are listed in the Table.Continuing their exhaustive investigation of alkaloids as chemotaxonomic markers of the Leguminosae (Fabaceae) (cf. Reference 3i) van Wyk and Verdoorn have published further reports on the constituents of the tribe Crotalarieae. Problems in alkaloid-based chemotaxonomy have been highlighted in a systematic survey of virtually all known species and subspecies of the genus Pearsonia which revealed large qualitative and quantitative differences in alkaloid content depending on geographical source developmental stage and plant parts e~amined.~’ Lupanine esters generally a good marker for the genus decreased markedly at the end of the growing season and were not well represented in seeds which accumulated hydroxylupanines (vide infra Section 10.2) instead.Another member of the Crotaliarieae the monotypic genus Robyn-siophyton shows a close affinity to Pearsonia and Rothia in its pattern of alkaloidal components a finding that bolsters morphological evidence for the relationship. lo2 The same authors have also begun to classify the alkaloids of the tribe Liparieae. Large and unexpected quantitative differences in the alkaloidal components of Liparia parvu and Liparia splendens may perhaps be ascribed to different pollination mechanisms enlarging the taxonomic distance between the otherwise related species.94 Two sections of the genus Priestleya (sect.Priestleya and Anisothea) contain a remarkably different array of alkaloids the former being very similar to the alkaloids of Liparia p~rva.~~~ The generic concept of Priestleya may thus well be artificial and the alkaloidal records support morphological evidence for recognizing two distinct genera. Another case in which generic revision is recommended occurs in the tribe Podalyrieae pink and white- flowered species contain tetracyclic quinolizidine alkaloids and alkaloid esters while yellow-flowered species contain carboxylic acid esters of the type previously found in the related genus Virgilia.looIncidentally these authors have now presented such persuasive evidence for 3P-hydroxylupanine rather than 4a- hydroxylupanine as the likely structure of ‘nuttalline’ that it is now becoming irksome to see other workers persisting in reporting the 4a-hydroxy isomer without comment.Chemotaxonomic studies by Greinwald el al. have con- centrated on genera within the tribe Geni~teae.~~,~~ The pattern of alkaloids from two subspecies of Adenocarpus hispanicus is distinguished by high concentrations of sparteine (148) and several dehydrosparteines (some apparently new alkaloids but not fully characterized as yet) in the leaves with the pyrrolizidine alkaloid decorticasine more prominent in other organs. The bispiperidine alkaloid adenocarpine a principal component of other Adenocarpus species was conspicuously absent.The results support the opinion that the genus should be divided into two phytochemical groups.89 Although the authors make no special mention of the fact one of the components detected in this study 8a-hydroxysparteine (149) was previously known only from synthesis,log and may thus be a new natural product. Taxonomic revision on the basis of alkaloid content is also indicated for plants of the genus Genista (section Spartioides) G. cinerascens is characterized by large concentrations of a-pyridone alkaloids especially cytisine while G. cinerea and G. majorica formally in the same aggregate are rich in 13a-hydroxylupanine and its benzoate and tiglate The seasonally dependent alkaloid pattern of the graft hybrid Laburnocytisus adamii (= Laburnum anagyroides + Cytisus purpureus) is very close to that of the Laburnum parent.92 Furthermore plant parts morphologically akin to those in L.anagyroides produced alkaloid concentrations as high as those in the parent whereas those parts originating from C. purpureus were poor in alkaloids. Some fourteen alkaloids mostly quinolizidines were detected by GC-MS and one apparently new compound was tentatively identified as N- ethyltetrahydrocytisine (1 50) on the basis of its mass spectral be haviour. The use of overpressured layer chromatography (OPLC) with ethyl acetate on alumina plates has led to easy separation of alkaloids from a range of plant sources including Lupinus species (lupanine lupinine 13-hydroxylupanine) and Saro-thamnus scoparius (sparteine).110 A sensitive new analytical technique for detecting alkaloids in lupin seeds employs an enzyme-linked immunosorbent assay (ELISA) based on poly- clonal antialkaloid antibodies from sheep antisera.ll1 Antisera showed a high specificity for (+)-lupanine and (+)-13-hydroxylupanine common antinutritional components in lupin species that are commercially important as stock feeds and protein sources. Continuing research into the chemical ecology of the moth Uresiphita reversalis has yielded some of the most significant results to date.l12 The alkaloid pattern in last instar larvae has been analysed by GC-MS and compared with that of the host plant Teline monspessulanus. Amongst many new minor alkaloids detected but not yet characterized are several apparently having the aphylline skeleton a dehydrobaptifoline and a hydroxylated N-methylcytisine.More noteworthy however are the startling differences in alkaloid distribution between host plant and insect. Whereas the plant contained NATURAL PRODUCT REPORTS 1994 0 (155) R = CHZCONH (1 56) R = CHzC02H (157) R=OH (1 52) (-)-Albine (1 53) Multiflorine R = H (154) R=OH mainly aphylline dehydroaphylline and epiaphylline larvae excreted dehydroaphylline and epiaphylline but selectively accumulated N-methylcytisine (a relatively minor plant con- stituent) which accounted for 90 % of the alkaloid in the insect. About 80% of the stored alkaloids were later transferred to cocoon silk after pupation 19% were found in larval exuviae and virtually none in the pupae themselves.The accumulated evidence suggests that alkaloids are mainly stored in the silk glands of the head segment and to a lesser extent in the integument. Perhaps the most important result is that the first evidence has been gathered for a carrier-mediated mechanism rather than simple diffusion for the differential uptake of quinolizidine alkaloids by the insect. Two recent studies have traced the fate of quinolizidine alkaloids through three trophic levels. The lupin aphid Macrosiphum albifrons when raised on bitter (alkaloid rich) lupins proved highly toxic when fed in turn to larvae of coccinelid (and to a lesser extent syrphid and chrysopid) predators;while aphids raised on sweet lupins caused only some developmental retardation in predators.113 Lupanine or 13-hydroxylupanine but not sparteine appears to be responsible for predator mortality. Another aphid Aphis cytisorum obtains and sequesters alkaloids principally cytisine from Laburnum anagyroides after which the alkaloids are transferred virtually unchanged to three species of ants that gather honeydew from the aphids.l14 The beetle Bruchidius villosus larvae of which feed on seeds of L. anagyroides excrete ingested alkaloids but are nonetheless able to pass on measurable amounts of the unchanged metabolites to several species of predatory insects one of which (Triaspis thoracicus) even succeeds in depositing cytisine in the cocoon during pupation.l14 10.2 Structural Spectroscopic and Biological Studies (-)-A5-Dehydroalbine (15 1) is an unusual 13-substituted tricyclic alkaloid isolated from the seeds of Lupinus termis and characterized by the full complement of spectroscopic techniq~es.~~ Its co-occurrence with (-)-albine (152) and some analogues of multiflorine (1 53) suggests that its biosynthetic origins lie in cleavage of 13-hydroxymultiflorine (1 54) followed by an aza-Claisen rearrangement of the ally1 chain from N to C- 13.Another new tricyclic alkaloid (-)-12-cytisineacetamide (155) was isolated from the roots of Sophora exigua; its 7R,9S absolute configuration was determined by comparison of CD spectra and Cotton effects with those of (-)-cytisine (147) and by direct comparison with a synthetic sample made by alkylating (-)-cytisine with a-chloroacetamide.lo4 The new amide is not an artefact of the isolation procedure and the corresponding N-acetic acid analogue (1 56) a known natural product is unequivocally absent from the plant extracts. (-)-12-Hydroxycytisine (1 57) isolated in the same work has received full spectroscopic characterization for the first time OWH (151) (-)-A5-Dehydroal bine (158) Desoxyangustifoline (159) R = P-OH (160) R = a-OH and its structure has been confirmed by oxidation of (-)-cytisine with m-chloroperoxybenzoic acid. Desoxyangustifoline (1 58) a new alkaloid isolated from aerial parts of Thermopsis mongolica was characterized by MS and 'H NMR spectroscopy only.lo8 Upon treatment with formaldehyde in aqueous buffer at pH 5.5 it was converted into 13-epi-hydroxysparteine (1 59) which was coincidentally identified as a new alkaloid in the same study.The sketchy spectroscopic data for this compound were compensated for by several chemical interconversions. Thus (159) could be produced by epimerization of the well-known 13a-hydroxy- sparteine (1 60) with p-toluenesulfonic acid ;while dehydrogen- ation of (159) with mercuric acetate followed by re-hydrogenation gave two epimeric 13-hydroxy-a-isosparteines both distinctly different from (1 59) and (1 60). Hydroxylated lupanines feature prominently in this year's collection of new alkaloids. (+)-3a-Hydroxylupanine (1 61) has been reported as a new alkaloid in extracts of Jordanian Leontice leontopetalumg3 by a group apparently unaware of the same compound's previous isolation from Ammopiptanthus mongolicu~.~~~ Differences in the optical rotations and melting points reported in the two publications are unimportant in view of the virtual identity of the reported 13C NMR data.The thorough high field 'H NMR characterization of (161) and its acetate in the more recent study should however be regarded as definitive ; and the chair-chair-boat-chair conformational sequence for the four rings of the alkaloid has been deduced from analysis of coupling constants. Definitive lH NMR data and connectivity correlations for the far commoner 13a-hydroxylupanine (162) were also reported.93 Reliable lH and 13C NMR and MS data have been collected for a suite of hydroxylated lupanines from several species of the genus Pearsonia :" the known116 but rare 3/3,13a-dihydroxylupanine (163) and the two new alkaloids 801,13a-dihydroxylupanine (164) and 3P,8a 1301-trihydroxylupanine (165).The structures of these alcohols were suggested by co-occurrence with the 13- angelate esters cajanifoline cryptanthine and pearsonine respectively (vide supra Section 10. l) and confirmed by comparison with products formed by basic hydrolysis of these esters. Two new alkaloids reported in the relatively inaccessible Chinese literature are noteworthy. The uncommon aloperine group of tetracyclic quinolizidine alkaloids has been augmented by (+)-1 1 -dehydroaloperine (1 66) isolated from Sophora alopecuroides the structure of which was deduced on the basis of one and two-dimensional lH and 13C NMR IR and UV spectrometry and mass ~pectroscopy.'~~ Although a similar range of techniques was employed in the structural deter- mination of 5a-hydroxy-7,17-dehydroisolupanine (1 67) isolated from Piptanthus concol~r,~~ anti-Bredt alkene the structure assigned will surely raise eyebrows.The new alkaloid (168) isolated from aerial parts of Genista NATURAL PRODUCT REPORTS 1994-5. P. MICHAEL R2 (161) (+)-3a-Hydroxylupanine (162) R' = R2= H R3 = OH (163) R' = R3 = OH R2= H (164) R' = H R2= R3 = OH (165) R' = R2 = R3 = OH 0 (170) (-)-Anagyrine sessilifolia possesses a feature hitherto unknown in the tetracyclic bisquinolizidine alkaloids a 16-carbon atom skel- eton the additional atom being appended as a hydroxymethyl group at C-10.91 A battery of spectroscopic measurements provided unambiguous confirmation of this unique structure.The biosynthetic origin of the hydroxymethyl substituent raises intriguing questions :does the group come from methylation by an agent such as S-adenosyl-L-methionine or does one of the lysine units from which sparteine is thought to be derived fail to undergo decarboxylation to cadaverine? Odd though this structure may be an even weirder new alkaloid has been isolated from leafy shoots of Sophora grzfithii.lo6 (+)-Sophazrine (169) is an unprecedented triazatetracyclic quinolizidine alkaloid which was characterized by means of extremely thorough NMR and other spectroscopic studies but which was otherwise not accorded the publicity that its unique structure deserves.How its biosynthesis squares with the proposed origin of the tetracyclic bisquinolizidine alkaloids from three lysine units (e.g. as recently deduced for (-)-anagyrine by Robins and co-worker~~~~) surely be a must matter for speculation. A polemic has arisen in the literature concerning the relative configuration of anagyrine and related alkaloids. The 'H NMR spectrum of (-)-anagyrine (170) was fully assigned after application of exhaustive experiments that included homo- nuclear spin decoupling NOE difference spectra and two- dimensional correlation spectra at 200 MHz and 600 MHz.'18 It was found that in solution rings c and D have chair conformations and are cis-fused and that the lone pair on N-16 has the p configuration.Assignment of the 13C NMR spectrum permitted the revision of some incorrect assignments in the literature. Shortly after the publication of this study an independent group reported (without reference to the previous research) a substantially different assignment of the 'H NMR spectra of anagyrine and related alka10ids.l~~ On the basis of the 'H and 15N NMR data the startling proposal was made that the accepted relative configurations of anagyrine (1 70) and thermopsine (171) were incorrect and should be reversed. A sharp retort from the first group summarized the convincing body of stereochemical correlations based on chemical inter- conversions between the two alkaloids concerned and other OH 0 (166) All-Dehydroaloperine (169) Sophazrine 0 (171) (-)-Thermopsine bisquinolizidine alkaloids of unambiguous relative and absolute configuration as well as evidence from crystallography and total synthesis.120 They presented a resumi of their own NMR evidence and gave an indication of problematic features in the spectra and interpretations of the rival group.As they cogently concluded ' . . .compelling evidence should be submitted before any change is made to the relative stereochemistry of anagyrine and thermopsine which has been accepted for the last 40 years'. An amusing footnote to the episode is that neither group seems to have come across the recently published crystallographic investigation of (-)-anagyrine which unequivocally supports the relative configuration depicted in (1 7O).lo6 Conformational studies on the tetracyclic bisquinolizidine alkaloids and synthetic analogues have been placed in per- spective in a timely review that discusses the influence of inter- and extramolecular factors on aspects as diverse as configurationalkonformational equilibria proton-acceptor behaviour and chemical and physical properties.12' IR and 13C NMR investigations of alkaloids related to multiflorine (1 53) as well as their perchlorate salts have shown a boat-chair conformational equilibrium in ring c that depends on steric interactions primarily involving the hydrogens on C-1 7.122 Crystallographic investigations of interest published during the period under review include the following 2-phenyl-sparteine perchl~rate,'~~ 1,16-endo-methylene sparteine dii~dide,l~~ N( 1)-methyl- 15-oxosparteine iodide and N( 1)-methyl-17-oxosparteine iodide m~nohydrate,'~~ 2-cyano-2-phenylsparteine perchlorate,126 6-methylsparteine diper-chlorate lZ7and dimethyl N-cytisinylamidophosphate.128 Bond energies heats of formation ionization potential and con- formational energies of the alkaloid lupinine have been determined with the aid of MIND0/3 calculations.129 Two- dimensional NMR spectra of N-methylcytisine sophocarpine N-oxide and other alkaloids of Sophora JIavescens have been reported.lo5 The kinetics and mechanism of hydrolysis of (-k)-lupanine to lupanic acid in the dark have been studied polar~graphically'~~ and spectrophotometrically,131the latter method allowing some conclusions derived from the former method to be corrected.Amongst the very large number of clinical studies devoted to the lupin quinolizidines the following are of greater interest to NPR I1 NATURAL PRODUCT REPORTS 1994 (172) 2,3-Dehydrosparteine (173) (2s)-Hydroxysparteine (174) (+)-(4s)-Hydroxypachycarpine (175) 0 0 (179a) (179b) H! iv 9 -4 & 62% 83 iv% * 59% *** iii wii Ph 0 0 0 (180) Lupinine R' = H R2 = CH20H (1 82) (183) (181) Epilupinine R' = CH20H R2 = H Reagents i CF,CO,H 20 "C then MeOH reflux;ii CF,CO,H-CF,SO,H (4:l) CH,Cl, 20 "C then NaOMe MeOH; iii I, MeCN r.t.; iv H,C=CHMgBr cat.CuI THF -35 "C;v 0, MeOH CH,Cl, -78 "C;vi NaBH, MeOH; vii AlH, THF r.t. Scheme 17 chemists. 2,3-Dehydrosparteine (172) formerly identified as the major urinary metabolite of (-)-sparteine (148) in the rat is an artefact produced under the strongly alkaline analytical work-up condition^.'^^ The primary metabolite under neutral conditions is actually (2S)-2P-hydroxysparteine (173) which results from stereospecificabstraction of the 2P-axial hydrogen of the alkaloid by a cytochrome P450 isozyme as demonstrated by deuterium labelling studies and 2H NMR spectroscopy. Lupanine is a secondary metabolite. The same enzyme system acts on pachycarpine [= (+)-sparteine ent-(148)] quite differently yielding (4S)-4P-hydroxypachycarpine (174) in-stead.In human subjects where the isozyme is of growing clinical importance in the metabolic control of a number of drugs both 2,3-dehydrosparteine (172) and 5,6-dehydro-sparteine are no longer to be regarded as the primary renal metabolites of (-)-~parteine.',~Instead alcohol (173) and the iminium species (175) could be detected in urine after administration of [2R-2H]-sparteine sulfate. They were characterized thoroughly by 'H 2H and 13C NMR spec-troscopy. Additionally iminium species (176) was shown to undergo complete conversion into (173) in the pH range 4-10 while (175) formed no carbinolamine. None of these results compromises a sensitive new GC-MS method for the sim-ultaneous detection of parent drugs and their metabolites demonstrated for sparteine and 2,3-dehydrosparteine in microsomal fractions of rat liver.', The synthesis and anticholinesterase activity of new and of lupinine and epilupinine have been reported.The anti-ulcer activity of Sophora viciifolia alkaloids may be due to compounds that are more potent than s~phocarpine.'~' 10.3 Synthesis A 1-bromoalkynyl substituent is the nucleophilic partner in the acyliminium ion cyclization shown in Scheme 17.13* The cyclization of lactam derivatives [(177) R = H or Et] easily prepared from glutarimide was investigated under various acidic conditions. When (177) was treated with trifluoroacetic acid followed by methanolysis of the putative bromoenol trifluoroacetate intermediate [(178) X = OCOCF,] a 45 :55 mixture of the esters (179a) and (179b) was obtained in 60% yield.Equilibration with sodium methoxide in methanol swung the ratio to 68 :32. When the cyclization was performed with a mixture of trifluoroacetic and trifluoromethanesulfonic acids bromoenol triflate [(178) X = OSO,CF,] -arguably the first compound of its kind in the literature -could be isolated (70 %) and then converted quantitatively into the esters (179) with sodium methoxide in methanol. The preparation of esters (179) completes formal ~yntheses~~~*'~~ of (f)-lupinhe (180) and (f)-epilupinine (181) in 37 % overall yield from glutarimide. Another short synthesis of (-t )-epilupinine shown in the same Scheme exploited the stereoselective transannular cyclization of the ten-membered unsaturated lactam (182) with iodine.141 The isomerically pure quinolizidine product (1 83) obtained in 62 % yield was readily converted into (f)-epilupinine (181) by the route shown.142 A biomimetic approach to the synthesis of quinolizidine systems involves the intermediacy of bispiperidines (185a) and (185b) prepared via (184) as shown in Scheme 18.14 Ammonia in methanol proved to be an effective catalyst for the recyclization of major bispiperidine (1 85a) to the quinolizidines (186a) and (186b) (2 :1).The ratio could be swung in favour of the thermodynamically more stable isomer (186b) (1 :4) on equilibration with DBU or sodium methoxide. These products were converted into N-acetyllupinamine (187a) and N-acetylepilupinamine (187b) respectively by straightforward transformations.The corresponding amines incidentally while not natural products themselves are useful synthetic intermediates for alkaloids such as lamprolobine (188). Unfortunately a proposed enantioselective version of the sequence in which (184) was treated with (R)-phenylglycinol to NATURAL PRODUCT REPORTS 1996-5.P. MICHAEL 7;yo 70% ii iii ou7Fp Ph3P 44:l (185a) (185b) viii 81%H 0YPh aH2 I 0 qONtq)0 42 * 1:4 CONH200 ( 189) (1 90) (186a) (186b) vi vii 52% vi,vii 53% ~ t NHAc 0 PiHAc (188) Larnprolobine (1 87a) (187b) Reagents i glutaraldehyde THF reflux; ii PhCH,NH, Bu,N+ BH,CN- CH,Cl, 0 "C then NEt, r.t.; iii H, Pd-C MeOH-AcOH; iv NH, MeOH; v DBU or NaOMe THF reflux; vi LiAlH, THF r.t.; vii Ac,O reflux; viii (R)-phenylglycinol NEt, MeCN reflux Scheme 18 aL@ 92% N 62% N (191) iii 58% + 9% + 30% I 0 :,To1 S (192a) (1 92b) 4.OH c 80% 80% (+)-( 181) (+)-Epilupinine (1 93a) (1 93b) (-)-( 180) (-)-Lupinine Reagents i LDA THF then (-)-( lR,2S,5R)-rnenthyl(S)-ptoluenesulfinate,-20 "C to -10 "C; ii LDA THF then I(CH,)$ -78 "C to -25 "C; iii NaBH, CeC1;7H20 MeOH 0 "C to 25 "C; iv LDA THF then EtOCOCN -78 "C to 25 "C; v LiAlH, THF-Et,O 0 "C; vi Raney Ni EtOH 25 "C Scheme 19 afford the chiral oxazolidine intermediate (1 89) was foiled when previously developed by this group in their chiral synthesis of the recyclization reaction was found to give racemic Elueocurpus alkaloids145(cf Reference 3j). Reduction of the quinolizidines.This undesired result probably comes about key intermediate (191) with sodium borohydride in the presence because the basic conditions induce some retro-Michael reaction of cerium(u1) chloride was diastereoselective giving to the lactam (190). quinolizidines (192a) and (192b) in 58% and 30% yields Enantioselective syntheses of (-)-lupinine ( -)-(180) and respectively. However acylation of the enolates derived from (+)-epilupinine (+)-(18 1) by Hua and co-workers (Scheme either of these compounds produced the same mixture of 19)lg4proceed by way of the chiral P-sulfinyl enamine approach separable esters (193a) and (193b) in an 8 1 ratio. Confirmation NATURAL PRODUCT REPORTS 1994 (195) Exochomine (1 96) Coccinelline H Bu'Me2Si0..i Ii-iV 67% Et02C-dq 79% Et02C -i HT Pco2Et EtO2C CO2Et EtO2C (200) [+ isomers] (201) [+ 4-epimer (85:15)] v vi 4743% I ~ ~ ~ ix-xiii ButMe2si0..v "iii ButMe2si0.ip vii ButMe2si0.;v 50% 93% 83% H "H -* H .-H ''H I I CH3 CH3 CH2 0 (1 99) epi-Hippodamine (202) [+ isomers (68:24:7:1)] Reagents i H,NOH.HCl NaOAc 120 "C then chromatography; ii Zn AcOH aq. EDTA reflux; iii DBU C,H, 20 "C; iv ButMe,SiC1; v LDA THF -78 "C; vi LiCI moist DMF reflux then chromatography; vii Ph,P=CH, Et,O; viii H, Pd-C MeOH; ix Et,NF THF reflux; x NaH imidazole THF; xi CS, reflux; xii MeI; xiii Bu,SnH AIBN toluene reflux Scheme 20 of their stereochemistry followed after conversion into the target alkaloids as shown in the Scheme. The use of optically pure sparteine as a chiral auxiliary in synthesis has become sufficiently common to demand notice.Recent applications include its influence on the asymmetric polymerization of N-substituted maleimide~,~~~ cycloalkyl-diphenylmethyl met ha cry late^,'^^ and diphenyl(2-pyridy1)-methyl metha~ry1ate.l~~ Synthetically useful transformations mediated by (-)-sparteine include asymmetric homogeneous hydrogenation of cc,P-unsaturated carbonyl compounds to allylic alcohols with an iridium-BINAP complex,149 asymmetric Ullmann coupling in the synthesis of 2,2'-dihydroxy- and 2,2'- diamino- 1,l '-binaphthyl~,l~~ and asymmetric allylic alkylation catalysed by palladium-sparteine complexes.151 The combi- nation of (-)-sparteine and alkyllithiums induces asymmetric deprotonation and has been exploited in forming allyltitanium reagents that are subsequently used in asymmetric homoaldol condensations 152 and in asymmetric synthesis of 2-substituted pyrr01idines.l~~ In view of the growing importance of asym- metric deprotonations the crystallographic structural eluci- dation of lithiodiphenylmethylisocyanide/(-)-sparteine bis- (tetrahydrofuran) complex is of A 6Li NMR study of the 1 :1 isopropyllithium/( -)-sparteine complex in ether solution has shown the presence of lithium in two different environments and structure (194) has been 11 9b-Azaphenalene Alkaloids A resurgence of interest in this long-dormant area is certain to follow the announcement of the discovery of a startling new alkaloid from the European ladybird Exochomus quadripustulatus.156 Exochomine an unprecedented 9b-azaphenalene/8b-azaacenaphthylenedimer was isolated from the extracts of 2500 insect specimens and purified as the dextrorotatory hydrochloride salt.The customary spectro-scopic evidence was obtained for its various structural features but X-ray crystallography on exochomine hydrochloride clinched matters by revealing the structure shown in (195). The absolute configuration depicted in this diagram was also determined crystallographically and is the same as in monomeric 9b-azaphenalene alkaloids. Disclosures concerning other dimeric ladybird alkaloids have been promised for the future. Coccinelline (196) the major defensive alkaloid of the seven- spot ladybird (Coccinellu septempunctatu) is secreted in a fluid exuded from the leg joints by 'reflex bleeding' when the insect is under threat.A recent study has shown that the alkaloid is also distributed throughout the body though at about a tenth of the concentration found in reflex blood. Ladybirds examined after hibernation produced little defence fluid but still contained sufficient alkaloid to provide (in conjunction with the insect's striking aposematic colouration) an effective deterrent to predator^.'^^ A stereochemically unselective cycloaddition between the nitrone formed in situ from hydroxylamine and aldehyde (197) and ethyl hexa-3,Sdienoate (198) provides the point of entry for a new synthesis of (f)-epi-hippodamine (199) an unnatural relative of the ladybird alkaloids (Scheme 20).15* In this reaction a mixture of three cycloadducts was formed in 67% yield from which the desired diastereoisomer (200) could be separated by flash chromatography.Slow but spontaneous cyclization to quinolizidine (201) speeded up in the presence of base took place on reductive cleavage of the N-O bond of (200). Dieckmann cyclization served to construct the third ring of the target compound though once again the reaction was not stereoselective. Nonetheless intermediate (202) possesses the tricyclic skeleton of several ladybird alkaloids [c$ coccinelline (196)] and its conversion into epi-hippodamine (199) was accomplished as illustrated in the Scheme. NATURAL PRODUCT REPORTS 1996-5.P. MICHAEL 35 Table 1 Isolation and detection of alkaloids of the lupinine<ytisine-sparteine-matrine-Ormosia group Species Alkaloid Ref. Adenocarpus hispanicus ssp. gredensis and hispanicus Aphylline 11,12-Dehydrosparteine *(?)8a-Hydroxysparteine (149) 89 a-Isolupanine a-Isosparteine /3-Isosparteine Lupanine Multiflorine (1 53) 17-Oxolupanine 17-Oxosparteine Sparteine (148) Genista cinerascens 1 1-Allylcytisine 90 5,6-Dehydrolupanine 1 1,12-Dehydrosparteine Epibaptifoline N-Formylcytisine /3-Isosparteine Lusitanine N-Meth ylcytisine Rhombi foline Genista cinerea and Genista majorica 13-Acetoxylupanine Angustifoline 90 13-Benzoyloxylupanine Cytisine (147) 5,6-Dehydroisolupanine (?) 5,6-Dehydrolupanine 1 1,12-Dehydrosparteine 4-H ydroxylupanine 13-Hydroxylupanine 14-Hydroxysparteine 13-Isobutyryloxylupanine a-Isolupanine a-Isosparteine 13-Isovalero yloxylupanine Lupanine Lusit anine 13-Propano yloxylupanine Sparteine Tetrahydrorhombifoline 13-Tigloyloxylupanine Genisla sessilifolia Laburnocytisus adamii * 10a-Hydroxymethylsparteine (168) N-Acetylcytisine Anagyrine (1 70) Cytisine 91 92 5,6-Dehydrolupanine Epibapti foline *N-Ethyltetrahydrocytisine(150) (tentative) N-Form ylc ytisine /3-Isosparteine Lupanine N-Methylcytisine Sparteine Leon tice leon topetalum ( +)-3a-Hydroxylupanine (161) (+)-13a-Hydroxylupanine (1 62) (+)-a-Isolupanine 93 Liparia parva 11 ,lZDehydrosparteine 3P-H ydroxylupanine 13a-H ydroxylupanine a-Isolupanine 94 a-Isosparteine /3-Isosparteine Lebeckianine 17-Oxohpanine 17-Oxosparteine Liparia splendens 11,12-Dehydrosparteine 3P-H ydroxylupanine 13a-H ydroxylupanine 94 a-Isolupanine a-Isosparteine Lebeckianine Lupanine 17-Oxolupanine 17-Oxosparteine Sparteine 36 NATURAL PRODUCT REPORTS 1994 Table 1 (contd) Species Alkaloid Ref.Lupinus albus 13a-Hydroxylupanine (+)-13a-Hydroxymultiflorine (1 54) (-)-13a-H ydroxy -5-dehydromultiflorine 95 Lupanine Multiflorine Lupinus termis (-)-Albine (152) 13a-Angeloyloxylupanine 96 *( -)-A5-Dehydroalbine (1 51) (-)-I 1 12-Seco-12,13-Didehydromultiflorine (-)-13a-Hydroxymultiflorine 13n-Tigloyloxylupanine Pearsonia spp." 13a-Angeloyloxylupanine Cajani foline 97 98 Cryptanthine 5,6-Dehydrolupanine 3P 13a-Dihydroxylupanine (163) *8a,13a-Dihydroxylupanine(1 64) 3/3-Hydroxylupanine 13a-Hydroxylupanine a-Isolupanine a-Isosparteine P-Isosparteine Lebeckianine Lupanine 17-Oxolupanine Pearsonine Sessili foline Sparteine *3,4,8a 13a-Trihydroxylupanine (165) Piptanthus concolor Anagyrine Cytisine 99 *Sa-Hydroxy-7,17-dehydroisolupanine(167) Thermopsine (171) Podalyria (white- and pink-flowered species)b 13a-AngeloyloxylupanineAphylline 100 Cajanifoline 3p 1 3a-Dihydroxylupanine 3P-H ydroxylupanine 13a-Hydroxylupanine a-Isolupanine Lebeckianine Lupanine 17-Oxolupanine Pearsonine Sessili foline Sparteine Podulyria (yellow-flowered species)c 13a-Hydroxylupanine 13a-Angeloyloxylupanine 100 a-Isolupanine Lupanine (trace) Oroboidine Sparteine (trace) Virgiline Virgiline pyrrolylcarboxylate Priestleya spp.(section Anisothea)d Lupininedsosparteine 101 Sparteine Priestleya spp. (section Priestleya)" 11 12-Dehydrosparteine I3a-H ydroxylupanine 101 a-Isolupanine a-Isosparteine Lupanine Sparteine Virgiline pyrrolylcarboxylate Robynsiophyton vanderystii 13a-Angeloyloxylupanine Cajani foline 102 Cryptanthine 3/? 13a-Dihydroxylupanine 3P-H ydroxylupanine 13a-Hydroxylupanine a-Isolupanine Lebeckianine Lupanine Pear sonine NATURAL PRODUCT REPORTS 1994-J. P. MICHAEL Table 1 (contd) Species Alkaloid Ref. Sessilifoline Sparteine 13a-Tiglo yloxy lupanine *3P,8a 13a-Trihydroxylupanine Rothia hirsuta Cryptanthine 3P-H ydrox ylupanine I 3a-H ydroxylupanine 102 a-Isolupanine Lebeckianine Pearsonine Sessilifoline Sparteine Sophora alopecuroides *A’l-Dehydroaloperine (1 66) 103 Sophora exigua (-)-Anagyrine (-)-Baptifoline 104 (-)-Cytisine *(-)-12-Cytisineacetamide (155) (+)-5,6-Dehydrolupanine (-)-N-Formylcytisine (-)-12-Hydroxycytisine (1 57) (-)-Lupanine (-)-N-Methylcytisine Sophora jlavescens (+)-Sophoranol 105 Sophora grifithii (-)-Anagyrine 106 10-Oxosparteine 107 Thermopsis mongolica *( +)-Sophazrine (169) (-)-Anagyrine (-)-Cytisine 106 108 5,6-Dehydrolupanine *Desoxyangustifoline (1 58) (+)-13a-Hydroxysparteine (1 60) *13-epi-Hydroxysparteine (1 59) a-Isolupanine N-Methylcytisine 17-Oxosparteine (+)-Sparteine (-)-Thermopsine Thermopsis turcica (-)-Anagyrine 106 * New alkaloids.a Pearsonia aristata P. bracteata P. cajanifolia (ssp. cajanifolia and cryptantha) P. Java P. grandifolia (ssp. grandifolia and latibracteola) P. merallifera P. obovata P. sessilifolia (ssp.Jilifolia marginata sessilifolia and swaziensis) P. unipora. Section Calyptratae; Podalyria calyptrata. Section Nitidae P. buxifolia P. glauca P. microphylla P. reticulata P. speciosa. Section Sericeae :P. argentea P. bipora P. cuneifolia P. leipoldtii P. myrtilljfolia P. pearsonii P. pulcherrima P. sericea. Section Villosae; P. burchellii P. canescens P. cordata P. hirsuta P. velutina. ‘ Podalyria chrysantha P. insignis P. tayloriuna. ‘‘ Priestleya eIliptica P. glauca P. guthriei P.schlechteri P. tecta P. tomentosa P. sp. nov. ‘ Priestleya calycina P. capitata P. hirsutu P. laevigata P. latifolia P. umbellifera three P. sp. nov. 12 References 10 R. J. Molyneux L. F. James K. E. Panter and M. H. Ralphs Phytochemical Analysis 199 1 2 125. 1 W. H. Pearson S. C. Bergmeier and J. P. Williams J. Org. Chem. 11 M. J. Donaldson C. Bucke and M. W. Adlard Microb. Util. 1992 57 3977. 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ISSN:0265-0568    

DOI:10.1039/NP9941100017

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Plant Polyphenols (Vegetable Tannins*) Gallic Acid Metabolism E. Haslama and Y. Caib aDepartment of Chemistry University of Sheffield Sheffield S3 7HF ’Department of Pharmacognosy The School of Pharmacy University of London Brunswick Square London WCIN IAX 1 Introduction 1.1 Properties and Classification 1.2 Isolation and Structure Elucidation 2 Biosynthesis 2.1 Secondary Metabolism 2.2 Biosynthesis of Gallic Acid and its Esters 2.2.1 Depside Metabolites 2.2.2 Hexahydroxydiphenoyl? Esters and Related Metabolites 2.2.3 Oxidative Metabolism -Pathway (b) 2.2.4 Oxidative Metabolism -Pathway (c) 2.2.5 Oxidative Metabolism -Pathway (d) ‘Open-chain ’ Derivatives of D-Glucose 2.2.6 Comments and Conclusions 3 Epilogue 4 References 1 Introduction Emil Fischer at the turn of the century made some characteristically brilliant and perceptive contributions to the study of the constitution of the gallotannins from Chinese and Aleppo (Turkish) galls.’ His work and that of Paul Karrer and Karl Freudenberg stimulated a great deal of interest amongst chemists.These initial enthusiasms waned however as the great complexity of many plant extracts (often natural but frequently induced by the many and varied post mortem processes required to derive them) was realized. By the 1950s the topic had become one of the dark impenetrable areas of Organic Chemistry. Its renaissance coincided with the advent of new methods of analysis and separation in the 1950s and the 1960s.Today the composition of many plant extracts can usually be adequately defined in terms of their polyphenolic (tannin) and simple phenolic constituents. There is thus for the first time a firm base from which to embark upon studies of the biological properties of plant polyphenols and in particular their complexation reactiom2 If there are exceptions to this generalization then these relate to the polyphenolic metabolites obtained from the wood and bark of trees. Here post mortem events multiply the complexities of normal metabolism. As a result the nature and total composition of many of these commercially important polyphenolic extracts remain uncertain. 1.1 Properties and Classification It is now possible to describe in broad terms the nature of plant polyphenols.They are secondary metabolites widely distributed in various sectors of the higher plant kingdom. They are distinguished by the following general features. (a) Water solubility. Although when pure some plant poly- phenols may be only sparingly soluble in water in the natural state polyphenol-polypheno1 interactions usually ensure some minimal solubility in aqueous media. * Vegetable Tannins -because of its imprecision the authora has over the past 25 years sought to use this terminology as little as possible. However like original sin it declines to disappear; hence its use in the title of this review. t Hexahydroxydiphenoyl is used throughout this review as a convenient trivial name for the 6,6’-dicarbonyl-2,2’,3,3’,4,4’-hexahydroxybiphenyl radical.41 (b) Molecular weights. Natural polyphenols encompass a substantial molecular weight range from 500 to 3-4000. Suggestions that polyphenolic metabolites occur which retain the ability to act as tannins but possess molecular weights up to 20000 must be doubtful in view of the solubility proviso. (c) Structure andpolyphenolic character. Polyphenols per 1000 relative molecular mass possess some 12-1 6 phenolic groups and five to seven aromatic rings. (d) Intermolecular complexation. Besides giving the usual phenolic reactions they have the ability to precipitate some alkaloids gelatin and other proteins from ~olution.~ These complexation reactions are not only of intrinsic scientific interest as studies in molecular recognition and possible biological function but also they have important and wide- ranging practical applications -in the manufacture of fashion leathers in foodstuffs and beverages in herbal medicine and in chemical defence and pigmentation in plants.(e) Structural characteristics. Plant polyphenols are based upon two broad structural themes :-(i) Galloyl and hexahydroxydiphenoyl esters and their deriva- tives. These metabolites are almost invariably found as multiple esters with D-glucose2,4-11 and a great many can be envisaged as being derived from the key biosynthetic inter- mediate p-1,2,3,4,6-pentagalloyl-~-glucose.Derivatives of hexahydroxydiphenic acid are assumed to be formed by oxidative coupling of vicinal galloyl ester groups in a galloyl D-glucose ester.Gallic acid is most frequently encountered in plants in ester form. These may be classified into several broad categories (1) Simple esters. (2) Depside metabolites (syn-gallotannins). (3) Hexahydroxydiphenoyl and dehydrohexahydroxydi- phenoyl esters (syn-ellagitannins) based upon (a) 4C1con-OH OH Galloyl ester -2H OH OH Hexahydroxydiphenoyl ester yyoH OH Flavan-3-01olgomer unit formation of D-glucose ; (b) ‘C conformation of D-glucose ; (c) ‘open-chain ’ derivatives of D-glUC0Se. (4) ‘Dimers ’ and ‘higher oligomers ’ formed by oxidative coupling of ‘monomers’ principally those of class (3) above.(ii) Condensed proan thocyanidins. The fundamental struc- tural unit in this group is the phenolic flavan-3-01 (‘catechin’) nucleus. Condensed proanthocyanidins exist as oligomers (soluble) containing two to five or six ‘catechin’ units and polymers (insoluble). The flavan-3-01 units are linked prin- cipally through the 4 and the 8 positions.2 In most plant tissues the polymers are of greatest quantitative significance but there is also usually found a range of soluble molecular species -monomers dimers trimers etc. Oligomeric condensed proanthocyanidins have been held (Bate-Smith et to be most commonly responsible for ~1.~~9~~) the many distinctive properties of plants typically attributed to ‘condensed tannins ’. On the basis of solubility differences Sir Robert and Lady Robinson14- l5 subdivided the leuco- anthocyanins (condensed proanthocyanidins) into three classes (1) those that are insoluble in water and the usual organic solvents or give only colloidal solutions.(2) those readily soluble in water but not readily extracted therefrom by means of ethyl acetate. (3) those capable of extraction from aqueous solution by ethyl acetate. In so far as the total complement of condensed pro-anthocyanidins (procyanidins and prodelphinidins) found in plant tissues is concerned the soluble oligomeric forms (monomers dimers trimers . . .) are in metabolic terms but the ‘tip of the iceberg’. According to the Robinsons’ classification they represent category (3) above. For the generality of plants it is quite clear that condensed proanthocyanidins which fall within the two other categories (1 and 2) invariably strongly predominate over the more freely soluble forms.They are metaphorically speaking the base of the ‘metabolic iceberg ’. Indeed in the tissues of some plants such as ferns and fruit such as the persimmon (Diospyros kaki) there is an overwhelming preponderance of these forms. They are also of frequent occurrence in plant gums and exudates. 1.2 Isolation and Structure Elucidation Real and substantial progress in the chemistry of the proanthocyanidins began to be made in the 1960s following the pioneering work of Weinges and his collaborators in Heidelberg.16 l7 As techniques and strategies for the separation and isolation of plant proanthocyanidins developed then so did work on their structure chemistry and biosynthesis.These researches have been regularly reviewed,2- 18-20 particularly since 1975; the most recent by Porter21 in 1988. This last article gives a detailed and comprehensive summary of flavans and proanthocyanidins nomenclature ; a comprehensive register of plant sources and botanical distribution ; biosynthesis ; biomimetic synthesis ; chemistry ; and conformational characteristics. Other reviews which have recently been published deal with chemical transformations and con-formational features of this group.22-24 Although such statements are inevitably dangerous ones to make in science it is difficult not to conclude that this area has now become a scientifically mature one.The most spectacular recent advances in the chemistry and biochemistry of plant polyphenols have undoubtedly been NATURAL PRODUCT REPORTS 1994 H” 0 H’ HO OH 6 = 6.97 * 6 = 7.08 6,= 6.92 ’ =G HO I \*. OH 6‘= 6.94 ‘6 = 7.02 Figure 1 Proton chemical shift values for the galloyl ester protons (*) of p-1,2,3,4,6-pentagalloyl-~-glucose (D,O at 60 “C) made2q4-11 in the field defined by the first structural group -the galloyl and hexahydroxydiphenoyl esters and their derivatives -the most dramatic feature of which has been the increase by several orders of magnitude of the number of known compounds in this class now well over 700. Much of this work has emerged from two schools in Japan; those of Okuda in Okayama and Nishioka in Fukuoka.Substantial progress has been made possible by the application of new techniques of isolation and analysis,’ i.e. MPLC and HPLC using Sephadex gels Toyo pearl (TSK HW-40) Diaion HP-20 Mitsubishi MCI gel CHP-20P reverse phase C-8 and C-18 supports centrifugal partition and droplet counter current chromatography etc. High resolution NMR spectroscopy has provided a mine of structural information and tables of diagnostic ‘H and 13C chemical shift and coupling constant data have been published.2v4.8q 25-29 Extensive use has been made of the nuclear Overhauser effect but particular note should be made of the use of IH-13C long range 2D NMR spectra which provide specific information concerning the orientation and location of different phenolic acyl groups such as galloyl hexahydroxydiphenoyl valoneoyl dehydrodigalloyl sanguisorboyl euphorbinoyl trilloyl chebuloyl elaeocarpinu- sinoyl on the polyol (usually D-glucose) core of the polyphenolic e~ter.~’~-‘~ This technique is based on the ability to establish connectivity between the aroyl proton(s) of an acyl group (*) and the proton(s) at the position of acylation on the polyol (usually D-glucose) core (m).This connectivity is established via the three bond couplings of the two groups of proton(s) to the ester carbonyl carbon atom (@ JCH -5 Hz). The method has been fully described30 and permits for example each of the five two-proton singlets associated with each of the five galloyl ester groups of /?-1,2,3,4,6-pentagalloyl-D-glucose to be defined Figure 1.This type of information is also of crucial importance for studies of the complexation of polyphenolic esters with other 32 e.g. caffeine cyclodextrins anthocyanins peptides and small proteins. 2 Biosynthesis 2.1 Secondary Metabolism The distinctive features of gallic acid metabolism in higher plants bear all the hallmarks of secondary metabolism. 33-36 Thus three prominent characteristics are (a) Structural diversity. At least 750 metabolites of gallic acid which fall within the remit of the description polyphenol given above have now been described. Despite their number the structures of the overwhelming majority of these metabolites may be envisaged as being derived by chemical ‘embellishment and embroidery ’ of one key intermediate /?-1,2,3,4,6-penta-O-galloyl-D-glucopyranose.2 4 lo,11 36 In this sense they bear a very close analogy to other groups of secondary metabolites such as the various classes of terpenes and alkaloids where derivation from a common precursor is postulated.(b) Accumulation and storage. Gallic acid containing NATURAL PRODUCT REPORTS 1994-E. HASLAM AND Y. CAI OH OH OH R = H (-)-Epigallocatechin R = H (-)-Epicatechin R = G (-)-Epigallocatechin-3-Ogallate R = G (-)-Epicatechin6-Ogallate 0 galloyl group G = *m OH Shikimate Pathway Phosphoenolpyrwate + 13-Erythrose-4-phosphate I 1 it co 0fiOH OH M1 M2 ? f 3-Dehydroshikimate t OH ~1,2,3,4,6-Pentagalloyl-~-glucose, M I t Gallic acid G-OH L-Pheny lalanine Figure 2 Secondary metabolism -gallic acid an idealized picture; M, M, M, efc.-secondary metabolites derived from the key secondary intermediate /3-1,2,3,4,6-pentagalloyl-~-glucose, M metabolites often accumulate in substantial quantities in plant tissues. The apotheosis of this characteristic is the storage (up to 70% of the dry weight) of complex polyphenols of the gallotannin class in Chinese galls (Rhus semialata). Similarly the vegetative tissues of the green tea flush (Camellia sinensis) may contain up to 25-30 YOof phenolic flavan-3-ols prominent amongst which are ( -)-epigallocatechin and ( -)-epicatechin and their 3-gallate (c) Taxonomic distribution. Gallic acid containing metabolites are not universally distributed in higher plants.They occur within clearly defined taxonomic limits in both woody and herbaceous dicotyledons. l3 Ellagitannins are widely distributed in the lower Hamamelidae Dilleniidae and Rosidae (the HDR complex) and have been used as prominent chemotaxonomic markers. It has been suggested that the low degree of diversification in gallate-dominated taxa may be a result of the electron scavenging properties of these metabolites which in turn inhibit oxidation the most important reaction in the biosynthesis of secondary metabolite^.^^ One extant theory34 36 suggests that secondary metabolism provides organisms with a means of adjustment to changing circumstances. The synthesis of enzymes designed to execute the processes of secondary metabolism thus permits the network of enzymes operative in primary/intermediary metabolism to continue to function until such time as conditions are propitious for renewed metabolic activity and growth.Within this framework Bu'Lock and formulated a sequence of events which they envisaged would lead to the expression of secondary metabolism a termination of balanced growth leading to a sudden accumulation of intermediates in a primary metabolic pathway leading to the induced synthesis of secondary metabolites. In their idealized picture they suggested that a key secondary metabolite (P) was first formed and then transformed by secondary metabolic reactions to a diverse array of secondary metabolites P, P, P, .. . P,. These reactions would not have a high substrate specificity and their interplay in related organisms would result in the production of characteristic overlapping patterns of secondary metabolites. The bio-synthesis of the myriad of gallic acid derivatives in plants may be most readily comprehended within the compass of this hypothetical sequence of events Figure 2. NATURAL PRODUCT REPORTS 1994 HO OH OH Gallic acid G-OH HHO Oq1 OH UDP Uridine diphosphate glucose (UDP-glucose) I A HHO O a OH 0-1-0Galloyl-D-glucose (P-o-Glucogallin) \ P-1,2,3,4,6-Pentagalloyl-D-glucose P-1,2,3,6-Tetragalloyl-D-glucose Figure 3 Biosynthesis of p-1,2,3,4,6-pentagalloyl-~-glucose; P-D-glucogallin as galloyl group donor 2.2 Biosynthesis of Gallic Acid and its Esters Gallic acid is unique amongst the various naturally occurring hydroxybenzoic acids'l 40 both in respect to its relative ubiquity in the plant kingdom and of the quantitative significance of its metabolism in many plants.Although some evidence exists to show that gallic acid may arise by oxidative degradation of ~-phenylalanine,~l the weight of experimental data favours the view that it is nevertheless formed primarily via the dehydrogenation of 3-dehydro~hikimate,~~-~~ Figure 2. In this context and that of Bu'lock and Powell's general hypothesi~,~~ observations made with genetically engineered strains of Escherichia ~oli~~. significant. These demonstrate that 46 are under conditions of an artificially induced high carbon flux through the Shikimate pathway the organism responds by the production of enzymes which act solely and specifically to remove excessive concentrations of the intermediate 3-dehydroshikimate as they arise (in this instance as protocatechuate and the P-ketoadipate pathway).P-Glucogallin (p-1-0-galloyl-D-glucose) first isolated from Chinese rhubarb (Rheum oficinale) in 1903,47 is following the extensive studies of G~oss,~~-~~ considered to be the key intermediate in the biosynthesis of esters of gallic acid. Work with cell-free extracts from oak leaves and subsequently with the partially purified glucosyl transferase verified that P-glucogallin is generated by the reaction of gallic acid with UDP-glucose.Thereafter P-glucogallin undergoes a series of further galloyl transfer reactions to yield ultimately P-1,2,3,4,6-pentagalloyl-D-glucose. It is very interesting to note that P-glucogallin acts as the principal galloyl-group donor in these reactions. Thus in the first of these reactions a partially purified enzyme from young oak leaves (EC 2.3.1 .90) catalyses the formation of P-1,6-digalloyl-~-glucosefrom two molecules of P-glucogallin. The sequence continues in an analogous fashion with P-glucogallin as prime galloyl donor via P-1,2,6-trigalloyl-D-glucose and P-1,2,3,6-tetragalloyl-~-ghcose,to give finally P-I ,2,3,4,6-pentagalloyl-~-glucose, Figure 3. One of the most striking features of this biosynthetic pathway is that the sequence of esterification steps with gallic acid 1-OH then 6-OH 2-OH 3-OH 4-OH exactly parallels the sequence in the chemically mediated esterification of the hydroxyl groups of D-glucopyranose.53 This ~-D-glUCOgallin dependent pathway is however by no means exclusive.Studies with enzyme extracts of sumach (Rhus typhina) have shown that in addition to P-D-glucogallin P-1,6-digalloyl-D-glucose,p-1,2,6-trigalloyl-~-ghcose,and P-1,2,3,6-tetragalloyl-D-glucose may also act although with progressively decreasing efficiency as galloyl group donors (from the 1- position of the galloyl-ester) Figure 4.Thus two molecules of P-1,6-digalloyl-~-glucose disproportionate Figure 4(i) to give p-1,2,6-trigalloyl-~-glucose and 6-O-galloyl-~-glucose ; simi-larly P-1,6-digalloyl-~-glucose may substitute for P-D-glucogallin as galloyl group donor in the conversion of p-1,2,6-trigalloyl-D-glucose to P-1,2,3,6- tetragalloyl-D-glucose Figure 4 (ii).Although alternative explanations are possible these observations may have some bearing upon the observation (vide infra Section 2.2.6) that many polygalloyl (and hexahydroxydiphenoyl) esters of D-glucose are frequently found in plant extracts in a form in which the anomeric hydroxyl group is unacylated. Strong circumstantial evidence now exists to support the proposition2-4 lo.11*36 that the metabolite p-1,2,3,4,6-penta- NATURAL PRODUCT REPORTS 1994-E. HASLAM AND Y. CAI p-1,6-DigalloyCD-glucose HOGoG (i) HHO o g OG ';i;*HO OH OG p-1,6-Digalloyl-O-glucose t p-1,2,6-Trigalloyl-~-glucose HHOO k O H OH 6-Gallo yl-D-glucose HHO O a a OH p-1,6-Digalloyl-o-glucose I p-1,2,6-Trigalloyl-D-glucose ; p-1,2,3,6-Tetragalloyl-D-glucose i FOG Ho*OH HO OH 6-Galloyl-D-glucose Figure 4 Biosynthesis of galloyl esters of D-glucose p-1,6-digalloyl-~-glucose as galloyl group donor Pathway(b) Oxadative coupling; Pathway (d) Oxidative coupling; Dehydrogenation,4-6and 2-3; ring opened -open chain derivatives Oligomerization by GO coupling Go*m OG GO ~-1,2,3,4,6-Pentagalloy~-D-glucose ~Glucopyranose-~C~ conformation J'/ 4 ococ p-1,2,3,4,6-Pentagalloyl-D-glucose Pathway (a) Additional galloyl groups esterified as mdepsides D-Glucopyranose-'C4 conformation to the performed galloyl glucose I -1% J Pathway (c) Oxadative coupling; Dehydrogenation 3-6 1-6 and 2-4; Dehydmhexahydmydiphenoylesters Figure 5 Biogenesis of the gallotannins and ellagitannins ;the metabolic embellishment of ~-1,2,3,4,6-pentagalloy1-~-glucose, principal pathways galloyl-D-glucose Figure 3 then plays a pivotal role Figure 2 the terpene-ind~le~~ alkaloids respectively.Four distinctive in the formation of the vast majority of gallotannins and and principal pathways (a) (b) (c) and (d) are then presumed ellagitannins which occur in many plants. Its biosynthetic to lead from /?-1,2,3,4,6-pentagalloyl-~-glucosegive by to position is analogous to those of norlaudanosoline and appropriate chemical embellishment the various classes of strictosidine in the formation of the benzylis~quinoline~~ metabolites Figure 5.and n 0 G= HO HO 6H OY0 =G-G ‘0 QOH OH Chinese gallotannin tannic acid OH ~ -2H @OH ___) C02Me HO OH HO OH OH OH Methyl gallate Dimethylhexahydroxydiphenoate -2MeOH 1 OH HO OH Ellagic acid 2.2.1 Depside Metabolites The ability to metabolize depside derivatives of gallic acid [Figure 5 pathway (a)] may be used as a guide to inter- relationships in particular plant families55 and there is on present evidence a close association of this form of metabolism with the Rhoideae tribe in the Anacardiaceae. Many of the products of this form of metabolism were often grouped together in the earlier literature under the generic term ‘gallotannin’.The most common and familiar example is Chinese gallotannin or tannic acid (galls Rhus semialata) which possesses the overall composition of a hepta-to octagalloyl-P-D-glucose and in which on average two to three additional galloyl groups are esterified in depside form to a pre- existing p-1,2,3,4,6-pentagalloyl-~-glucose core. A novel method of analysi~~~,~~ based on the use of HPLC and 13C NMR reveals the full heterogeneity of the typical Chinese gallotannin extract. This ranges from /3-pentagalloyl-D-glucose itself to compounds with up to five or six additional galloyl residues linked as m-depsides to this core. The proportion of each type determines the final overall composition of the gallotannin extract.Using 13C NMR the position of the additional depside residues has been determined to be pre- dominantly to the galloyl groups at C-2 or C-3 C-4 and C-6. This polygalloyl-D-glucose is the most widely encountered ester of this type found in plants,2~4~27 but others have also been described. The galls of various oaks (Quercus infectoria Q. NATURAL PRODUCT REPORTS 1994 lusitanica) yield a gallotannin in which additional galloyl groups are linked as m-depsides to a mixture of p-1,2,3,4,6- pentagalloyl-D-glucose and p-1,2,3,6- tetragalloyl-~-glu- COS~.~~,~* Likewise the fruit pods of Caesalpinia spinosa give a gallotannin based on a trigalloyl-quinic acid and similar polygalloyl esters have been isolated from Castanopsis cuspidata and Acer saccharinum respectively which are based upon shikimic acid59 and 1,5-anhydro-~-glucitol.27v Hofmann and GrossG1 have very recently described enzymic studies with extracts of Rhus typhina which begin to chart the biosynthetic pathway from ~-1,2,3,4,6-pentagalloyl-~-glucose to the gallotannins in sumach (mixtures of hexa- hepta- and octagalloyl-D-glucose derivatives). Detailed ‘H and 13C NMR analysis of the hexagalloyl-D-glucose fraction showed it to contain at least three hexagalloyl esters in which additional galloyl ester groups were linked as m-depsides to the galloyl ester groups attached to C-2 (2-3 and C-4 of the D-glucopyranose ring. 2.2.2 Hexahydroxydiphenoyl Esters and Related Metabolites In the thirty year period from 1950 to 1980 the Heidelberg school of Otto Schmidt and Walter Mayer made distinguished and seminal contributions to the study of naturally occurring hexahydroxydiphenoyl ester~.~~-~l They isolated and identified key metabolites such as corilagin ;68v 70-72 pedunculagin ;75 ;653 chebulinic and chebulagic acids 71 73 dehydrodigallic valoneic and brevifolin carboxylic acids ;66 67 78 trilloic acid ;87 ter~hebin~~ the dehydrohexahydroxydiphenoyl esters -and brevilagin 1 and 2 ;76v 77 vescalin castalin vescalagin and castalagin ;*O 83*85,88.91 punicalin and punicalagin ;** castava-loninic acid valolaginic acid and isovalolaginic acid.82 In addition as the work progressed they continued to pro-Vide62-64,69,79,92 an intellectually satisfying biogenetic rationale for the derivation of this group of naturally occurring polyphenolic esters (syn.ellagitannins). This pioneering work has securely underpinned all subsequent developments in this field particularly the explosive increase in knowledge of the past fifteen years which has resulted in the identification of at least 500 discrete compounds in this class. The following discussion does not attempt to be totally comprehensive but classifies the major groups of metabolites within a structural and biogenetic framework. Whilst there is as yet no formal experimental proof it is generally assumed following the hypo thesis enunciated by 92 Schmidt and Ma~er,~’. that naturally occurring hexahydroxydiphenoyl esters and their derivatives are derived by oxidative coupling of galloyl esters (with the formation of new C-C and C-0 bonds) and oxidative and hydrolytic aromatic ring fission.Support for the initial step in the putative biogenetic scheme has been obtained by oxidation of methyl gallate (potassium iodate,28 peroxidaseg3) to give dimethyl hexahydroxydiphenoate. In the context of any consideration of the range and chemical structure of metabolites now identified in plant extracts (vide infra) it is important to note the lability of dimethyl hexahydroxydiphenoate in aqueous media. Thus the biphenyl ester is readily transformed to the highly insoluble bis-lactone ellagic acid on standing in water. This trans-formation is undoubtedly facilitated by the proximal juxta- position of the phenolic and ester groups on separate aromatic nuclei and by free rotation about the biphenyl linkage.Strong circumstantial evidence now also exists to suggest that the vast majority of metabolites are derived bio-synthetically cf. Figure 5 (with subsequent possible modifications in vivo by facile hydrolytic reactions) by oxidative transformations of the key precursor /3-1,2,3,4,6-pentagalloyl-D-glucose following a scheme first put forward in 1982,4 Figure 6. In the ellagitannin metabolites now described numerous intramolecular ‘C-C ’ linked ester groups have been located in the ‘monomers ’ and similarly various intermolecular ‘C-0 ’ linking ester groups have been defined in the formation of the NATURAL PRODUCT REPORTS 1994-E. HASLAM AND Y.CAI 47 p-1,2,3,4,6-PentagalloyI-D-glucose intramolecular +I GC coupling I hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl esters ('monomers') intermolecular GO coupling 1 [hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl esters] ('oligomers',n = 2,3,4) Figure 6 Overall patterns of oxidative metabolism of p-1,2,3,4,6-pentagalloyl-D-glucose in higher plants to yield ellagitannins4 OH 0 I HO HO HO OH HO co I HO HO 'OH OH I (R)-Hexahydroxydiphenoyl (S)-Hexahydroxydiphenoyl Flavogallonyl Gallagyl Figure 7 Principal derivatives of hexahydroxydiphenic acid formed by intramolecular C-C oxidative coupling Ho&voH 0'/ OH OH -OH 3H HO 0 0 I Chebuloyl De hydrochebuloyl ?H 0 De hydo hexahydroxydip henoyl \c+ 0 -0c OH L-Ascorbic acid OH OH \? b 0 Brevifolyl Trilloyl Figure 9 Ester derivatives of hexahydroxydiphenic acid in which one aromatic ring has undergone hydrolytic cleavage Elaeocarpusinoyl and gives the molecule much greater rigidity.Where the Figure 8 The dehydrohexahydroxydiphenoyl ester group and its bridging occurs 1,6 3,6 or 2,4 the D-glucopyranose residue is derivatives forced to adopt a thermodynamically unfavourable C conformation. One specific chirality is imposed upon the oligomeric' structures. The principal members of these two hexahydroxydiphenoyl group as it is formed and this chirality classes of ester group are shown in Figures 7 to 10. is determined by the need of the new ester group to bridge In the intramolecular formation of a hexahydroxydiphenoyl particular positions in the polyol (usually D-glucose) portion of ester group the generation of a large-membered ring containing the molecule.The absolute configuration of the twisted biphenyl two cis (2)double bonds reduces conformational flexibility system in corilagin has been deterrnined9,sg5 as (R)by relation 4 NPR 11 NATURAL PRODUCT REPORTS 1994 W W@ OL HOC OH OH OOH H H HO O OH OH OH HO$O@ I I 0 occo oc co / \ OH 'HO '/ OH -II II -oc -co OH HO OH I OH I Dehyd rodig al loy I (S)-Sanguisotboyl (R)-Valoneoyl \/ -I I oc oc co I OH II II (S)-Valoneoyl (R)-Macaranoyl (R)-Tergalloyl -OH HO OH (R )-Eup horbi noy I Figure 10 Principal ester groups formed by intermolecular C-0 oxidative coupling of galloyl and hexahydroxydiphenoyl esters -2H ___) bb-Galloyl ester Hexahydroxydiphenoyl ester HO OH OH OH HO OH MeOOMe OMe Me0 Me0 OMe OMe eOwOM -Me -Me02C COfle Me Me Ho\-I Dimethyl(R)-(+)-hexamethoxydiphenoate Schizandrin Corilagin G = galloyl Figure 11 Determination of the absolute configuration of (+)-hexahydroxydiphenic acid in the metabolite corilaging4* 95 NATURAL PRODUCT REPORTS 1994-E.HASLAM AND Y. CAI Gemin D Strictinin Tellimagrandin 1 Pedunculagin p-1,2,3,4,6-Pentagalloyl-D-glucose Tellimagrandin 2 (Eugeniin) Casuariitin OH HO G-G = (S)-Hexahydroxydphenyl PterocatyaninC SanguinH-4 Potentillin G= 0 HO Galloyl Figure 12 pentagalloyl-wglucose ; conformation ; pathway (b) Table 1 Principal naturally occurring ‘monomeric ’ (S)-hexahydroxydiphenoyl esters ; 4C D-glucopyranose.Structures -positions of esterification to the D-glucose core Principal ‘monomeric’ hexahydroxydiphenoyl esters formed by oxidative coupling of vicinal galloyl ester groups in B-1,2,3,4,6-the D-glucopyranose core may be deduced from theoretical considerations.4 28 These arguments also strongly suggest that the absolute configuration of the hexahydroxydiphenoyl esters is determined largely if not solely by the inbuilt stereo-chemistry of the sugar molecule. The principal mode of transformation (Figure 5 pathway (a)) is by oxidative C-C coupling of galloyl ester groups (4-6 and 2-3) in the thermodynamically most stable con-formation of p-1,2,3,4,6-pentagalloyl-~-glucose followed by oxidative oligomerization (C-0 coupling).Two further modes of elaboration are also both oxidative in character. Pathway (c) (Figure 5) occurs via oxidative C-C coupling of galloyl ester groups (3-6 1-6 and 2-4) in the thermodynamically least stable ‘C4 conformation of p-1,2,3,4,6-pentagalloyI-~-glucose followed again by oxidative oligomerization (C-0 coupling). Metabolites in this class are also often characterized by the presence of the dehydrohexahydroxydiphenoyl ester group and derivatives e.g. chebulinic and chebulagic 71 in which one aromatic nucleus of this functionality has undergone hydrolytic ring fission. Finally in pathway (d) the oxidative transposition of p-1,2,3,4,6-pentagalloyl-~-glucose takes place by ring opening and the formation of unique open-chain derivatives of D-glucose.2.2.3 Oxidative Metabolism -Pathway (b) This represents the most commonly encountered biogenetic route to the ellagitannins. A series of metabolites (‘monomers ’) is first formed by C-C oxidative coupling of vicinal galloyl ester groups 4,6and 2,3 in p-1,2,3,4,6-pentagalloyl-~-glucose in its thermodynamically preferred 4C conformation. Some details of this pattern of metabolism were hinted at in earlier work by Schmidt and Ma~er,~~. 75* 78 Hillis and Siekel,96 and Wilkins and B~hm.~’ Plants whose phenolic metabolism places them within this category furnish as principal metabolites one or more of the (S)-hexahydroxydiphenoyl esters shown in Figure 12 Table 1.Interesting exceptions to this generalization are 4-2 Trivial name Galloyl Tellimagrandin I1 p-1,2,3 (Eugeniin) Tellimagrandin I 233 Casuarictin P-1 Potentillin a-1 Pedunculagin -I Gemin D 3 Strictinin P-1 Heterophyllin A a-1,3 Sanguin H-1 a1,6 Sanguin H-4 a-1 Nobotanin D P-176 -Roxbin B Pterocaryanin B 4 Pterocaryanin C B-1,4,6 Hexahydroxy-diphenoyl 4,6 496 2,3:4,6 2,3:4,6 2.3 :4.6 8-8-C-(+)-catechin derivatives I Stenophynin A -2,3 :4,6 Stenophynin B 6 2,3 Ref. 97,99 97 28 lol 28 102 103 75 104 105 106 107 108 111 109 110 112 113 114 115 116 117 117 to the lignan schizandrin Figure 11 and the chirality of other hexahydroxydiphenoyl esters may be determined by measure- ments of circular dichroism (CD) and comparison with corilagin.The CD spectra of hexahydroxydiphenoyl esters are characterized by a distinctive couplet centred at -200-210 nm with a positive or negative maximum at 228-238 nm. The AE values are approximately incremental for the number of hexahydroxydiphenoyl ester groups in the 94 95 It is of interest to note that the same conclusions regarding the chirality of the hexahydroxydiphenoyl ester groups bound to NATURAL PRODUCT REPORTS 1994 provided by cercidins A and B and cuspinin all of which Table 2 Principal naturally occurring ‘dimeric’ galloyl/(S)-hexahydroxydiphenoyl esters ;4C D-glucopyranose; dehydrodigalloyl ester C-0 linking group.Structures -positions of esterification of dehydrodigallic acid to the D-glucose cores a* Trivial name Monomer-I (a*) Gemin A Gemin B Gemin C Coriariin A Coriariin C Agrimoniin Potentillin (1) Sanguin H-4 (1) Potentillin (1) Tellimagrandin 2 (1) Tellimagrandin 2 (1) Potentillin (1) Laevigatin B Potentillin (I) Laevigatin C Sanguin H-4 (1) Laevigatin D Potentillin (1) b* Monomer-I1 (b*) Casuarictin (1) Casuarictin (1) p-1,2,3-Trigalloyl-D-glucose (1) Tellimagrandin 2 (1) Rugosin A Potentillin (1) Sanguin H-4 (1) Potentillin (1) 2-0-Galloyl-4,6-(S)-hexahydroxy-diphenoyl-D-glucose (2) Positions of esterification of the linking dehydrodigallic acid indicated as ‘a*’ and ‘b*’ and by the figures in parentheses.Gernin A; dehydrodigallic acid linking group dehydrodigalloyl group 0 Ref. 109 118 109 118 109 118 119 119 120 120 120 120 group are contain a 2,3-(R)-hexahydroxydiphenoyl ester group.98 It is then presumed that as a second phase by oxidative intermolecular C-0 coupling dimeric trimeric and tetrameric structures are subsequently formed Figure 6 Table 2. The isolation and structure determination of two ‘dimers ’ formed by C-0 oxidative coupling of intermediates such as are shown in Figure 12 were first reported in 1982.28,120 Since that time more than seventy five ‘oligomers’ have been described. These are broadly divisible into several sub-types dependent on the mode of C-0 coupling between a phenolic hydroxyl group in one ‘monomer’ and an aromatic ring carbon in another ‘monomer’.The three principal modes of C-0 coupling Figure 10 are those between two galloyl groups (to give a dehydrodigalloyl linking group) Table 2 and between one galloyl group and an (S)-hexahydroxydiphenoyl ester group to yield either a valoneoyl or the positionally isomeric sanguisorboyl linking ester group. Present evidence suggests that the (S)-valoneoyl linking ester group is the one most commonly formed Table 3. For some time the most frequently encountered situation was that in which the linkage involved a galloyl ester group at the anomeric centre of at least one of the ‘monomers’. Linkage through galloyl ester groups at other positions on the glucose ring have however now been noted in several instances Table 3.Typical examples -gemin A sanguin H-6 calamanin B cornusiin C and calamanin C [G = galloyl G-G = (S)-hexahydroxydiphenoyl] -are shown in Figures 13 and 14. ‘Dimers’ with macro-ring structures formed by C-0 oxidative coupling between two galloyl ester groups and an (S)-hexahydroxydiphenoyl ester group have been reported Sanguin H-6; (S)-sanguisorbic acid linking group -potentillin *.** tellimagrandin 2 potentillin 0 Calarnanin B; (S)-valoneic acid linking group OH potentillin tellirnagrandin 2 HO (S)-valoneoyl group OH Figure 13 ‘Dimeric ’ ellagitannins :different modes of C-0 oxidative coupling (--) to give dehydrodigalloyl sanguisorbyl and valoneoyl ester groups [G-G = (S)-hexahydroxydiphenoyl G = galloyl] NATURAL PRODUCT REPORTS 1996E.HASLAM AND Y. CAI ~ ~ ~~ Table 3 Principal naturally occurring ‘dimeric ’ galloyl/(S)-hexahydroxydiphenoyl esters ; 4C D-glucopyranose ; (S)-valoneoyl ester C-0 linking group. Structures -positions of esterification of (S)-valoneic acid to the D-glucose cores OH Trivial name Monomer-I (a*) Rugosin D Tellimagrandin-2 (1) Rugosin E Tellimagrandin-2 (1) Rugosin F Tellimagrandin-2 (1) Cornusiin A Tellimagrandin-1 (2) Cornusiin D Tellimagrandin-2 (2) Cornusiin E Tellimagrandin-2 (2) Camptothin A Tellimagrandin-1 (2) Camptothin B Tellimagrandin-1 (2) Roxbin A Casuarictin (1) Coriariin D Rugosin A (1) Coriariin E Tellimagrandin-2 (1) Nobotanin A 4,6-Digalloyl-2,3-hexahydroxydiphenoyl-~-glucose (4) Nobotanin B Pterocaryanin C (4) Nobotanin F Pterocaryanin C (4) Nobotanin G p-1,4,6-Trigalloyl-~-glucose(4) Nobotanin H Rugosin A Medinillin B 4,6-Digalloyl-2,3-(S)-hexahydroxydiphenoyl-~-glucose (4) Isorugosin D Tellimagrandin-2 (1) Phillyraeoidin B p-1,2,3,4,6-pentagalloyl-~-glucose (4) Phillyraeoidin C /3-1,2,3,4,6-pentagalloyl-~-glucose (4) Phillyraeoidin D p-1,2,3,4,6-pentagalloyl-~-glucose (4) Phillyraeoidin E 2,3,4,6-Tetragalloyl-~-glucose (4) Woodfordin A p-1,2,3,6-Te tragalloy l-~-glucose (2) Woodfordin B Tellimagrandin-1 (2) Eusupinin A Tellimagradin-2 (1) Calamanin B Tellimagrandin-2 (1) Camelliin A Tellimagrandin-1 (2) OH Monomer-I1 (b* c*) Ref.Tellimagrandin-2 (6,4) 119 121-123 Tellimagrandin-1 (6,4) 119 121-123 Casuarictin (6,4) 119 121-123 Tellimagrandin- 1 (4,6) 124-125 Tellimagrandin-I (4,6) 124-125 Tellimagrandin-2 (4,6) 124125 Gemin D (4,6) 126 Tellimagrandin- 1 (4,6) 126 Tellimagrandin-1 (6,4) 127 Tellimagrandin-1 (6,4) 119 Gemin D (6,4) 119 Casuarictin (6,4) 112 113 Casuarictin (4,6) 112 113 Casuarictin (6,4) 112 113 Casuarictin (3,2) 128 Casuarictin (3,2) 130 Pedunculagin (6,4) 112 113 Tellimagrandin-2 (4,6) 129 Tellimagrandin-2 (6,4) 130 Tellimagrandin-1 (6,4) 130 p-1-Galloyl-4,6-(S)-hexahydroxydiphenoyl-~-130 glucose (4,6) p-1 -Galloyl-4,6-(S)-hexahydroxydiphenoyl-~-130 glucose (4,6) Tellimagrandin-2 (6,4) 131 132 a-1,2,3-Trigalloy1-4,6-(S)-131 132 hexahydroxydiphenoyl-D-glucose(6,4) Rugosin A (6,4) 133 Potentillin (6,4) 134 Pedunculagin (6,4) 135 Positions of esterification of the linking (S)-valoneic acid group are indicated as ‘a*’ ‘b*’ and c* and by the figures in parentheses.Table 5 Principal naturally occurring higher ‘oligomeric’ galloyl/(S)-hexahydroxydiphenoylesters ; 4C D-glucopyranose ; (S)-valoneoyl ester C-O linking groups Table 4 Principal naturally occurring ‘macrocyclic ’ galloyl/(S)-hexahydroxydiphenoylesters ;4C D-glucopyranose ; (S)-valoneoyl ester C-O linking groups Trivial name Rugosin G Cornusiin C Cornusiin F Calamanin C Trapanin B Trapanin A ‘Monomer ’ composition Ref. 3 x Tellimagrandin 2 119 121-123 3 x Tellimagrandin 1 124,125 2 x Tellimagrandin 1+Gemin D 125 2 x Tellimagrandin 2 +Potentillin 134 4 x Tellimagrandin 1 136 3 x Tellimagrandin 1 136 2 x Tellimagrandin 2 137 +Tellimagrandin 1 4,6-Digalloyl-2,3-(S)-138 hexahydroxydiphenoy1-D-glucose+Casuarictin + Pterocaryanin C Pterocaryanin C +Casuarictin + 138 Pterocaryanin C Trivial name ‘Monomer’ composition Camelliin B Tellimagrandin 1 +Tellimagrandin 2 Oenothein B 2 x Tellimagrandin 1 Oenothein A 3 x Tellimagrandin 1 Nobatannin I Rugosin A +Casuarictin Woodfordin C Tellimagrandin 1 +a-1,2,3-(Woodfructicosin) Trigalloyl-4,6-(S)-hexahydroxydiphenoyl-D-glucose Woodfordin D 2 x Tellimagrandin 1 +a-1,2,3-Trigalloyl-4,6-(S)-hexahydroxydiphenoyl-D-glucose Ref.135 139 140 141 131 132 Prostatin B Nobotanin C 140 Nobotanin E NATURAL PRODUCT REPORTS 1994 Cornusiin C-2x(S)-valoneoyl linking groups Catamanin C-2x(S)-valoneoyl linking groups G (S)-valoneoyl group (S)-valoneoyl group OH Go HO ' tellimagrandin 2 HO OH OH tellimagrandin 1 OH OH OH 0 -..--.\ teliirnagrandin 2 HO (S)-valoneoyl OH tellimagkndin 1 G = galloyl; G-G = (S)-hexahydroxydiphenoyl Figure 14 'Trimeric' ellagitannins formed by C-0 oxidative (--) coupling to give (S)-valoneoyl linking ester groups HO Ho \ J5 OH H&H i'--1 H"y co 0 '9 \ OH / Ho Hovco OH OH 0-co HO OH HO OH Cornusiin A Oenothein B Figure 15 Suggested pathway of biogenesis of oenothein B by intermolecular C-0 coupling of two molecules of tellimagrandin 1 ; G = galloyl NATURAL PRODUCT REPORTS 1994-E.HASLAM AND Y. CAI OH 'OG Rugosin A Stenophynin A Table 6 Principal naturally occurring 'monomeric ' (R)-hexahydroxydiphenoyl esters. Structures -positions of esterification to the D-glucose core Hexahydroxy-Trivial name Galloyl groups diphenoyl groups Ref. 'C,D-glycopyranose Corilagin Punicafolin Tercatain p-1 p-1,2,4 p-1,4 376 3,6 3,6 68 70 71 150 151 152 149,151 Nupharin B p-132 p-1-m-digalloyl a-1,2,4 396 3,6 396 116 153 116 153 154 4C1D-glucopyranose Cercidinin A Cercidinin B p-1,4,6 4,6 273 273 155 155 Table 4 as have higher oligomers (seven 'trimers' and two 'tetramers') based on the same C-0 oxidative oligomerization processes Table 5.Typical examples of macrocyclic poly- phenolic esters are those of camelliin B oenotheins A and B and woodfordins C and D. The biogenesis of oenethein A is presumed to be typical and to follow a pathway such as that shown in Figure 15. In addition to the various oligomeric (S)-hexa-hydroxydiphenoyl and galloyl esters which have been described (Tables 1-S) 'monomeric ' esters have been isolated from plants containing principally the (S)-valoneoyl or dehydrodigalloyl ester groups either in a lactonized form or in a state in which one of the carboxyl groups is free. Typical examples of such metabolites are rugosins A B and C,142*143 praecoxins A C and D,lg2* 147 144* 145 cornusiin B,146 phillyraeoidin A,130 isorugosin B,12 coriariins B and F,'19 isocoriariin F,12,calamanin A,134schimawalin A,146oenothein C,lg6- lg7 medinillin A,128 tirucallin A,147 prostatins A and C,lg7.sanguin H-2,11' and ma~aranin.'~~ "* The important question of whether these are true natural products or OH PhillyraeoidinA Stenophynin B Table 7 Principal naturally occurring 'monomeric ' (S)-hexahydroxydiphenoyl esters ; 'C,D-glycopyranose. Structures -positions of esterification to the D-glucose core Hexahydroxy-Trivial name Galloyl groups groups diphenoyl Ref. Macarangdnin /3-1,2,4 336 152 Davidiin Helioscopinin B Nupharin A 2,394 3 01-1,2,4 p-1,6 p-1,6 376 29,156 I57 154 derivatives which are formed by mild hydrolysis in either the plant cell or during extraction is addressed later in this review (vide infra Section 2.2.6).Finally stenophynins A and B117 represent an interesting structural variation upon the poly- phenolic esters outlined above with the linking by a C-C bond at the anomeric centre of the ,C D-glucopyranose ring of a ( +)-catechin residue. 2.2.4 Oxidative Metabolism -Pathway (c) According to present evidence a rather smaller group of plants adopts an alternative metabolic variation in which oxidative coupling of adjacent galloyl ester groups occurs 'one-three ' to form both (R)-and (S)-hexahydroxydiphenoyl esters (and their derivatives) in a D-glycopyranose precursor which itself adopts the less favourable lC4 or an intermediate skew-boat conformation. An additional significant feature of this form of metabolism is that one or more of the hexahydroxydiphenoyl ester groups may be further dehydrogenated to give derivatives of the dehydrohexahydroxydiphenoyl ester group Figure 8.Phenolic metabolites of this class have been discerned in members of the plant families Cercidiphyllaceae Ericaceae Onagraceae Combretaceae Nyssaceae Aceraceae Punicaceae Simaroubaceae and Ge~aniaceae.~~ Some of the principal 'monomeric' esters of this class are listed in Tables 6 to 9. NATURAL PRODUCT REPORTS 1994 Table 8 Principal naturally occurring 'monomeric ' dehydrohexahydroxydiphenoyl esters. Structures -positions of esterification to the D-glucose core. I OH OH OH 0@ 0 OH C D-Glucopyranose Trivial name Dehydrohexahydroxydiphenoyl Hexahydroxydiphenoy1 Ref.'C D-glucopyranose Terchebin (R)-2,4* 74 116 152 157 Geraniin (R)-2,4* 29 137 147 156 158 Deh ydrogeraniin (R)-2,4* :3,6* 159 Furosin (R)-2,4* 160 Furosinin (R)-2,4* :3,6* 159 Carpinusin (R)-2,4* I57 Helioscopinin A (S)-2*,4 157 Tanarinin (R)-3*,6 152 Granatin A (S)-2*,4 29 161 Granatin B (S)-2*,4 29 161 Supinanin (S)-2*,4 123 Euphorscopin p-1934s1 123 Mallotusonic acid (R)-2,4* 116 Macaranin C (R)-2,4* 149 ,C1D-glucopyranose Isoterchebin (R)-4*,6 158 Brevilagin 1 p-1,3:4,6 76 Brevilagin 2 p-1,3 77 Table 9 Principal naturally occurring 'monomeric ' elaeocarpusinoyl esters ; 'C D-glucopyranose ;positions of esterification to the D-glucose core. I 0-0 OH Elaeocarpusinoyl Trivial name Galloyl Elaeocarpusinoyl Hexahydroxydiphenoyl Ref.Elaeocarpusin Helioscopin A Helioscopin B Mallonin P-1 3 p-1,3,6P-1 2,4* 2,4* 2,4* 2,4* (R1-336 p-1964s) - 116 162 163 157 157 116 Mallojaponin P-1 2,4* 3,6-(R)-valoneoyl 116 For its routine metabolic processes Nature appears to prefer metabolite in this particular sub-class is the beautifully yellow the conformationally most stable sugars and amongst the crystalline compound geraniin first isolated from Geranium and D-aldohexoses glucose mannose and galactose are widely Euphorbia species by Okuda et al.137,147*15s7'5a and by the distributed ;those with less favourable steric interactions occur Sheffield group from Acer and Cercidiphyllum species.29 In this rarely. It is a point of some curiosity therefore that in this as in other derivatives of the dehydrohexahydroxydiphenoyl particular form of oxidative metabolism of galloyl esters of D-ester group the dehydroester is found as an internal hemiacetal.glucose the transformations apparently occur with the galloyl On dissolution in aqueous media equilibration occurs with D-glucopyranose derivative in an energetically unfavourable other internal hemiacetal forms Figure 8. Other significant chair ('C,) or related skew-boat conformation. The difference 'monomeric' species found in this mode of metabolism include in free energy between the 'C and the ,C1 forms of D-corilagin davidiin elaeocarpusin tanarinin and helioscopin glucopyranose has been calculated as +5.95 kcal mol-' A e.g. Figure 16 Tables 6-9.(24.8 kJ mol-l) and this difference may in part explain why The elaeocarpusinoyl ester group presents an interesting oxidative coupling of galloyl ester groups via the ,C1con-structural variation on the theme of the dehydrohexahydroxy- formation of the D-glucopyranose precursor (pathway (b) diphenoyl ester Table 9. A significant number of metabolites above) is much more widely encountered in the plant kingdom have now been recorded which contain this unusual func- than the alternative (pathway (c)) which is presumed to proceed tionality and there is prima facie evidence to suggest that its via a chair (lC,) or related skew-boat conformation. A key biosynthetic origin is probably a result of the interaction of a 55 NATURAL PRODUCT REPORTS 1994-E.HASLAM AND Y. CAI HO OH OH OH HO \ 04 HOwo \ HO OH OH 0 Geraniin Carpinusin Elaeocarpusin HO Davidiin Corilagin Figure 16 Monomeric' metabolites of p-1,2,3,4,6-pentagalloyl-~-glucose -oxidative conversions of the 'C,form pathway (c) OH OH OH How \ / OH HOWOH Go* qc-0 HO 1 OH HO OH Nupharin C (Dehydrodigalloyl) HO Euphorbin C (Euphorbinoyl) hexahydroxydiphenoyl ester group with L-dehydroascor-pathway (b) of oxidative metabolism. Compounds in which the bate,116* 162 during the generation of a dehydrohexahydroxy- linking ester group is dehydrodigalloyl (nupharins C D and diphenoyl ester Figure 8. E,164and jolkianinlZ3) (R)-valoneoyl (e~phorelin,~~~ euphor-More recently 'dimeric ' species involving these various bins A and B,148*165,166 ex-euphorbin F,148tirucallin B,148 types of hexahydroxydiphenoyl ester and dehydrohexahydroxy- coecarianin,167 and eumaculin A133) and euphorbinoyl diphenoyl ester metabolites have been described.These natural (excoecarinins A and B,167euphorbins C166and have been products are all based upon the typical C-O coupling patterns described as has a 'trimeric' species nupharin F.164 noted earlier for hexahydroxydiphenoyl esters formed via Perhaps because of their ready crystalline nature two NATURAL PRODUCT REPORTS 1994 Table 10 Principal naturally occurring phenolic esters derived from hexahydroxydiphenic acid in which one aromatic ring has been modified? by ring cleavage (chebulic) or contraction (brevifolin); esterification to a 'C,D-glucopyranose core (* ; Figure 17).Trivial name Gallo yl 'Ring-opened' ester? Other ester groups Ref. Chebulinic acid 2,4*-Chebulo yl Chebulagic acid 2,4*-Chebuloyl Repandusinic acid A 4-Deh ydrochebuo yl Repandusinic acid B 4-Deh ydrochebuo yl Repandusinin 4-Brevifol yl Mallorepandusic acid 2,4*-Chebulo yl Heterophyllin E 3-Brevifolyl Macaranin A 2,4*-Chebuloyl -3,6-Hexahydroxydiphenoyl (R) 3,6-Hexahydroxydiphenoyl (R) 3,6-Valoneoyl (R) 3,6-Valoneoyl (R) 3,6-Tergalloyl 4,6-Hexahydroxydiphenoyl (S) 3,6-Macaranoyl 1 4 5 65 69 169-171 71 73 169-171 172 173 172 173 172 173 149 174 I49 I Hexahydroxydiphenoyl ester Dehydrohexahydroxydiphenoylester I Ho2c*o" '? \ O H O H OH HO OH 0 0 Chebulic acid (bound form) Brevifolin cahoxylic acid (bound form) Go&; 4 '-*OH% cl HOZC HO 0 Chebulinic acid G = galloyl Figure 17 Putative biogenetic pathways to ' ring-opened ' hexahydroxydiphenoyl esters chebulic and brevifolin carboxylic acids; structure of chebulinic acid metabolites dominated much of the early chemistry of the ellagitannins chebulinic acid' 4 5*65,69*169 and the closely related chebulagic a~id.~~.~~ These compounds are now seen to belong to a relatively small group of metabolites of the hexahydroxy- diphenoyl ester class in which one of the aromatic rings has apparently undergone hydrolytic cleavage to generate one or more additional carboxylate groups Table 10.The significance of this presumed biogenetic process was first highlighted by Schmidt and MayeP9 and Haworth et uI.,'~~ Figure 17.Valolaginic acid valolinic acid isovalolaginic acid and isovalolinic acid are all metabolites based upon the unique ' open-chain ' D-glucose structure (pathway (d) vide infra). 82987*90 They are formulated as derivatives of trilloic acid which are presumed to be formed analogously by hydrolytic ring fission of one aromatic ring of a nonahydroxytriphenoyl ester. 2.2.5 Oxidative Metabolism -Pathway (d). 'Open-chain ' Derivatives of &Glucose An intriguing and distinctive group of polyphenolic compounds derived from gallic acid are esters formed with the open-chain form of D-glucose; such esters are probably unique in natural product chemistry.Vescalin vescalagin castalin and castalagin are compounds which typify this group and whose structures testify to this uniqueness. They were first isolated from oak and chestnut species and their structures determined by Mayer and his colleague^.^^-^^^^^* 88 91 They characterize this very dis- tinctive pattern of gallic acid metabolism which occurs in particular members of the plant families Casuarinaceae Fagaceae Juglandaceae Myrtaceae and Stachyuraceae. lo'*'04 The ability to bring about both 4,6and 2,3oxidative coupling of vicinal galloyl ester groups in p-1,2,3,4,6-pentagalloyl-~- NATURAL PRODUCT REPORTS 1994-E. HASLAM AND Y. CAI HO AH OH Valolaginic acid lsovalolinic acid HO HO OH co a-0 H O W O H HO OH OH OH HO OH OH OH Potentillin Pedunculagin LA HO’ OH OH OH C-1 p -OH Stachyurin C-1 p -OH Vescalagin C-1 p -OH Vescalin C-1 a-OH Casuarinin C-1 a-OH,Castahgin C-1 a-OH Castalin 18 Oxidative metabolism of /3-1,2,3,4,6-pentagalloyl-D-glucose,pathway (d) suggested biogenetic relationships in ‘open-chain’ Figure polyphenolic esters glucose [pathway (b) vide supra] is retained in these plant families and the metabolites pedunculagin casuarictin and potentillin (Figure 12) generally co-occur with these open-chain ester derivatives of D-glucose.Whilst it is possible that these unique open-chain esters are formed from pedunculagin by opening of the D-glucopyranose ring at the hemiacetal anomeric centre formation of a C-glycosidic link to the hexahydroxydiphenoyl group bridging the 2,3 positions and finally galloylation at C-5 a plausible biogenetic route to their formation can also be elaborated via redox reactions directly from the a-glucoside potentillin by ring opening and concommitant galloyl group transfer from C-1 to C-5.In this context it is interesting to note that all of the recorded ‘open-chain ’derivatives of D-glucose contain a hexahydroxydiphenoyl ester group bridging C-2 and C-3 of the sugar. The formal biogenetic relationship of the principal metabolites in this class are shown in Figure 18 and Tables 11 to 17. Perhaps the most significant discoveries amongst this class of NATURAL PRODUCT REPORTS 1994 Table 11 Naturally occurring ‘open-chair ’ polyphenolic esters related to vescalagin OH Trivial name R Ref.Vescalagin Hydroxyl 80 91 183 Acutissimin A (+)-Catechin; position C-8 177 Acutissimin B (+)-Catechin; position C-6 177 Eugenigrandin A (+)-Gallocatechin ; position C-8 185 Vescalagin carboxylic acid Carboxyl 181 Grandinin C alcohol from L-ascorbate 185 Mongolicin A Taxifolin-3-P-~-glucoside ; position C-8 180 Mongolicin B Taxifolin-3-/3-~-glucoside;position C-6 180 Mongolicanin Procyanidin B-3 ; position 8’ 181 Table 12 Naturally occurring ‘open-chain ’ polyphenolic Table 13 Naturally occurring ‘open-chain ’ polyphenolic esters related to castalagin esters related to casuariin HO OH OH OH Trivial name R‘ R2 Ref. Castalagin H H 80 88 183 Trivial name R1 R2 Ref.1-0-Galloyl castalagin galloyl H 184 Casuariin Hydroxyl H 101 104 Castovaloninic acid H Gallic acid 81 Casuarinin Hydroxyl Galloyl 101 104 position C-2 Flosin B Hydroxyl Valoneoyl dilactone 188 compound are the ~tenophyllanins,”~ ac~tissimins,~” species. All these compounds possess structures in which a camelliatannins 178 guavin~,~’~ mongolicins 180 mongolicanin,180 flavan-3-01 unit is linked through a carbonsarbon bond to the mongo1inin,lS1 and mongo1icainslS2 derived from a range of anomeric centre of an ‘open-chain ’ hexahydroxydiphenoyl or botanical sources including the bark of Castanea and Quercus related polyphenolic ester. They are thus phenolic metabolites NATURAL PRODUCT REPORTS 1994-E. HASLAM AND Y.CAI Table 14 Naturally occurring ‘open-chain ’ polyphenolic esters related to stachyurin HO OH Trivial name R’ R2 Ref.Stachyurin H ydroxyl Galloyl 101 104 5-Desgalloylstachurin Hydroxyl H 101 104 105 186 Stenophyllanin A (+)-Catechin; position C-8 Galloyl 176 Stenophyllanin B (+)-Catechin ; position C-6 Galloyl 176 Stenophyllanin C (+)-Catechin; position C-8 H 176 Camelliatannin A (-)-Epicatechin ;position C-8 H 178 Camelliatannin B (-)-Epicatechin; position C-6 H 178 Pterocarinin A C polyalcohol from L-ascorbate Galloyl 187 5-Desgalloylpterocarinin A C polyalcohol from L-ascorbate H 187 Pterocarinin B C polyalcohol origins unknown H 187 Lagerstromin Hydroxyl Valoneoyl 186 dilactone ~~ ~ Table 15 Miscellaneous ‘open-chain ’ derivatives of Table 17 Naturally occurring polyphenolic esters.‘Dimeric ’ hexahydroxydiphenic acid structures in which at least one ‘monomeric ’ component is derived from an ‘open-chain ’ polyphenolic ester metabolite Trivial name ‘Monomeric’ components Ref. Direct C-C link between ‘monomers’ OH Alienanin A Alienanin B Castamollinin Anogeissusin A Anogeissusin B Pedunculagin +stachyurin Casuarinin +stachyurin 2 x Vescalagin/castalagin 2 x Vescalagin/castalagin ( +)-catechin 2 x Vescalagin/castalagin (+)-gallocatechin 189 189 183 185 185 Trivial name Punicacortein A Punicacortein B Punicacortein C Punicacortein D Epipunicacortein A R’ H H H OH OH R2 OH OH OH H H Other esters 5-Galloyl 6-Galloyl 4,6-(S,S)-gallagyl 4,6-(S,S)-gallagyl - Ref. 190 190 190 190 189 Heterophyllin B Heterophyllin C Reginin A Reginin B Reginin C Reginin D Tellimagrandin 2 +casuarinin Casuarinin +casuarictin Casuarinin +pedunculagin Stachyurin +pedunculagin Pterocarinin A +pedunculagin Casuarinin +pedunculagin (S)-valoneoyl linking ester group 174 174 186 186 188 188 Table 16 Miscellaneous ‘open-chain ’ derivatives of nonahydroxytriphenic acid which embrace the structural and chemical features associated with both the hydrolysable and condensed groups of tannins.A typical example of this class of metabolite is acutissimin A (derived presumably from vescalagin/castalagin and ( +)-catechin). The alcoholic hydroxyl group at C-1 of metabolites such as castalin castalagin vescalin and vescalagin is benzylic and therefore in principle subject to possible displacement and the formation of a resonance stabilized carbocation at C-1.This OH provides a chemical rationale for a possible biogenetic pathway Trivial name R’ R2 Ref. to metabolites such as the stenophyllanins acutissimins Vescalin OH H 85 camelliatannins guavins mongolicins mongolicanin and Acutissimin C (+)-Catechin position C-8 H 183 mongolicains. It is presumed that such metabolites may be Castalin H OH 88 derived by interaction of the transient C-1 carbocation species in a metabolite such as vescalagin with the electron rich A-ring NATURAL PRODUCT REPORTS 1994 OH Vescalagin/Castalagin HoqoH HO OH (+)-Catechin t 6H Acutksimin A Figure 19 Suggested pathway of biogenesis from castalagin/vescalagin of acutissimin A OH OH OH Anogeissinin Alienanin B NATURAL PRODUCT REPORTS 1994-E.HASLAM AND Y. CAI OH Grand inin HO HO 0 OH HO L-Ascorbic acid HO OH OH VescalagirdCast alagin Figure 20 Suggested biogenesis of grandinin of a flavan-3-01 such as (+)-catechin Figure 19. Anogeissinin represents an interesting variation on this theme. In this molecule two molecules of vescalagin/castalagin are linked by carbon-carbon bonds to C-6 and C-8 of (+)-catechin. Similar biogenetic rationalizations may be employed to explain the origins of metabolites such as grandinin and the pterocarinins A and B which bear a C polyalcohol with the lyxose configuration at C-1. In the case of these compounds it has been suggested that the C alcohol is derived from L-ascorbate which in its enolic form attacks the C-1 carbocation Figure 20.So far more than thirty structurally related compounds of the 'open-chain' class have been isolated and described in the literature. From the accumulated data relating to the absolute stereochemistry at C-1 and using 2D NOE and NOE difference spectroscopy Nishioka and his concluded in 1990 that 'all the proposed structures sofar reported must be revised'. These revisions of stereochemistry are all incorporated into the structures shown here. Ni~hioka'~~ also determined the absolute stereochemistry of the twisted nonahydroxytriphenoyl ester group which forms an integral part of many of these natural product structures. The mode of biosynthesis of metabolites from vescalagin/castalagin such as grandinin and anogeissinin which contain a new carbon<arbon bond at C-1 of the sugar molecule may also be presumed to be operative in the generation of dimeric species such as the alienanins A and B.Other dimeric species in this class contain the more common linkage through the creation of a new carbon-oxygen bond and an (S)-valoneoyl ester Table 17. Finally it is of interest to note that the creation in castalagin/vescalagin of three C-C biphenyl linkages and a C-glycosidic bond results in the formation of relatively inflexible propeller-shaped molecules which contrast sharply with the conformationally mobile structure of their presumed biosynthetic precursor p-1,2,3,4,6-pentagalloyl-~-glucose. This indeed appears to be a common feature of a great many of the polyphenolic metabolites formed by the pathways (b) (c) (d) outlined -namely the progressive development of more highly condensed conformationally restricted structures by oxidative (dehydrogenation) reactions.The physical properties of the resultant metabolites is however not readily predicted. Thus vescalagin castalagin and geraniin are all formally derived from p-1,2,3,4,6-pentaga~~oy~-~-g~ucose by the loss of six hydrogen atoms. Geraniin is a beautifully crystalline molecule that despite the presence of 14 hydroxyl groups is virtually insoluble in water. Vescalagin and castalagin are also both crystalline and possess I5 hydroxyl groups but in contrast to geraniin and p-1,2,3,4,6-pentagalloy1-~-glucose, are highly soluble in water from which they are very difficult to extract with organic solvents.This feature is of very great importance when considerations are given to the association of these molecules with proteins and other substrates their phar-macological characteristics and their suggested role in the protection and chemical defence of plants. 2.2.6 Comments and Conclusions The putative biogenetic classifications (pathways (b) (c) and (d)) outlined above to the major classes of ellagitannins satisfactorily rationalize the formation of a very wide range of phenolic metabolites. They also draw attention to certain questions and observations which invite comment and possible explanation (a) If the ellagitannins originate by processes initiated by phenolic oxidation what influences do enzymic control on the one hand and the intrinsic chemical reactivity of reaction intermediates on the other exert upon the ultimate metabolic profile? (b) In the biogenesis of the ellagitannins the intramolecular oxidative processes appear to proceed exclusively with the formation of new carbon-carbon linkages but the intermolecular oxidative processes namely those of oligomerization occur invariably with the generation of new carbon-oxygen bonds.(c) Although the assumption has been made that the major pathways to these metabolites proceed directly through p-1,2,3,4,6-pentagalloyI-D-glucoseas the key biosynthetic in-termediate a significant number of these ellagitannin metabolites are found in which the anomeric centre is unacylated or if acylated occurs with the a-configuration.(d) If the ellagitannins are formed by the oxidative transformation of naturally occurring galloyl esters (cf Schmidt and MayeP9) what is the biogenetic origin of metabolites such as rugosin A and coriariin B (vide supra containing respectively (S)-valoneoyl and the dehydrodigalloyl groups but in both of which a carboxyl group remains unesterified) and punicalin (containing the unusual gallagyl esterifying group)? The researches conducted over the past two decades have fully vindicated the original ideas of Schmidt and MayeP9 and the key elements of their biosynthetic proposals. Whilst phenolic oxidation has been very widely invoked as a mechanism for the formation of many natural products from usnic acid to morphine knowledge of the nature of these processes at the enzymic level remains fragmentary.Suggested mechanisms rely heavily upon the analogy to in vitro chemical transformations of phenolic substrates where a vast amount of data has been collected and is collated in several reviews. lg1-lg4The oxidation of phenols with 'one electron' oxidants leads to coupling reactions involving both oxygen and carbon centres. The results of these experiments are fully in accord with the view that the first step in such oxidations is the generation of the phenoxy radical. If oxidative oligomerization of the substrate OMe HO (S)-(+)-N-Met hylcoclaurine OH Cocsulin MeO- 'Me 'Me (S)-(+)-Orientaline lsothebaine molecule then ensues at least three general mechanisms for this process must be considered (a) homolytic coupling 2Ar0' -+ [ArO] (b) radical insertion ArO' + ArO-+ [ArO] + e-or ArO' + ArOH -+ [ArO] + H' (c) heterolytic coupling ArO' -+ [ArO]' + e-[ArO]' + ArOH -,[ArO] + H' Although the mechanism of radical insertion cannot be entirely disregarded it has generally been considered ~nlikely.'~~-~~~ Whether the mode of phenolic oxidation and coupling then proceeds via a phenoxy radical or a phenoxonium ion these are both potentially very reactive species.Despite the seemingly limitless array of metabolites of gallic acid now described there is clear evidence to suggest that the highly reactive intermediates assuming they are formed do not react indiscriminately but are channelled along particular pathways to give a particular range of metabolites.Thus there are distinct taxonomic limits to the formation of individual metabolites.2*8,lo* 11*27-299 lol Likewise there can also be little 559 doubt that phenoxy radicals or phenoxonium ions would constitute particularly reactive intermediates whose subsequent reactions would require little if any catalysis in the con-ventional sense. Thus it seems reasonable to conclude that although the products of these oxidative pathways may be generally dictated by the inherent chemistry of the intermediates themselves the crucial role of the enzyme(s) is to direct and; constrain intermediates to follow particular reaction pathways and thus lead to a given range of metabolites.The question of C-0 as opposed to C-C oxidative coupling of phenolic substrates is an intriguing one. In the context of the biosynthesis of the dimeric isoquinoline alkaloids such as those of the berbamine and tubocurarine type,195*196 it has been suggested that intermolecular biphenyl ether formation (C-0 coupling) is favoured only when C-C coupling is sterically hindered. This type of explanation might be invoked anal- ogously to rationalize the specific formation of C-0 bonds in ellagitannin oligomerization vide supra pathways (b) and (c). However it is possible to consider other explanations to NATURAL PRODUCT REPORTS 1994 rationalize the distinctions between C-C and C-0 coupling processes.Thus the biosynthesis of the bisbenzylisoquinoline alkaloid cocsulin has been shown to occur by oxidative dimerization of ( + )-(S)-N-methylcoclaurine with the form- ation of three new ether linkages.ls7 The very closely related (S)-(+ )-orientaline however undergoes oxidative cyclization to give ultimately isothebaine by initial C-C bond formation ;lSs clearly other factors than simply steric ones are necessary to explain this discrimination in biosynthetic pathways. WaterslS9 made some interesting comments twenty years ago upon the duality of coupling pathways which result from one- electron oxidation of phenolic substrates ; on the basis of these observations he proposed an alternative interpretation of the enzymically induced oxidative coupling reactions of plant phenols.It was suggested that those biochemical oxidations of phenols which lead to Ar-0-Ar structures in plants probably involve the one-electron oxidation of aryloxy anions to give ArO' radicals which then dimerize by C-0 coupling but that those oxidations which lead to Ar-Ar (C-C) coupled products involve the electrophilic attack on phenolic molecules of ArO' cations. The diversity of reaction pathways observed Waters suggested may be due to the influences of pH and the oxidation potential of the active enzyme. Clearly these ideas may be utilized to rationalize the different patterns of C-C and C-0 coupling observed in the case of the ellagitannins.A third alternative explanation is based on the premise that intermolecular oxidative carbonsarbon bond formation does in fact occur alongside C-0 oxidative oligomerization but that the final metabolic profile only contains products of C-0 coupling. In vitro studies clearly indicate that hexahydroxydiphenoyl esters generated by C-C coupling and in which free rotation around the newly created C-C biphenyl linkage remains possible would under the conditions of cell pH or of chemical isolation be rapidly converted to ellagic acid (c$ above the stability of dimethyl hexahydroxydiphenoate). This possible situation is illustrated in Figure 21 for the case of tellimagrandin 2 (eugeniin) and for a situation in which oxidative coupling occurs at the C-1 galloyl ester group.Such an explanation would also provide a very neat rationale for the widespread occurrence of galloyl and hexahydroxydiphenoyl ester derivatives (e.g. tellimagrandin 1) in which the anomeric centre is unacylated if as is presumed below oxidation is primarily initiated at the anomeric position. By comparison linking dehydrodigalloyl and valoneoyl ester groups formed by C-0 coupling are relatively stable under the conditions noted and are therefore isolable metabolites. Dehydrodigalloyl and valoneoyl ester linking groups them- selves are nevertheless prone to hydrolytic cleavage under more stringent conditions. Thus the valoneoyl ester group in rugosin D hydrolyses rapidly in water at 90 "C and also undergoes methanolysis during chromatography in methanol on Sephadex LH 20 to give tellimagrandin 1 and rugosin A or its methyl The effect has been attributed to neighbouring group participation facilitating ester hydrolysis or methanolysis Figure 22.This observation indicates that the many similar ' monomeric ' compounds to rugosin A containing the dehydrodigalloyl or valoneoyl groups in which one carboxyl group is free vide supra may simply be the products of hydrolytic breakdown of more complex esters during isolation. Acceptance of the validity of such conclusions suggests that the original hypothesis of Schmidt and Ma~er,~' which states that hexahydroxydiphenoyl and other related esters are all derived initially by the oxidation of galloyl ester precursors still holds true.Parenthetically it also makes the drawing up of a prospectus of 'true natural products ' in this class of secondary metabolites extraordinarily problematical. Finally note may be made of the possible biogenetic origins of galloyl and hexahydroxydiphenoyl esters which possess the unusual a-configuration at the anomeric centre e.g. potentillin. The majority of these compounds are found in hexahydroxydiphenoyl esters which bridge the 2,3-positions. The ability to stabilize radical species at the anomeric centre of NATURAL PRODUCT REPORTS 1994-E. HASLAM AND Y. CAI OH [O.C-C coupling] G D OH 0 Tellimagrandin 2 0-G OH OH 0 HO Tellimagrandin1 OH Ellagic acid Figure 21 Oxidative dimerization of polyphenolic esters ;creation of a carbon-carbon linkage and subsequent facile cleavage to give ellagic acid and a modified monomer molecule OH GCO-0"8 OG HO - ROH HO OH HO OH Rugosin A; R = H Rugosin A methyl ester; R = Me OH Rugosin D Tellimagrandin 1 HO OH via neighbouring group paticipationof adjacent phenyl group Figure 22 Solvolysis of linking valoneoyl ester group in rugosin D; formation of rugosin A and tellimagrandin 1 NPR 11 NATURAL PRODUCT REPORTS 1994 OH OH OH Casuarictin P-configuration I t OH Potentillin a-configuration Figure 23 Suggested mechanism for the oxidative epimerization of the configuration at the anomeric centre in polyphenolic esters casuarictin to potentillin carbohydrates is well documented200 and a putative oxidative biogenetic scheme which takes note of this fact is shown in Figure 23 to account for the generation of the a-configuration at the anomeric centre of polyphenolic esters such as potentillin.3 Epilogue Carl Wilhelm Scheele’s research in a sense marks him as one of the founding fathers of organic chemistry. Although it formed the last of the distinguished Swedish scientist’s published studies his work on gallic acid dates back to about 1770. By exposing a solution of gall-nuts to air for several weeks Scheele obtained a sediment of the ‘essential salt of galls or gall-nut salt’ (gallic acid). A Frenchman (Henri Braconnot 178 1-1855 Professor of Natural History and Director of the Botanical Garden in Nancy) first named the substance as gallic acid in 1831 and its etymological origin derives from the French name for its source galle.Braconnot is also credited along with Michel Eugene Chevreul with the first isolation of the very closely related ellagic acid from gall nuts. Gallic acid and its derivatives as they occur in oak galls indeed constitute a chemical reagent of considerable antiquity. The blue-black colour produced when an aqueous infusion is treated with salts of iron was first described by Pliny; its use in the analysis of mineral waters and as a component of invisible ink were noted as early as the 16th century. Stories such as this one are never finished. Charting the progress made in this area since Scheele’s first isolation of gallic acid is a fascinating pursuit but in the context of secondary metabolism in which this particular account was first set thc story may be said to have just begun.As the distinguished natural products investigator T. A. Geissman predicted ‘the future ...is to use the chemical information as the starting point for questions that lie in the realms of biology’. 4 References 1 E. Fischer ‘Untersuchungen uber Depside und Gerbstoffe’ Springer-Verlag Berlin 1919. 2 E. Haslam ‘Plant Polyphenols -Vegetable Tannins Revisited’ Cambridge 1989. 3 E. C. Bate-Smith and T. Swain in ‘Comparative Biochemistry’ ed. H. S. Mason and A. M. 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NATURAL PRODUCT REPORTS 1994 121 T. Okuda T. Hatano and N. Ogawa Chem. Pharm. Bull. 1982 30 4234. 122 T. Okuda T. Hatano N. Ogawa and T. Shingu Chem. Pharm. Bull. 1990 38 3341. 123 I. Nishioka S. H. Lee T. Tanaka and G. Nonaka Chem. Pharm. Bull. 1991 39 630. 124 T. Okuda T. Hatano N. Ogawa N. Kira and M. Matsuda Chem. Pharm. Bull. 1984 32 4662; 1989 37 2083. 125 T. Okuda T. Hatano and T. Yasuhara Chem. Pharm. Bull. 1989 37 2665. 126 T. Okuda T. Hatano Y. Ikegami and T. Shingu Chem. Pharm. Bull. 1988 36 2017. 127 T. Okuda T. Yoshida T. Hatano M. Fukushima and X.-M. Chen Chem. Pharm. Bull. 1987 35 1817. 128 T. Okuda T. Yoshida T. Chou K. Haba Y.Okano T. Shingu K. Miyamoti and R. Koshiura Chem. Pharm. Bull. 1989 37 3174. 129 T. Okuda T. Hatano R. Kira and T. Yashuhara Chem. Pharm. Bull. 1988 36 3920. 130 I. Nishioka S. Nakayama and G. Nonaka Chem. Pharm. Bull. 1989 37 2030. 131 T. Okuda T. Yoshida T. Chou and A. Nitta Heterocycles 1989 29 2267. 132 S. Kadota Y. Takamori K. Nyein Nyein T. Kikuehi K. Tanaka and H. Eikimoto Chem. Pharm. Bull. 1990 38 2687. 133 T. Okuda T. Hatano T. Yoshida I. Agata Y. Nakaya T. Sugaya and S. Nishibe Chem. Pharm. Bull. 1991 39 881. 134 I. Nishioka T. Tanaka A. Morita T. Lin and G. Nonaka Chem. Pharm. Bull. 1991 39 60. 135 T. Okuda T. Yoshida Y. Maruyama and T. Chou Chem. Pharm. Bull. 1990 38 268 1. 136 T. Okuda T. Hatano and T. Yoshida Heterocycles 1990 30 1195.137 T. Okuda T. Yoshida 0. Nauba L. Chen and Y. Liu Chem. Pharm. Bull. 1990 38 3296. 138 T. Okuda T. Yoshida K. Haba Y. Okano H. Ohbayashi K. Ishihara and W. Ohwashi Chem. Pharm. Bull. 1991 39 2264. 139 T. Okuda T. Yoshida T. Hatano T. Yasuhara M. Matsuda and K. Yazaki J. Chem. SOC. Perkin Trans. I 1990 2735. 140 T. Okuda T. Yoshida T. Hatano T. Chou M. Matsuda T. Yasuhara K. Yazaki and A. Nitta Chem. Pharm. Bull. 1991,39 1157. 141 T. Okuda T. Yoshida K. Haba Y. Okano T. Chou K. Miyamoto R. Koshiura and T. Shingu Chem. Pharm. Bull. 1989 37 3174. 142 T. Okuda T. Hatano K. Yazaki and N. Ogawa Chem. Pharm. Bull. 1982 30 4230. 143 T. Okuda T. Hatano T. Yasuhara and N. Ogawa Chem. Pharm. Bull. 1990 38 3308. 144 T. Okuda T.Hatano and K. Yazaki Chem. Pharm. Bull. 1983 31 333. 145 T. Okuda T. Hatano K. Yazaki and A. Okonogi Chem. Pharm. Bull. 1991 39 1689. 146 T. Okuda T. Yoshida T. Chou and A. Nitta Chem. Pharm. Bull. 1991 39 2247. 147 T. Okuda T. Hatano T. Yoshida 0. Namba T. Yasuhara and K. Yazaki Heterocycles 1990 31 1221. 148 T. Okuda T. Yoshida 0. Namba and K. Yokoyama Chem. Pharm. Bull. 1991 39 1137. 149 I. Nishioka G. Nonaka J. H. Lin M. Ishimatsu and T. Tanaka Chem. Pharm. Bull. 1990 38 1844. 150 I. Nishioka G. Nonaka M. Hayahi R. Saijo and T. Tanaka Chem. Pharm. Bull. 1990 38 861. 151 I. Nishioka G. Nonaka and T. Tanaka Chem. Pharm. Bull. 1986 34 1039. 152 1. Nishioka G. Nonaka and J. H. Lin Chem. Pharm. Bull. 1990 38 1218. 153 I. Nishioka G.Nonaka R. Saijo I. S. Chen and T. H. Hwang Chem. Pharm. Bull. 1989 37 129. 154 I. Nishioka G. Nonaka T. Tanaka M. Ishimatsu M. Nishizawa and T. Yamagishi Chem. Pharm. Bull. 1989 37 129. 155 I. Nishioka G. Nonaka M. Ishimatsu and M. Ageta Chem. Pharm. Bull. 1989 37 50. 156 T. Okuda T. Hatano S. Hattori Y. Ikeda and T. Shingu Chem. Pharm. Bull. 1990 38 1902. 157 I. Nishioka G. Nonaka T. Tanaka and S. H. Lee Chem. Pharm. Bull. 1990 38 1518. 158 T. Okuda T. Yoshida and T. Hatano J. Chem. SOC. Perkin Trans. I 1983 961. I59 T. Okuda K. Yazaki and T. Hatano J. Chem. Soc. Perkin Trans. I 1989 2289. 160 T. Okuda K. Yazaki and T. Hatano Chem. Pharm. Bull. 1982 30 1113. 161 I. Nishioka G. Nonaka and T. Tanaka Chem. Pharm. Bull. 1990 38 2424.162 I. Nishioka G. Nonaka T. Tanaka K. Miyahara and T. Kawasaki J. Chem. SOC.,Perkin Trans. I 1986 369. 163 I. Nishioka G. Nonaka and S. Morimoti Chem. Pharm. Bull. 1986 34 941. 164 I. Nishioka G. Nonaka T. Tanaka M. Ishimatsu M. Nishizawa and Y. Yamagishi Chem. Pharm. Bull. 1989 37 1735. 165 T. Okuda T. Yoshida L. Chen and T. Shingu Chem. Pharm. Bull. 1988 36 2940. 166 T. Okuda 0.Namba and L. Chen Chem. Pharm. Bull. 1990,38 86. 167 I. Nishioka G. Nonaka T. Tanaka J. H. Lin and I. S. Chen Chem. Pharm. Bull. 1990 38 2171. 168 T. Okuda T. Yoshida 0. Namba and L. Chen Chem. Pharm. Bull. 1990 38 1113. 169 M. Uddin and E. Haslam J. Chem. SOC. (C) 1967 2381. 170 T. Okuda T. Yoshida and R. Fujii Chem. Pharm. Bull. 1980,28 3713. 171 T.Okuda T. Yoshida T. Koga and N. Toh Chem. Pharm. Bull. 1982 30 2655. 172 I. Nishioka G. Nonaka and R. Saijo Chem. Pharm. Bull. 1989 37 2624. 173 I. Nishioka G. Nonaka and R. Saijo Phytochemistry 1989 28 2443. 174 T. Okuda Z.-X. Jin and T. Yoshida Chem. Pharm. Bull. 1991 39 49. 175 R. D. Haworth J. Grimshaw and H. K. Pindred J. Chem. SOC. 1955 833. 176 I. Nishioka G. Nonaka and H. Nishimura J. Chem. SOC. Perkin Trans. 1 1985 163. 177 I. Nishioka G. Nonaka and K. Ishimaru Chem. Phurm. Bull. 1987 35 602. 178 T. Okuda T. Hatano T. Shida and L. Hau Chem. Pharm. Bull. 1991 39 876. 179 T. Okuda T. Hatano T. Yoshida K. Yazaki Y. Ikegami and T. Shingu Chem. Pharm. Bull. 1987 35 443. 180 I. Nishioka G. Nonaka K. Ishimaru M. Ishimatsu K.Mihashi and Y. Iwase Chem. Pharm. Bull. 1988 36 3312. 181 I. Nishioka G. Nonaka K. Ishimaru M. Ishimatsu K. Mihashi and Y. Iwase Chem. Pharm. Bull. 1988 36 3319. 182 I. Nishioka G. Nonaka K. Ishimaru M. Ageta K. Mihashi and Y. Iwase Chem. Pharm. Bull. 1988 36 857. 183 I. Nishioka G. Nonaka T. Sakai T. Tanaka and K. Mihashi Chem. Pharm. Bull. 1990 38 2151. 184 I. Nishioka G. Nonaka K. Ishimura M. Watanabe T. Yamauchi and A. C. S. Wan Chem. Pharm. Bull. 1987 35 217. 185 I. Nishioka G. Nonaka T. Tanaka T.-C. Lin and T. J. Young Chem. Pharm. Bull. 199I 39 1 144. 186 I. Nishioka G. Nonaka T. Tanaka T. Sakai and Y. M. Xu Chem. Pharm. Bull. 1991 39 639. 187 I. Nishioka G. Nonaka K. Ishimaru R. Azuma and M. Ishimatsu Chem. Pharm. Bull. 1989 37 2071.188 I. Nishioka G. Nonaka T. Tanaka and Y. M. Xu Chem. Pharm. Bull. 1991 39 647. 189 I. Nishioka G. Nonaka T. Sakai and K. Mihashi Chem. Pharm. Bull. 1991 39 884. 190 I. Nishioka G. Nonaka and T. Tanaka Chem. Pharm. Bull. 1986 34 656. 191 D. H. R. Barton and T. Cohen ‘Fetschr. A. Stoll’ Birkhauser Basel 1956 117. 192 W. I. Taylor and A. R. Battersby ‘Oxidative Coupling of Phenols’ Dekker New York 1967. 193 A. I. Scott Quart. Rev. 1965 19 1. 194 D. A. Whiting in ‘Comprehensive Organic Chemistry’ ed. J. F. Stoddart Pergamon Press Oxford and New York 1979 Vol. 1 p. 707. 195 H. Musso Angew. Chem. Int. Ed. Engl. 1963 2 723. 196 K. Mothes H. R. Schutte and M. Luckner ‘Biochemistry of Alkaloids’ VEB Deutsch. Verlag der Wissensch.Berlin 1985. 197 D. S. Bhakuni V. M. Labroo A. N. Singh and R. S. Kapil J. Chem. SOC. Perkin Trans. I 1978 125. 198 A. R. Battersby R. T. Brown J. H. Clements and G. G. Iverach J. Chem. SOC.,Chem. Commun.,1965 230. 199 W. A. Waters J. Chem. SOC. (B) 1971 2026. 200 B. Geise Angew. Chem. Int. Ed. Engl. 1990,30,969;Acc. Chem. Res. 1991 24 296.

ISSN:0265-0568    

DOI:10.1039/NP9941100041

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Pigments of Fungi (Macromycetes) M. Gill School of Chemistry University of Melbourne Parkville Victoria 3052 Australia Reviewing the literature published between July 1986 and August 1992 1 Introduction 2 Pigments from the Shikimate-Chorismate Pathway 2.1 Compounds Derived from Arylpyruvic Acids 2.1.1 Grevillins and Pulvinones 2.1.2 Terphenylquinones 2.1.3 Pulvinic Acids and Related Butenolides 2.1.4 Badione Group 2.2 Compounds Derived from Phenylalanine and Tyrosine 2.3 Compounds Derived from Cinnamic Acids 2.4 Miscellaneous Compounds Possibly Derived from the Shikimate-Chorismate Pathway 3 Pigments from the Acetate-Malonate Pathway 3.1 Tetraketides 3.2 Heptaketides 3.3 Octaketides 3.3.1 Anthraquinones and Anthraquinone Carboxylic Acids 3.3.2 Monomeric Pre-anthraquinones 3.3.3 Coupled Pre-anthraquinones 3.3.4 Further Octaketides 3.4 Nonaketides 3.5 Higher Polyketides and Compounds of Fatty Acid Origin 4 Pigments from the Mevalonate Pathway 5 Nitrogen Heterocycles 5.1 Phenoxazin-3-ones 5.2 Indole Pigments 5.3 Necatarone and Miscellaneous N-Heterocyclic Pigments 6 Further Pigments Containing Nitrogen 7 References 1 Introduction The isolation characterization and chemistry of pigments from fungi belonging to the Macromycetes (previously referred to as the Higher Fungi) was reviewed comprehensively for the first time in 1987.l That review focused on colouring matters produced by fungi that to the observer in the field are recognized as forming conspicuous fruit bodies and it covered the chemical biological and mycological literature from its inception during the latter half of the 19th century to the early part of 1986.Also included were pigments from slime moulds (Myxomycetes) and in certain circumstances pigments pro- duced by macromycetes grown in mycelial culture and colourless metabolites where these provided additional chemical interest or taxonomic information. The aim of this Report is to review within the same terms of reference work that has appeared in the literature between the middle of 1986 and the present time (August 1992). As before,' the pigments are classified according to their probable biogenesis although in many cases there still remains little or no experimental evidence to support the biosynthetic pathways chosen.2 Pigments from the Shikimate-Chorismate Pathway 2.1 Compounds Derived from Arylpyruvic Acids 2.1.I Grevillins and Pulvinones The grevillins e.g. grevillin A (1) and B (2) are a unique group of pyrandione pigments isolated from the fruit bodies of boletes belonging to the genus Sui1lus.l The pulvinones are a family of hydroxylated 5-benzylidene-4-hydroxy-3-phenylfuran-2(5H)-one natural products of which only one member 3',4,4'-trihydroxypulvinone (3) has been found within Basidiomycetes. Grevillin B (2) and the pulvinone (3) occur together in the fruit bodies of Suillus grevillei and share a close biosynthetic relationship with each other and with several other classes of fungus pigments including the terphenylquinones (Section 2.1.2) and pulvinic acids (Section 2.1.3).l A new synthesis of grevillins and pulvinones (Scheme l)z employs di benzylacyloins of the type (4)3 as common precursors in which the aryl substituents may be effectively differentiated if required.Deprotonation of the acyloin (4)and interception of the resulting dianion (5) with carbonyldiimidazole (for pulvinone synthesis) or with oxalyldiimidazole (for grevillin synthesis) followed by conjugation and cleavage of protecting groups in each case gave the pigments (2) and (3) indistinguishable from the natural products. Grevillin A (1) its pulvinone counterpart aspulvinone E (a metabolite of the mould Aspergillis terreus) and the as yet unnatural isomers of (2) and (3) in which the R Me0 OH HO 0 0 (1) R=H (3) (2)R = OH 67 NATURAL PRODUCT REPORTS 1994 -0 A,lyCN Arl,-,,&A? OSiMea OH (4) liii A12 OMe A..0- Ar' (5) I ]vi 1. A12 OMe vii1 lx A? OMe 2(2) viii xi Ar' (3) - Ar' = 3,4-(OMe)&Ha Ar ' A? = 4-OMe-C6H4 Reagents i Ar'MgCl; ii HCl; iii LDA (2.3 equiv.) THF -78 "C; iv oxalyldiimidazole; v Me'SO, K,CO, acetone; vi NBS hv CCl,; vii Hiinig's base; viii BBr, CH,Cl,; ix carbonyldiimidazole; x DBU; xi LiBr DMF Scheme 1 phenolic substituents are interchanged have been synthesized in the same way. A conceptually similar route to grevillin B (2) involving Dieckmann cyclization of the acyloin oxalate ester (6) has also proved effective.2.1.2 Terphenvlquinones It has been established by feeding 13C-and 14C-labelled precursors to cultures of Punctularia atropurpurascens that phlebiarubrone (7) and its mono- di and trihydroxylated derivatives (8)-( lo) respectively arise by initial condensation between two molecules of either phenylpyruvic acid or phenylalanine but that tyrosine is not incorporated into the hydroxylated quinone~.~ The fact that the phlebiarubrone derivatives (8)-(10) are evidently produced by a series of consecutive hydroxylations starting with phlebiarubrone (7) itself is extraordinary since earlier experiments had shown that the biosynthesis of terphenylquinones such as atromentin (1 l) involves 4-hydroxyphenylpyruvic acids or tyrosine in the initial condensation step.l Several papers have appeared from the Steglich group that give a full account of their work on the terphenylquinone and terphenylquinol derivatives present in Boletopsis leucornelaena,6 in several species of Anthrac~phyllum,~and in Paxillus atrotornentosus and P.panuoides.*,' Since most of this work has been discussed in detail in the earlier Review1 only a brief summary is necessary here. When fruit bodies of Boletopsis leucomelaena (Polyporus leucornelas in the older literature) were extracted with acetone the leucoperacetate (12) of thelephoric acid was isolated together with the leucohexaacetate (13) a leucotetraacetate [either (14) or (1 5)] the leucotriacetate (16) and a mixture of leucopentaacetates of cycloleucomelone (17).6 From the blue-green methanolic extracts of the same fungus were obtained the leucotriacetate (16) cycloleucomelone (17) itself and a blue-green crystalline compound to which the novel ortho-quinone structure (18) was assigned from the spectroscopic data.The properties of Akagi's 'leucomelone ' and 'protoleucomelone ' (for historical aspects see Ref. 1) correspond to those of cycloleucomelone (17) and its leuco- peracetate (1 3).6 Cycloleucomelone derivatives are also responsible for the coloured reactions that occur when the flesh of various Anthracophyllum species comes into contact with aqueous alkali. Fruit bodies of A.discolor (from Chile) and A. archeri (from Western Australia) contain up to 7 YOof their dry weight of anthracophyllin (1 9) which is the 2,8-diacetate of cyclo- leucomelone along with a lesser amount of a mixture of the monoacetates (20) and (21) (probably artefacts of the purification procedure) and cycloleucomelone (17) itself. Anthracophyllum archeri also contains the 2,Sdiacetate (22) of atr~mentin.~ From an unnamed Anthracophyllum species (ZT 73/208) collected in Papua New Guinea have been isolated the mono- and triacetyl derivatives (23) and (24) respectively of cyclovariegatin (25) together with the known terphenylquinones (1 7) (19)-(21).' Cyclovariegatin (25) a pigment from the brown cap skins of the bolete Suillus grevillei,' has been synthesized via pyrandione intermediates as summarized in Scheme 2.137 NATURAL PRODUCT REPORTS 1994-M GILL R2 AcO OAc HR3 \ 04 R' (7) R' = R2= R3= H HO (8) R' =OH R2= R3= H (11) R=H (22) R = AC (9) R' = R3=OH R2= H (10) R' = R2 = R3 = OH OAc HO bR' '15; = R2 = R3= Ac (17) R'=R2=H (14) H'=Ac R2=R3=H (19) R' = R2 = Ac (15) R'= R3= H R2=Ac (20) R' = Ac R2= H (16) R' = R2 = R3 = H (21) R' = H R2=Ac / OAc 0#OH0 OAc (23) R' = R3= H R2= AC (24) R'=R2=R3=Ac (25) R' = R2= R3= H OMe ?Me 6""' ?Me -I ii Me0 OMe Me0s"' OMe OMe iii OH OH Reagents i 2,4,5-(MeO),C,H,CHO AcOH; ii NaOMe MeOH; iii BBr, CH,CI,; iv MeOH H,SO Scheme 2 NATURAL PRODUCT REPORTS 1994 OR2 HO 0 (30) Me 0 H A= H at Me 0 H HO Nm II / OR HO \ 0 (32)R= (35) Y-H HOMe Me (34) R= *-OH HO Me (39)R = AC HO (37) OMe OMe ?R Reagents i NaP(O)(OMe) (2 equiv.); ii NaH toluene 0 "C; iii 4-MeO-C6H,COCO,Me (43) reflux 36h; iv HC1; v hv;vi Me$ Scheme 3 NATURAL PRODUCT REPORTS 1994-M.GILL (44)R'=Me R2=R3=R4=H (45)R'=R3=R4=H R2=OH (46)R'=R4=H R2=R3=OH (47) R' = H R2= R3= R4= OH Atromentin (1 1) occurs in the intact fruit bodies of Paxillus atrotomentosus mainly as the colourless leucomentins 2 (26) 3 (27) and 4 (28) which have been isolated after extraction of the freeze-dried fungus with acetone. The leucomentins are all esters of leucoatromentin (29) with (22,4S,5S)-4,5-epoxyhex-2-enoic acid.The absolute stereochemistry in the ester moiety was determined by acetylation and acid catalysed cleavage of leucomentin 3 (27) that gave O-acetyl-( +)-osmundalactone (30).8The leucomentins (26)-(28) are the immediate precursors of the large quantities of atromentin (11) that are obtained when fresh fruit bodies of P. atrotomentosus are extracted with ethano1.l The leucomentins are also closely related to the orange-yellow flavomentins A-D (3 1)-(34) and the violet spiromentins A-D (35)-(38) isolated from P. atrotomentosus and P. panuoides. Paxillus panuoides also produces 3-0-acetylatromentin (39).9 The structures of these orange-yellow and violet quinones were deduced mainly from the spectroscopic data and subsequently confirmed by elegant synthetic and biomimetic studies that have been reviewed.' 2.1.3 Pulvinic Acids and Related Butenolides A new route to pulvinic acids that includes a synthesis of the permethylated derivative (40) of the fungal metabolite gomphidic acid (41) employs phosphonate esters such as (42) (Scheme 3).'* In contrast to the lack of reactivity exhibited by their triphenylphosphorane analogues phosphate esters such as (42) undergo Wadsworth-Emmons olefination with aroyl- formate esters e.g.(43) to give pulvinic acids in acceptable yields. During the reaction sequence depicted in Scheme 3 a 3 :2 mixture of 2 and E isomers of permethylated gomphidic acid was obtained that could be photoisomerized by deliberate exposure to laboratory daylight to afford exclusively the E geometrical isomer (40).'O Demethylation of (40) to yield the natural product (4 1) by using iodotrimethylsilane was known from earlier w0rk.l' Fruit bodies of Pulveroboletus ravenelii collected in Australia* * This fungus was mistakenly referred to in Ref.1 as Boletus subglobosus. OH (48) R=H (49) R=OH (51) R = H 0 (52)R =PI' contain vulpinic acid (44) (0.12% of the fresh weight) atromentic acid (45) (5.6 x YO),isoxerocomic acid (46) (1 .O x YO),variegatic acid (47) (1.O x %) xeroco-morubin (48) (1.6 x YO) and variegatorubin (49) (1.3 x O/0).l2 Vulpinic acid (44) was isolated earlier from P. ravenelii collected in Japan13 and the hydroxylated pulvinic acids (45) (47) and (49) occur widely among fungi belonging to the order Boletales.' Isoxerocomic acid (46) and xeroco- morubin (48) however were known previously only from mycelial cultures of the 'dry rot' fungus Serpula lacrimans and as synthetic materials.' The occurrence of vulpinic acid (44) together with the hydroxylated pulvinic acids (43449) is of biogenetic significance in that it suggests a sequence of consecutive hydroxylations beginning with the parent pulvinic acid (44; R' = H) that is contrary to the normal biosynthetic pattern established for these pigments.'Pulveroboletus ravenelii also produces a colourless optically active metabolite ravenelone to which the novel butenolide structure (50) has been assigned on spectroscopic and chemical grounds.The absolute stereochemistry of ravenelone is not known but molecular modelling suggests the (7R* 8s*) relative configuration. l2 The structure (50)of ravenelone suggests a biosynthesis from three molecules of phenylpyruvic acid. Analogously the novel structure (51) that has been assigned to retipolide A a colourless antibiotic produced by the bitter tasting fruit bodies of the North American bolete Boletus retipes is consistent with a biosynthesis involving three molecules of 4-hydroxyphenyl- pyruvic acid.14 The structural elucidation of retipolide A (51) was complicated by extensive line broadening in the 'H and 13C NMR spectra that resulted from a rapid equilibration between the hemiacetal(5 1) and the corresponding ring-opened forms.However the isopropyl acetal (52) is configurationally stable and showed a complete set of 'H and 13C NMR signals. It is noteworthy that conformational rigidity in the macrocyclic lactone ring of retipolide A (51) results in a magnetic nonequivalence of the protons of the 1,4-disubstituted phenyl ring and also that strong shielding of the proton at C-2 by the neighbouring orthogonal phenyl ring causes that proton to resonate at 84.83 in the 'H NMR ~pectrurn.'~. An effective method based on the Mitsunobu reaction for macro- NATURAL PRODUCT REPORTS 1994 QH+Br\ Po\ tly ~ OMe i OMe ii,iii OMe \ \ OBn OBn OBn OH OH 0 0 0 0 IN t \ 9<\ vi \ &-.\ OH cod 0 (53) Reagents i CuO K,CO, pyridine 140 "C 18h; ii Ph,P=CHOMe THF -78" +25 "C; iii PTSA aq.dioxane; iv NaBH,; v H, Pd-C (3 atm.); vi DEAD Ph,P toluene under precisely defined conditions (see Ref. 15) Scheme 4 'OH OH (57) lactonization of the hydroxycarboxylic acid (53) to generate the the formation of a 1:1 complex between the pigment (56) and 14-membered ring in the retipolide A mimic (54) has been caesium chloride and furthermore demonstrated that nor-developed and is shown in Scheme 4.15 badione A is a much better ligand for caesium than 'simple' pulvinic acids such as atromentic acid (45).16 Several naphthalenoid pulvinic acids particularly the potassium chelate 2.1.4 Badione Group of norbadione A (56),are produced in very high concentrations High concentrations of radionuclides in the fruit bodies of by the important ectomycorrhizal gasteromycete Pisolithus Xerocornus badius after the nuclear reactor accident at arhizus ( = Pisolithus tinctorius).' In the white-skinned fruit Chernobyl have been ascribed to the complexation of 13'Cs by bodies of a variant of this fungus collected from Eucalyptus the naphthalenoid pulvinic acids (55) and (56) that are present forest in Western Victoria Australia norbadione A (56) is normally as their potassium salts in the cap skin of this accompanied by pisoquinone (57) a new member of the toadstoo1.l6 The binding of caesium to norbadione A (56) has badione group.l7 The structure of pisoquinone followed from been corroborated by laboratory experiments that established the spectroscopic data and from the formation of a quinoxazo- NATURAL PRODUCT REPORTS 1994-M.GILL cleavagea J Vb Scheme 5 Reagents i Me,Sn (Ph,P)Pd(O) dioxane reflux ; 80 % yield Scheme 6 purified enzyme preparation with metapyrocatechase activity has been isolated from the cap skin of A. muscaria.20 When it was subsequently incubated with L-DOPA(62) (Scheme 5) this preparation effected extradiol cleavage of the aromatic ring in (62) to afford a mixture of the dienoic acids (63) and (64). The instability of these hitherto hypothetical biosynthetic inter- mediates precluded their isolation but they could be separated by HPLC allowing their UV/VIS spectra and some kinetic properties to be measured. They cyclized without enzyme catalysis; 4,5-secodopa (63) produced betalamic acid (60) whilst 2,3-secodopa (64) afforded muscaflavin (61).20.21 The secodopas (63) and (64) were subsequently detected by HPLC in extracts of Amanita muscaria and Hygrocybe conica.21 A review of the synthesis and chemistry of naturally occurring OH betalaines that includes a list of betalaine pigments isolated from toadstools has recently appeared. 22 Preliminary progress towards new syntheses of muscaflavin (61) and other azepines has been reported.23 Rdo HOw (65) R =OH (66) R = H (67) (68) R = NH2 (69) R = NO;! line derivative with 1,2-diaminobenzene. Sequestration of pot- assium ions and subsequent provision of this essential element to the mycorrhizal partner are probably the most important roles that these pigments play in the ecology of P.arhizus. However the fungus may also protect the host plant by generating antimicrobial antibiotics. Thus when grown in culture P. arhizus produces phenolic metabolites that are active against a significant number of phytopathogenic and dermatopathogenic microorganisms. l9 Two of these metabolites have recently been identified as 4-hydroxy-benzoylformic acid (58) and (R)-(-)-4-hydroxymandelic acid (59) by comparison with commercial samples. l9 2.2 Compounds Derived from Phenylalanine and Tyrosine The complex mixture of pigments that is responsible for the familiar red colour of the cap skin of the toadstool Amanita muscaria (‘fly agaric’) is composed of Schiff bases (so-called betalaines) formed between the aldehyde group of betalamic acid (60) and a variety of amino acids.Similarly the bright colours of various Hygrocybe species are due to amino acid conjugates formed with muscaflavin (6 1) a yellow pigment that is also present in Amanita muscaria.’ Recently a partially 2.3 Compounds Derived from Cinnamic Acids The styrylpyrone pigments hispidin (65) and bisnoryangonin (66) enjoy widespread distribution among fungi belonging to the genera Gymnopilus Hypholoma and Pholiota in the Agaricales and among a number of genera belonging to the family Hymenochaetaceae in the Aphyllophorales. In both Orders they have proved to be of considerable taxonomic value. Unexpectedly hispidin (65) and bisnoryangonin (66) have recently been found as the major tractable constituents of Cortinarius abnormis a new Australian taxon and the chemotaxonomic implications of this observation have been addressed.24 2.4 Miscellaneous Compounds Possibly Derived from the Shikimate-Chorismate Pathway 6-Nitro-iso-vanillic acid (67) the first nitroaromatic pigment from an agaricoid fungus was mentioned briefly in the earlier review.l Details of the isolation of (67) as its potassium salt from an as yet unnamed toadstool belonging to the genus Cortinarius subgenus Sericeocybe have now appeared.25 The biogenesis of the pigment (67) has been studied by feeding [carboxyl-13C]labelled anthranilic acid (68) 4-methoxybenzoic acid 4-hydroxybenzoic acid and 2-nitrobenzoic acid (69) in turn to fruit bodies of the organism growing in their natural habitat.Of the putative precursors administered only 2-nitrobenzoic acid (69) was incorporated to a significant extent.26 3. Pigments from the Acetate-Malonate Pathway 3.1 Tetraketides A 5-methyltropolone structure originally assigned to the yellow pigment isolated from Onnia tomentosa ( = Polyporus tomentosus) and dubbed ‘veracruzalone’ (see Ref. 1 for details) has been shown to be in error.27 Authentic 5-methyltropolone (70) was synthesized by using the palladium-mediated cross- coupling of 5-bromotropolone (71) (Scheme 6) with tetra- NATURAL PRODUCT REPORTS 1994 O/H’. 0 o,H*.o (74) R’ =Ac R2 = H R3 = OH R4 = Me (75) R’=H R2=Ac R3=Me R4=OH methylstannane and its physical and spectroscopic properties were shown to bear no resemblance to those reported for the supposed natural product.3.2 Hept ake tides The synthesis of model pigments including the metal chelates (72; M = Zn Co Ni and Mn) has corroborated the structure of the analogous 2 1 complex formed between the green pigment (73) and zinc ions in fruit bodies of the ascomycete Roesleria pallida (= Roesleria hypogea).2s Hypocrellin (74) is a photodynamic perylenequinone pigment from the bamboo fungus Hypocrella bambusae. ’ Recently the perylenequinones (75) and (76) have been isolated from the deep-red mycelium of the Chinese bamboo fungus Shiraia bambusicola and from their CD and ‘H NMR spectra they have been shown to be stereoisomers of hypocrellin (74).29 Shiraiachrome A (75) has the same (R)axial chirality as hypocrellin (74) but differs in absolute configuration at the two chiral centres.Shiraiachrome B (76) on the other hand is the antipode of the pigment (74). The structure of shiraiachrome C (77) a third red pigment from S. bambusicola was deduced from spectroscopic data and from the fact that it is formed when both hypocrellin (74) and the shiraiachromes A (75) and B (76) are treated with aqueous alkali. The complex naphthoquinone pigment TFl (78) is a minor constituent of the delicate sporophores of the slime mould Trichia ~7oriformis.~~ 3.3 Octaketides Since the first review in 1987,l our knowledge of fungus pigments of octaketide origin has grown more rapidly than that of any other group.This growth has been due principally to increased activity in the study of Australian toadstools belonging to the genera Cortinarius and Dermocybe that has brought to light many new anthraquinones and biogenetically related metabolites. Hopefully the characterization of these new pigments will promote and facilitate much-needed de- velopment of the taxonomy of those indigenous Australian fungi that belong to these and perhaps other genera.31 Due to -&-+gMe Me HO $HO Me0 .Me OMe 6noH o,H..o 00 (77) this problem many of the species discussed in the following paragraphs remain identified only to the level of genus. Wherever the chemistry of unnamed species of this kind is discussed the organisms are referred to by accession numbers under which voucher specimens of these fungi have been lodged in reputable herbariums.3.3.1 Anthraquinones and Anthraquinone Carboxylic Acids The isolation of 6-methylxanthopurpurin-3-0-methylether (79) austrocortinin (80) and xanthorin (81) from the ethanolic extract of the fresh fruit bodies of Dermocybe splendida* was recorded earlier.’ Recently the 8-0-P-~-gentiobiosides (82) (83) and (84) of these quinones have been isolated from the water-soluble fraction obtained from the same fungus and fully characterized as their acetyl derivative^.^^ The gentiobioside (83) of austrocortinin (80) is crystalline and was also characterized in its native state. Treatment of (83) with p-D-glucosidase gave the aglycone (80) while mild acid hydrolysis gave (80) and D-glucose which was isolated.The gentiobiosides (82) (83) and (84) are the first anthraquinone disaccharides to be found in Macromycetes. Two other more simple derivatives of xanthorin (81) have also come to light. Thus from the orange- brown fruit bodies of the Australian Dermocybe species WAT 22963 have been isolated xanthorin- 1-0-methyl ether (85) and w-hydroxyxanthorin- 1-0-methyl ether (86).34 w-Hydroxyanthraquinones such as (86) are rare in Macromycetes. Citreorosein (w-hydroxyemodin) (87) a pigment previously known from several Pencillium species and from lichens insects and plants has now also been isolated from a purple Dermocybe species (WAT 21 566).35 Fallacinol (the 6-0-methyl ether of citreorosein) is the major pigment from the European toadstool Dermocybe cinnabarina.The bright-yellow fruit bodies of Dermocybe canaria collected in New Zealand contain physcion (88) as the major pigment.36 Physcion has also been detected in many other Cortinarius and Dermocybe species where it usually appears only as a minor * In Ref. 1 Table 25 the species from which these pigments were isolated is referred to as ‘Dermocybe sp.’. It has subsequently been identified as D . splendida.32 NATURAL PRODUCT REPORTS 1994-M. GILL R' 0 OH 0 R' 0 0 R2 MeO,($$,,Me M e O mII M/2 e R20wCII H20H M e O wII M e I I 7\ OR2 0 OR' 0 OR2 OH 0 OR2 OR' 0 OH (79) R' = R2 = H (81) R' = R2= H (86) R'=OH R2=Me (88) R' = R2 = H (80) R' (82)R' (83) R' = OH R2= H = H R2 = = OH R2 gent.= gent. (84) R' =gent. (85) R'=H R2 R2= =Me i (89) R' (90)R' (91) R' = H R2 = = H R2 = = glu. R2 OH NH2 = H (92) R' = glu. R2 = OH glu.= gent. = HO HO HO HO 0 0 Me OMe OH OH (93) (94) 0 OMe 0 OH 1 reMeOk:e e:e i-iii vi-viii OH 0 OMe -Me0m I Me0 ti Me Me OH Me OSiMe2But OSiMe2But 0 bSiMe2But 0 (98) (97) Reagents i ButMe,SiC1 imidazole DMF; ii BunLi; iii ClC0,Me; iv H,C=C(OMe), 200 "C 24h; v 2-chloro-8-hydroxy-6-metho-xynaphthoquinone 160 "C 4h; vi H,SO, THF; vii Me,SO, K,CO, acetone reflux; viii BCI, CH,Cl, -80 "C Scheme 7 component.' It occurs in this capacity for example in extracts of several fungi in which dihydroanthracenones are the principal colouring matters (see Section 3.3.2).The minor pigments of D. canaria are erythroglaucin (89) and a new quinone 4-aminophyscion (90).36 4-Aminophyscion is the first naturally occurring anthraquinone bearing an amino group in the aromatic nucleus. The spectroscopic properties and chemistry on which this unique structure was based have been reviewed.' In the fresh fruit bodies of D.canaria collected in Tasmania it was found that physcion (88) and erythroglaucin (89) are accompanied by their 8-O-/3-~-glucosides (9 1) and (92) re~pectively.~~~~~ The glucosides (91) and (92) were best characterized as their acetyl derivatives and the position of the carbohydrate residue was established unequivocally by 2D{lH-l3C) NMR correlation shift experiment^.^^ In the bright-yellow subterranean mycelium of D.canaria physcion and erythroglaucin and their glucosides play a subordinate role alongside a group of unique coupled octaketides that have been collectively termed the dermocanarins.35*37 Chemical studies involving wild mycelium are rare but were facilitated in this case by the striking yellow colour of the dense mycelial mats. Purification of the dermocanarins was made difficult by c'ontamination of fungal tissue with solid debris and the consequent presence of humic and lignicatious matter in the ethanolic extract. Nevertheless after extensive chromatography on silica gel and Sephadex LH-20 the dermocanarins 1 (93) 2 (94) and 3 (95) were obtained in pure form. The structures (93 j(95) were deduced mainly from spectroscopic data.Interestingly dermocanarin 3 (95) is a dehydro-dimer of dermocanarin 1 (93) in which the naphthalenoid moiety exists in the keto form rather than as the corresponding fully aromatic naphthol. It has been suggested that sp3 hybridization at the binaphthyl bond is preferred for steric reasons.35 Spectroscopic evidence and molecular modelling support the conformation and relative stereochemistry depicted in the formulae (93)-(95) however the absolute configuration of the dermocanarins 1-3 is still Four more members of the dermocanarin class in which the anthraquinone functionality is incompletely developed are discussed in Section 3.3.3. The Australian Derrnocybe species WAT 19352 has often been confused with the European Cortinarius cinnabarinus Fr.[= Derrnocybe cinnabarina Fr. Wunche]. The orange sporophores of the Australian toadstool produce a group of anthraquinones each one of which contains a novel two-carbon side chain at C-3 in the quinone nucleu~.~~*~~ The major pigment (R)-(+)-austrocorticin (96) was assigned the unique anthraquinone y-lactone structure from spectroscopic data. The (R) absolute configuration of (+)-austrocorticin (96) has been established by the synthesis of its laevorotatory antipode (97) beginning from (S)-(-)-3-butyn-2-01 (98) according to the reactions summarized in Scheme 7.,O Co-metabolites of NATURAL PRODUCT REPORTS 1994 v vi 1 OMe 0 OMe OMe 0 OH e (103) -wz xiii xii viii-ix ~ Me Me0 Me0 0 Br 0 x-xii Ivii 1 (96)+ (97) (99) Reagents i MEK NaH; ii MeO,CCH,COCH,CO,Me NaOMe; iii NaOH EtOH; iv PPA; v CH,N,; vi CAN aq.HOAc; vii LiOH DMF 85 "C; viii Me,SO, K,CO, acetone reflux; ix NBS CCl, hv;x CF,CO,Ag DMF 100 "C; xi NaOH 0 "C; xii BCl, CH,Cl, -80 "C; xiii CF,CO,Ag Na,CO, DMSO 65 "C Scheme 8 OMe 0 OH OMe 0 OH Me0 Me0 Me Me0 Me 0 O R 0 R2 0 (96)R = Me (107) R= H (99)R= H (101) R=OH (100) R' = R2 = H (102) R' =H R2=OH austrocorticin in WAT 19 352 include austrocorticinic acid (99) austrocorticone (1 00) and their 4-hydroxy derivatives (101) and (102) respecti~ely.~~~~~ The ketones (100) and (102) are acutely insoluble in common organic solvents and were most conveniently purified and characterized in the form of their respective methyl esters (103) and (104).Austrocorticinic acid (99) has been synthesized not only from but-l-yne by a route that parallels the chemistry depicted in Scheme 7 but also by using Friedel-Crafts chemistry (Scheme 8). Methyl austro- corticinate (105) was easily transformed via the benzylic bromide (1 06) into (+_)-austrocorticin [(96) +(97)] and into the austrocorticone ester (103).,O The administration of 13C enriched putative precursors to fruit bodies of WAT 19 352 growing in their natural habitat has established that the anthraquinones (96) and (99)-(102) share a unique octaketide mode of biosynthesis in which the C side chain at C-3 originates from propi~nate.~~. 39 While propionate is well known to initiate decaketide formation for example during anthracyclinone biosynthesis propionate-triggered octaketide assembly was not known previously.The nature of the labelled compounds that were fed to the toadstools and the sites at which isotopic enrichment occurred are summarized in Scheme 9. Briefly the label from sodium [3-13C]propionate was incorporated exclusively into the methyl carbon of the C-3 substituent in all of the quinones (96) and (99H102). On the other hand [Me-13C]methionine while it enriched the methoxyl carbons to a remarkable level (-30 %) played no part in the introduction of the side chain methyl group. Noraustrocorticin (107) a co-metabolite of the pigment (96) in WAT 19352 arises by way of a conventional acetate-triggered octaketide (103) R' =Me R2=H (104) R' =Me R2=OH pathway that must operate in this organism in tandem with the predominant propionate-initiated pathway.39 3.3.2 Monomeric Pre-anthraquinones The biogenetically important dihydroanthracenone torosa- chrysone first known from the medicinal plant Cassia torosa,l has been isolated for the first time as a fungal metab~lite.~~ (S)-Torosachrysone (1 08) occurs together with several related tetrahydroanthraquinones (vide infra) in the fruit bodies of Dermocybe ~plendida~~ and along with its intensely fluorescent 8-O-P-~-gentiobioside (109) in the fruit bodies of the Australian Dermocybe species WAT 20 880.,, 41 The identity and location of the disaccharide residue in (109) was established by NMR methods that included a 2D (lH-13C} COSY experiment on a heptaacetyl deriyative that showed clear correlation between C-8 and the innermost anomeric proton.41 Physcion (88) is a minor constituent of WAT 20880 and indeed of most other fungi that also produce dihydroanthracenones of the torosa- chrysone The (R)-enantiomer (1 10) of torosachrysone and its ~-O-P-D-gentiobioside (1 1 1) occur in two brown Australian Dermocybe toadstools WAT 20934 and WAT 24274.,' (R)-Torosa-chrysone (1 10) has also been reported recently as a constituent of the bark of the tree Araliorhamnus vaginata a species endemic to Madagascar.* The presence of low concentrations of torosachrysone in extracts of the Australian Dermocybe species WAT 19351 WAT 21 567 and WAT 21 568 has been detected by TLC., The absolute configuration of torosachrysone (1 08) isolated NATURAL PRODUCT REPORTS 1994-M.GILL 'MeC02Na } oE *MeCH2C02Na WAT 19352 OSEnz + o~cosEm tMe-methionine fie major the* minorI MetO 0 OH MetO 0 OH - (101) MetO 0 Me* 0 / (99) (107) O/O, Enrichment in I3C content over and above natural abundance (1.1"/o) *1&16 o/o ;t2634 O/O per methoxyl ;'0.2-1.5 9 o/o at the acetate starter in (107) Scheme 9 7\ o M~OW! M e\/woL OR OH 0 OR OH 0 (108) R=H (110) R =H (109) R = gent. (1 11) R = gent. MeO H Me0 H (118) R = ,,%\ (117) R= ph%\ 0 0 OMe OMe 0 OMe he OH (1 12) Reagents i CH,N, 15 min.; ii Me,SO, K,CO, acetone; iii LiBH, THF; iv H, 10% Pd/C 50 lb. p.s.i.;v RuCl, NaIO, MeCN CCl, H,O; vi CH,N Scheme 10 from the plant Cassia torosa was originally determined as S of its chiroptical properties with those of the plant by the application of Nakanishi's chiral exciton coupling and subsequently confirmed by a series of derivatization and method to the benzoate derivative of torosachrysone-8,9-di-O-degradation reactions (Scheme 10) that linked the fungal The ester (1 13) methyl ether (1 12).The stereochemistry of torosachrysone metabolite (108) with the (R)-ester (1 13).44,45 from WAT 20880 was in turn established as S by comparison has been synthesized unequivocally starting from geraniol NATURAL PRODUCT REPORTS 1994 (1 14) with chirality being introduced by using the Sharpless asymmetric epoxidation process (Scheme 11). The ester (1 13) is also available albeit less efficiently beginning from (S)-citramalic (S)-Torosachrysone-8-O-methyl ether (1 15) occurs in the (114) ii I MeAMe Reagents:i ButOOH Ti(OPr'), diethyl D-( -)-tartrate; ii Red-Al; iii O, acetone -78 "C; iv Jones reagent -60" +0°C; v CH,N Scheme 11 European Cortinarius fulmineus C.pseudosulfureus C. splendens Tricholoma auratum and T. sulphureum.' It has been synthesized from (-)-quinic acid (116) (Scheme 12) and the CD spectrum of the synthetic material was used in the determination of the absolute configuration of several fungal and plant dihydroanthracenones. 47 An attempt has been made to determine the enantiomeric purity of (S)-torosachrysone (108) (from WAT 20880) and (R)-torosachrysone (1 10) (from WAT 20934) by using the lH NMR spectra of the corresponding esters (1 17) and (1 18) formed with (S)-O-methylmandelic acid.41 At 400 MHz the low field (ca.814.4) signals from the chelated C-9 hydroxy protons in each diastereoisomeric ester (1 17) and (118) are well separated (A8 ca. 10 Hz) and significantly both spectra clearly display resonances from both esters. Integration of the major and OMe OH 0 OMe OH 0 (115) Reagents i see ref. 1 p. 145; ii PhCOC1 pyridine DMAP; iii HOAc PPTS; iv p-toluenesulfonyl chloride pyridine; v NaI; vi BuiSnH; vii dihydropyran PPTS; viii KOH MeOH; ix PCC NaOAc CH,Cl,; x methyl 4,6-di-O-methylorsellinate LDA THF -78 "C;xi DDQ benzene; xii PPTS EtOH Scheme 12 COSEnz -O 'MOTMe+ Me-CO2Na m M e WCOSEnz YYY 000 000 (119) r SAM C02H OH OH 0 OH OH 0 Scheme 13 NATURAL PRODUCT REPORTS 1994-M.GILL 79 "WM" 0 II OH :H I I :H I 0 I le OH OH 0 0 OH R OH 0 R OH 0 OH (121) R=OH (123) R= H (122) R=OH (124) R=H OH 0 II gent0 0 OH OH0 R OH 0 OH (128) R =OH (130) R =H Table 1 Occurrence of tetrahydroanthraquinones in Dermocybe" Natural Product Species Ref. (R)-Deoxyaustrocortilutein(124) Dermocybe spendida. 50 (S)-I-Deoxyaustrocortilutein (1 30) Dermocybe spp. WAT 20934 WAT 21 568. 41 43 I-Deoxyaustrocortilutein(t.1.c.) Dermocybe spp. WAT 19351 WAT 20934 WAT 21 567. 35 43 35 (R)-1-Deoxyaustrocortirubin(123) D. splendida D. erythrocephela. 50 35 (1S,3S)-Austrocortirubin (121) D. splendida D. erythrocephela Dermocybe sp.WAT 20 882. 49 35 51 (1S,3S)-Austrocortilutein (122) D. splendida Dermocybe spp. WAT 20 882 WAT 19 35 1 49 51 35 43 WAT 21 567. (lS,3R)-Austrocortilutein (125) D. splendida Dermocybe spp. WAT 20882 WAT 19351 49 51 35 43 WAT 21 568 WAT 20934. (1R,3R)-Austrocortilutein (128) Dermocybe spp. WAT 20934 WAT 21 568. 43 (lR,3S)-Austrocortilutein (129) Dermocybe sp. WAT 21 567. 43 (1R,3R,4S)-4-Hydroxyaustrocortilutein(1 33) Dermocybe sp. WAT 21 567. 55 56 (1 S,3R,4S)-4-Hydroxyaustrocortilutein(134) Dermocybe sp. WAT 21 567. 55 56 (1R,3S,4S)-4-Hydroxyaustrocortilutein(1 35) Dermocybe sp. WAT 21 567. 55 56 a 6-Methylxanthopurpurin-3-0-methyl ether (79) and austrocortinin (80) are found in most fungi that produce austrocortilutein and austrocortirubin respectively.These anthraquinones may arise at least in part during the isolation and purification procedure. minor signals in each case led to the deduction of enantiomeric excesses to be 83 and 88% respectively for these samples of (108) and (llo).'' Labelling experiments with the toadstool WAT 20880 have shown that sodium [2-13C]acetate sodium [1,2-13C,]acetate and [Me-13C]methionine are efficiently incorporated into torosachrysone (108) by the intact fruit 48 The pattern of incorporation is entirely consistent with the formation of torosachrysone from an octaketide precursor itself assembled (at least formally) by head-to-tail linkage of acetate units and folded as shown in (119) Scheme 13. (S)-Atrochrysone (120) has been found as a natural product for the first time.32 It is a co-metabolite of (S)-torosachrysone (108) in the fruit bodies of the Australian toadstool WAT 20881 ; the stereochemistry followed from a comparison of its CD spectrum with that of (S)-torosachrysone.(R)-Atrochrysone was known previously from the European species Cortinarius atrovirens and C. odoratus.' A full account of the isolation and structural elucidation of the tetrahydroanthraquinone pigments present in the ethanolic extract of the beautiful red Australasian toadstool Dermocybe splendida has appea~ed.'~ The major red and yellow pigments (1S,3S)-austrocortirubin (121) and (1 S,3S)-austrocortiIutein (122) are accompanied by their (R)-1-deoxy derivatives (123) and (124) respe~tively,~~ and by the (lS,3R)-epimer (125) of austrocortilutein.The relative stereochemistry in the tetra-hydroaromatic rings of the pigments (121) (122) and (125) was deduced from 'H NMR data and the formation or otherwise of cyclic acetonide and arylboronate derivatives. The absolute configuration of (I S,3S)-austrocortirubin (12 1) was determined after catalytic hydrogenolysis that gave the 1-deoxy quinone (1 23) which after oxidative degradation could be correlated with the (R)-ester (1 13). The absolute stereochemistry of (1 S,3S)-austrocortilutein (1 22) was determined along the same lines and confirmed by a single crystal X-ray analysis of the ace tonide derivative. 49 More recently it has been shown by cautious extraction and chromatography that the tetrahydroanthraquinones (12 1) and (122) exist in the intact fruit bodies of D.splendida mainly as their respective 8-O-P-~-gentiobiosides (126) and (127).33 A biosynthetic pathway from (S)-torosachrysone-8-@~-~-gentiobioside (1 09) through the austrocorilutein glycoside (127) to the red gentiobioside (126) and then to the aglycone (121) appears eminently feasible but is yet to be proved experimentally.Whereas (lS,3S)-austrocortirubin (121) and (R)-1-deoxyaustrocortirubin (123) are the only red tetrahydro-anthraquinones isolated to date from Macromycetes all four stereoisomers of austrocortilutein [(122) (1 25) (128) and (1 29)] and both enantiomers of 1 -deoxyaustrocortilutein [(124) and 130)] are now known from within a group of closely related Australian Dermocybe species (Table 1).The structures of these compounds were deduced from spectroscopic data and the stereochemistry was ultimately determined in each case by chemical correlation with the (R)-ester (1 13) or its antipode.43- The tetrahydroanthraquinones (12 I)-( 130) are all active at NPR 11 NATURAL PRODUCT REPORTS 1994 \ 0 OH OH 0 OH0 0 OH (1311 (1 32) vi vii 0 OH 0 OH OH OH II II II c-. 0 OH OH 0 OH 0 OH (+( 121) (?)-(123) lxi O O "' II m LH 2" ' II w LH OH 0 OH OH 0 (&)-(122) (&)-(124) Reagents i Ph,CCl, K,CO, MeCN r.t. 23h; ii isoprene tetraacetyl diborate benzene r.t. 5h; iii BCl, CH,Cl, workup; iv CF,SO,H CHC1,; v CH,N,; vi mCPBA; vii H,SO, acetone 50 "C; viii H, Pd-C pyridine; ix Br2 CCI, hv; x 0.1 M NaHCO, THF 0 "C; xi H, Pd-C MeOH HOAc Scheme 14 Meow-wO OH Me "'"*-OH Me \ II I I I I OH 0 OH OH 0 6I-l OH 0 OH 6 1.81 ddd 6 1.66 ddd (14.6,4.4 2.2 HZ (1 3.9 9.2,l.a Hz 6 2.39 dd 6 4.57 d 6 2.46 dd <6 1.8 1.8 4.61 dd Hz 14.6 2.9 Hz 2.2 HZ 13.9 6.2 HZ HO 63.83 d,/ OH 2.6 Hz Me 6 4.20 d 1.8 Hz f 0-H 0-H 65.1 5 dddd 6 4.42 d 6 3.28 d 2.2 Ht 9.2 6.2,2.6 1.8 Hz c6 2.64 d 1.8 Hz 8.8 Hz (4 (b) Figure 1 'H NMR data (in CDCl,) for the protons associated with the tetrahydroaromatic ring in (a) the quinone (1 33) and (b) the quinone (1 34).low concentrations against a range of Gram positive and Gram Three stereoisomeric 4-hydroxyaustrocortiluteins have been negative bacteria and fungi. (1 S,3S)-Austrocortirubin (1 21) isolated from the Australian Derrnocybe species WAT 21 567 shows promising selective cytotoxicity against melanoma cells (Table l).55 56 The structures (1 33)-( 135) for these pigments and is undergoing in vivo trials against skin cancer.49 followed from careful analysis of the 'H NMR spectra.Of Following model studies involving the synthesis of several particular importance were the chemical shifts and mutual analogues of austrocortirubin (121) that lack the 6-methoxy coupling of the various protons around the tetrahydroaromatic group,52 the natural products (121)-( 124) themselves have been rings ;the data for these protons in the quinones (1 33) and (1 34) synthesized in racemic form from naphthopurpurin (1 3 1) are displayed in Figure 1.Especially noteworthy is a small W-according to the reactions depicted in Scheme 14.53 A more type coupling observed between the axial proton at C-2 and the direct approach towards ( )-austrocortirubin (121) involv- tightly hydrogen-bonded proton of the axial C-3 hydroxyl in ing a Diels-Alder reaction between the naphthopurpurin each case. The (1R,3R,4S) absolute configuration of the acetal (I 32) and 3-methyl-I -trimethylsilyloxybuta- 1,3-diene quinone (1 33) was established by synthesis of its antipode (1 36) foundered at an advanced via benzylic hydroxylation of (1 S,3R)-austrocortilutein (1 25) 81 NATURAL PRODUCT REPORTS 1994-M. GILL 0 0 Br Reagents i (CF,CO),O CHCl, 0 "C; ii Br2 CCI, hv 50 "C; iii (CF,CO,),Ag DMSO 30 "C; iv 0.5 M NaOH.0 "C Scheme 15 Table 2. Nomenclature of coupled pre-anthraquinones HO 'Me "OyqJ Me .Me OH OH 0 (137) OH 0 OH Site of biaryl coupling in (I 37) Pigment type 5 5' Atrovirin 7 7' 5 10' Flavomannin Pseudophlegmacin OH 0 OH 7 10' 10 10' Phlegmacin Tricolorin OH OH 0 OH HO obtained from Derrnocybe splendida (Scheme 15). Similarly HO Me 18 hydroxylation of (1 S,3S)-austrocortilutein (122) gave a pair of epimeric 4-hydroxyaustrocortiluteins,one of which proved to " O W M e be identical in all respects with the natural product (134) the other being the enantiomer of the quinone (135).55*56 OH 0 OH OH 0 6I-i 3.3.3 Coupled Pre-anthraquinones Dihydroanthracenones of the atrochrysone (137; R = H) and OH OH 0 torosachrysone (137; R = Me) types have been implicated in the biosynthesis of a large number of oxidatively coupled OH dimers found in Cortinarius Dermocybe and Tricholoma.' Me More than fifty pigments formally derived in this way OH principally from European fungi were known prior to 1987 HO and they were classified (Table 2) according to the site in the Me respective pre-anthraquinone nuclei at which the initial biaryl coupling had occurred.Large numbers of potential variants OH OH 0 materialize once it is recognized that coupling at the torosa- chrysone (or atrochrysone) level can be followed by further hydroxylation or methylation and by dehydration (to anthrones) and oxidation (to anthraquinones) changes that OH OH 0 can take place in one or in both halves of the molecule.During the biaryl coupling process itself a bond is formed about which subsequent rotation is severely restricted. Atropisomers result that are readily differentiated by characteristic Cotton effects in HO HO Me the CD spectrum. A large negative Cotton effect to longer wavelength and a large positive effect to shorter wavelength in lo the vicinity of 270 nm defines an A-type dimer; in the spectrum of a B-type dimer the signs of the Cotton effects are inverted.' HowMe The absolute stereochemistry at the chiral biaryl bond of A and B-type atropisomers belonging to the atrovirin and the flavomannin groups (Table 2) is now known (vide infra). OH 0 OH Since 1987 the number of coupled pre-anthraquinones has continued to grow due mainly to work on Australasian (145) Cortinarius and Derrnocybe species.In the paragraphs that purified in the absence of oxygen and light.5s Austrovenetin has follow new natural products are discussed in order of class S chirality at the axis and may be a progenitor of (S)-skyrin membership as listed in Table 2. (141) which is the major orange pigment of D. au~troveneta.~~.~~ It has been shown that protohypericin (138) and hypericin (S)-Skyrin (141) is the principal pigment of the New Zealand (139) are artefacts formed from austrovenetin (140) during its toadstool Derrnocybe icterinoides that also contains atrovirin B isolation from Derrnocybe austroveneta. 57* In order to avoid (1 42) (previously isolated from Cortinarius atrovirens') and the oxidation to (138) and subsequent photocoupling to give (139) new pigments icterinoidin A (143) icterinoidin B (144) and austrovenetin (140) must be extracted from D.austroveneta and icterinoidin C (145).59 The determination of the axial chirality 6-2 NATURAL PRODUCT REPORTS. 1994 0 OH HO OH OH Me Cocl Cocl HO Me OH (146) + (147) Me Me HO OH (14) Scheme 16 OMe O OaC02Me HO (150) (151) (152) 0 OH OH 0 OH Me OH 0 OH Me 0 (153) HO OMe Me (1 55) 0 OH HO Me OMe Me 0 OH OH 0 (1 57) in atrovirin B (142) is discussed in more detail below. The stereochemistry at the axis in the icterinoidins A (143) and B (144) followed from comparison of their CD spectra with that recorded for (142). The absolute configuration at the stereogenic centres in (143) and (144) has not been determined but since the molecules are diastereoisomers it follows that it must be the same in both.The absolute configurations at the biaryl linkages in atrovirin Me 0 OH OH (156) 0 OH Me (158) B (142) and flavomannin A (146) (from Cortinarius odoratusl) have been determined as S and R respectively by kinetic resolution experiments involving (f)-2-phenylbutanoic an-hydride (Horeau’s method) and (f)-dinitrodiphenic acid dichloride (147).47 After calibrating the effects using the atropisomeric (R)-and (S)-2,2’-dihydroxy- 1,l ’-binaphthyls the method was applied to the more complex coupled pre-anthraquinones. For example in the case of flavomannin A NATURAL PRODUCT REPORTS 1994-M.GILL 83 OMe OH 0 OMe OH 0 OMe 0 OH Me0 Me0 Me0 Me Me OH 0 OMe 0 OH OMe (159) (161) R = H (162) R=OH 0 OH 0 OMe OH OH 0 ?H !? ?H OH Me Me0 Me Me0 Me Me0 Me Meo% \0OH OH 0 OH (146) reaction with (&)-(147)(Scheme 16) gave the ester (148) and a residual excess of the laevorotatory (S)-diphenic acid (149) which is consistent with an (R)axial configuration for flavomannin A. Because the CD spectra of these dimers are dominated by interactions between the naphthalene chromophores and are not significantly influenced by sub-stituents or chiral centres elsewhere in the molecule other pigments of the same class can then be correlated. Comp-lementary results were obtained using Mosher methodology and in the case of the flavomannins by synthesis of model dihydroanthracenone dimers in atropisomerically enriched f0rm.47 Flavomannin-6,6’-di-O-methylether A (FDM A,*) (150) occurs in homochiral form in Corinarius citrinus and Dermocybe crocea from Europe and in the Australian Dermocybe species WAT 20 933.35v60The absolute configuration at the chiral centres in FDM A (150) has been established as (3R,3’R) as shown by chemical correlation with the (S)-lactone (151) following a route that parallels the method outlined in Scheme 10.45961 Since FDM A (150) and FDM B (from Cortinarius pseudosulphureus and Tricholoma sulphureum’) are atro-pisomers (from their CD spectra) but not enantiomers (by ‘H NMR) it follows that FDM B must possess the stereo-structure (1 52).45,61 Fruit bodies of WAT 20933 mentioned above also contain anhydroflavomannin-9,1 O-quinone-6,6’-di-O-methyl ether (153) and (R)-( +)-7,7’-biphyscion (154).35,60The 6,6’,8-tri-O-methyl ether (155) of flavomannin A is the major pigment of the fruit bodies of WAT 24274 a small orange-capped Australian Dermocybe species that has proved to be a particularly rich source of a variety of dihydroanthracenone dimers (vide infra).62 * The subscript numerals are used where necessary to differentiate dia-stereoisomers that possess the same axial configuration.OH 0 OH The diminutive deep brown-violet fruit bodies and purple mycelium of the Australian Dermocybe species WAT 21 566 contain new hydroxylated and highly oxidized flavomannin A-type The major green-yellow constituent has been assigned the structure and relative (central) stereochemistry (156) from the spectroscopic data of both the natural product and its bis-acetonide derivative.The principal red pigments are the new quinones (157) and (158). A pair of diastereoisomeric green-blue pigments isolated from WAT 24274 (videsupra) have been assigned the condensed pseudophlegmacin structure (159) principally from the results of extensive NMR experiments. The extended quinone (160) is a minor red constituent of the same toadstool.62 Coupled pre-anthraquinones of the phlegmacin type (7,lO’-coupling) constitute two of the three yellow-orange pigments present in the bright yellow fruit bodies of Cortinarius sinapicolor.35, 60 Anhydrophlegmacin-9,1O-quinone-8’-0-methyl ether A (161) is accompanied by its cis-2’-hydroxy derivative (162).The relative stereochemistry of the vicinal hydroxy groups in (162) was deduced from the ‘HNMR spectrum of the pigment itself and of an acetonide derivative. Absolute stereochemical assignments of chiral centres and axes in the phlegmacin series have not yet been made. The third yellow-orange pigment of C. sinapicolor is dermocanarin 4 (163),35,60a close relative of the pigments (93)-(95) from Dermocybe canaria. ‘H NMR data including the results of NOE experiments suggest that the relative stereochemistry of the biaryl axis and the chiral centre in the lactone bridge is that implied by formula (163). Further members of the dermocanarin class that have recently come to light include the dermocanarins 5 and 6 (164) which are epimeric at C-3 and have been isolated from the Australian Dermocybe species WAT 24273 and WAT 24723 respe~tively.~~ The toadstool WAT 24274 mentioned above also contains the ‘trimeric ’ dermocanarin 7 (165).51It is remarkable to note that WAT NATURAL PRODUCT REPORTS 1994 OH 0 q)Q3 0 24 274 produces not only coupled pre-anthraquinones of the flavomannin pseudophlegmacin and dermocanarin types as detailed above but also pigments of the tricolorin class in the form of the novel pigment (166) and physcion- 10,lO'- bianthrone (1 67).51 The pigment (166) was isolated after mild acidic hydrolysis of the water soluble component of the fungus extract and is probably present in the intact toadstools as a glycoside.The bianthrone (167) consists of a mixture of meso-and ( -t)-diasteroisomers. 3.3.4 Further Octaketides A full account of the structure elucidation and synthesis of vesparione (1 68) a naphtho[2,3-b]pyrandionederivative from the slime mould Metatrichia vesparium has appeared. 61 3.4 Nonaketides The blood-red fruit bodies of the Australian toadstool Derrnocybe sunguinea (sensu Cleland) contain the novel dihydroanthracenones (169)-( 171) and the closely related anthraquinones (1 72)- 174).65 The S absolute stereochemistry of (+)-dermochrysone (169) was evident on comparison of the CD spectrum with those of the fungal dihydroanthracenones (108) and (I 20) of known chirality.The dermochrysonols (1 70) and (1 7 1) are present in trace amounts as a mixture of epimers. Dermolactone (1 72) as it occurs in D. sunguinea (sensu Cleland) is weakly dextrorotatory {[a],+46 "1. In contrast homochiral (S)-dermolactone (179 which was synthesized from (3-propylene oxide (176) by the method outlined in Scheme 17 exhibits [a],+ 169 The implication that the natural product (172) is partially racemic was borne out by the results of lH NMR experiments involving the permethyl ethers of natural synthetic (Q and racemic dermolactone with tris[3-(hepta- fluoropropylhydroxymeth ylene) -(+)-camphorato]europium (111) that showed that the natural product consists of a 29% excess of the (S)-quinone (175) over its antip~de.~" Feeding experiments with the intact fruit bodies of D.sanguinea (sensu Cleland) have shown that sodium [1-13C]-acetate is efficiently and specifically incorporated into the dermochrysone (169) and dermolactone (1 72) molecules in a OH OH 0 OH OH 0 OH OH 0 Me0 Me Me0 Me Me0 Me OH 0 OH 0 OH 0 OH Me0Jy$y& OR Me Me0 Me 0 (172)R=H (173)R =OH (174) OH 0 OMe C0,Me 1LMeM 0(176)H e O x.*H Me OSiMe2Bu' Bu'Me2SiO' H Me OSiMe2But vi viiI OH 0 OH 0 OH 0 OMe 0 -H -H Me0 Me0 0 0 Reagents i LiCECH ethylenediamine DMSO; ii ButMe,SiC1 imidazole DMF; iii Bu"Li ClC9,Me; iv H,C=C(OMe), 165 "C 24h; v 2-chloro-8-hydroxy-6-methoxynaphthoquinone,160 "C 4h; vi H,SO, THF; vii PTSA THF 4A sieves; viii BCl, CH,Cl, 0 "C Scheme 17 NATURAL PRODUCT REPORTS 1994-M.GILL Me (177) R =H (179) (178) R =Ac (180) R=Me (181) R=CO*H OH 0 Me Me OMe NHAc NHAc NHAc NHAc NHAc ~ Bu'Me2Si0 C02Me VI Bu'MeSiOWCHO t NHAc NHAc 0 C02H viiiix ___c (182) Reagents i BBr,; ii ButMe,SiC1 DABCO; iii Ph,P=CHCH=CHCO,Me benzene 25 "C; iv DIBAL -78 "C; v MnO, 25 "C; vi Ph,P+-CH=CHCH=CHCO,Me .Br- KOBut THF 25 "C ;vii K,CO, MeOH 25 "C; viii 4,6-diphenylthieno[3,4-d]-1,3-dioxo1-2-one 5,Sdioxide; ix (Me,Si),NCH(CH,CH,CONH,)CO,SiMe,;x MeOH Scheme 18 pattern consistent with the involvement of a nonaketide precursor. The stereochemical inhomogeneity of dermolactone (1 72) suggests that it is closely aligned with the diastereoisomeric dermochrysonols (I 70) and (1 7 1) in this nonaketide pathway.40 Trace amounts of anthraquinones of presumed nonaketide origin have been reported previously from Cortinarius subgenus Leprocybe.3.5 Higher Polyketides and Compounds of Fatty Acid Origin The green colour of the cultured mycelium of the ascomycete Hypoxylonfragiforme has been ascribed to the presence of the substituted dibenzo[b,h]xanthone hypoxyxylerone (I 77).66 The structure of hypoxyxylerone was deduced from the spectro- scopic data and confirmed by an X-ray analysis of the blue tetraacetate (178). The structure (177) is suggestive of an undecaketide biosynthesis. Cultures of Xerula melanotricha produce the orange-yellow polyenes dihydroxerulin (1 79) xerulin (180) and xerulinic acid (181) that are inhibitors of cholesterol bio~ynthesis.~' The structure (1 8 1) for xerulinic acid supersedes an earlier proposal.Plasmodia of the slime mould Physarum polycephalum produce the yellow pigment physarochrome A (182) that may be implicated as a photoreceptor in the physiology of this 69 The structure (1 82) was established largely on spectroscopic groundP and has been corroborated by syn- thesis (Scheme I 8).,O Colourless slime mould metabolites that display significant ultraviolet absorption such as fuligopyrone (183) (from Fuligo septica) and ceratiopyrone (1 84) (from Ceratiomyxa fruticulosa) may also be involved in the light response of Myxomy~etes.~~- 69 Fruiting bodies of the ascomycete Xylaria polymorpha 'Dead Man's Fingers ' contain the hydroxyphthalide xylaral (185) which exhibits a violet coloured reaction with aqueous ammonia.'O NATURAL PRODUCT REPORTS 1994 Me Me OMe I OR Me (189)" [* relative stereochemistry only] (190) R= H (191) R = CO(CH2)isMe 0 'C02Et Me 1 Me (1 95) Reagents i BuiSnH AIBN benzene 60 "C; 80 % yield Scheme 19 (197) R' (198) R' (199) R' (201) R' (202) R' = CH~OAC,R2= C02H R3 = NH2 (200) = CHO R2 = Cod R3 = NH2 = CH20H R2 = C02Me R3 = NHMe = CHZOH R2 = C02H R3 = NH2 = R2 = R3 = H 4 Pigments from the Mevalonate Pathway The isolation of guaiane sesquiterpenes both genuine natural products and artefacts from the flesh and latex of toadstools belonging to the genus Lactarius has a long hist0ry.l' Lipophiles lactarioviolin ' was the name given to a wine-red compound of unknown structure that was detected by TLC and regarded as the main genuine pigment in extracts of L.sanguifluus.l This substance has now been isolated from cold acetone extracts of L. sanguzJuus and identified as 1,3,5,7(11),9-pentaenyl- 14- guaianal (186).'l It is accompanied by the red-violet azulene (1 87) that is probably an artefact. The fulvene sesquiterpenoid leaianafulvene (1 88) is an orange-yellow pigment with anti- biotic and cytostatic properties that has been isolated from mycelial cultures of Mycena leaiana. 72 Cultures of Hemimycena cucullata and H. candida produce the yellow antibiotic hemimycin (189).73 Intact fruit bodies of Lactarius fuliginosus and L.picinus contain the isoprenoid quinol (190) as its stearate ester (191). The pink-red stain and acrid taste that develop when the toadstools are damaged are due to lipase mediated trans-formation of (191) to (190) followed by oxidation to a variety of red benzofurans and chromene~.~~ Mycenone (192) a chlorinated benzoquinone of partial isoprenoid origin that has been isolated from cultures of the Mycena species TA 87 202 is an inhibitor of isocitrate lya~e.~~ Closely related to the pigment (192) is the dark red omphalone (193) a cytoxic phytotoxic antibiotic that is produced in fermentations of a Canadian strain of the Basidiomycete Lentinellus omphalodes. 76 Pleurotin (194) a complex polycyclic sesquiterpenoid benzo- quinone first isolated from Pleurotus grieseus' has been synthesized in racemic form in twenty-six steps from benzoic An important intermediate step involved the assembly of the trans-perhydroindane ring system by stereoselective cyclization of the radical (195) to the lactonic ester (196) (Scheme 19).The complete synthesis of pleurotin (194) has recently been re~iewed'~ and further details need not be repeated here. 5 Nitrogen Heterocycles 5.1 Phenoxazin-3-ones From the bright-orange brackets of the fungus Pycnoporus sanguineus collected on the Seychelles have been isolated the new phenoxazin-3-ones (197)-( 199) and the phenoxazine (200).79980These pigments along with the well-known cinnabarin (201) and phenoxazin-3-one (202) itself,l were separated and characterized after permethylation of the total acetone extract of the fungus.To discriminate between endogenous and introduced methyl groups an aliquot of the extract was separately methylated using [2H3]methyl iodide. Infusions of Pycnoporus sanguineus serve medicinal purposes in parts of Africa and Latin America where they are noted among NATURAL PRODUCT REPORTS. 1994-M. GILL R& \ I\ R&R Y H H HH (203) R = H (205) R = H (204) R=OH (206) R=OH H H NH H ?2 R' (209) R' = R2 = H (210) R' =OH R2= H (211) R' =OMe R2= Me other things for their ability to produce necrosis of warts." Phenoxazin-3-ones are formed biogenetically by oxidative coupling of anthranilic acid precursors.' Methyl anthranilate an important natural flavouring is produced by certain strains of P.cinnuburinus in laboratory culture.82 5.2 Indole Pigments The bisindolylmaleimides e.g. the arcyriarubins A (203) and B (204) and arcyriaflavin A (205) are a unique group of indole pigments elaborated by Arcyriu denudutu and related slime moulds (Myxomycetes).l Recent additions to the class are arcyriaflavin D (206) which possesses an unusual 5,6'-dihydroxylation pattern from Dictydiuethulium plumbeum and Me Br H Me HO% HO HO H H H the colourless dihydro derivatives (207) and (208) of arcyriacyanin A and arcyroxocin A respectively from Arcyriu n~tuns.~O A symmetrical structure previously proposed' for the minor red pigment arcyroxepin A of Arcyriu denudutu has been revised.l4 The observation that arcyroxepin A yielded arcyroxocin A (209) both on prolonged standing in deuterio- acetone and on brief heating in toluene suggested that arcyroxepin A has the unique N-hydroxyindole structure (2 10).This was confirmed by quantitative reduction of this pigment to arcyroxocin A (209) with titanium trichloride and by methylation which produced a trimethyl derivative to which formula (21 1) could be unequivocally assigned by extensive NOE experiments. Several Arcyriu species contain substances that display prolonged green phosphorescence on TLC plates after ir- radiation with ultraviolet light has ceased. Two compounds that are jointly responsible for this effect arcyrin A (212) and arcyrin B (213) have been isolated and characterized by spectroscopic comparison with other natural products and with synthetic The structural similarity between the bisindolylmaleimides and various physiologically active indolo[2,3-u]carbazole alkaloids such as the protein kinase inhibitor staurosporine and the anti-tumour agent rebeccamycin has engendered con-siderable synthetic activity in this area.Arcyriarubins possessing both symmetrical [e.g. (203)] and unsymmetrical [e.g. (204)] substitution patterns are now available from indolylmagnesium bromide and N-methyl-2,3-dibromo-maleimide according to the reactions shown in Scheme 20.30,83 Me Me Br Boc BOC H kii Me -& / ii iii / -A(203) (204)z \ I\ I\ / \ I\ I\ / Y Y H A H H H H Reagents i N-methyl-2,3-dibromomaleimide,toluene reflux; ii KOH reflux; iii 2 M HCl; iv NH,OAc 140 "C; v N-methyl-2,3-dibromomaleimide THF 20 "C;vi di-t-butyl dicarbonate DMAP THF 0 "C;vii 6-(tetrahydropyranyloxy)indolylmagnesium bromide THF ; viii 180 "C Scheme 20 NATURAL PRODUCT REPORTS 1994 (214) 2(203) H H H Reagents i BunLi 2 equiv.ButLi 1 equiv. THF -78 “C; ii I, 0.5 equiv.; iii H,O+; iv Ac,O; v DDQ CH,Cl, r.t.; vi see Scheme 20 Scheme 21 HO H-0 H-0 (216) (217) R’ = R2= OH (218) R’=OH R2=H (219) R’ = R2 = H H-0 (222) R = H (223) R=Me Arcyriarubin A (203) has also ‘been prepared in biomimetic fashion by condensation between P-indolylacetamide and P-indolylglyoxylic acid30 and via oxidative coupling of the trianion of P-indolylacetic acid (Scheme 2 The arcyriarubin chromophore can be easily converted to other bisindolyl-maleirnide~.~~ Arcyriaflavin A (205) has been synthesized by double Fischer indolization of the bis(pheny1hydrazones) (214)s5 and (21 5)86 in nitromethane using polyphosphoric acid trimethylsilyl ether (PPSE) as catalyst.5.3 Necatarone and Miscellaneous N-Heterocyclic Pigments Necatorone (216) its dehydrodimer (217) and the 10-deoxy dehydrodimer (218) are the principal pigments of the green- brown flesh and cap skin of the toadstool Lactarius necator.lV8’ In young specimens necatorone (216) and its dimer (217) are found in almost equal proportions whereas in aged fruit bodies the dimer predominates. These alkaloids are responsible for the characteristic purple colour that develops when the flesh of L.necator is exposed to alkali. In the green fruit bodies of the American species Lactarius atroviridis the pigments (2 16)-(2 18) are subordinate to 10,10’-dideoxy-4,4’-binecatorone(219) as the major a1 kaloid. Details of the isolation and characterization of fuligorubin A (220) from the yellow plasmodia of the slime mould Fuligo septica have appeared.sa The absolute stereochemistry of fuligorubin A was established by synthesis of a model compound and points to a biosynthesis of (220) involving condensation of D-glutamic acid with a heptaketide chain.30 The acyltetramic acids (22 1)-(224) from the orange-yellow HO HO&+H Ye HcCO2H Me plasmodia of Leocarpus fragilis are each derived biogenetically from L-tyrosine.Like fuligorubin A (221) their role may be to protect the vulnerable plasmodia against microbial attack ; alternatively they may be involved in phototaxis or metal ion ~helation.~~ Orellanine (225) is a bipyridyl bis-N-oxide responsible for the acute toxicity of the toadstools Cortinarius orellanus and C. speciosissimus.’ The I3CNMRs9 and mass spectraso of orellanine have been analysed and a single crystal X-ray structure of an orellanine-trifluoroacetic acid complex has been published.g1 Cyclic decapeptide structures put forward earlier for the nephrotoxic constituents of C.speciosissimus have been seriously questioned and must now be regarded as incor- rect.s2-s4 NATURAL PRODUCT REPORTS 1996M.GILL 89 Sydowia 1987 40 81; G. Keller M. Moser E. Horak and W. 6 Further Pigments Containing Nitrogen Steglich Sydowia 1987 40,168; C. A. Grgurinovic Mycotaxon The unusual complex amavadin formed between vanadium 1989,36,47; N. L. Bougher and R. N. Hilton Mycol. Res. 1989 ions and two molecules of N-(1-carboxyethyl)-N-hydroxy-93 424; E. Horak and A. E. Wood Sydowia 1990 42 88. For similar work on N. American species see J. F. Ammirati alanine was originally assigned the structure (226).l This pale- Mycotaxon 1989 34,21. blue compound was first isolated from aqueous extracts of 32 M. Gill A. Gimenez A. G. Jhingran and A. F. Smrdel, Amanita muscaria and since then has been found at still higher Phytochemistry 1989 28 2647. levels in extracts of A.regalis (from Finland) and A. velutipes 33 M. Gill A. Gimenez S. Saubern and A. F. Smrdel Nat. Prod. (from the U.S.A.).95Recent complexation studies with the N-Lett. 1992 1 187. (1-hydroxyethyl)-N-hydroxyalanineligand and various cations 34 M. Gill A. Qureshi and R. Watling J. Nat. Prod. 1992 55 517. have discovered exceptionally high selectivity for and strong 35 A. Gimenez Ph.D. Thesis University of Melbourne 1990; binding of vanadium (IV)’~,’~ and have led to the revised manuscripts in preparation. structure (227) for amavadin in which the N-hydroxy group and 36 G. Keller and W. Steglich Phytochemistry 1987 26 2119. both carboxylate residues are 98 37 M. Gill and A. Gimenez Tetrahedron Lett. 1990 31 3505. 38 M. Gill and A. Gimenez J. Chem. SOC. Chem.Commun. 1988 1360. 39 M. Gill and A. Gimenez J. Chem. SOC. Perkin Trans. I 1990 1159. 7 References 40 A. S. Cotterill Ph.D. Thesis University of Melbourne 1992; 1 M. Gill and W. Steglich Prog. Chem. Org. Nat. Prod. 1987 51 A. S. Cotterill and M. Gill Tetrahedron Lett. 1993 34 3155. 1. 41 S. N. Eagle M. Gill S. Saubern and J. Yu Nat. Prod. Lett. 1993 2 M. Gill and M. J. Kiefel Tetrahedron Lett. 1988 29 2085; M. 2 151. Gill M. J. Kiefel D. A. Lally and A. Ten Aust. J. Chem. 1990 42 W. Mammo E. Dagne and W. Steglich Phytochemistry 1992 43 1497. 31 3577. 3 M. Gill M. J. Kiefel and D. A. Lally Tetrahedron Lett. 1986,27 43 M. Gill A. Gimenez A. G. Jhingran and A. Qureshi 1933. Phytochemistry 1992 31 947. 4 G. Pattenden N. A. Pegg and R. W. Kenyon Tetrahedron Lett.44 M. Gill A. Gimenez A. G. Jhingran and A. R. Palfreyman 1987 28 4749; G. Pattenden N. A. Pegg and R. W. Kenyon Tetrahedron Lett. 1990 31 1203. J. Chem. SOC. Perkin Trans. I 1991 2363. 45 M. Gill A. Gimenez A. G. Jhingran and A. R. Palfreyman 5 R. Boeker T. Anke I. Casser and W. Steglich DECHEMA Tetrahedron :Asymmetry 1990 1 62 1. Biotechnol. Conf. A 1990 4 225. 46 M. Gill and A. F. Smrdel Tetrahedron Asymmetry 1990 1,453. 6 E. Jagers E. Hillen-Maske and W. Steglich Z. Naturforsch Teil 47 G. Billen U. Karl T. Scholl K. D. Stroech and W. Steglich in B 1987 42 1349. ‘Natural Products Chemistry I11 ’ ed. Atta-ur-Rahman and P. W. 7 E. Jagers E. Hillen-Maske H. Schmidt W. Steglich and E. Le Quesne 1988 Springer Berlin pp. 305-315. Horak Z. Naturforsch Teil B 1987 42 1354.48 M. Gill A. Gimlnez and R. Watling J. Nat. Prod. 1992,55 372. 8 M. Holzapfel C. Kilpert and W. Steglich Liebigs Ann. Chem. 49 M. Gill A. F. Smrdel R. J. Strauch and M. J. Begley J. Chem. 1989 797. SOC. Perkin Trans. I 1990 1583. 9 H. Besl A. Bresinsky G. Geigenmuller R. Herrmann C. Kilpert 50 M. Gill and A. F. Smrdel Phytochemistry 1987 26 2999. and W. Steglich Liebigs Ann. Chem. 1989 803. 51 M. Gill and J. Yu unpublished results. 10 G. Pattenden M. W. Turvill and A. P. Chorlton J. Chem. SOC. 52 C. J. Burns M. Gill and S. Saubern Aust. J. Chem. 1991 44 Perkin Trans. I 1991 2357. 1427. 11 D. R. Gedge G. Pattenden and A. G. Smith J. Chem. Soc. 53 C. J. Burns and M. Gill Aust. J. Chem. 1991 44,1447. Perkin Trans. I 1986 2127. 54 C. J.Burns M. Gill A. H. Othman B. W. Skelton and A. H. 12 M. Gill and M. J. Kiefel Life Science Advances -Phytochemistry White Aust. J. Chem. 1991 44,1715. 1992 11 171. 55 C. J. Burns M. Gill and A. Gimenez Tetrahedron Lett. 1989,30 13 R. Murumoto C. Kilpert and W. Steglich 2.Naturforsch Teil C 7269. 1986 41 363. 56 C. J. Burns M. Gill and A. Gimenez Aust. J. Chem. 1991 44 14 W. Steglich B. Steffan T. Eizenhofer B. Fugmann R. Herrmann 1729. and J.-D. Klamann in ‘ Bioactive Compounds from Plants (Ciba 57 M. Gill A. Gimenez and R. W. McKenzie J. Nat. Prod. 1988 Foundation Symposium 154)’ 1990 Wiley Chichester pp. 5665. 51 1251. 15 K. Justus and W. Steglich Tetrahedron Lett. 1991 32 5781. 58 M. Gill and A. Gimenez Phytochemistry 1991 30 951. 16 D. C. Aumann G. Clooth B.Steffan and W. Steglich Angew. 59 P. M. Morgan B.Sc. (Honours) Thesis University of Melbourne Chem. Int. Ed. Engl. 1989 28 453. 1992. 17 M. Gill and M. J. Kiefel Phytochemistry submitted. 60 A. R. Palfreyman B.Sc. (Honours) Thesis University of 18 H.-W. Suh D. L. Crawford R. A. Korus and K. Shetty J. Znd. Melbourne 1989. Microbiol. 1991 8 29. 61 M. Gill A. Gimenez A. G. Jhingran and A. R. Palfreyman Aust. 19 Y. S. Tsantrizos H. H. Kope J. A. Fortin and K. K. Ogilvie J. Chem. 1990 43 1475. Phytochemistry 1991 30 1 113. 62 M. Gill A. Gimenez A. R. Palfreyman and J. Yu manuscripts in 20 F. Terradas and H. Wyler Helv. Chim. Acta 1991 74 124. preparation. 21 F. Terradas and H. Wyler Phytochemistry 1991 30 3251. 63 M. Gill N. M. Milanovic and A. Qureshi manuscript in 22 W.Steglich and D. Strack in ‘The Alkaloids Vol. 39’ ed. A. preparation. Brossi 1990 Academic Press New York pp. 142. 64 L. Kopanski D. Karbach G. Selbitschka and W. Steglich 23 W. Steglich H. Bauer M. Grosse-Bley R. Jeschke J. Josten and Liebigs Ann. Chem. 1987 793. J. Klein J. Heterocyclic Chem. 1990 27 107. 65 M. Gill and A. Gimenez J. Chem. Soc. Perkin Trans. 1 1990 24 R. Watling M. Gill A. Gimlnez and T. W. May Mycol. Res. 2585. 1992 96 743. 66 R. L. Edwards V. Fawcett D. J. Maitland R. Nettleton L. 25 M. Gill A. Gimenez and R. J. Strauch Phytochemistry 1987 26 Shields and A. J. S. Whalley J. Chem. SOC. Chem. Commun. 2815. 1991 1009. 26 A. D. Huntington B.Sc. (Honours) Thesis University of 67 D. Kuhnt T. Anke H. Besl M. Bross R. Herrmann U.Mocek Melbourne 1989. B. Steffan and W. Steglich J. Antibiot. 1990 43 1413. 27 M. G. Banwell J. M. Cameron M. P. Collis G. T. Crisp R. W. 68 B. Steffan M. Praemassing and W. Steglich Tetrahedron Lett. Gable E. Hamel J. N. Lambert M. F. Mackay M. E. Reum 1987 28 3667. and J. A. Scoble Aust. J. Chem. 1991 44,705. 69 I. Casser B. Steffan and W. Steglich Hoppe-Seyler’s Z. Physiol. 28 M. Hofmann and H. Musso Liebigs Ann. Chem. 1990 11 19. Chem. 1988 369 1088. 29 H. Wu X.-F.Lao Q.-W. Wang R.-R. Lu C. Shen F. Zhang M. 70 S. Gunawan B. Steffan and W. Steglich Liebigs Ann. Chem. Liu and L. Jia J. Nat. Prod. 1989 52 948. 1990 825. 30 W. Steglich Pure and Appl. Chem. 1989 61 281. 71 S. De Rosa and S. De Stefano Phytochemistry 1987 26 2007. 31 For some recent advances in our knowledge of the taxonomy of 72 U.Harttig T. Anke A. Scherer and W. Steglich Phytochemistry Cortinarius and Dermocybe species of Australasia see E. Horak 1990 29 3942. 73 J. Bauerle T. Anke E. Hillen-Maske and W. Steglich Planta Med. 1986 418. 74 M. De Bernardi G. Vidari P. V. Finzi and G. Fronza Tetrahedron. 1992 48 7331. 75 R.Hautzel H. Anke and W. S. Sheldrick J. Antibiot. 1990 43 1240. 76 A. Stark T. Anke U. Mocek and W. Steglich Z. Naturforsch. Teil C 1991 46,989. 77 D. J. Hart H.-C. Huang R. Krishnamuirthy and T. Schwartz J. Am. Chem. SOC. 1989 111 7507. 78 R. H. Thomson in ‘The Total Synthesis of Natural Products Vol. 8’ ed. J. ApSimon 1992 John Wiley and Sons New York pp. 311-531. 79 H. Achenbach and E. Bliimm Arch.Pharm. (Weinheim) 1988 321 674. 80 H. Achenbach and E. Bliimm Arch. Pharm. (Weinheim) 1991 324 3. 81 E. Pkrez-Silva E. Aguille-Acosta and C. Pirez-Amador Rev. Mex. Mic. 1988 4 137. 82 B. Gross G. Yonnet D. Picque P. Brunerie G. Corrieu and M. Asther Appl. Microbiol. Biotechnol. 1990 34 387. 83 M. Brenner H. Rexhausen B. Steffan and W. Steglich Tetrahedron 1988 44 2887. 84 J. Bergman and B. Pelcman Tetrahedron Lett. 1987 28 4441. NATURAL PRODUCT REPORTS 1994 85 J. Bergman and B. Pelcman J. Org. Chem. 1989 54 824. 86 G. W. Gribble and S. J. Berthel Tetrahedron 1992 48 8869. 87 J.-D. Klamann B. Fugmann and W. Steglich Phytochemistry 1989 28 3519. 88 I. Casser B. Steffan and W. Steglich Angew. Chem. Int. Ed. Engl. 1987 26 586.89 S. Rapior and A. Fruchier Anales de quimica C 1989 85 69. 90 J.-M. Richard and J. Ulrich Biological and Environmental Mass Spectrometry 1989 18 1. 91 C. Cohen-Addad J.-M. Richard and J.-C. Guitel Acta Crystallogr. Sect. C 1987 43 504. 92 H. Laatsch and L. Matthies Mycologia 1991 83 492. 93 L. Matthies and H. Laatsch Experientia 1991 47 634. 94 L. Matthies H. Laatsch and W. Patzold 2. Mykol. 1991 57 273. 95 E. Koch H. Kneifel and E. Bayer Z. Naturforsch Teil C 1987 42 873. 96 G. Anderegg E. Koch and E. Bayer Inorg. Chim. Acta 1987 127 183. 97 E. Bayer E. Koch and G. Anderegg Angew. Chem. Int. Ed. Engl. 1987 26 545. 98 E. Bayer in ‘Natural Products Chemistry 111’ ed. Atta-ur- Rahman and P. W. Le Quesne 1988 Springer Berlin pp. 335-344.

ISSN:0265-0568    

DOI:10.1039/NP9941100067

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Triterpenoids J. D. Connolly R. A. Hill and 6. T. Ngadjui” Department of Chemistry Glasgow University Glasgow G 12 800 Reviewing the literature published between January 1988 and December 1989 (Continuing the coverage of literature in Natural Product Reports 1989 Vol. 6 p. 475) 1 Introduction 2 The Squalene Group 3 The Fusidane-Lanostane Group 4 The Dammarane-Euphane Group 4.1 Tetranortriterpenoids 4.2 Quassinoids 5 The Lupane Group 6 The Oleanane Group 7 The Ursane Group 8 The Hopane Group 9 Miscellaneous Compounds 10 References 1 Introduction This article follows the pattern of the previous report. A handbook of triterpenoids has been published in two volumes. The tri terpenoid saponins isolated during the period 1979 to 1986 have been reviewed ;included are details of recent techniques used in isolation and structure elucidation.Tri- terpenoids isolated from Betula species have also been surveyed. 2 The Squalene Group The structure4 and absolute stereochemistry4* of braunicene (l) a new C, hydrocarbon from a strain of Botryococcus braunii have been established. Other related cyclized botryo- coccenes reported from B. braunii include isobraunicene (2) wolficene (3) isowolficene (4),6 and compound (3.’ The tetramethylsqualene derivative (6) has been isolated from B. braunii var. showa8 The C, botryococcene (7) reported from B. braunii var. showa in 1985,9 has been named showacene and has been reisolated along with isoshowacene (8) from B. braunii var.showa.1° Turbinaric acid (9) is a cytotoxic secosqualene carboxylic acid from Turbinaria ornata. l1 The regular hexaprenol (1 0) has been isolated from Phyffanthus niruri.12 The anti-viral squalene derivative venustatriol (1 1) has been synthesized by an enantioselective approach in which the key step is the coupling of the cerium reagent derived from the bromide (12) with the aldehyde (13).13 Venustatriol (11) and thyrsiferol (14) have been synthesized by a route involving the coupling of the sulfide (15) with the epoxide (16).14 Stereo- selective syntheses of teurilene (17) involving vanadium catalysed oxidation of the hydroxyfuran (1 8)15 or the hydroxy- tetraene (19)16 have been published. A total synthesis of botryococcene (20) has been reported.” The C, botryococcene (21) has been synthesized using a modified Julia reaction for the key coupling of sulfone (22) with the aldehyde (23).18 The biosynthesis of the botryococcenes has been investigated.l9 12-(Dimethylsila)squalene (24) has been prepared. 2o The mechanism of squalene synthetase has been studied * Present Address :Department of Organic Chemistry University of Yaounde Yaounde Cameroon. 91 NATURAL PRODUCT REPORTS. 1994 y7LGH 0 R' k BrCH2CH2--* eHo Br Br (11) R=OH RLH, R~=P-CH~ (12) (13) (14) R = H R' = OH R2 = a-CH3 OMOM OMOM CH20H N H using ammonium analogues of carbocationic intermediates.21 catalyse the rearrangement of a substituent other than a It was concluded that squalene synthetase has a single active hydrogen or methyl group.site which catalyses the formation of presqualene diphosphate from farnesyl diphosphate and its subsequent conversion into squalene. The trisnorsqualene alcohol (25)22 and the tris- 3 The Fusidane-Lanostane Group norsqualene cyclopropylamine (26)23 are inhibitors of squalene The protostane derivatives alisol D (29) and 11-deoxyalisol C epoxidase. Oxidosqualene-lanosterol cyclase from yeast has (30),26 and 16P-hydroxyalisol B monoacetate (31) and the been used to cyclize hydroxylated oxidosqualene epoxides to corresponding 16P-methyl ether (32)'' have been reported from and the oxido-A lisma plantago- aquat ica . the corresponding hydroxylan~stanes~~ homosqualene (27) to the homolanostanetriene (28).25 The Further additions to the mariesane group of rearranged latter transformation shows that the enzyme has the ability to lanostanes have been reported.(24E)-3a-Hydroxy-23- NATURAL PRODUCT REPORTS 1996-5. D. CONNOLLY R. A. HILL AND B. T. NGADJUI (29) R = H,H; R’ = Ac; R2 = OH; 13P,17P-epoxy (30) R=O; R’=R~=H (31) R = H P-OH; R‘ = Ac; R2 = OH (32) R = H,P-OMe; R’ = Ac; R2 = OH 0 (35) (36) R = H a-OMe (37) R =o;A24 (38) R = H a-OH; A24 (39) R = 0; A22824 as (44)\* as (40) (43) (45) R = H (46) R = OH (47) R = OAC (49) R=H R .*.-\ oxomariesa-7,14,24-trien-26-oic acid (33) the corresponding 2-isomer and its 3-methyl ether have been isolated from Abies sibirica.28 The ring A seco derivatives anhydrosibiric acid (34) and cis-sibiric acid (35) were also pre~ent.~’ A.sibirica also contains several normal lanostanes including 24,25-dihydro- abieslactone (36) 3-0~0-7,24-lanostadien-26,23-olide (37) and the corresponding 3a-hydroxy derivative (38),30 3-oxolanosta- 7,22,24-trien-26,23-olide (39) and its As-isomer (40),31 and the di keto-acid (4 1). 32 The 14(13 412)-abeolanostanes neokadsuranic acids A (42) (50) R = H a-OH (51) R = H CX-OAC (52) R = H @-OH (53) R = H P-OAC B (43) and C (44)have been isolated from Kadsura heteroclita where they occur with their probable biogenetic precursors 3- oxo-8,24-lanostadien-26-oicacid (49 its l2a-hydroxy de- rivative (46) and the corresponding acetate (47).33* Seconeokadsuranic acid A (48) and its probable precursor (49) have also been reported from K.heter~clita.~~ The same source has provided a series of 12-substituted lanostanes 1201-hydroxycoccinic acid (50) and its acetate (51) and 12p-hydroxycocconic acid (52) and its acetate (53).36 The mushroom Ganoderma lucidum is a seemingly endless NATURAL PRODUCT REPORTS 1994 HO CH20H OH R R (54) R = 0; R’ = H a-OEt (56) R = H j3OH; R’ =O; R2=H (57) R=0; R’ =CH20H (55)R = R’ =O (60) R = 0; R’ = H a-O-Me; R2 = H aOH (64) R = 0; R‘ = CH3; (24S 25S)-epoxy (56) R = 0; R’ = H a-OMe (65) R = H p-OH; R‘ = CH,; (24S 25s)-epoxy (59) R =H P-OH; R’ =O 0 “OH (61) R= H (63) R = CH20H (24S 25S)-epoxy (62) R= OH (66) R=CHO R2 (67) R=H,a-OH; R’=OH; R2=H (74) R = H R’ =Ac (77) R = R2= H P-OAC; R‘ = AC (68) R= H P-OH; R’ =OH; R2=H (75) R = R’ = AC (78) R = H CX-OAC;R’ = H; R2 = H P-OH (69) R = H a-OAc; R’ =OH; R2 = OAc (76) R =Ac R’ = H (79) R = R2 = H a-OH; R’ = H (70) R = H j3-OH; R’ = R2 = OAC (80) R = R2 = H P-OH; R’ = H (71) R = H P-OH; R’ = OAC; R2 = H (81) R = H a-OAc; R’ = Ac; R2 = H a-OH (72) R = H P-OAC; R’ =OH; R2 = H (82) R = H p-OAc; R’ = Ac; R2 = H a-OH (73) R = 0; R’ =OAC; R2 = H (83) R = H a-OH; R’ = H; R2 = H P-OAC (84) R = H P-OH; R’ = H; R2 = H j3-OAC R@Orvl‘C02H p 0 (86) R = R’ = 0 (87) R=O; R’=H,a-OH (88) R = H P-OH; R’ = 0 (89) R = H P-OH; R’ = H P-OH source of lanostanes (see previous reports in this series).New compounds from an ethanolic extract include ganoderiols C (54) D (55) E (56) F (57) G (58) H (59) and I (60) and ganolucidic acid E (61).The known ganolucidic acid D (62) was also isolated and its configuration at C-23 determined by CD.37 The epoxides (63) (64) and (65) of ganoderiols A B and C respectively co-occur with the aldehyde ganoderal B (66).38 0 The confusion in the nomenclature of this series increases with the appearance of ganodermic acids Ja (67) Jb (69 PI (69) P2 (70) T-N (71) T-0 (72) and T-Q (73).39*40 A further 95 NATURAL PRODUCT REPORTS 1994-J. D. CONNOLLY R. A. HILL AND B. T. NGADJUI OH 1 H? (96) R = H02CCH2CCH2C0 R' = H CH3 H? (97) R = HO,CCHzCCH,CO R' = OH CH3 RO (102)R=H (104) R=Ac twelve compounds have been reported -mercifully without trivial names.These include the ganodermic acid derivatives (74)-(84) and 3p 15cc-diacetoxy-8,24-lanostadien-26-oic acid (85).41* 42 The related mushroom species G. applanatum produces ganoderenic acids F (86) G (87) H (88) and I (89) in addition to ganoderic acid AP (90) and furanoganoderic acid AP (91).43 The 'H and 13C NMR assignments of selected Ganoderma lanostanes are discussed in two publications.44- 45 The structure of (22S)-22-acetoxylanosta-8,23-diene-3a,25-diol(92) was determined by X-ray analysis. It is a metabolite of the fungus Pisolithus tinctorius which also produces 3-oxopisolactone (93) and (22S)-24-methylenelanost-8-ene-3P,22-diol (94).46 A further metabolite of this fungus pisosterol 7 (94) R = R' = H (95)R=Ac R'=OH OH OH H? (98) R = H02CCH2NHCOCH2CCH2CO I CH3 as (94) {F (103) (95),47 was also isolated from the related species Pisolithus arhizus and named mutum01.~~ In both cases the structure was confirmed by crystal structure analysis.Three new fasciculol esters fasciculic acids A (96) B (97) and C (98) have been reported from the toxic mushroom Naematoloma fasci~ulare.~~ Other lanostanes include onekotanogenin (99) from Psolus fabri~ii;~~ anwuweizonic acid (1 00) and manwuweizic acid (101) from Schisandra propinqua;51 the trishomolanostane lansiol (102) from Clauseaa lansium ;52 29-norlanosta-8,24-diene- la,2a,3P-triol (103) from Commiphora incisa ;53 parkeyl acetate (104) from Leuzea carthamoides ;54 and lanosta-8,25- dien-3P-01 (105) from Cereus gigante~s.~~ The last compound was previously reported from Fomes fastuosus.56 Lanosterol has been transformed into zymosterol and other NPR 11 NATURAL PRODUCT REPORTS. 1994 as (102) HO (107) R=H as (108) p+ HOA ,I RO (109) R= H :R (108) R=Ac (110) R = R' = CH (111) R=H R'=CH3 (112) R = H R' = CH3CH2 0 as (113) [FH (116) R = P-D-glU (118) R = H a-OMe (117) R=H (119) R = H P-OMe NATURAL PRODUCT REPORTS 1994-5. D. CONNOLLY R. A. HILL AND B. T. NGADJUI R’ (128) R = H a-OH; R’ =OH; R2 = R3 = H (129) R = H P-OH; R’ = OH; R2 = R3 = H (130) R = H P-OH; R2= OH; R’ = R3 = H (131) R = H a-OH; R’ = R2= H; R3 = OH related Studies on the enzyme responsible for removal of the 14-methyl group of lanosterol derivatives have ap- pea~ed.~** 59 Bivittosides A-D are oligoglycosides from the sea cucumber Bohadschi bivittata based on the aglycone (106).60 Nemogenin (107) is a norlanostane sapogenin from Duasmodactyla kurilensis.61Four new glycosides lefevreiosides A, A, A, and D have been isolated from Cucumaria lefevrei.62 The following saponins have been investigated the antifungal pervilosides A B and C from Holothuria per~icos,~~ cucumariosides C and C from Eupentacta fraudatrix ;64 cucumarioside H from E.pseudoquinquisemita ;65 cladolosides A and B from a Cladolabes species;66 pseudostichoposide A from Pseudostichopus trachus ;67neothyoside A from Neothyone gibbosa ;68 psolusoside B from Psolus f~bricii;~’ and muscarosides G-N from Muscari armeniacum and Muscari botry~ides.~~ Tritium labelled parkeol but neither lanosterol nor cycloartenol was transformed into 14a-methyl-5a-cholest-9( 1 l)-en-3/3-01 by the sea cucumber Holothuriu areni~ola.~~ This result suggests that this organism cyclizes 2,3-epoxysqualene directly to parkeol.Many sponges can transform cycloartenol and lanosterol into 4,4,14-demethyl This indicates that not all of their sterol requirement comes from the diet. Cyclopomenyl acetate (108) is an unusual C, cycloartane derivative from the rhizomes of Polypodium ~ulgare.~~ 26,26-Dimethylcycloartenol (I 09) has been reported from Euphorbia s~ongarica.~~ Cyclotirucanenol (1 10)75and cycloeuphordenol (1 1 1)76 have been found in E.tirucalli while the closely related cyclocaducinol (1 12) occurs in E. caducifolia.ii The (2)-p-hydroxycinnamate of 24-methylenecycloartanol pholidotin has been isolated from Phalidota rubra and Cirrhopetalum el~turn.~* The side-chain stereochemistry of cyclogalagigenin (1 13) and cyclosieversigenin (1 14) from Astragalus species has been revised following an X-ray analysis of cyclogalagigenin (1 13).” Asernestioside C is a minor saponin of A. ernestii based on the aglycone (1 14).*O Cycloorbigenin B a sapogenin from A. arbiculatus has structure (1 1 5).*l The crystal structure analysis of abruside A (1 16) a highly sweet constituent of Abrus precatorius has been published.82 The corresponding genin abrusogenin (1 17) has been reported together with four saponins abrusides A-D in A.prec~torius.~~ Other genins include squarrogenins 1 (1 18) and 2 (1 19) from Thalictrum sq~arrosurn,~~ cyclocanthogenin (1 20) from . Astragalus tr~gacantha~~ and heinsiagenin A (12 l) an unusual amide obtained following hydrolysis of the saponin of the root bark of Heinsi crinata.86 The corresponding A9(11)-lanostane heinsigenin B (122) was also obtained. The cycloartanes isolated from Astragalus species have been reviewed.*? The following new cycloartanes have appeared in the literature 1a-acetoxycycloart-24-en-3~-ol (1 23)53 from Commiphoru incisa; 29-norcycloart-23-ene-3/3,25-diol (124) and 24,25-epoxy-29-norcycloartan-3~-ol (125) from Aglaiu roxburghiana ;** gardenolic acid A (1 26) from Gardenia jasminoides ;*’ buxatenone (1 27) from Bums papillosa;90and the four 26-carboxylic acid derivatives (128)-( 13 1) from Mangifera indicagl The structure of 3-oxocycloart-24-en-2 1-oic acid (132) from the leaves of Lansium domesticum has been confirmed by X-ray analyskg2 Some derivatives of (132) show significant tumour in hi bi ting activity .Studies on the following saponins have been reported asernestiosides A and B from Astragalus erne~tii;’~ acanthosides K and K from Acanthopanax sessilijlorus ;94 cycloorbicoside G from Astragalus orbiculatus ;95 cyclocanthoside D from A. tragacantha ;96 cycloaraloside A from A. amarus ;9i squarrosides Al A2 B1 ,and B2 from Thalictrum squarrosum ;’* and mollic a-L-araO (134) R=H R'=O 0 HO (139) R = P-D-glU R' = 0 (1 43) R = P-D-gIU acid 3-O-a-~-arabinopyranoside (1 33) from Combretum ed~ardsii.~~ The conformation of cycloartenol in solution has been studied by 'H and 13CNMR spectroscopy.100 Cucurbitacin T (I 34) from Colocynthis vulgarislO1 and cordifolin A (1 35) from Fevillea cordifolia102 are interesting new cucurbitacins.23,24-Dihydro- 1 I -deoxocucurbitacin I (1 36) occurs in Desfontainia spinosa together with the cytotoxic glycosides spinosides A (137) and B (138).lo3 Several other glycosides have been reported including 2-O-p-~-gluco-pyranosylhexanorcucurbitacin I (139) from Citrullus colo~ynthis~~~ and compounds (140)-( 143) from Picrorhiza k~rrooa.~~~~ lo Cucurbitacin B (144) has significant anti-inflammatory activity.lo7 4 The Dammarane-Euphane Group Reissantenol oxide (reissantiol oxide) (145) is the first example of a triterpenoid with a reissantane skeleton. Biogenetically this skeleton may arise by backbone rearrangement of a dammaryl cation or by partial rearrangement of a euphane intermediate. Reissantenol oxide (145) was isolated from the root bark of Reissantia indica and its structure was confirmed by X-ray analysis.1os Three further compounds (24R)-reissant-5-ene- 3/3,24,25-triol (146) and the corresponding 3-and 24-ketones have been reported from the same source.1o9 Aonena-3,24- diene (147) from the fresh rhizomes of Polypodiodes niponica is the first example of a dammarane which has undergone a complete backbone rearrangement.110 NATURAL PRODUCT REPORTS 1994 pH -OH as (134) I as (134) (136) R=H; R' =H,H OR2 (137) R = R2 = H; R' = H,H (138) R = H; R' = H,H; R2 =Ac 0 HO (140) R=H,H; R'=H (141) R = H,H; R' = H; 22,23-dihydro (142) R =O; R' =Ac p as (1 43) { -OH c (144) R =H Ginsenoside La (148) is a minor saponin of the leaves of Punax ginseng and has an unusual 12,23-oxide link."l Papers have appeared on dammarane saponins of Gynostemma pentaphyllum ;lI2 luperosides A-H from Lufa operculata whose genins are the dammaranes (149) and (15O);ll3ginsenoside Rg from Panax ginseng;l14 saponins from the flower buds of P. ginseng;l15majorosides F and F from Panax japonicus ;l16 and the antisweet saponin ziziphin from Ziziphus jujuba.'l' Six 3,4-secodammaranes (1 5I)-( 156) have been isolated from the male flowers of Alnus japonica.lls A study of the 13C NMR shifts of dendropanoxide and other dammaranes has resulted in the correction of some earlier assignments.119 Phyllanthenol(l57) phyllanthenone (1 58) and phyllantheol (1 59) are euphane derivatives from Phyllanthus niruri. 120 Five new tirucallane derivatives (1 60)-( 164) have been isolated from Picrasma quassioides.121 Definitive assignments of the IH and 13C NMR resonances of the tertiary methyl groups are included in this work. While Turraea nilotica produces nilotocin (169 dihydroniloticin (1 66) and the trio1 (1 67),122 Phellodendron chinense yields (1 65) (166) and the acetate (1 68).123 The side-chain stereochemistry of flindissone lactone (1 69) flindissol lactone (1 70) and (22S)-22-hydroxy-7,24-tirucalladiene-3,23-dione(1 7 1) from Aucomea klaineana has been established by X-ray ana1~sis.l~~ Flindissone (172) has also been isolated from the same source.125 Skimmiarepins A (173) and B (174) have been isolated from Skimmia japonica var.intermediu f. repens.12 The latter shows insect growth inhibitory activity. 21-O-Methyltoosendanpentol (1 75) has been reported from Melia toosendan. 127 NATURAL PRODUCT REPORTS 1996-5. D. CONNOLLY R. A. HILL AND B. T. NGADJUI OH as (149) I HO OH R’ OH I (ys-K H02Cf R02C as (151) I )co2H (151) R=H ( 1 53) (154) R=R1 = H (152) R=Me (155) R= H R’ =OH (156) R=OH R2=H H ‘%W R,’* C H20H as (159) R@ I (160) R = 0; R’ = CH3 (157) R=OH (159) R = H a-OH (161) R=0; R‘ =CHO (158) R=H A’ (162) R = 0; R’ = C02Me (164) R = H P-OH; R’ = CH3 OH R’ fl *OH as (159) OR’ as(159){p OH as (159) (165) R=0; R’=H (167) R =O (169) R = R’ = 0 (166) R = H P-OH; R’ = H (170) R = H a-OH; R’ = 0 (168) R=0; R’=Ac (172) R = 0; R’ = H,OH OH I HO& OH Me0 as (159) { R0’-HO”P (171) R=O (175) (173) R = (174) R = \\\ co 4.1 Tetranortriterpenoids The full details of the elegant structure elucidation of the highly cleaved tetranortriterpenoid guyanin (176) have appeared.lZ8 The structure was confirmed by X-ray analysis. The series of dukunolide derivatives from Lansium domesticum continues with dukunolides D (177) E (178) and F (179).12' Several papers dealing with the continuing impressive contribution of the Ley group to the chemistry of azadirachtin and derivatives have appeared.These include syntheses of the AB fragments (180)130 and (18 1),131 studies on the reactivity of the enol ether double bond of a~adirachtin,~~~ chemical modification of azadirachtin derivatives and ~alannin,'~~ and the rearrangement of dihydroazadirachtin derivatives to dihydroazadirachtinin (1 82).134 The rearrangement involves opening of the 13,14-epoxide. Compound (183) has been synthesized as a simple model of the enol ether system of a~adirachtin.~~~ The new azadirachtin derivative (184) has been isolated from the seeds of Azadirachta indic~.'~~ Azadiradione (1 85) has been synthesized.137 The following new compounds have been reported :mzikonone (1 86) from the root bark of Turraea robusta ;13* 1-cinnamoyltrichilinin (1 87) and the corresponding tiglate (188) and acetate (189) from Melia ~olkensii,~~~ limbocinin (1 90) and limbocidin (1 9 1) from 0 0 0 "H (176) (177) R = a-OH (1 78) 8a 9a-epoxy; R = a-OH (1 79) 8a 9a-epoxy; R = P-OH AcO= 0 'OAc 9% HO NATURAL PRODUCT REPORTS 1994 Azadirachta indica;lgO compound (1 92) from Cedrela odorata;lg1 and the glucoside (193) from Melia azad~rach.~~~ The 'H and 13CNMR resonances of gedunin have been assigned.Ig3 Glaucin B (194) from Evodiu glauca has an unusual cis AB ring junction.144 Jangomolide (acidissimin) (1 95) has been isolated from Limonia acidissima.145 During this work some of the I3CNMR resonances of obacunone were reassigned. Other new compounds include 5,6-didehydrooriciopsin (5-dehydro- oriciopsin) (1 96) from the root bark of Harrisonia abyssini~a,~~~ ichangensin (197) from the seeds of Citrus ichungensi~,'~' and clausenarin (1 98) and clausenolide- 1-ethyl ether (I 99) from Clausenia anisata. 14* The 17-O-P-~-glucopyranosides(as in (200)) of most Citrus limonoids have been identified in various Citrus species.lg9,I5O The list includes limonin nomilin deacetylnomilin obacunone nomilic acid deacetylnomilic acid isoobacunoic acid epiisoobacunoic acid and trans-obacunoic acid. 14C-labelled calamin (20 1) is converted to cyclocalamin (202) in the detached stem of ~alamondin.'~' On the basis of an X-ray analysis the structure of pseudrelone B (203) from Pseudocedrela kotschyii has been revised.152 The 1lcc,l9-ether is an unusual feature of (203). Atomasins A (204) and B (205) from the trunk bark of Entandrophrugma ~andollei,~~~ are of interest since they lack the orthoacetate normally found in this series. Structures (204) and (205) were omitted from the original paper. A crystal structure of the swietenine derivative (206) from Carapa procera has been ~ep0rted.I~~ This compound was originally isolated from Khaya species in 1969.155 Two further swietenine derivatives swietemahonins A (207) and B (208) have been found in the cotyledons of Swietenia mahogani together with 3-acetyl-swietenolide (209).156 All three compounds are antagonists of platelet aggregation factor.The 6-deoxyswietenolide derivative (2 10) has been isolated from Capuronianthus mahafalensis. 157 The limonoids of the seeds of Entundrophragma caudatum have been in~estigated.~~~ Volkensin (21 l) from the fruits of Melia volken~iz,~~~ undergoes an allylic rearrangement in acid solution to give the aldehyde (212) which is readily converted into salannin (21 3).160 Ac? 0 0 AcO'. "OH (187) R = PhwCo (189) R=Ac :' (190) R = H (191) R=OH NATURAL PRODUCT REPORTS 1994-5. D. CONNOLLY R. A. HILL AND B. T. NGADJUI 101 (194) Rope 0 (197)R=R’ =H (1 99) R = Et R’ = OH I0) .I 0 0 ‘OAc OAc OAc OR (207)R=fico (204) (208)R=dc0 (205)R=pcO Me02p0 H.4 ‘..40 R2 ’R’ OR (209)R=Ac R’ = H R2= OH (210)R= dc0, R’ =OH R2= H (217)R =C02Me R’ = OH (218)R =CHO R’ = /6.Volkensin (21 1) has insect antifeedant properties. Nimbilin (21 7),164 and nimbanal (21 8) and 3-acetylsalannol (219)165 are (214)16’ and nimbolicin (21 5),162 from Azadirachta indica are further examples of limonoids from Azadirachta indica. structurally similar to volkensin (21 1) but appear to differ in the Dictamdiol (220) is a degraded limonoid from Dictamnus configuration at C-17. Deoxynimbolide (2 16),163 isonimbinolide angustifolius.166 NATURAL PRODUCT REPORTS 1994 OMe 0 HO.. ooc AcO..R=O; R’=H R = H P-OMe; R‘ = OH .. (226) R = H P-o-p-D-glU; R’ = H (223) OR1 ?H o@Me R2 \ RO ”0 0 (228) (229) R =TBS R’ =Ac R2=H (230) R = R’ = H R2 = J HO R HO (236) R= H H; R’ =OH (237) R=H,P-OH; R’=H; (239) R =O; R1 =OH A12 (238) R=CH3 (241) R=CH20H A12 (242) R = HO (243) R = H #I as (244) J. HO 0 0 OH (244) (245) (246) R = 0;R’ = CHO (249) (247) R = H P-OAC; R’ = CHO (248) R = 0; R’ = CH20H J NATURAL PRODUCT REPORTS 1996-5. D. CONNOLLY R. A. HILL AND B. T. NGADJUI R (252) R = R' = 0; R2 = H (253) R = 0; R' = H H; R2 = H (254) R=H,P-OH; R'=O; R2= H (255) R = R' = 0; R2 = OH 4.2 Quassinoids The bark of Picrasma jauanica contains the new quassinoids javacinins A (221) C (222) and D (223).167 Nigakilactone 0 (224) is found in Picrasma ailanthoides.168 Bruceanol C (225) from Brucea antidysenterica shows cytotoxic activity.16s The structure of javanicinoside A (226) a quassinoid glycoside with a norpicrasane skeleton from Picrasma javanica has been confirmed by X-ray ana1y~is.l~~ Eurycomanol 2-0-p-~-glucopyranoside (227) has been isolated from Eurycoma longifolia.17' Synthetic effort in the quassinoid area continues. Total syntheses of klainean~ne'~~ and picrasin B173 have been reported. The protected 15-deoxybruceolide derivative (228) has been synthesized,174 however it was found that the derivative (229) was required for the synthesis of bruceantin (230).175* 176 A mild efficient method for the elaboration of the sensitive C/E ring of chaparrinone should prove very useful in quassinoid A method for regioselective reductive de-methylation of the ring A 0-methyldiosphenol system of quassin has been deve10ped.l~~ A paper has appeared on the synthetic efforts towards quassimarin.17s A review of quassinoid synthesis has been published.lsO 5 The Lupane Group The lupane hydrocarbons (23 l) (232) and the corresponding As isomer have been identified as constituents of pond mud where they occur with similarly degraded oleananes and ursanes.181 24,25-Dinorlupa- 1,3,5( 10)-triene (233) and des-A- 26-norlupa-5,7,9-triene (234) have been synthesized and shown to occur in various geological samples.182 The history of betulin lup-20(29)-ene-3P,28-diol (235) first isolated in 1788 has been reviewed.la3 Betulin 3-caffeate has been isolated from Quercus suber.la4 Psoracinol (236) from PsoreZea plicata la5 is unusual in its lack of an oxygen at C-3. Other simple lupanes include magnifico1 (237) from Achillea magni$ca,laS lup- 13( 18)-en-3/?- 01 (238) from Swertia petio1ata,la7 7P-hydroxylup-20(29)-en-3-one (239) from Salvia pratensis,lss lup-20(29)-ene-3P,24-diol (240) from Phyllanthys ~e~uosus,~~~ and obtusalin (24 1) from Plumeria obtusa.lS0 Querspicatins A (242) and B (243) from Quercus spicata have a tertiary hydroxyl group at C-9.191 H0'' Oleander01 (244) from Nerium oleander has rare C-27 oxygenation.lS2 Several trioxygenated lupanes have been reported including kanerodione (245) from Nerium oleander,1s3 and skimmianone (246) skimmial (247) and skimmiol (248) from Skimmia laureolu.lS4 Lup-20(29)-ene-3/3,7,9,15a-triol(249) occurs as a mixture of 3-esters in Hyphear tanakae.lS5 The callus tissue of Paeonia japonica produces 3P,23-dihydroxylup- 20(29)-en-28-oic acid (25O).lg6 Sambuculin A from Sambucus formosana is the hexadecanoyl ester of lupeol. Columbrinic acid was first isolated in 1978 from Columbrina granulosa. lS7It has now been isolated from Columbrina texensis and its structure (251) confirmed by X-ray analysis.1s8 Zizyberanalic acid from Zizyphus jujuba has been assigned the same structure (25l).ls9 Glycosides of 3a-hydroxylup-20(29)-ene-23,28-dioicacid and 3-epibetulinic acid have been identified in Scheflera octophylla.200An X-ray crystal structure analysis has revealed a 'sofa' conformation for ring A of 3-0xolupane-28-nitrile.~~~ The 13C NMR resonances of a series of lupanes have been assigned and the data used to derive the conformation of ring ~~~ A.Treatment of 3P-hydroxytriterpenoids with excess m-chloroperbenzoic acid affords ring A lactones.203 6 The Oleanane Group Four new pfaffic acid derivatives (252)-(255) have been isolated from Pfafia p~luerulenta.~~~ Consideration of the 'H NMR shifts of 2,3-diols and 2,3,23(24)-triols in the oleanane and ursane series has led to the structural revision of 2a,3a- dihydroxyolean- 12-en-28-oic acid (formerly 2p,3a) from Rosmarinus oficinalis and Melissa oficinalis and 2p,3p,23- trihydroxyolean- 12-en-28-oic acid (formerly 2a,3a) from Pru-nella u~lgaris.~~~ 'The latter is identical with bayogenin.The structures of the 28-noroleanene (256) and the derivative (257) from MelandriumJirmum have been confirmed by X-ray analysis.2o6 Other noroleananes include 3a,24-dihydroxy-30- noroleana- 12,20(29)-dien-28-0ic acid (258) from Akeba quinata callus 3P-hydroxy-30-noroleana-12,18-dien-29-oic acid (259) from Brussingaultia gracilis,208 and des-A-oleana- 5( lo) 12-diene (260) des-~-26,27-dinoroleana-5,7,9,11,13-pentaene (261),lS1 and 24,25-dinoroleana- 1,3,5( lo) 12-tetraene (262)lE2 from sediments. NATURAL PRODUCT REPORTS 1994 0 HO HO (267) R = H (268) R = OH HO R’O eRHOg} as (270) as (270) HOg} HO a-~-rhaOHzC‘ :, ’ CH20H (271) R=H,H (272) R = H H; R’ = H (270) R=O (273) R=H H; R’=Ac R AcO R (274) R = H P-OH; R’ = H (277) R=OH (280) R = 0 (282) R = H a-OH; R‘ = CH20H (275) R=0; R’ = H (278) R = H (281) R = H j3-OH (283) R = H a-OAc; R’ = CHflH (276) R=0; R’=OH (284) R = H P-OAC; R‘ = CH20H (279) R = H P-OAC;R’ =H (285) R = H P-OAC; R’ = C02H (286) R = H a-OAc; R’ = C02H as (288) {&OH HOeR3 HO @(270) as ,# .‘R = (293) (292) R = H H CH3; R3 = H H (287) R = R’ = CHzOH; R2 (288) R = R’ = CH3; R2 = CH20H; R3 = H H (289) R = R2 = CH20H; R’ = CH3; R3 = H H (290) R = R’ = R2 = CH3; R3 = 0 105 NATURAL PRODUCT REPORTS 1996-5.D. CONNOLLY R. A. HILL AND B. T. NGADJUI HO@} as(262) as (262) HOg] K (296) R = H R' =OH (299) R = CH20H (297) R=OH R'=H (306) R=CH3 (298) R = R' = OH K R4 (300)R = R' = H P-OH (304) (301) R = R' = H P-OAc (302)R = 0; R' = H CY-OAC (303) R = 0; R' = H P-OAC (308)R = H a-OH (309)R = 0 A crystal structure of medicagenic acid (2/3,3/3-dihydroxyolean- 12-ene-23,28-dioic acid) from Medicago sativa has been published.209 Belleric acid (263) occurs in Terminalia bellerica as the glycosyl ester bellericoside.210 The y-lactone glycuranolide (264) has been obtained from Glycyrrhiza uralensis.211The antitumour agent hyptatic acid A (265) from Hyptis capitata,212 and barringtogenol C (266) from Loesclia me~icana,~'~ have had their structures confirmed by X-ray analyses. Two oleanane 28-O-P-~-xylopyranosides from Centipeda minima have the tetraol(267) and the pentaol (268) respectively as genin~.~~~ 22a-Hydroxyhederagenin (269) is the genin common to kalopanax saponins La Lb and Lc from Kulopanax septemlobus.215 Melilogenin from Melilotus oflcinalis is 3P,24-dihydroxy-22-oxo- 12-oleanen-29-oic acid (270).216 Imberbic acid (271) is a constituent of the leaves of Combretum imberbe.217 23-Hydroxyimberbic acid 23-0-w~- rhamnopyranoside (272) and the corresponding 1-acetate (273) have also been isolated from C.imberbe.218 The 19a-hydroxyoleanenes (274)-(276) have been reported from Osteospermum corymbo~um.~~~ The roots of Rubia cordifolia are the source of rubiprasins A (277) B (278) and C (279).220 A crystal structure analysis provided confirmation of the structure of rubiprasin A (277).Wistariasapogenols A (280) and B (281) have been isolated from Wistaria brachybotrys. 221 The callus tissue of Stauntonia hexaphylla contains five new oleananes including 3-epi-mesembryanthoidigenic acid (282) and its 3-acetate (283) the acetate (284) of mesembryanthoidigenic acid the 3-acetate (285) of serratagenic acid and the corresponding 3-epimer (286).z22 Hydrolysis of the crude saponin fraction of Abrus cantoniensis yielded abrisapogenols B (287) D (288) E (289) F (290) and G (29 1).223 Structural confirmation of abrisapogenol G (291) was obtained by X-ray analysis. Myrianthinic acid from Myrianthus arboreus is 3/3,6P-dihydroxyolean- 12-en-29- oic acid (292).224 Lysikokianoside the most molluscicidal saponin of Lysimachia skokiana is a glycoside of (293).225 Olean- 12-ene- 2a,3,8,23-triol (294) from Commiphortl merkeri shows anti- inflammatory and analgesic activity.226 Olean- 12-ene- 3P,9a,l la-trio1 (295) has been isolated from Euphorbia ~upina.~~' Three oleanenes (296)-(298) and the diene (299) have been isolated from Phyllanthus ~E~xuosus.'~~ The 3/3,15a- diol(296) has also been isolated from Baccharis magellanica.228 The palmitate of longispinogenin has been found in Trichocerus ch ilens is.229 Four olean- 18-enes (300)-(303) have been reported from The SchaeJfferia c~neifolia.~~~ 28-noroleana-9,12,17- triene- 3a,23-diol (304) occurs in Clonopodium polycephalum.231 The 9( 1 l) 12- and 11,13( 18)-dienes (305) and (306) have been found in the stem bark of Phyllanthus JEexuo~us.~~~ Other oleananes include the putative 3-hydroxyolean- 12-en- 1-one (307) from Randia dumetorum ;233 olean- 12-ene-3a 16P-diol (308) from Canarium album ;234 (E)-4-hydroxycinnamoylerythrodioland the corresponding (E)-3,4-dihydroxy-derivative from Larrea tridentata ;235 6-amyrin formate from Euphorbia ~upina;~~~ and the acetate of oleanolic lactone from Hyptis m~tabilis.~~~ Crystal structure analyses of P-amyrone and P-amyrin acetate have been published.238 A multivariate data analytical approach to the determination of the configuration at C-18 in pentacyclic triterpenoids has been developed.239 Papers on the mass-spectroscopic frag- mentation pattern of 18a- and 18P-1 1-oxooleanolic acid derivatives240 and the 13C NMR spectra of glycyrrizic acid derivativesz4' have appeared.The conformation of ring A in a series of 2,3-ketols 2,3-diols and their acetates has been studied by 'H NMR.242 An investigation of the conformation of allobetulone (309) in both solid (X-ray) and solution (NMR) has been published. 243 Computational methods have been used to work out a predictive basis for the Barton reaction.244 Studies on the biosynthesis of ursolic and oleanoiic acids in tissue cultures of Rabdosia japonica have appeared.245 The novel hexacyclic triterpenoids 2a,3a,24-trihydroxy- NATURAL PRODUCT REPORTS 1994 (310) R = CH20H (312) R = CH3 /\ /\ (317) R=H (320) R= \ \ co (318) R = H P-OH HO/o“ (319) R=O ‘g}#) HO as (321) as (321) Hoei&} as (321) R (321) R=0; R’ =CHO (323) R’ =C02H (324) R’ = CH3 (326) R =CH3 R’ =CH3 R2= OH (329) R’ =CH3 (322) R = H j3-OH; R‘ = CH20H (327) R =CHO R’ =CH3 R2= H (328) R = CHZOH R’ = CH, R2 = H x x HO HO 12,27-~yclotaraxer-14-en-28-oic acid (310) and 2a,3a,24-dzflus~.~~~ Reduction of (32 1) gave friedelane-3/3,29-dioI (322) trihydroxy- 13,27-~ycloolean- 1 1-en-28-oic acid (3 11) have been identical with a metabolite from Mortonia palmerii previously isolated from Prunella vulgaris.246 These compounds are described as friedelane-3P,28-di01.~~~ Friedelane-3/3,20-dioI described respectively as 12,13-cyclo and 13,14-cyclo in the (322) has also been isolated from Euphorbia antiquorum together reference.Two similar hexacyclic compounds przewanoic with its 3-acetate 29-acetate and 3,29-dia~etate.~~~ The acids A (312) and B (313) are found in Salvia pr~ewalskii.~~~ diosphenol (323) has been found in Austroplenkia p~pulnea.~~~ Maprounic acid isolated from Maprounea africana previously Several triterpenoids lacking an oxygen at C-3 have been believed to be 3P-hydroxyurs- 12-en-29-oic has now isolated from Euphorbia species.E. tirucalli contains friedelan- been shown by X-ray analysis to be aleuritolic acid (314).249 la-01 (324) which has been assigned the trivial name The genuine 3P-hydroxyurs- 12-en-29-oic acid was isolated euphorcin01.~~~ from Hyptis ~uaveolens.~~~ 1 la 12a-Epoxytaraxerol (3 15) has A crystal structure analysis has revealed that trichadenic acid been obtained from Euphorbia sup in^^^^ while euphorginol B is the 27-carboxylic acid (325)259 and not the 26-carboxylic (3 16) occurs in Euphorbia tiru~alli.~~~ acid as previously assigned.260 The X-ray analysis shows that Karounidiol (317) and its 3-benzoate derivative are multi- both stretched and folded ring conformations exist in the floradiene derivatives from Trichosantes kirilo~ii.~~~ The struc- crystal.Friedelan-7P-01 (326) has been transformed into ture and C-20 configuration of karounidiol(3 17) were revealed friedelan-25-01 (327) and friedelan-25-a1 (328).261 3P,24- by X-ray analysis and this result together with NMR evidence Epoxyfriedelan-3a-01 (329) has been synthesized from necessitates the revision of the C-20 configurations of bryonolic friedelin.262 The structure of putrone (330) fom Putranjiva acid (318) bryononic acid (3 19) and bryocoumaric acid (320).roxburghii has been confirmed by 21,29-Crystal structure analyses of two bryonolic acid derivatives Cyclofriedelan-3-01 (33 1) has been claimed as a constituent of have been Conyza aegyptiaca. 264 3-Oxofriedelan-29-dioI (32 1) has been isolated from Mortonia The use of both X-ray analysis and molecular force field 107 NATURAL PRODUCT REPORTS 1994-5. D. CONNOLLY R.A. HILL AND B. T. NGADJUI OH & 0 HOO I W T R HO (332) R = CH3 R’ = H (333) R = CH3 R‘ =OH (334) R = C02Me R’ = H (335) R = CH3 R’ = C02Me R2= H R3= H H (336) R = CH3 R’ = H R2 = OH R3 = 0 (337) R=CH3 R’ = H R2=OH R3= H H (339) (338) R = H R’ = CH3 R2 =OH R3 = H P-OH (340) R = C02H R’ = CH3 (344) R’ =CH3 (345) R = a-CH3 (347) (341) R=CHO R’ =CH3 (346) R = P-CH3 (342) R = R’ = H (343) R = H R’ = CH3 OR’ AR’ Scheme 1 calculations for the study of the most favoured conformation of the friedelane skeleton has been A crystal structure analysis of 29-hydroxyfriedelan-3-one from Pristimera gruhamii has appeared.266 The Celastraceae quinone methide group of friedelane derivatives continues to expand. Netzahualcoyonol (332) netzahualcoyondiol (333) and netzahualcoyol (334) occur in Orthosphenia mexicana while netzahualcoyene (335) is found in Sugar0 Maytenus h~rrida.~~~ The outer root bark of Cassine balae is the source of balaenonol (336) balaenol (337) and balaendiol (348) (349) R = Ac R’ = 7’’ (338).268 Balaenol was previously thought to have structure (339).269 Several ring A aromatic derivatives have been reported including zeylasterone (340) and zeylasteral (34 1),270 and the (350) R = Ac R’ = To 23-nor derivatives (342) and (343)271 from Kokoona zeylanica.(351) R = H R’ = Yo Celastranhydride (344) is a ring A cleaved anhydride which occurs in K. zeylanica Cassine balae and Reissantia indi~a.~~~ (352) R = H R’ = 7’’ The two bis-triterpenoid ethers (345) and (346) were isolated from the roots of Rzedowskia tolantonguensi~.~~~ Reaction of pristimerin (347) with DDQ resulted in formation of (345) (346) and netzahualcoyene (335). through the epoxide as shown in Scheme 1. Thermal cleavage Full details of the structural assignments of soyasapogenols of the glycosides of steroids and triterpenoids is prevented by A B and C and soyasaponins I 11 and I11 have been acetylation.276 The structure of gymnemagenin (348) the The mechanism of cleavage of the 3-O-glycoside sapogenin of the antisweet saponins from Gymnema sylvestre link in gypsogenin 3-O-glycoside has been investigated.275 The has been confirmed by X-ray analysis.277 Four gymnemic acids presence of the aldehyde is essential and the reaction proceeds I (349) I1 (350) I11 (351) and IV (352) have been isolated from NATURAL PRODUCT REPORTS 1994 HO i @02R3 RO R1\ AH R=R2=H R1=CH3 R=Ac R’ = CHO R2= CH3 Hog} as (353) as (353) og} HOHS‘ (355) R2=CH3 ‘OH (358) R2=H (359) R = R2= H (357) R2=CH3 (360) R=OH R2=H R = Ac R’ = C02Me R2 = CH3 HO HO d R’ (361) R =C02H R’ = CH3 R2 = H (363) R = H a-OH; R2= H (362) R = CH3 R’ = CH,OH R2 = H (364) R = H P-OH; R2 = H (367) (369) R = H a-OH; R’ (371) R = H P-OH; R’ the leaves of G.sylve~tre.~~~ In a separate publication compound (351) has been called gymnemic acid I1 and (352) gymnemic acid I.,’’ The first names should take preference. A new class of ellagitannins castanopsinins A-H containing an oleanane/ ursane triterpenoid core has been isolated from Castanopsis cuspidata. The Cyclamen saponin cyclomeritin C has been shown to be identical with cyclamigenin C. The authors suggest the latter name should be dropped. Isocyclamin is a new oleanane saponin from Cyclamen.281Several studies on the metabolism and activities of the saikosaponins have ap-peared.282,283,284 The discovery of oleanane saponins continues unabated.Saponins isolated include acaciaside from Acacia auriculi-for mi^;^^^ anchusoside I1 from Anchusa oficinalis;2s6 ardisioside from Ardisia faberi;,* ardisiosides A and B from Ardisia neriifolia asiaticoside B from Centella asiatica ;28s astersaponins A B C and D from Aster tataric~s;~’~ bubiosides A B and C from Thladiantha bubia;,,l ciwujianosides A, H02C “OH H02C (365) R2=H = H (370) R2 = H = OH denticulata ;320 pseudoginsenoside RI from Panax pseudo- ginseng subsp. himalaicus var. angustifolius ;,,,quillajasaponin from Quillaja saponaria ;322 radianin from Radia dumetorum ;323 raddeanosides R and R from Anemone raddeana ;324 saponin C from Polyscias scutellaria ;325 songoroside A from Scabiosa soongorica ;326 soyasaponins A3 from Glycine rnax3, and V from Phaseolus vulgaris;328 taurosides B and C from Hedera ta~rica;~~’ tuleimosides I1 and I11 from Bolbestemma paniculatum ;330 udosaponins A-E from Aralia cordata;,, and yemuosides YM, YM,, YM,, and YM14,332 and YM, and YM,2333 from Stautonia chinensis.Also the following plant sources have been reported to contain saponins Albizzia anthelminti~a,~~‘ Chenopodium alfa-alfa,,,j Caltha p~lypetala,~~~ q~inosa,~~’ Combretum padoides,,, Kalopanax pi~tum,~~’ Mussatia hyacinthina,,, Nigella sativa,,,l Oxytropis glabra,,, Phaseolus vulgari~,~~~ Polygala ja- Phytolacca thyr~ilora,~~~ Pueraria l~bata,,~~ Scheflera poni~a,~~~ Randia ~liginosa,~‘~ impres~a,~~~ Solidago gigan tea,,,, 350 Tetrapleura tetra~tera,,~~ A, A, A, and D from Acanthopanax clemontanoside A from Clematis rnontana;,, codonoside B from Codonopsis lanceolata;294 corchorusins C, D, D, and D from Corchorus acutangulus ;295 crocosmiosides A-I from Crocosmia crocosmiiJEora;296 diploclisin from Diploclisia glaucescens ;,,’dipsacobioside from Scabiosa soongari~a~~~ and Dipsacus azureus;299 entadasaponins I1 and IV from Entada phaseoloides ;,OO esculentoside H from Phytolacca esculenta ;,O1 foetidissimoside from Cucurbita foetidissima ;,02 fulvomentoside A from Lonicera fulvotomento~a;~~~ guiaiacins A and B,,04 A1,,05 C,,07,D and E,,08 and F and G309 from Guaiacum oficinale ;glochiosides N and Q from Glochidion heyneanum ;,lo hederosides A, B E, and F from Hedera taurica;,, kalopanaxsaponins C D and F from Kalopanax and Thaliantha hookeri var.pentada~tyla.,~, senti~osus;~~~ 7 The Ursane Group A series of ursene carboxylic acids has been reported from Uncaria Jl~rida.,~ The compounds were isolated as the methyl esters (353)-(356) following methylation with diazomethane. The artefact (357) resulting from reaction of diazomethane with the aldehyde (354) (cf. Scheme l) was also obtained. The parent acid of the nor compound (355) has been named floridic acid. Goreishi a Chinese medicine consisting of the faeces of Trogopterus scanthipes contains the (Z)-and (E)-coumaroyl esters of tormentic acid (358).354 Two saponins from Centipeda minima are the 28-O-P-~-xylopyranosyl esters of (359) and (360).,14 Many 19a-hydroxyursane derivatives have appeared.semtemlobus;312 kotschyioside from Aspilia kots~hyi;~~~ lobatosides A-H from Actinostemma lobatum ;,14* medicoside These include rotundioic acid (361) and rotungenic acid (362) H from Medicago sativa;,16 momordins Id and IId from from Ilex rotunda;355 the tetraols (363) and (364) from Agromia Mornordica cochinchinensis ;,17 polysciasaponins P and P pilosa ;356 lp-hydroxyeuscaphic acid (365) from the fruits of from Polyscias scutellaria ;,189 319 primulanin from Primula Rosa sterilis ;357 the 2,3-seco-tricarboxylic acid musangic acid 109 NATURAL PRODUCT REPORTS 1994-J. D. CONNOLLY R. A. HILL AND B. T. NGADJUI (373) (377) HY-7 as (379) &02H (378) (379) R = H P-OH (380) (381) R = H a-OH p2R co2cH3 \!J$2 HO @*-OH ’OAc as (379) 0 (382) R = HI P-OeW (383) R = H P-OH (384) R=CH3 (386) R = H (385) (387) R = H P-OH (388) R = 0 (389) (390) R = CH3 R’ = C02H (391) R = COZH R’ = CH20Et (392) R = H a-OH (393) R = H a-OH as (379) {$ as(379) [$CH20H \ (394) R = H P-OH (366) from Musanga cecropioides;358 myriaboric acid (367) from Myrianthus arboreus ;359 hyptalic acid B (368) from Hyptis capitata;2123-epipomolic acid (369) from Hyptis mutabilis;237 fupenzic acid (370) from Rubus ~hingii;~~O 3-epitormentic acid (371) from Cunila lythrif~lia;~~’ and the 29-0-p-~-glucopyranosyl ester of 6P-hydroxytormentic acid (372) from Aphloiu the if or mi^.^^^ Structural revision of two 19a-hydroxyursane derivatives has been reported :205 roxburic acid from Rosa roxburghii is 2~,3a,7/3,19a-tetrahydroxyurs-12-en-28-0ic acid (previously thought to be 2p) and myrianthic acid from Myrianthus arboreus is 2a,3a 19~,23-tetrahydroxyurs- 12-en-28-oic acid (not 24-hydroxy) and is the same as the compound isolated from Castanospermum australe.205 Bryophollone (373) is a 30-norursane derivative from Bryophyllum pinnatum. 363 The norursanes (374)-(377) have been found in sediments and geological samples.lS1* 182 The leaves of Nerium oleander contain the norursane kanerin (378) and 12,13-dihydoursolic acid (379).364 N. oleander also contains urs-12-ene (380) named oleanderene the ring E diene kanerocin (381),365 and oleanderolic acid (382).lg3 The ring c diene (383) has been found together with the acetate of glut-5-en-3p-01 in (398) R = CH20H (399) Euphorbia mac~lata.~~~ Regelindiol A (384) and regelin C (385) are accompanied by the corresponding oleananes in Tripterygium regelii.367 Triptotriterpenic acid C (386) has been isolated from the related species Tripterygium wilf~rdii.~~~ 3&23-Dihydroxyurs- 12-en-28-oic acid (387) and the corre-sponding 3-ketone (388) have been isolated from Agirrilla mexic~na~~~ and the twigs and leaves of Cussonia natalen~is,~~~ respectively.Other new ursanes include crotolarol (389) from Crotolaria ~altiana,~~~ obtusic acid (390) and obtusilinic acid (39 1) from Plumeriu obt~sa,~’~ 3-epiuvaol (392) from Salvia le~cantha,~~~ urs- 12-ene-3a 16P-diol (393) from Canarium album,234 and a-amyrin tetratricontanoate from Scolymus hispanic~s.~~~ calotropenyl acetate (394) has The A19(29)-ursene been reported from Calotropis pr0~er-a.~~~ Careyagenolide from Careyu arb ore^^^^ has been from betulin.Tamarixone (395) and tamarixol (396) are rearranged compounds from Tamarix chinensi~.~’~ Reports have appeared on the following ursane saponins kajiichigoside and rosamultin from Rosa roxb~rghii;~~~ cornutasides A-D from Ilex corn~ta;~~~ matesaponin 1 from Ilex paraguariensis ;381 rotungenoside from Ilex rotunda;382 NATURAL PRODUCT REPORTS 1994 (400)R=NH2 HO@(402) (401)R=OH (402)R = H a-OH; R' = CH3 (403)R = H,a-OAc; R' = CH3 (407) (404)R = H,a-OAc; R1 = C02H (405)R=O; R1 =CH3 OH HO (409)R =a-OH (410)R =P-OH (413)R = H a-OH; R' = 0 (414)R =O;R' = H p-OH (415)R = R' = 0 @...(@ '-.* .,C02H-.( @..f C02H \ HO (416) (417)A7 (418)A' (420) (419) asiaticoside A from Centella asiatica ;zas quinovic acid glycosides from Guettarda platyp~da~~~* 384 and Uncaria tomento~a.~~~+ 386 Saponins have also been isolated from Scheflera impress^^^^ and Fagonia indi~a.~~~ The taraxastanes 27-deoxyphillyrigenin (397) and 23-hydroxyphillyrigenin (398) have been isolated from Pittosporum phillyraeoide~.~~~ Carissic acid (399) from Carissa carandas appears to be a taraxa~tane.~'~ The 4-methylpent-3-enoyl ester of taraxast-20(30)-en-3P-ol has been obtained from the latex of Calotropis procer~.~~~ 8 The Hopane Group The absolute configuration of aminobacteriohopanetriol (400) has been determined by correlation with bacteriohopanetetraol (401).3s2 Studies on the biosynthesis of bacteriohopanetetraol (401) have shown that ribose is the origin of the side chain.3s3v3s4 The full details of the isolation and characterization of A6- All- and A6*"-hopanoids from Acetobacter acetii ssp.xylinum have been The occurrence of zeorin (402) in lichens and ferns has been Zeorin 6-acetate (403) and aipolic acid (404) have been found in Physica aipolia while Rinodina thiomela contains zeorinone (405).3s7 Other new hopanes include lageflorin (406) from Lagerstroemiu parviJl~ra,~~~ hopane- 1,8,3,8,22-triol (407) from Mangifera indi~a,~l and mollugogenol G (408) from Mollugo hirt~.~~~ Mollugogenol A from Mollugo pentaphylla and M.hirta400has been shown to have antifungal The 'H and 13C NMR assignments of several fernanes have been published.402 An interesting series of 3,4-seco adiananes has been isolated from Euphorbia ~upina.~O~ The compounds are espinendiols A (409) and B (410) espinenoside (411) and tris-norisoespinenoside (412). The structures of espinendiol A (409) and espinenoside (41 1) were confirmed by X-ray analysis. E. supina also contains several fernane derivatives including supinenolones A (413) B (414) and C (415),404 and ferna- 7,9( 1 l)-dien-3/3-01 (41 6).236 The isomeric 6'441 7) A*-(418) and A9(11)-(41 9) fernen-28-oic acids have been reported from the rhizomes of Microsorium brachylepis and Microsorium normale where they occur with adian-5-en-28-oic acid (420).405 9 Miscellaneous Compounds The swertane carbon framework of swertanone (421) a pentacyclic triterpenoid constituent of Swertia chirata is novel NATURAL PRODUCT REPORTS 1994-J.D. CONNOLLY R. A. HILL AND B. T. NGADJUI HO LOdC Oglc OH! H OH OH (438) 13 P-H (439) 13 a-H and presumably arises by a backbone rearrangement of the gammacerane cation (422).406 The structure of swertanone (421) was established by X-ray analysis. Three unusual A16-gammaceranes (423)-(425) directly derivable from the cation (422) by loss of a proton from position 16 have been obtained from the roots of Picris hieraci~ides.~~’ The structures were confirmed by X-ray analysis of the derived 3-ketone.On treatment with acid the acetate (425) underwent a backbone rearrangement to give isopichierenyl acetate (426) which has also been isolated from P. hieracioides. It is accompanied by the A9(11)-i~~mer pichierenyl acetate (427).408 Achilleol (428) which has a new monocyclic triterpenoid skeleton has been isolated from Achillea odorata where it occurs as a mixture of esters of linoleic and oleic acids.409 An Asteropus species of marine sponge is the source of a series of triterpenoid galactosides pouosides A (429) B (430) C (43 l) D (432) and E (433) with a novel carotenoid type Two interesting triterpenoid glycosides xestovanin A (434) and (423) R = H CX-OH (424) R = H P-OH (425) R = H P-OAC OR2 (429) R = OAC R’ = Ac R2 = R3 = H (430) R = OAc R‘ = R2 = R3 = H (431) R = R2 = R3 = H R’ = Ac (432) R = OAC R’ = R2 = Ac R3 = H (433) R = OAC R’ = R3 = Ac R2 = H I OH OH (437) (440) A7 (441) A’ secoxestovanin A (435) have been obtained from the marine sponge Xestospongia vanilla.411Secoxestovanin A (435) can arise from xestovanin A (434) by a simple retroaldol reaction.The C, xestolide (436) and C, secoxestenone (437) also from X. vanilla probably arise from degradation of secoxestovanin A (435).412 Lemnaphyllum microphyllum is a rich source of triterpenoid hydrocarbons and has now been found to contain the isomeric malabaricatrienes (438) and (439). 413 The migrated malabaricane derivatives podioda-7,17,21 -triene (440) and podioda-8,17,2 1-triene (44 1) have been isolated from Polypodioides niponica.110 The absolute configurations of the cycloiridals from various Iris species have been established.414 An X-ray analysis of 22a-hydroxystictan-3-one a constituent of Pseudocyphellaria lichens has been The 13CNMR assignments of a series of serratanes have been reported.416 Syntheses of (+)-tricyclohexaprenol (442) a possible precursor of tricyclic geoterpanes and its isomer (443) have been described.417 NPR 11 10 References 1 S. 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Fenwick J. Nat. Prod. 1988 51 122. 328 C. L. Curl K. R. Price and G. R. Fenwick J. Sci. Food Agric. 1988 43 101. 329 A. A. Loloiko V. I. Grishkovets A. S. Shaskov and V. Y. Chirva Chem. Nat. Compd. (Engl. Transl.) 1988 24 320. 330 R. Kasai M. Miyakoshi R.-L. Nie J. Zhou K. Matsumoto T. Morita M. Nishi K. Miyahara and 0.Tanaka Phytochemistry 1988 27 1439. 331 H. Kawai M. Nishida Y. Tashiro M. Kuroyanagi A. Ueno and M. Satake Chem.Pharm. Bull. 1988 37 2318. 332 H.-B. Wang D.-Q. Tu X.-T. Liang N. Watanabe M. Tamai and S. Omura Planta Med. 1989 55 303. 333 H.-B. Wang D.-Q. Tu X.-T. Liang N. Watanabe M. Tamai and S. Omura Yaoxue Xuebao 1989,24,444 (Chem. Abstr. 1990,112 1 15703e). 334 G. Carpani F. Orsini M. Sisti and L. Verotta Phytochemistry 1989 28 863. 335 M. Levy U. Zhavi M. Naim and 1. Palacheck Carbohydr. Res. 1989 193 115. 336 M. M. Vugalter G. E. Dekanosidze 0.D. Dzikiya A. S. Shashkov and E. P. Kemertelidze Chem. Nat. Compd. (Engl. Transl.) 1988 24 193. 337 W.-W. Ma P. F. Heinstein and J. L. McLaughlin J. Nat. Prod. 1989 52 1132. 338 C. B. Rogers J. Nat. Prod. 1989 52 528. 339 D.-R. Hahn T. Oinaka R. Kasai and 0.Tanaka Chem. Pharm. Bull. 1989 37 2234.340 C. Jimenez M. C. Villaverde R. Riguera L. Castedo and F. Stermitz Phytochemistry 1989 28 2773. 341 A. A. Ansari S. Hassan L. Kenne Atta-ur-Rahman and T. Wehler Phytochemistry 1988 27 3977. 342 R. Su Z. Jia and Z. Zhu Chin. Sci. Bull. 1989 34 609 (Chem. Abstr. 1990 113 55 800t). 343 D. C. Jain R. S. Thakur A. Bajpai and A. R. Sood Phytochemistry 1988 27 1216. 344 M. Haraguchi M. Motidome and 0.R. Gottlieb Phytochemistry 1988 27 2291. 345 Z. Fang and G. Yin Zhiwu Xuebao 1989,31,708 (Chem. Abstr. 1990 113 74789n). 346 J. Kinjo T. Takeshita Y. Abe N. Terada H. Yamashita M. Yamasaki K. Takeuchi K. Murakami T. Tomimatsu and T. Nohara Chem. Pharm. Bull. 1988 36 1 174. 347 0.P. Sati S. Bahuguna S. Uniyal and D. S. Bhakuni Phytochernistry 1989 27 575.348 S. K. Srivastava J. Nat. Prod. 1989 52 1342. 349 G. Reznicek J. Jurentitsch G. Michl and E. Haslinger Tetrahedron Lett. 1989 30 4097. 350 G. Reznicek W. Kubelka J. Jurentitsch G. Michl and E. Haslinger Bull. Magn. Reson. 1989 11 402. 351 M. Maillard C. 0.Adewunmi and K. Hostettmann Helv. Chim. Acta 1989 72 668. 352 R.-L. Nie T. Tanaka M. Miyakoshi R. Kasai T. Morita J. Zhou and 0.Tanaka Phytochemistry 1989 28 171 1. 353 N. Aimi K. Likhitwitayawuid J. Goto D. Ponglux J. Haginiwa and S.-I. Sakai Tetrahedron 1989 45 4125. 354 A. Numata P. Yang C. Takahashi R. Fujiki M. Nabae and E. Fujita Chem. Pharm. Bull. 1989 37 648. 355 M. Nakatani Y. Miyuzaki T. Iwashita H. Naoki and T. Hase. Phytochemistry 1989 28 1479. 356 I.Kouno N. Baba Y. Ohni and N. Kawano Phytochemistry 1988 27 297. 357 L. Guang-Yi A. I. Gray and P. G. Waterman J. Nat. Prod. 1989 52 162. 358 D. Lontsi B. L. Sondengam and J. F. Ayafor J. Nat. Prod. 1989 52 52. 359 F. N. Ngounou D. Lontsi and B. L. Sondengam Phytochemistry 1988 27 2287. 360 M. Hatori K.-P. Kuo Y.-Z. Shu Y. Tezuka T. Kikuchi and T. Namba Phytochemistry 1988 27 3975. 361 G. Delgado J. Herandez and R. Perada-Miranda Phytochemistry 1989 28 1483. 362 N. Gopalsamy D. Vargras J. Guiho C. Ricaud and K. Hostettmann Phytochemistry 1988 27 3593. 363 S. Siddiqui S. Faizi B. S. Siddiqui and N. Sultana Phytochemistry 1989 28 2433. 364 S. Siddiqui S. Begum B. S. Siddiqui and F. Hafeez J.Nat. Prod. 1989 52 57. 365 S. Siddiqui S.Begum B. S. Siddiqui and F. Hafeez Planta Med. 1989 55 292. NATURAL PRODUCT REPORTS 1994 366 S. Matsunaga R. Tanaka and M. Akagi Phytochemistry 1988 27 535. 367 G. M. Pang C. J. Zhao H. Hori and S. Inayama Yaoxue Xuebao 1989 24 75 (Chem. Abstr. 1989 111 74779t). 368 C. P. Zhang Y. G. Zhang Q. T. Zheng and H. 0. He Yaoxue Xuebao 1989 24 225 (Chem. Abstr. 1989 111 228967s). 369 R. Mata L. Rios M. del R. Camacho M. T. Reguero and D. Lorence Phytochemistry 1988 27 1887. 370 T. G. Fourie E. Matthee and F. 0. Snyckers Phytochemistry 1989 28 2851. 371 M. Manzoori-i-Khuda A. K. Chawdury T. Reza and S. A. Chawdury Bangladesh J. Sci. Ind. Res. 1986 21 40 (Chem. Abstr. 1989 111 4206e). 372 S. Siddiqui B. S. Siddiqui A. Naeed and S. Begum Pak. J.Sci. Ind. Res. 1989 32 381 (Chem. Abstr. 1991 114 203467~). 373 K. S. Mukherjee and C. K. Chakravorty J.Ind. Chem. Soc. 1988 65 458. 374 E. Erciyas and M. Baysal Pharmazie 1989 44 580. 375 A. Q. Khan Z. Ahmed S. N. Kasmi and A. Malik J.Nat. Prod. 1988 51 925. 376 M. C. Das and S. B. Mahato Phytochemistry 1982 21 2069. 377 J. Sejbal E. Klintova M. Bludska J. Klinot and M. BudEinsky Collect. Czech. Chem. Commun. 1989 54 1036. 378 Y. Q. Jiang and C. X. Zu Yaoxue Xuebao 1988,23 749 (Chem. Abstr. 1989 110 132221~). 379 G. Liang Zhiwu Xuebao 1988 30,409 (Chem. Abstr. 1989 110 132 172g). 380 W. Qin J. Zhao A. Fukuyama and T. Yamada Zhongcaoyao 1988 19 434; 448 (Chem. Abstr. 1989 110 101 570f). 381 G. Gosmann E. P. Schenkel and 0. Seligmann J.Nat. Prod. 1989 52 1367. 382 M. Nakatani S. Hatanaka H. Komura T. Kubota and T. 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Chem. Res. (S) 1986 356; J. Chem. Res. (M) 1986 3037. 396 S. Inayama H. Hori G.-M. Pang H. Nagasawa and H. Ageta Chem. Pharm. Bull. 1989 37 2836. 397 A. L. Wilkins J. A. Elix K. L. Gaul and R. Moberg Aust. J. Chem. 1989 42 1415. 398 B. R. Barik and A. B. Kundu Phytochemistry 1988 27 3679. 399 A. K. Barua S. Gosh K. Basu and A. Patra J. Indian Chem. SOC., 1989 66,64. 400 P. Chakrabarti Tetrahedron 1969 25 3301.401 M. Hamburger G. Dudan A. G. R. Nair R. Japaprakasam and K. Hostettmann Phytochemistry 1989 28 1767. 402 A. L. Wilkins J. A. Elix A. G. Gonzalez and C. Perez Aust. J. Chem. 1989 42 1185. 403 R. Tanaka S. Matsunaga T. Ishida and T. Shingu Tetrahedron Lett. 1989 30,1661. 404 R. Tanaka and S. Matsunaga Phytochemistry 1989 28 3149. 405 K. Masuda R. Kamaya S. Ikegami Y. Ikeshima and H. Ageta Chem. Pharm. Bull. 1989 37 1673. 406 A. K. Chakravarty B. Das S. C. Pakrashi D. R. McPhail and A. T. McPhail J. Chem. Soc. Chem. Commun. 1989,438. 407 K. Shijima K. Masuda T. Lin H. Suzuki and H. Ageta Tetrahedron Lett. 1989 30 4977. 408 K. Shijima K. Masuda Y. Ooishi H. Suzuki and H. Ageta Tetrahedron Lett. 1989 30 6873. NATURAL PRODUCT REPORTS 1994-J.D. CONNOLLY R. A. HILL AND B. T. NGADJUI 409 A. F. Barrero E. J. Alvarez-Manzaneda R. and R. Alvarez- 413 K. Masuda K. Shiojima and H. Ageta Chem. Pharm. Bull. Manzaneda R Tetrahedron Lett. 1989 30 3351. 1989 37 1140. 410 M. B. Ksebati F. J. Schmitz and S. P. Gunasekera J. Org. Chem. 414 F.-J. Marner and L. Jaeniche Helv. Chim. Acta 1989 72 287. 1988 53 3917. 415 A. L. Wilkins and E. M. Goh Aust. J. Chem. 1988 41 143. 411 P. T. Northcote and R. J. Anderson J. Am. Chem. SOC.,1989 416 H. Seto K. Furihata X. Guangyi C. Xiong and P. Deji Agric. 111 6276. Biol. Chem. 1988 52 1797. 412 P. T. Northcote and R. J. Anderson Can. J. Chem. 1989 67 417 D. Heissler and C. Ladenburger Tetrahedron 1988 44 2513. 1359.

ISSN:0265-0568    

DOI:10.1039/NP9941100091

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Book Review The Chemistry of Natural Products ed. R. H. Thomson Blackie Academic & Professional Glasgow 2nd edn 1993 x+452 pp €79 (Hardback). ISBN 0 7514 0014 9. The last ten years have seen many significant developments in natural product chemistry stimulated in particular by the search for novel medicinal substances to combat various cancers and viruses including HIV. This book succeeds in bringing together many of these developments in natural product chemistry. The first edition of The Chemistry of Natural Products was published in 1985 and the various chapters then described progress in the ten years preceding 1982/3. This new edition covers the period between then and mid-1992 and in most respects it is a new book rather than a new edition of an existing text.Although the book has the same format as its predecessor the detailed content and many of the authors of the individual chapters are different. Inevitably the selection of material has to be arbitrary but the authors have succeeded in showing the direction in which natural product chemistry is progressing. The chapter on carbohydrates by K. J. Hale and A. C. Richardson is mainly devoted to two topics novel methods in glycoside formation and the use of carbohydrates as chiral templates reagents and starting materials for synthesis. The chapters on aromatic compounds and on terpenoids by M. Gill and R. A. Hill respectively are surveys of the wide range of new natural product structures that have been reported in the period together with an outline of some of the synthetic studies.The steroids continue to provide a valuable framework for exploring the scope of various reactions. Rearrangements remote oxidations photochemistry and partial synthesis are topics covered in the chapter by A. B. Turner. Developments in the synthesis of amino acids and peptides are found in the chapter by C. Bladon whilst the chapter on alkaloids by J. Leonard is also devoted to aspects of their synthesis. Much of the chapter by J. B. Hobbs on nucleosides nucleotides and nucleic acids reviews as would be expected synthetic studies in this area. The chapter on porphyrins by L. R. Milgrom and F. O’Neill covers a number of topics including the biosynthesis of the macrocycle studies on haemoprotein models porphyrin photochemistry and DNA-porphyrin interactions. The final chapter by D. R. Kelly describes a number of miscellaneous aspects of aliphatic natural products including insect semio- chemicals marine natural products and the enediyne antibiotics. Each chapter has a useful list of literature references. The book is well-produced and can be recommended as providing a varied interesting and useful account of progress in different aspects of natural product chemistry over the last ten years. J. R.Hanson 119

ISSN:0265-0568    

DOI:10.1039/NP9941100119

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Corrigenda We apologize to Professor D. J. Robins for an editorial error that led to a number of incorrect formulae appearing in his article ‘Pyrrolizidine Alkaloids’ (Natural Products Reports 1993 10 487). The following should have appeared -.C 0-0 OTS i-iii QI 0 NCH2C02Et Scheme 7 (105) R=Ac (106) R=H 121

ISSN:0265-0568    

DOI:10.1039/NP9941100121

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

The Fluorinated Natural Products D. B. Harpere and D. O'Haganb a Department of Food and Agricultural Chemistry The Queens' University of Belfast Newforge Lane Belfast BT95PX UK Department of Chemistry University of Durham Science Laboratories South Road Durham DH 1 3LE UK 1 Introduction 2 Fluorinated Natural Products in Plants 2.1 Fluoroacetic Acid 2.2 w-Fluorofatty acids 2.3 Fluoroacetone 2.4 (2R,3R)-2-Fluorocitrate 3 Fluorinated Natural Products in Microorganisms 3.1 Nucleocidin 3.2 4-Fluorothreonine and Fluoroacetic Acid 4 Fluorinated Natural Products in Mammals and Insects 5 The Origin of Organofluorine Metabolites 5.1 Pyridoxal Phosphate-catalysed Incorporation of Fluoride 5.2 Nucleophilic Substitution by Fluoride 5.3 Acetate or Ethylene as a Precursor 5.4 The Haloperoxidase Reaction 5.5 A Halometabolite Precursor 5.6 Fluorophosphate as an Intermediate 6 References 1 Introduction Fluorine is the most abundant halogen in the Earth's crust ranking 13th in abundance of all the e1ements.l The fluorine content of most igneous and sedimentary rocks (270-740 ppm) is higher than that of chlorine (10-180 ppm) but much of this fluorine is in an insoluble form which is biologically unavail- able.2 Thus sea water contains only 1.3 ppm of fluoride in contrast to 19000 ppm of chloride.Nevertheless inorganic fluoride can occur in significant quantities in both marine and terrestrial organisms. The sponge Halichondria moorei is reported to accumulate as much as 10% fluorine on a dry weight basis as potassium fluor~silicate.~ Certain terrestrial plants and in particular those of the genus Camellia which includes the tea plant (Thea sinensis = Camellia sinensis) can selectively concentrate inorganic fluoride from relatively low concentrations in the ~oil.~,~ Thus commercial tea itself can contain 70-180 ,ug g-' dry weight fluoride and levels of up to 3000 ,ug g-' dry weight have been observed in older leaves of ornamental Camellia species such as C.japonica.In areas with fluoride-rich bedrock or those polluted with fluorospar (CaF,) mining waste some plant species can contain up to 10000 ,ug g-' dry weight fl~oride.~,' Table 1 X Bond dissociation energy CH,-X (kcalmol-')* Bond length Co-X (A) Dipole moment CH,X (Debye units) F 110 1.39 1.82 C1 85 1.78 1.94 Br 71 1.93 1.97 I 57 2.14 1.64 H 99 1.09 0 * 1 kcal = 4.184 kJ.On the other hand organically bound fluorine appears to be comparatively rare in Nature. It has been identified in only a relatively small number of tropical and subtropical plants and amongst microorganisms in only two actinomycetes. Not a single organofluorine compound has been isolated either from the animal kingdom or from any organism in the marine environment. The underlying reason for this dearth of fluorinated natural products compared with the relative abundance of other halogenated metabolites is to be found in the unique chemical attributes of fluorine.In this respect fluorine has been referred to as a 'superhalogen ',8 a description emphasizing how distinct its properties are from those of the other halogens. Fluorine is compared in Table 1 with other halogens as regards some significant physicochemical parameters and the Van der Waal's radius of fluorine is contrasted with those of other substituent groups in Table 2.*11 It is the smallest of the halogens with a radius only slightly greater -than that of hydrogen. It is also the most electronegative of all the elements forming the strongest single bond to carbon with a bond dissociation energy exceeding that of the C-H bond. Electron withdrawal by fluorine results in a strong polarization of the C-F bond and the pronounced electronic effects can have implications for reactions at adjacent carbon centres.Thus the presence of fluorine in a molecule has minor steric but potentially major electronic consequences. This influence is exemplified in substrate+nzyme binding where the presence of fluorine can alter the acidity of neighbouring functional groups and affect the binding affinity of an enzyme for substrate. Although fluoride is not a particularly good leaving group its propensity for hydration can assist fluoride elimination under certain circumstances. Thus attack by a nucleophilic group such as SH located at the active site of an enzyme can result in displacement of fluoride with formation of a covalent link between the organic moiety and the enzyme. These attributes are not only relevant to the mechanism of biosynthesis of natural organofluorine compounds but also contribute more generally to the biological activity of many fluorinated analogues of intermediary metabolites and natural products.1@15 Probably the factor of greatest importance in restricting the participation of fluorine in biochemical processes is the high heat of hydration of the fluoride ion.The resultant ease of solvation renders the small fluoride ion only weakly nucleophilic Hydration energy X-Electronegativity (kcal rnol-l)* (Pauling scale)* 117 4.0 84 3.O 78 2.8 68 2.5 -2.2 Standard oxid./red. potential EDfor 2X-e X +2e (V) -3.06 -1.36 -1.07 -0.54 -123 Table 2 Substituent X Bond 1Fngth C-X (A) Van deroWaal's radius (A) H 1.09 1.20 F 1.39 1.35 0 (in OH)c1 1.43 1.78 1.40 1 .80 S (in SH) Br 1.82 1.93 1.85 1.95 I 2.14 2.15 and therefore circumscribes a whole chemistry based on displacement reactions.Also the greater heat of hydration of fluoride ion compared to the other halide ions is largely responsible16 for the substantial differences in redox potential for oxidation of the respective ions a phenomenon which has far-reaching implications for the generation of F' or F+ species and therefore single electron transfer or electrophilic synthesis of the C-F bond. This is discussed in the context of the haloperoxidase reaction in Section 5.4. A useful property of fluorine arises from the fact that the single naturally occurring isotope of the element 19F,possesses like hydrogen a spin quantum number of one half (I= f)and also a magnetogyric ratio similar to that of the proton.As fluorine coupling constants and chemical shifts are at least an order of magnitude larger than those of the corresponding proton analogues l9FNMR spectroscopy is therefore a powerful analytical tool for investigation of the role of fluorine in biological systems. Indeed in the broader context the use of 19FNMR spectroscopy is a most effective method for studying the metabolism of fluorinated compounds and with the dramatic improvement in the sensitivity of NMR instrument- ation in recent years the technique is an attractive tool with which to screen for novel fluorinated metabolites.2 Fluorinated Natural Products in Plants 2.1 Fluoroacetic Acid Fluoracetic acid (1) is the most common naturally occurring organofluorine compound. It was first identified by Marai~'~.'~ in 1943 as the toxic principle in the South African plant Dichapetalum cymosum which is responsible for considerable cattle loss in the Transvaal region.lg The young leaves of the plant which are particularly toxic in early spring can accumulate fluoroacetate up to 2500 pg g-' dry weight.20,21 Since then many other species of the Dichapetalaceae have been found to produce fluoroacetate. Most recently22 levels of fluoroacetate up to 8000 pg g-' dry weight have been recorded in the young leaves and seeds of D. braunii from Southeastern Tanzania.These are the highest recorded levels of the compound reported in a plant to date. Fluoroacetate also occurs in high concentrations in the leaves of D. toxicari~m,~~-~~ a West African species which accumulates w-fluorinated lipids in the seeds (see Section 2.2). The leaves of D. he~delotti~~ and the leaves and seed of D. ~tuhlmanniz~~~~~ have also been shown to contain the compound. There is good toxicological evidence24 to suggest the presence of fluoroacetate in D.michelsonii,26 D. g~ineense,~~ D. r~hlandii,~' D. venenatum,28 D. macrocarp~m,~~ D. barterie,31 D. dejlex~m,~~?~~ and D. D . m~ssambicense,~~~~~ tomento~um.~~ Fluoroacetate has also been identified in Spondi-anthus preussi from West A variety of Australian plants are known to accumulate the toxin; the most widely studied is Acacia georginae (gidyea) found in Queensland.The leaves and seeds of this species are reported to contain up to 250 and 4OOpgg-' dry weight re~pectively.~~-~~ However amounts appear to vary depending on geographic location suggesting considerable genetic varia- bilit~.~~,~~ Many plants of the Gastrolobium and Oxylobium NATURAL PRODUCT REPORTS 1994 genera which belong to the Leguminosae accumulate relatively high levels of the to~in.~~,~~,~~ The most toxic species Oxylobium parviform (box poison) can accumulate41 as much as 2500 pg g-' dry weight. The toxicity of many other plants in Western Australia has been long recognized as evidenced by their local names. Those in which fluoroacetate has been positively identified include G.bennettsianum (cluster poison) G. bidens G. bilobium (heart leaf poison) G. callistachys (rock poison) G. calycinum (York Road poison) G. jloribundum (woodjil poison) G. grandzjlorum (wallflower poison) G. laytonii (kite leaf poison) G. microcarpum (sandplain poison) G. oxylobiodes (Champion Bay poison) G. rotundifolium (gilbernine poison) G.spinosum (prickly poison) G. stenophyllum G. villosum 0. graniticum (granite poison) 0.racemosum (net leaf poison) 0.rigidum (rigid leaf poison) 0.spectabile (Roe's poison) and 0. tetragonophyllum (brother-br~ther).~~~~ Although fluoroacetate-containing species are not so wide-spread on other continents a Brazilian species Palicourea margravii of the Rosaceae can biosynthesize substantial amounts of the toxin with organofluorine concentration^^^^^^ in the seeds and flower stalk attaining 5000 pg g-l dry weight and fluoroacetate has been detected44 in low concentrations (10 pg g-l dry weight) in guar gum derived from the Indian legume Cyamopsis tetragonolobus.The distribution of fluoro- acetate-producing plants is therefore global in tropical and semitropical regions. Fluoroacetate concentrations vary markedly between dif- ferent plant organs within a species and for a comparison of the fluorine content (organic and inorganic) in the various tissues of many of the foregoing plants the reader is referred to a comprehensive study by Hall.37 The level of fluoroacetate found in a particular species can in addition change dramatically with the season and age of the plant; in general young shoots and leaves have high levels of the toxin in spring and as the plants mature these levels fall becoming negligible within a few This may account for the wide range of fluoro- acetate levels reported by different investigators for the same species although genetic variability climate and geographical location are also important considerations.Tissue cultures capable of fluoroacetate production are potentially attractive systems in which to study the metabolism of fluoride and the biosynthesis of organofluorine compounds (see Section 5.1). Callus cultures of A. georginae were first establi~hed~~,~~ in 1970 from stem sections of the plant. Fluoroacetate production was maximal when the medium was supplemented with 10 mM sodium fluoride but decreased at 100m~ when cell growth was retarded.Independently a decade later another A. georginae culture with similar characteristics was generated from leaf Unfortunately no quantitation of fluoroacetate production was conducted in either case. A tissue culture of D.cymosum developed48 in South Africa from immature fruits of the plant was reported to produce fluoroacetate optimally at 1200pg g-l dry weight with 6 mM sodium fluoride. However this level of production was not sustainable and the culture now yields about 150 pg g-l dry weight an order of magnitude less.49 It is noteworthy that some crop and forage plants will synthesize trace quantities of fluoroacetate (and fluorocitrate) when grown in the presence of fl~oride.~O-~~ Both soya bean (Glycine max) and crested wheat grass (Agropyron cristatus) appear to have this ability.Cell cultures of Glycine max accumulated fluoroacetate at 4 pg g-l dry weight when grown in 1 mM Traces of fluoro- acetate were detected in concentrations up to 0.21 pg g-l dry weight in 75 % of over 100 samples of plant material collected from areas with high fluoride-containing bedrock in Finland.54 The authors of this report also noted concentrations of fluoroacetate ranging from 0.06 to 0.48pgg-' dry weight in samples of commercial tea (see Section 2.4). These observations clearly suggest that plants more generally may have the latent capacity to biosynthesize the toxin and that plants producing high levels of fluoroacetate in nature may simply have refined and amplified this pathway during the evolutionary process.NATURAL PRODUCT REPORTS 1994-D. B. HARPER AND D. O'HAGAN n = 4,6,7,8 stearoyl / 1 desaturase incorporatedas lipid esters 0 F SACP wfluorooleoyI-SACP (3) wfluorooleate (4) other polysaturated o-fluorinated lipids 0 0 F SACP OH 0 F OH OH (6) Scheme 1 Plants that accumulate high levels of fluoroacetate clearly have a resistance mechanism to counter the toxic effects of the compound. As outlined in detail in Section 2.4 the conversion of fluoroacetate to (2R,3R)-fluorocitrate is responsible for the toxicity of fluoroacetate. For this to occur fluoroacetate must first be activated to fluoroacetyl-CoA before being processed by citrate synthase.It was demonstrated recently55 that a mitochondria1 extract from a tissue culture of D. cymosum was efficiently able to hydrolyse fluoroacetyl-CoA but not acetyl-CoA. The presence of such a specific fluoroacetyl-CoA hydrolase in this plant may represent a defence strategy as fluoroacetate per se is essentially innocuous. Whether other fluoroacetate-accumulating plants contain this hydrolase remains to be determined. Other resistance mechanisms postulated include segregation of fluoroacetate in parts of the cell remote from the mitochondria thus avoiding incorporation of fl~oroacetate,~' the presence of plant citrate synthase unable to utilize fl~oroacetyl-CoA,~~ and the insensitivity of some plant aconitases to fluorocitrate inhibiti~n.~',~~ None of these processes have been convincingly demonstrated.2.2 w-Fluorofatty Acids The ability of the West African shrub D. toxicarium to accumulate fluoroacetate (1) in the leaves is mentioned in Section 2.1.However the most toxic part of the plant is the seed which can contain up to 1800 pg g-' dry weight of organic was isolated from the saponified seed This compound which accounted for about 1 % of the organic fluorine in the seed could be derived metabolically from w-fluorooleic acid via an intermediate 9,lO-epoxide (5). Indeed the dihydroxy com- pound may not occur as such in the oil but may instead arise by hydrolysis of the 9,lO-epoxide during extraction.The biosynthesis of o-fluorofatty acids by D. toxicarium is readily explained by the action of the relevant fatty acid synthase employing fluoroacetyl-CoA (2) as a starter unit. The broad substrate specificity of fatty acid synthases enables them to utilize a range of starter units other than acetyl-CoA for condensation with malonyl acyl carrier protein (malonyl-ACP) in the initial stage of fatty acid biosynthe~is.,~ However the restriction of fluorine to the o-position implies the existence of enzymic constraints at subsequent stages of the biosynthetic process. Thus either the acetyl-CoA carboxylase enzyme does not readily synthesize fluoromalonyl-CoA or the substrate flexibility of the malonyl-ACP transacylase does not extend to fluoromalonyl-ACP during chain elongation.Presumably the stearoyl desaturase of the seed cannot discriminate between stearoyl-ACP and its o-fluorinated analogue and so processes the fluorinated compound to o-fluorooleoyl-ACP (3) which can be hydrolysed to w-fluorooleate (4) or further elaborated into a range of polyunsaturated and functionalized lipids as illustrated in Scheme 1. The results of a study on the distribution of fluoroacetate within D.toxicarium suggest that fluoroacetate used in o-fluorine hardly any of which is in the form of fluoroa~etate.~'.~~ fluorofatty acid biosynthesis in the seed is not formed in ~itu.,~ The principal fluorinated component comprising about 80 YO As discussed above fluoroacetate is practically undetectable in of the total organic fluorine present and 3% of the seed oil was isolated by Peters and co-workers in 1959 and was identified as o-fluorooleic acid (C18:1).59-61 The presence of w-fluoropalmitic acid (C,,,,) was also confirmed and small quantities of o-fluorocapric (C,,,,) and o-fluoromyristic (C,,,,) acids were tentatively identified by gas chromatography.A reexamination of the seed oil in 1990 using gas chromato- graphy/mass spectrometry (GCMS) established in addition the presence of w-fluoro derivatives of palmitoleic (C,, ,) stearic (C,,,,) linoleic (C,,:,) arachidic (C,,,,) and eicosenoic (C,,,,) acids., Recently threo-18-fluoro-9,lO-dihydroxystearicacid (6) the seed itself but leaves have much higher concentrations ranging from 60 pg g-l dry weight in mature leaves to 450 pg g-l dry weight in young leaves.In the small leaves adnate to the inflorescence fluoroacetate levels can attain 1100 pg g-l dry weight during flowering declining to 25 pg g-' dry weight when the flowers have died. The most feasible explanation for this distribution is that fluoroacetate is synthesized in the young leaves and then stored in those adjacent to the inflorescence before transport after fertilization to the developing embryo where as fluoroacetyl-CoA it is incorporated into the long- chain fatty acids. NATURAL PRODUCT REPORTS 1994 Scheme 2 attack Scheme 3 2.3 Fluoroacetone In 1967 Peters and Shorthouse noted a significant loss of total fluorine after incubation of homogenates of Acacia georginae and other plant^^^.^^ with inorganic fluoride.When the volatiles from Acacia georginae homogenates were passed through a solution of 2,4-dinitrophenylhydrazine,the formation of the 2,4-dinitrophenylhydrazonederivative of fluoroacetone (9) was observed and the amounts found were correlated with the concentration of fluoride in the hom~genate.~~ The fluorine recovered as the hydrazone constituted only 13 YOof that lost from the homogenates and the generation of other volatile organofluorine compounds was inferred by these workers. Fluoroacetone may be derived from 4-fluoroacetoacetyl-ACP (7) formed by the condensation of fluoroacetyl-CoA (2) with malonyl-ACP the first step in the biosynthesis of the w-fluorinated fatty acids (see Section 2.2 and Scheme 1).Hydrolysis to 4-fluoroacetoacetate (8) followed by decarboxyl- ation would yield fluoroacetone (9) as shown in Scheme 2. It is noteworthy that fluoroacetone (9) has been identified68 in rat liver perfused with fluoroacetate and a similar process may operate here. The level of accumulated fluoroacetate in plants can change over a relatively short time span. For example in the spring the leaves of Dichapetalum braunii possess levels22 up to 7200 pg g-' dry weight but within a few months concentrations can fall to 200 ,ug g-l dry weight. It could be argued that the conversion of fluoroacetate into volatile organofluorine compounds offers an effective detoxification strategy for such fluoroacetate accumu- lators when their requirement for the toxin diminishes.However it must be stressed that there is no evidence collected in vivo for such a pathway (see Section 5.3). 2.4 (2R,3R)-2-Fluorocitrate (2R,3R)-2-Fluorocitrate (1 1) is a common co-metabolite of fluoroacetate arising by condensation of fluoroacetyl-CoA with oxaloacetate (1 0) mediated by the citric acid-cycle enzyme citrate synthase. Forage plants such as soya bean alfalfa and crested wheatgrass all accumulate low levels of fluoroacetate The stereochemical course of the citrate synthase reaction with fluoroacetyl-CoA has been studied in detai1.70-72 The reaction is stereospecific and the 2-pro-S hydrogen of fluoroacetyl-CoA is abstracted excl~sively.~~ This observation implies restricted rotation around the carbon-carbon bond of the fluoroacetyl moiety when bound to the enzyme or stereo- electronic control during the reaction either of which must be attributed to the presence of the fluorine atom.The condensation proceeds with inversion of onf figuration^^ at C-2 to generate (2R,3R)-2-fluorocitrate (1 1) as the only stereo- isomer.73 These stereochemical conclusions are summarized in Scheme 3. The toxicity of fluoroacetate to mammals was first attributed to the 'lethal synthesis'74 of (2R,3R)-2-fluorocitrate (the other three stereoisomers being nontoxic) by citrate synthase. (2R,3R)-2-Fluorocitrate is a competitive inhibitor of aconitase the enzyme that follows citrate synthase in the citric acid cycle and interconverts citric and isocitric acids; consequently fluoroacetate poisoning blocks the citric acid cycle.More recently however inhibition of citrate transport has been implicated as a more significant factor10'75 in the toxicity of fluorocitrate. The studies of Kun and co-w~rkers'~~~ have revealed that l4C-radiolabelled fluorocitrate forms a covalent bond with a citrate carrier protein leading to inhibition of citrate transport across the mitochondrial membrane. Such inhibition would account for discrepancies in the kinetic data. K values for inhibition of aconitase by fluorocitrate vary but are typically in the region of 1 p~, whereas fluorocitrate is toxic at ,UMlevels. Therefore the inhibition of aconitase widely promulgated by Peters may make only a minor contribution to fluorocitrate toxicity.This explanation is consistent also with other studies where fluorocitrate toxicity has been shown to be associated with inhibition of mitochondrial aconitase but not the cytoplasmic enzyme.79 3 Fluorinated Natural Products from Microorganisms 3.1 Nucleocidin An adenine-containing antibiotic named nucleocidin (12) was and fluorocitrate when they are incubated with fl~oride.~~~~ purified in 1957 from the fermentation broths of the micro- Cell cultures of the tea plant (Thea sinensis) can form 5-10 pg fluorocitrate g-l dry weight in the tissue and commercial tea69 can contain up to 30 pug g-l dry weight but fortunately these levels are well below those of toxicological significance.Fluorocitrate at concentrations up to 60 ,ug g-' dry weight has also been detected in oatmeal.6g Such reports lend further support to the view that the capacity to biosynthesize fluoroacetate from fluoride is widespread in plants (see Section 2.1). organism Streptomyces calvus isolated from an Indian soil sample.8o Initially an empirical formula of Cl,Hl,N6S08 was proposed for the compound which displayed a broad spectrum of antibiotic activity being a particularly effective antitrypano- soma1 agent.81-83 Unfortunately clinical use of the compound was curtailed by its toxicity. The empirical formula of nucleocidin was revised to Cl0H,,N,SO7 (9-[4-O-sulfamoyl- pentofuranosyl] adenine) in 196ga4 before it was realized in NATURAL PRODUCT REPORTS 1994-D.B. HARPER AND D. O'HAGAN -F ,$.F OH 0 F&OH H P NH H O 1969 that the doubling of certain lines in the 'H NMR spectrum previously attributed to hindered rotation within the molecule was actually due to coupling with fl~orine.'~ On the basis of new spectroscopic evidence including 'H and 19FNMR analyses the empirical formula was further revised to C,,H,,N,SO,F and a new structure 4'-fluoro-5'-O-sulfamoyl-adenosine (12) was advanced.85A P-D-configuration of the ribose moiety was postulated.86 That this was a correct representation of the molecule was finally confirmed by total synthesis in 1976.87 The source of fluorine for microbial biosynthesis of the compound in the fermentation broth from which initial isolation was accomplished is not clear as no fluorine-containing salts were used in the formulation of the culture medium and the only non-defined component was corn steep liquor.However the reported yield of nucleocidin 2-5 mg l-' was such that the fluorine requirement could well have been supplied by trace impurities in the mineral salts or indeed the tap water employed in preparation of the medium. It is quite possible that the yield of nucleocidin could have been markedly enhanced by supplementation of the medium with fluoride ion. Recent attempts to re-isolate nucleocidin from S. calvus have proved singularlyunsuccessful.88This is particularly frustrating for future enzyme studies as nucleocidin is not obviously derived from fluoroacetate and the biosynthesis of the compound might therefore involve a C-F bond-forming enzyme unique to S.calvus. 3.2 4-Fluorothreonine and Fluoroacetic Acid In the course of studies in 1986 on improving the production of the P-lactam antibiotic thienamycin by the actinomycete Streptomyces cattleya Sanada et al.'g discovered that under certain conditions the organism biosynthesized an antimetabo-lite which was isolated and identified as 4-fluorothreonine (13). The amino acid exhibited antimicrobial activity against a range of bacteria apparently acting as a metabolic analogue of L-threonine since growth inhibition could be reversed by L-serine and L-threonine. The compound was an optically active single stereoisomer shown in structure (13) as stereochemically analogous to L-threonine.However chemical proof of this assignment has not yet been obtained. 4-Fluorothreonine was formed at concentrations up to 150 mg 1-' (-1 mM) when S. cattleya was cultured on a complex medium to which no supplemental fluoride had been added. However as with the investigations leading to the isolation of nucleocidin (see Section 3. l) extraneous fluoride contamination had occurred. Analysis of soya bean casein one of the major components of the medium revealed the presence of 0.7 YOfluorine as inorganic fluoride. On exclusion of casein from the medium no 4-fluorothreonine was formed but biosynthesis could be re-established by the addition of 2 mM fluoride. Supplementation of the medium with other halide ions failed to result in the production of the corresponding 4-halothreonines.Evidence was obtained by 19F NMR studies that under conditions conducive to 4-fluorothreonine biosynthesis fluoro-acetate also accumulated in the culture medium to a con-centration of 2-3 mM. Resting cells of the organism were able to utilize fluoride fluoroacetate and 4-fluoroglutamate as a source of fluorine for synthesis of 4-fluorothreonine and conversely both 4-fluorothreonine and 4-fluoroglutamate were converted to fluoroacetate. Fluorocitrate appeared meta-(14) Scheme 4 OH 0 1 II bolically inactive in S. cattleya. Sanada et al.89suggested that fluoroacetate was the initial product of enzymatic fluorination and that 4-fluorothreonine (13) was biosynthesized via con-densation of fluoroacetaldehyde (14) and glycine as shown in Scheme 4.Further work on this microbial system by Reid et al.90 does not offer any support for this hypothesis. No evidence was found of significant formation of 4-fluorothreonine from fluoroacetate other than by de novo synthesis utilizing fluoride ion released during microbial defluorination. These workers concluded that 4-fluorothreonine or the corresponding 2-keto acid is likely to be the initial product of fluorination and that fluoroacetate is formed by cleavage of the compound reversing the process in Scheme 4. Similar retroaldol condensations of p-hydroxy-a-amino acids have been described recently catalysed by an aldolase from another Streptomyces SP.~'Interestingly another unusual amino acid (2S 3R)-2-amino-3-hydroxypent-4-ynoic acid (15) also capable of acting as a metabolic analogue of L-threonine was isolated during purification of 4-fluorothreonine from the fermentation broth of S.~attleya.~~ Whether the close similarity in structure between this acetylenic amino acid and 4-fluorothreonine (13) indicates a common biosynthetic origin is a matter for speculation. 4 Fluorinated Natural Products in Mammals and Insects Although there is no direct evidence of de novo biosynthesis of fluorinated natural products by animals there are indications in the literature that the occurrence of organofluorine compounds in nature may not be restricted to the plant and microbial kingdoms. As mentioned above (Sections 1,2.1,and 2.4) the tea plant can accumulate substantial quantities of inorganic fluoride.Japanese investigators have demonstrated that a moth Nygmia pseudoconspersa (Euproctis conspersa) feeding on the tea plant selectively concentrates fluoride to a level of 5000 pg g-' dry weight in the wings and 1100 pg g-' dry weight in the cocoon.93No attempt was made to determine whether the fluorine was in organic form but it is perhaps significant that the scales of the insect are toxic on skin contact a characteristic of w-fluorofatty acids. The young leaves and fruit of the fluoroacetate-containing plant D.cyrnosum (see Section 2.1) are parasitized by caterpillars of the moth Sindris albimaculatus. The caterpillars are highly toxic to predators and it has been postulated that fluoroacetate is accumulated in vacuoles or sacs within the larvae.94 Plasma from humans but not other animals is reported to contain 14 ,UM organic fl~orine.~~~~~ Approximately 30 YOof such fluorine is accounted for by the synthetic perfluorofatty acids (C,-C,) widely employed as water and oil repellants for fabric treatment and in the formulation of various waxes.97The nature of the remainder has not been elucidated and so the question of whether it is of natural or synthetic origin has yet to be resolved.In regions of western Australia where there are a variety of NATURAL PRODUCT REPORTS 1994 Scheme 5 indigenous fluoroacetate-producing plants herbivorous mam- mals such as the kangaroo bush rat possum emu,98 and other birds,gg have apparently evolved a resistance to fluoroacetate.lOO For an excellent recent review of this literature see reference 101.Thus the brush-tailed possum Trichosurus vulpecula of south-western Australia which shows an LD, for fluoroacetate of -100 mg kg-' is approximately 150 times less susceptible to fluoroacetate poisoning than the same species found in eastern Australia which is outside the range of plant species containing the toxin. The biochemical basis for this remarkable tolerance has been investigated but with inconclusive results.lo2 Although a glutathione-dependent defluorinating enzyme was found in the liver of the brush-tailed possum no difference in defluorin- ation rates was observed in vitro between animals from the two populations.Fluoroacetate was rapidly converted to fluoro- citrate and aconitase was inhibited to a similar extent by fluorocitrate in animals from both western and eastern Australia. Nevertheless the western animals required a dose of fluoroacetate 200-fold higher than the eastern population to induce the same increase in plasma citrate levels. These investigators were unable to draw any firm conclusions but tentatively suggested that glutathione could play a role in resistance either by binding fluorocitrate thus preventing inhibition of citrate transport through the mitochondria1 membrane (see Section 2.4) or by an effect on aconitase. Further work is clearly required in this area. It is quite likely that evolution of fluoroacetate tolerance has also occurred in populations of herbivores in other parts of the world where fluoroacetate-containing plant species are indigenous e.g.South Africa and South America. 5 The Origin of Organofluorine Metabolites The 50 years that have elapsed since the original discovery of fluoroacetate in nature by Marai~"*'~ have not been marked by any major progress in understanding the mechanism of biological C-F bond formation in either plants or micro-organisms. This should not be regarded as implying that the literature has been bereft of speculation on the subject nor should it be seen as belittling the considerable achievements by Peters and co-workers in the area. Rather it serves to illustrate the intractable nature of the problem caused mainly by the difficulties hitherto associated with detection and determination of fluorinated compounds and the problems involved in acquiring regular fresh supplies of uniform genotype of the tropical plants capable of fluoroacetate biosynthesis many of which are confined to the less accessible areas of Africa Australia and South America.Our knowledge of the fluorination process in the plant is so restricted that Hall and Cain103 have even called into question whether C-F bond formation actually occurs in the plant at all. The surprisingly large amounts of fluoroacetate (-100 pg g-' dry weight) in soils in which D.cyrnosurn and D. toxicarium grow in the wild led to the suggestion that perhaps fluoroacetate was synthesized by microorganisms living symbiotically on the root surface and was absorbed by the root for translocation to the aerial parts of the plant.Organic fluorine is certainly present in high concentrations in roots of these species but the demonstration that fluoroacetate is produced from fluoride in sterile tissue cultures of A. georginae4' and D. cyrno~urn~~ (see Section 2.1) has finally dispelled any lingering doubts as to the ability of plants to accomplish de novo synthesis. Several developments in recent years have helped to resolve many of the problems hindering progress in this field. The discovery of microorganisms capable of C-F bond synthesis and the establishment of callus tissue cultures of fluoroacetate- producing plants have provided more accessible and convenient biological systems in which to study fluorination processes.Secondly the developments of analytical techniques such as gas chromatography/mass spectrometry the use of fluoride ion- selective electrodes and in particular the advent of 19FNMR spectroscopy have facilitated the assay of fluorinated metabo- lites. The time is therefore ripe for progress in the field and the 50th anniversary of Marais's discovery is perhaps an appro- priate juncture at which to review the mechanisms for C-F bond biosynthesis that have been proposed in the literature since 1943.'' These are considered below in the light of the limited scientific evidence garnered to date. 5.1 Pyridoxal Phosphate-catalysed Incorporation of Fluoride A plausible mechanism for the biosynthesis of fluoroacetate involving pyridoxal phosphate has been proposed by Mead and Segal.lo4 Their reasoning was based largely on the presence in plants of a wide range of P-substituted alanines e.g.(17)-(22).lo5-ll1 The biosynthesis of these compounds in a variety of plants is believed to proceed by the attack of a nucleophilic NATURAL PRODUCT REPORTS 1996D. B. HARPER AND D. O’HAGAN F F-l wCo2H F H203PO X = OH SH or even OAc F Scheme 6 species at C-3 of a pyridoxal phosphate enamine adduct (16) arising by elimination of the /?-substituent from serine or cysteine as shown in Scheme 5. The occurrence of seven p-substituted alanines in Acacia spp. suggests that the process must be mediated in this genus at least by a relatively nonspecific synthase which can utilize a variety of nucleophiles.It is perhaps significant that the fluoroacetate-producing species A. georginae can also elaborate three /?-substituted alanines including albizziine (2l) presumably derived from urea. The central tenet of Mead and Segal’s hypothesis is that not only may each of the amino acids (17)-(22) be derived from the pyridoxal phosphate enamine intermediate (16) by the attack of the appropriate nucleophile but that the enzyme possesses a sufficiently relaxed substrate specificity to allow attack of F-with the formation of pyridoxamine phosphate-bound fluoro- pyruvate (23). This intermediate may undergo hydrolysis to fluoropyruvate (24) and then oxidative decarboxylation to fluoroacetic acid (1) as shown in Scheme 6.Alternatively direct decarboxylation and hydrolysis to fluoroacetaldehyde followed by oxidation to fluoroacetic acid could occur. Some evidence for the former transformation is provided by recent studies of fluoropyruvate metabolism in D. cymosum tissue cultures. Intact cells of the culture can efficiently mediate an oxidative decarboxylation of fluoropyruvate (24) to fluoroacetate.l12 The pyruvate dehydrogenase complex (PDC) catalyses the anal- ogous transformation of pyruvate to acetyl-CoA in most organisms but fluoropyruvate is quantitatively and stoichio- metrically defl~orinated’l~ by the thiamine pyrophosphate 114 enzyme pyruvate decarboxylase which constitutes the first enzyme of PDC. Thus incubation of fluoropyruvate with cell- free extracts115 of D.cymosum results in rapid defluorination of fluoropyruvate due to the high level of PDC activity in the extract.However in the presence of monomethyl acetylphos- phonate (MAP) a powerful PDC inhibitor (Ki = 5 x mM), the extract was able to convert fluoropyruvate to fluoro-acetate. It would appear that in the whole cells of D.cymosum fluoropyruvate decarboxylation is compartmentalized and isolated from the sites of high PDC activity particularly the mitochondria. This study demonstrates that fluoropyruvate (24) is a feasible intermediate in fluoroacetate biosynthesis in D.cymosum but as the presence of endogenous fluoropyruvate in the plant has not yet been demonstrated the evidence must remain circumstantial at present.Mead and Segal1lG attempted to validate their hypothesis by examining the effect of cyanide and fluoride on the conversion of L-cysteine to pyruvate by acetone powders of A. georginae. An a,/?-eliminase in these preparations catalysed the pyridoxal phosphate-dependent formation of pyruvate from cysteine presumably via the enamine adduct (16) shown in Scheme 5. On addition of cyanide this transformation was almost completely inhibited and the production of p-cyanoalanine (17) was observed suggesting that the enamine intermediate had under- gone nucleophilic attack by CN-. @-Cyanoalanine (17) has not been reported as a metabolite of Acacia spp. so the in vitro production of this compound does seem to reflect a lack of substrate specificity by the enzyme in A.georginae. Disap-pointingly no evidence was obtained for formation of p-fluoroalanine (25) on addition of fluoride ion to extracts under similar conditions (see Scheme 6). No fluoride uptake was apparent with cysteine serine or 0-acetylserine as substrate and efforts to show fluoropyruvate formation were unsuc- cessful. Unfortunately the investigators did not appear to be aware that /?-fluoroalanine (25) is relatively unstable above pH 7.0 decomposing with elimination of fl~0ride.l~’ As the assays were conducted at pH 8.5 the failure to detect the compound cannot alone be regarded as refuting their theory. Also fluoropyruvate is rapidly defluorinated by the pyruvate dehydrogenase complex (PDC) in cell-free extracts of plants as discussed above with reference to D.cymosum.It is therefore conceivable that any organofluorine compounds synthesized in these experiments were degraded as soon as they were formed to fluoride in situ. These experiments utilized material from seeds of plants devoid of fluoroacetate. A further explanation for the negative findings may therefore be that the ability to NATURAL PRODUCT REPORTS 1994 Scheme 7 0 H20 0 0 EW-SPFOH -F + FOH -EnzSH + F) (SEnz OH Scheme 8 0 )=CH2 F Scheme 9 Scheme 10 biosynthesize fluoroacetate in this species is dependent on highly variable genetic factors governing the specificity of enzymes involved in P-substituted alanine biosynthesis. It is not without significance that P-substituted alanines are predominantly found in the order Leguminales to which most fluoroacetate-producing genera belong.An exception is Dichapetalum which is placed in the order Rosales but it is noteworthy that D. cymosum displays an unusual pattern of serine and alanine metabolism forming large quantities of the N-methyl derivatives of both amino acid~.ll~*~~~ 5.2 Nucleophilic Substitution by Fluoride If the C-F bond energy in fluoroacetate is similar to that in an alkyl fluoride conversion of glycolate to fluoroacetate should occur in aqueous solution with minimal energy absorption.lZ0 Thus the C-F bond could be synthesized by this route under normal physiological conditions if the reaction was coupled to one which took place spontaneously.It is therefore possible to envisage formation of fluoroacetate by nucleophilic displace- ment of the phosphate group of phosphoglycolate (26) or other activated glycolate species as shown in Scheme 7. Enzymes mediating the reverse conversion of fluoroacetate to glycolate have been isolated from a number of micro- organisms capable of using fluoroacetate as a sole carbon ~ite.'~~,'~~ A mechanism has been proposed in which a thiol group of the enzyme attacks the substrate displacing fluoride to form a thioether which is subsequently hydrolysed releasing glycolate as illustrated in Scheme 8. The reversibility of this reaction has been investigated by Goldman and Milnelz2 by incubating the enzyme from a Pseudomonas sp. with glycolate and fluoride in the presence of [180]water.It was argued that even if the amount of fluoroacetate present at equilibrium is chemically undetectable the reversibility of the reaction should be reflected in the incorporation of oxygen-1 8 isotope into glycolate. Mass spectrometry of the glycolate reisolated after incubation failed to demonstrate significant oxygen- 18 incorporation consistent with an essentially irreversible process. Nevertheless it might be rewarding to duplicate this experiment with the enzyme systems isolated by Walker and Liedz3 for which fluoride apparently acted as a competitive inhibitor. 5.3 Acetate or Ethylene as a Precursor As the methyl group in acetate is not activated for attack by fluoride ion it would seem most unlikely that the compound could act as a precursor of fluoroacetate.This reasoning is confirmed by the observation that incubation of both young and old leaves of D.cymosum with [2-14C]acetate failed to result in the incorporation of label into fl~oroacetate.~~~ Peters and Shorthou~e~~ lZ6demonstrated that homogenates of the fluoroacetate-producing plant A. georginae that were able to volatilize as much as 30% of added inorganic fluoride could also produce the plant hormone ethylene. A small proportion of the volatile fraction was identified as fluoro- acetone but over 80 % was not characterized6' (see Section 2.3). PeterP speculated on the basis of these findings that fluoroacetate could be derived from ethylene via vinyl fluoride or fluoroethane as shown in Scheme 9 but did not indicate a pathway or plausible mechanism.Another possibility is the pathway in Scheme 10 via ethylene oxide (27) which is known to be a major product of ethylene rnetab~lism.'~'~~~~ No convincing evidence has been adduced for either of these pathways. Indeed the significance ascribed by Peters to the volatilization losses of fluoride is to a large extent nullified by his observations that losses of fluoride by as much as 50% occurred in homogenates of non-fluoroacetate-synthesizing plants tested at random including Pisum sativum Poa annua Asclepsia curassavica Aquilegia canadensis and Acacia a~mata.~~ Hence if Peters' hypothesis is correct in order to explain why biosynthesis of fluoroacetate occurs in only A.georginae and a few other species it becomes necessary to postulate that such plants alone have a mechanism for converting the volatile fluoro compound to fluoroacetate. Furthermore if the ability to volatilize fluorine is as common amongst plant species as the study would appear to indicate and if the resultant compounds are not normally subject to further metabolism they should be readily detectable as trace components in the atmosphere. Fluorocarbons in general tend to be both biologically recalcitrant in the environment and chemically long lived in the atmosphere. However the intensive investigation of atmospheric composition over the last 20 years which has been a consequence of the controversy surrounding the effects of chlorofluorocarbons on the ozone layer has not revealed the present of any fluorocarbon for which an anthropogenic source has not been clearly ident- ified.129.130 5.4 The Haloperoxidase Reaction Despite the remarkable variety of halogenated compounds source e.g.Pseudomonas spp.121-124 and Fusarium ~olani.~~~ found in nature the insertion of halogens other than fluorine Fluoroacetate is the preferred substrate in terms of K and into biological substrates normally occurs with only a single VmaX for such haloacetate halidohydrolase enzymes although the reported exception131 by the haloperoxidase reaction chloro- bromo- and iodo- analogues are also dehalogenated. As such enzymes are very sensitive to thiol blocking agents S+X-+H++H,O -+S-X+2H,O it is believed that a thiol group is located at the active (where X-can be C1- Br- or SCN- and S is substrate.) NATURAL PRODUCT REPORTS 1994-D.B. HARPER AND D. O'HAGAN F Brt/,l Brer Scheme 11 Table 3 Haloperoxidase Ions oxidized Bromoperoxidase Chloroperoxidase Iodoperoxidase I- SCN- Br- I- SCN- Br- C1- I- The substrate can be an alkene alkyne cyclopropane phenol aniline or P-diketone. As can be appreciated from a consider- ation of the mechanism (Scheme 1l) the nature of the reaction product is dependent on the relative concentrations of ions in the reaction medium.132* 133 Active incorporation of halogen to form a halonium ion is followed by passive incorporation of a nucleophile (which in dilute aqueous solution is usually hydroxide) leading to the formation of the halohydrin.However in the presence of high concentrations of halide ion the nucleophile incorporated can be another halide ion leading to the formation of the homogenous dihalide or if different halide ions are present the heterogenous dihalide. Haloperoxidases can be categorized on the basis of the halide ions utilized as shown in Table 3. These classes are directly related to the magnitude of the oxidation/reduction potential generated by the haloperoxidase after reduction of H,O,. A haloperoxidase with a redox potential large enough to oxidize C1- ion (EO = -1.36 V) is also able to oxidize Br- (EO = -1.07 V) and I- (EO = -1.54 V) but an enzyme with a redox potential just sufficient to oxidize Br- is able to oxidize I-but not C1-.The redox potential of SCN- oxidation is between those required for I-and Br- oxidation with the consequence that every chloro- and bromoperoxidase can oxidize SCN- but only some iodoperoxidases. Vickery et have speculated that fluoroacetate may be formed in nature by fluoro-decarboxylation of malonate in the presence of a fluoro-peroxidase a conjecture based on the detection of small amounts of fluoroacetate on incubation of sodium hypochlorite abiotically with malonic acid and sodium fluoride. However it is quite clear that it is thermodynamically impossible for the activation of fluoride to be accomplished by reduction of H,O, as the redox potential for fluoride oxidation is greatly in excess of that for H,O reduction.2F-e F +2e (EO = -3.06 V) H20,+2H++2e$2H,0 (EO = + 1.71 V). If indeed fluoroacetate is formed under the experimental conditions described by Vickery et the most feasible explanation would seem to be passive incorporation of fluoride by displacement of chloride from chloromalonic acid (Section 5.5). 5.5 A Halometabolite Precursor The possibility that an organochlorine compound such as chloroacetate is an intermediate in fluoroacetate biosynthesis in A. georginae was investigated by Peters et a/.135Although they observed a high chloride uptake by both leaves and roots of the Scheme 12 plant no ether-soluble organic chlorine was detectable in the plant extract. Neidleman and Geigert136 proposed an alternative mech- anism based on their interesting observation that under certain circumstances incorporation of fluoride ion can occur in vitro during haloperoxidase attack on an a1kene.l3 Thus in the presence of an oxidizable halide ion such as Br- H,O, and high concentrations of fluoride nucleophilic attack by the fluoride ion on a halonium ion intermediate gave a vicinal bromofluoro compound.To account for the biosynthesis of fluoroacetic acid in vivo these workers speculated that an w-unsaturated fatty acid is attacked by an iodoperoxidase in the presence of both fluoride and iodide ions leading to the formation of a fluoroiodo derivative (28) as illustrated in Scheme 12. The compound would then be enzymatically reduced and deiodinated to the w-fluorofatty acid which in turn could be degraded to fluoroacetic acid by P-oxidation.Although Neidleman and Geigert present no experimental data for the existence in vivo of such a pathway they suggest that an examination of the iodine content of fluoroacetate-producing plants might be revealing. A more straightforward approach might simply involve a search for haloperoxidase activity in the tissues of such plants. This conjecture clearly arose from the presence of w-fluorofatty acids found in D. toxicarium seeds; however the evidence suggests that these fatty acids arise from fluoroacetate and are not precursors of the compound (see Section 2.2). Further more detailed GCMS studies6 have not indicated the co-occurrence of any w-iodofatty acids in D. toxicarium seed extracts and their intermediacy is purely conjectural.It was concluded in Section 5.4 that the biosynthesis of fluoroacetate by direct activation of fluoride by a fluoro-peroxidase as conjectured by Vickery et was highly unlikely on theoretical grounds. Nevertheless the empirical observations by these workers of the abiotic synthesis of fluoroacetate from malonic acid deserve further consideration as a possible biomimetic model. Chloroacetate was reported as the major product of the reaction of malonic acid with sodium hypochlorite at 25 "C the compound presumably resulting from oxidative decarboxyl- ation of the chloromalonic acid initially formed by attack of C1+ on the activated methylene group.137 When fluoride was added to the reaction mixture small quantities of fluoroacetate were detected in addition to chloroacetate.The formation of the C-F bond under these conditions can be quite adequately explained without invoking the generation of F' implied by Vickery et Nucleophilic attack by fluoride ion on the C-Cl bond would lead to a passive incorporation of fluorine. Decarboxylation would then generate fluoroacetate. In nature a haloperoxidase could conceivably catalyse a similar reaction in a cell compartment sequestering a high local concentration of fluoride ion. A mechanism of this type whilst dispensing with a requirement for a dehalogenating enzyme of the type postulated by Neidleman and Geigert136 possesses the major 132 shortcoming of necessarily involving the simultaneous bio- synthesis of large amounts of chloroacetate.5.6 Fluorophosphate as an Intermediate A ‘fluorokinase ’ enzyme mediating the C0,-dependent phos- phorylation of fluoride by ATP was isolated from pig heart by Ochoa and co-workers in 1957.138 ATp + F-fluorokinase f CC??,Mg2+ * ADP + F/?\OH OH f luorophosphate The enzyme co-purified with pyruvate kinase which normally catalyses the conversion of phosphoenolpyruvate to pyruvate in glycoly~is.~~~ Not only did the two enzyme proteins exhibit similar properties but phosphoenolpyruvate and pyruvate inhibited fluorophosphate formation leading the investigators to conclude that both ‘fluorokinase’ and pyruvate kinase activities resided in the same protein. By implication therefore all cells have the capacity to generate fluorophosphate if they are exposed to fluoride and fluorophosphate must emerge as a likely metabolite of fluoride.Peters14a surmised that such an enzyme could have a role to play in C-F bond formation. Although he could not confirm fluorophosphate formation in A. georginae he obtained some evidence for metabolism of the compound in tissue homo- genates from the ~1ant.l~’ The scarcity of fluorinated natural products may in part be attributable to the problems associated with the lack of reactivity and the difficulties involved in transporting a heavily hydrated ion such as fluoride within the cell (see Section 1). However a fluoride carrier such as fluorophosphate could facilitate passage of fluoride through membranes and provide a convenient vehicle for the specific binding of fluoride at the active site of C-F bond forming enzymes.6 References 1 E. A. Paul and P. M. 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ISSN:0265-0568    

DOI:10.1039/NP9941100123

出版商:RSC    

年代:1994

数据来源: RSC