~ Lignans neolignans and related compounds Robert S. Ward Chemistry Department University of Wales Swansea Singleton Park Swansea UK SA2 8PP Covering January 1994 to December 1995 Previous review 1995 12 183 1 Introduction 1.1 Analysis and identification 1.2 Biological activity 1.3 Biosynthesis and metabolism 2 Lignans 2.1 Dibenzylbutanes and dibenzylbutanediols 2.2 Dibenzylbutyrolactones 2.3 Substituted tetrahydrofurans 2.4 2,6-Diaryl-3,7-dioxabicyclo[3.3. Oloctanes 2.5 Arylnaphthalene derivatives 2.6 Dibenzocyclooctene derivatives 2.7 Miscellaneous lignans 3 Neolignans 4 Oligomeric lignans and neolignans 5 Hybrid lignans 6 Norlignans 7 References 1 Introduction This report is presented in essentially the same style and format as the previous two reports in the series.',2 In addition the abbreviations used for different aryl groups are continued (Fig.1). Although with hindsight a more logical classification is conceivable for the sake of continuity and ease of cross referencing the previous practice is retained. A regrettable feature of the literature coverage of this and presumably other areas of natural product chemistry is the proliferation of incorrect names and structures which lead not only to con- fusion but also result in several names often being assigned to the same compound. In an effort to collect together the names given to known members of some of the main lignan series a number of charts are included in this report which list known members of some lignan classes.Others can be added in future reports and notification of any errors or omissions would be appreciated for inclusion at that time. Two recent reviews deal with the occurrence and distri- bution of lignans and the evolution of lignan and neolignan biochemical pathway^.^,^ A strong case is made to support the idea that the phenylpropanoid pathway and associated meta- bolic routes can be used as an aid to the classification of plant OH LOMe species. Based on existing chemotaxonomic data organisms can be distinguished by differences in the degree and extent of phenylpropanoid metabolism. It is proposed that these differ- ences could be of considerable importance in cataloguing the biodiversity of plant life and in charting metabolic evolution.Two further reviews survey the lignans isolated from Linurn and Fursythia species with particular emphasis on in vitro cell culture studies including their use for the production of cytotoxic lignans and in defining biosynthetic pathway^.^,^ A further recent review covers the occurrence and distribution of lignans in ~oniferae.~ 1.1 Analysis and identification Increasing attention is being focused on finding appropriate methods for the analysis of lignans and neolignans from plant sources and in body fluids. A comparison of different methods applied to lignan analysis of seed oils from sesame seeds has been publi~hed.~,~ It concluded that although GC was good for qualitative analysis it has a number of limitations for quantita- tive work most notably the preparative steps involved the difficulty of finding a suitable internal standard and the mark- edly different response factors of the compounds studied.In contrast HPLC was found to be a better method for rapid quantitative analysis although both normal-phase and reverse- phase columns were necessary to deal with the varied compounds present. Reverse-phase HPLC has been used in combination with photodiode array detection to analyse neo- lignans isolated by supercritical CO extraction from Magnolia virginiana flowers.lo Reverse-phase HPLC has also been used to provide a rapid and reliable method for the routine analysis of podophyllotoxin and related compounds in Podophyflum extracts.11,12 Chiral HPLC combined with FAB mass spectrometry has been used to study the enantioselective formation of (-)-secoisolariciresinol in cell-free extracts of Forsythia koreana. l3 Both LC-MS and GC-MS have been applied to analysing samples containing the mammalian lignans enterolactone and enterodiol and their precursors matairesinol and secoisolar- iciresinol. These studies are particularly important in view of the claimed protective effects of these compounds against breast prostate and colon cancer (see Section 1.2).Thus HPLC coupled with either ionspray or continuous-flow FAB mass spectrometry provides a rapid method for the detection and identification of secoisolariciresinol diglucoside in flaxseed extracts.14,15 Interestingly two isomers presumed to be OMe OMe OMe \ Med OMe Fig. 1 Abbreviations used for different aryl groups Ward Lignans neolignans and related compounds diastereoisomers were revealed by this work. It is claimed that identification and characterisation of such samples can be carried out on crude extracts with minimal sample manipu- lation since there is no need for preparative isolation of each component. So far GC-MS using single ion monitoring would seem to be the method of choice for analysing the mammalian lignans and isoflavonoid phytoestrogens in human plasma. l6 The combi- nation of isotope dilution GC-MS using the deuteriated com- pounds as internal standards provides a powerful tool for quantitative determination of plasma phytoestrogen levels as low as 0.2-1.0 nmol 1 -'.l77l8 A simple and reliable method involving single ion monitoring with GC-MS has also been developed for the determination of schizandrin in human plasma." It is anticipated that this will be invaluable in monitoring pharmacokinetic studies on this compound.A comprehensive compilation of I3C NMR data for lignans and neolignans has been published which will be especially useful for establishing the parent skeleton and substitution pattern of the side chains.20 1.2 Biological activity Analogues and derivatives of podophyllotoxin continue to be investigated in an effort to improve upon the antitumour activity of the clinical drug etoposide. A wide range of derivatives have been ~repared.~'-~' Some which show particu- lar promise in terms of improved activity or have other advantages are shown in Fig.2. Aa 1 R = CHO (ref. 23) 3 R = N3 (ref. 24) 2 R = CH=NNHPh (ref. 23) 4 R = NH2 (ref. 24) NHAr 5 (refs. 25,26) 6 Ar = 4-FCeH4 (refs. 27,29) 7 Ar = 4-N02C6H4 (ref. 27) n 8 (ref. 28) 9 Ar = 4-N02C6H4 (ref. 31) Fig. 2 Biologically active podophyllotoxin analogues Thus 4-O-butanoyl-4'-demethylpodophyllotoxin5 is cyto- toxic at concentrations 100-1000 times lower than conven-tional drugs and is active against several drug resistant tumour cell line^.^^,^^ Similarly the 4-arylamino derivatives 6 and 7 are up to 100 times more active than etoposide and also show activity against etoposide resistant while compounds such as 8 which can form water soluble salts have increased antitumour activity and improved drug resistance,28 and compounds such as 9 which probe the 'intercalating domain of the pharmacophore' exhibit improved activity and have a novel mechanism of action.31 Both forcefield calculations and a three-dimensional QSAR study have been implemented in the quest for compounds based on podophyllotoxin with enhanced acti~ity.*~>~' The antitumour activity of the foliage of Libocedrus plumosa has been shown to be due to the presence of b-peltatin (Section 2.5).32 Although often overlooked due to the considerable atten- tion devoted to podophyllotoxin derivatives it is worth remembering that other classes of lignans also exhibit anticancer activity.According to a recent paper some 36 naturally occurring lignans having anticancer activity have been reported.33 They include arctigenin and trachelogenin (Section 2.2) burseran (Section 2.3) liriodendrin and styraxin (Section 2.4) diphyllin (Section 2.5) and steganacin and steganangin (Section 2.6). Although the figure of 36 is probably a conservative estimate even based on current data it emphasises the need to broaden the scope of current investigations. A recent study has shown that four com-pounds machilin A 10 matairesinol 11 arctigenin 12 and honokiol 13 from a group of eleven lignans and neolignans studied had activity comparable to that of current anticancer agents.34 The menthyloxy substituted dibenzylbutyrolactones 14a and 14b also showed activities comparable to etoposide teniposide and ~isplatin,~~ whereas a series of chloro and iodo di benzyl butyrolac tone derivatives showed diminished activity when compared with yatein or podophyll~toxin.~~ Ar2 Ar5 Ar3 10 11 Ar=Ar3 12 Ar=Afl RO AS 0 13 14a R=H 14b R = CH2CHPOEt Meanwhile there is growing evidence that the consumption of foods rich in lignans can decrease the risk of contacting certain forms of Various mechanisms have been suggested whereby these compounds exert their protective effects.For example the lignans may contribute towards the prevention of breast cancer as a result of their antiestrogenic properties whereby they interact with the estrogen receptor and modulate the action of estrogen.Alternatively they may act as antioxidants and prevent the production of carcino- gens from estrogen or they may inhibit aromatase enzyme activity and thereby contribute to the prevention of hormone dependent cancers. Several other examples of useful biological activity have been reported. Thus both syringaresinol and yangambin (Section 2.4) show significant antiplatelet aggregation The Na and K salts of 15 and 16 which are known tetramers of caffeic acid have been isolated from Arnebia euchroma and shown to possess potent anti-HIV activity.44 A number of lignans isolated from Larrea tridentata including 3- O-methyl- nordihydroguaiaretic acid also display anti-HIV activity.45 Analogues of justicidin E (Section 2.5) have been shown to be potent inhibitors of leukotriene biosynthesis and non-redox inhibitors of 5-lipoxygenase As such they could form the basis of a new class of therapeutic agents for the treatment of disease states such as asthma inflammatory bowel disease 44 Natural Product Reports and rheumatoid arthritis.Some 4-hydroxyarylnaphthalene lig- nans are hypolipidemic agent^.^' The most potent which have greater activity than other known agents not only reduce serum cholesterol levels but also increase high-density lipoprotein levels in rats. HO 15 16 The inhibitory activity of podophyllotoxin derivatives on the root growth of Brassica campestris has been ascribed to the presence of the methylenedioxy group and the configur-ation of the lactone ring while the activity of matairesinol was enhanced by methylation of the two phenolic groups.48 Mean- while there is evidence that bis(methy1enedioxy)cinnanic acid derivatives inhibit the lignin peroxidase from Phanerochaete chryso~poriurn.~~ These results support the hypothesis that the accumulation of lignans at the site of a wound may inhibit the fungal enzymes involved in lignin degradation.The corre- sponding tetrahydro derivatives and the corresponding 3,4-dimethoxy compounds were considerably less active. The lignan components of Schizandra chinensis fruits which have been used in traditional Chinese medicine for many years have been shown to have a protective effect against liver damage caused by toxic chemicals. Gomisin A in particular induces liver microsomal enzymes accelerates liver regenera- tion and inhibits the promotion of hepatocarcinogene~is.~~~~~ The biological activities of several lignans and flavonoids iso- lated from traditional medicines have been summarised in a recent paper.s2 Finally the antioxidative properties of sesame seeds which have long been used as a health food to prevent ageing appear to be related to their lignan component^.^^ It has now been shown that the lignans act synergistically with a-tocopherol leading to an enhancement of vitamin E activity.1.3 Biosynthesis and metabolism A clear picture of the principle pathways of lignan biosynthesis in For~ythia,~.~~,~~ is emerging and also now in Zantho~ylum,~~ from studies using labelled precursors and cell free extracts.The sequence from coniferyl alcohol to (+)-pinoresinol (+)-lariciresinol ( -)-secoisolariciresinol and ( -)-matairesinol seems to be clearly established and the occurrence of ( -)- pinoresinol and ( -)-lariciresinol in these species is probably due to the intervention of a second non-selective pathway. The promotive effect of high intensity light on the induction of flowering of Morning Glory seedlings by low temperature treatment has been correlated with enhanced phenylpropanoid biosynthesis and may be due to an increase in hydrogen peroxide production in response to stress induced by the low temperature.57 Model experiments using isolated enzymes and inorganic reagents continue to be of interest in a biomimetic context Ward Lignuns neolignans and related compounds particularly when they yield novel and interesting products.For example oxidative coupling of methyl sinapate using horseradish peroxidase and H,O in methanol affords the dimeric products 17 and 18 whereas in aqueous acetone 19 is the major pr~duct.~' Treatment of 17 and 18 with aqueous acid gives 20. This is of interest in that it rules out the possibility of 17 and 18 being involved in the formation of 19 which must therefore be formed by direct cyclisation. Mb$*;;Me C02Me Me:hy*;;Me C02Me Me0 0 OMe 0 OMe 17 18 w MeOpCO2Me H OOMe 0 2 M e HO \ . C02Me Me0 \ . C02Me OMe Ar7 A17 19 20 Oxidation of the biphenyl derivatives 21 with horseradish peroxidase (HRP) and H202in the presence of an equimolar amount of coniferyl alcohol gave the novel eight-membered ring products 22 [reaction (l)].59 This ring structure has been identified as a component in softwood lignins.Me0 OH R R wR Ar3ZCHZ01 HRP R HO OMe Me0 21 R = Pr or CH20H APt-( CH20H 22 Silver oxide oxidation of isoeugenol in dichloromethane affords a dimeric quinone-methide which on quenching with methanol or water affords the neolignans 23 and 24 the latter being closely related to the natural product viriolin which has antileukaemic properties.60 In benzene solution oxidation yields the dihydrobenzofuran 25. Me OMe 23 R=Me 25 24 R=H Silver oxide oxidation of coniferyl alcohol in dry dichloro- methane or acetone affords dehydrodiconiferyl alcohol 26 while in 1:1 dichloromethane-water pinoresinol is the major product.61 Once again there is good evidence for the involve- ment of quinone-methide intermediates since reactions over shorter periods followed by quenching with aqueous acid or reaction in aqueous acidic solution leads to the formation of a-and P-linked aryl ethers 27 and 28.CH20H HO OMe A r3 OMe 26 27 CH20H Me0-Q o~~H~cH20H A r3 28 Silver oxide oxidation of ethyl ferulate gives the ethyl ester of dehydrodiferulic acid 29.62In fact seven dehydrodimers of ferulic acid (29-35) have been synthesised and shown to be present in extracts from saponified cell walls of various grasses. They are forrned in nature by dimerisation of ferulic acid residues which are esterified to grass cell wall polysaccharides.They have the potential to cross-link polysaccharides to lignin in the cell wall perhaps providing a template for lignification. Oxidative coupling of the 4-hydroxycinnamic acid esters 36a and 36b affords the dihydronaphthalenes 37a and 37b respectively as the major products [reaction (2)].63 The 2-hydroxycinnamic acid esters 38a and 38b in contrast yield OMe OMe 29 30 'O2'V $H o\ I I OMe AP C02H 31 32 OMe OMe 33 the enol acetate derivatives 39a and 39b respectively after acetylation [reaction (3)]. C02Me HO C02Me R2& 02Me MOMOR i C02Me ~ i. [O] ii. Ac20 MOM0 OH 2 Lignans 2.1 Dibenzylbutanes and dibenzylbutanediols Characterisation of the lignans from Larrea tridentata which display anti-HIV activity has led to the isolation of new compounds 4@-43.45 The absolute configurations of oleiferins A-C (4446) have been confirmed by acid-catalysed Friedel- Crafts cyclisation to (+)-isogalcatin ( -)-galcatin and ( -)-cagayanin re~pectively.~~ Anolignans A and B (47 and 48) are newly reported lignans which have been isolated from the stems of Anogeissus acuminata.66 Two further new lig- nans in this group are cinnamophilin 49 from the root of Cinnamonum philippinen~e~~ and 4"-O-methyl-3'-O-demethyl-secoisolariciresinol 50 from the needles of Taxus baccata.68 Fig.3 shows the structures of symmetrically substituted members of the dibenzylbutane and dibenzylbutanediol series.As illustrated by the names of some compounds already mentioned (e.g. 50) workers have often chosen to A P T Af'T Ar2F Ar27 A14 Ar16 Ari6 Ar' 40 41 42 43 Ar5 Ar 44 oleiferin A 45 Ar = Af' oleiferin 6 46 Ar = Ar5 oleiferin C Ar'T Ar2T:; HO A$f A14 "X Meomco2H HO C02H H02C A13 Ar' Ar' A+ 34 35 47 48 49 50 46 Natural Product Reports assign names to compounds based upon their structural relationship to supposedly well known parent compounds. It is not always obvious especially to newcomers to this field what the origins of such names are or what relationship exists between compounds with apparently similar trivial names. In the hope of providing clarification some examples of this practice are highlighted in this report.Thus the guaiaretic acid family are shown in Fig. 4 and the lariciresi- no1 family appear in a later figure (Fig. 11). Ar = Arl conocarpol Ar = Ar2 mesenordihydroguaiareticacid Ar = Ar3 mesedihydroguaiaretic acid Ar = Ar5 rnachilin A Ar = At7 meso-5‘,5-dimethoxydihydroguaiareticacid Ar Ar = Arlo pregornisin Ar = Ar2 (-)-nordihydroguaiaretic acid Ary Ar = A$ (-)-dihydroguaiaretic acid Ar = Ar5 (-)-austrobailignan-5 Ar Ar = Arl (-)-3’,3”-dernethoxysecoisolariciresinol OH Ar = AP (-)-secoisolariciresinol -..,,,,OH Ar = Ar5 (-)-dihydrocubebin Ar = Ar7 5’,5”-dimethoxysecoisolariciresinol Ar Ar = Ar2l enterodiol Fig. 3 Symmetrically substituted dibenzylbutanes and dibenzyl-butanediols Ar3 A13 (-)-guaiaretic aci d (-)-dihydroguaiaretic acid A13 Ar2 mesedihydroguaiaretic acid mesenordihydroguaiaretic acid The oxidative coupling of dibenzylbutanes to give tetrahydro- dibenzocyclooctene derivatives can be achieved using a wide- variety of reagents.For example treatment 53 and 54 with NH(CH2)2Ar1 NH(CH&Arl 0 52 DDQ in trifluoroacetic acid (TFA) gives 55 and deoxyschizan- drin 56 respectively [reactions (4)and (5)].71 Oxidation with ruthenium dioxide or thaflium(rrr) oxide in a mixture of TFA TFAA and BF etherate on the other hand gives a mixture of the dibenzocyclooctene (55 or 56) and an aryltetralin (57 or 58).72 The formation of 56 is accompanied by a small amount of the isomer 59 which is taken as evidence for the involvement of a spirodienyl intermediate in the reaction.AS 7 DDQ (4) TFA AS 53 Me0 55 Me0 \ A@p;;;@ Me0 (5) AP 54 Me0 56 NMR evidence indicates that both deoxyschizandrin 56 and its isomer 59 adopt a twist-boat-chair conformation 60. Of Meopq HO more interest is the fact that two stable conformers of 55 are formed and can be isolated. However while it seems generally AP agreed that the minor conformer is the twist-boat-chair dehydroguaiaretic acid Meow Fig. 4 The guaiaretic acid family One of the few known examples of a meso-2,3-dibenzylbutanediol 51 (c$ meso-secoisolariciresinol)has been isolated from the bark of Zanthoxylum heit~ii.~~ Cannabisin G 52 which occurs in Cannabis sativa fruits is one of the more highly functionalised lignans of this type.70 APT: “$7: AP A$ 51 mesesecoisolariciresinol Ward Lignans neolignans and related compounds Me0 Me0 OMe AP OMe A@ 57 58 Me0 OMe MeO@ Me H Me0 Me0 / Me0 \ \ Me0 Me0 OMe 59 60 R1 or R2 = OMe (?Me ?Me Me0 Me0 Me0 Me Me0 Me0 OMe OMe 61 Ri =Me; R2 = H 63 62 R1 = H; R2 = Me conformer 61 in which both methyl groups are axial opinion is divided between the twist-boat conformation 62 and the die- quatorial twist-boatxhair conformer 63 for the structure of the major ~onformer.~ 1,72 Oxidation of the phenolic dibenzylbutane 64 using the ru- thenium or thallium reagent gives mainly the para-coupled prod- uct 65 with a minor amount of the corresponding ortho isomer 66 [reaction (6)].73 Oxidation of 67a and 67b using iron(II1) perchlorate affords schizandrin 68a and gomisin A 68b respect-ively [reaction (7)] along with minor amounts (20%) of the corresponding steroisomer 69.74 Similarly 70a affords iso-schizandrin 71a along with the stereoisomer 72a while 70b gives 71b and 72b along with the aryltetralin 73 [reaction (S)].75 Me0 \ TI203 or Ru02 Me0 CH2CI2 R10 (6) TFA-TFAA BF3.Et20 R20 65 R1 = Me; R2 = H 66 R1 = H; R2 = Me R20 Me6 68a R1 = R2 = Me 68b R1R2= CH2 i.Fe(CIO4)3 -+ 171 \’ I ii. KOH Ars 67a Ar=AS 67b Ar=A$ Me0 69a R1 = R2 = Me 69b R1R2=CH2 2.2 Dibenzylbutyrolactones New lignans in this series include salicifoline 74 and iso- salicifoline 75 from the leaves of Bupleurum sali~ifolium,~~ 4’-O-demethylyatein 76 from the branch wood of Thuja occidentali~,~~ the aglycones haplodocin 77 and cappodocin 48 NaturaI Product Reports Me0 Me0 71a R1 = R2 = Me 7ib ~ 1= CH~ ~2 i.Fe(C104)3 w + (8) 11. KOH A6 70a Ar=AS 70b Ar=A$ Me0 Me0 Me0 72a R1 = R2 = Me 72b R1R2=CH2 78 from Haplophyllum c~ppadocium,~~ and compounds 79 80 and 81 from Cheirolophus species,79 Taxus baccata” and Protium tenuifolium,*’ respectively. In addition isopentenyl ethers of haplomyrfolin and pluviatolide and a dihydroxy-geranyl ether of matairesinol have been isolated from Haplo-phy llum pt ilosty lum .82 A short review of naturally occurring dibenzylbutyrolac- tones isolated since 1977 has been published.84 A complete analysis of the ‘H and I3C NMR spectra of matairesinol dimethyl ether has also been published.85 73 74 salicifoline 75 isosalicifoline 76 4’-Qdemethylyatein Ark0Ark0 / / 0 0 77 haplodocin 78 cappadocin Ar = $$o OH A$ h0 / Ar5&0 Ar5ko 0 0 Ar5 79 80 81 Ar = A$ (-)-matairesinol ArA ArB Ar = Ar" buplerol (ref.86) Ar5 I Ar5 (-)-gadain (isohibalactone) (refs. 95-97) Ar = Ar5 (-)-haplomyrfolin Ar5 / Ar" isosuchilactone Ar33 Ar = Ar7 thujaplicatin methyl ether ArB Ar16 I Ar5 isoguamarol Ar 0 Ar = Ar9 (-)-thujaplicatin A14 I Ar5 isokaerophyllin (chisulactone) (refs. 86,90) A r A Ar9 I Ar3 y-thujaplicatene Ar = A6 (-)-arctigeninin Ar = Ar" (-)-dimethyl matairesinol Ar5 / Ar5 (-)-savinin (hibalactone) (refs.95,96) Ar = Ar5 (-)-kusunokinin Ar5 / Ar" jatrophan (suchilactone) Ar = Ar6 thujaplicatin trimethyl ether Ar16/ Ar5 guamarol (ref. 90) 82 Ar = Ar7 (ref. 87) Ar" I Ar5 (-)-kaerophyllin (ref. 90) Ar 83 Ar = Arlo (ref. 87) (ref. 98) Ar = Ar16 prestegane A ArA 86 Arlo I A$ (ref. 98) 87Ar"lAr" (ref. 87) Ar = Ar3 (-)-pluviatolide A6 I Ar5 nemerosin Ar = Ar" (-)-methyl pluviatolide (bursehernin) 88 Afi I A@ Ar5 x Ar = Ar5 (-)-hinokinin Ar = Ar6 (-)-yatein Ar = AP (-)-methoxy-hinokinin (dehydrotrichostin) 89 Ar3 I AS (ref. 49) Ar Ar = Arlo (-)-3'-OdemethyI-yatein (refs. 88,89) Ar5 I Ar5 dihydrotaiwanin A (ref. 99) Ar = Ar16 guarmarolin (ref. 90) Ar5 I Ar" guayadequiene (ref.86) Ar = Ar3 (-)-traxillagenin (ref. 91) Ar = Ar5 (-)-isoyatein Ar = A6 (-)-cordigerine (cubebininolide) Ar 0 Ar=Ar7 hernolactone Ar = Are (-)-cubebinone (+)-calocedrin chasnarolide methyl chasnarolide (ref. 90) Fig. 6 Unsaturated butyrolactones guayarol 5"-methoxy-yatein Ar Ar Ar = Ar16 prestegane B HO ,OMe Ar = Ar21 (-)-enterolactone gnidifolin Ar =$*OH -(-)-wikstromol (-)-epiwikstromol meridinol epimeridinol (nortrachelogenin) (epinortrachelogenin) (ref. 100) (ref. 100) Fig. 5 Dibenzylbutyrolactones A large number of dibenzylbutyrolactones are known. The parent compounds are shown in Fig. 5. Recent references are Ar3 A13 included where available but for references prior to 1990 benchequiol guayadequiol (-)-trachelogenin (-)-epitrachelogenin readers are referred to the monograph on lignans published (ref.90) (refs. 86,101) (refs. 102,103) (refs. 101,102) at that time,92 to the review published by Gottlieb and Yoshida," or to the more recent database,94 for those with access to it. A r\\\" " 3 A f\\\" l 3 A r\\\" " 3 A r\\"' " 3 As indicated above an increasing number of unsaturated lac- tones are being discovered. Previously reported examples of OH 0 OH 0 OH 0 OH 0 this type are listed in Fig. 6. Another coherent group of com- Ar" Ar" AF AF pounds are the a-hydroxy lactones such as wikstromol and tra- 90 91 92 93 chelogenin. These are compounds shown collectively in Fig. 7. Several recent syntheses involve the preparation of a,p-OH unsaturated lactones of the savinin or gadain type (Fig.7). Such compounds are readily prepared from the corres-ponding monobenzylbutyrolactone by condensation. Hydro- genation affords the cis-disubstituted lactone 94 [reaction Ar7 (9)].72Wakamatsu and co-workers have used direct oxidative hydroxythujaplicatin dihydroxythujaplicatin coupling of the unsaturated lactones 95 to give precursors for methyl ether methyl ether the asymmetric synthesis of a variety of tetrahydrodibenzo- cyclooctene derivatives (Scheme 1).'O4-Io9 OH OH Such syntheses are based upon the availability of chiral non-racemic monobenzylbutyrolactones. A new route to such compounds involves the enantioselective deprotonation of an achiral cyclobutanone 96 (X= H) (Scheme 2).96 Interestingly continuation of this scheme affords mainly the (a-unsaturated thujastandin dihydroxythujaplicatin lactone 99 which can be converted into ( -)-savinin 100 in high yield by treatment with tributyltin hydride.Fig. 7 a-Hydroxybutyrolactones Ward Lignans neolignans and related compounds 49 i. Ac20ArCHO-Ar ,’r 2 ii. LDA A iii. DBU 0 0 (Ar = AP or A@) 95 R20 Me0 I ii. ButOOH Mg MeOH R20 R10@CH20H Me0 Me0 CH20H R’o&o V,O ~30 1330 0 I R4d ~40 steps Isteps Me0 R20 Me0 ~30 R40 (-)-kadsurin R1 = R2 = R3 = R4 = Me (-)-deoxyschizandrin R’ R2 = R3R4= CH2 (-)-wuweizisu C R’ = R2 = Me; R3R4 = CH2 (-)-gomisin N R’ R2 = CH2; R3 = R4 = Me (*)-y-schizandrin Scheme 1 ci2c=c=o Ar5 3: chiral~Ar5-Ar5- Li base OSiEt3 96 X=CI 97 X=H i.O3 ii. NaBH4 Ar5 iii. H+ 0 Ar5 0 iii.~& 0 100 99 98 (80% ee) Scheme 2 50 Natural Product Reports Two other new routes for the synthesis of homochiral monobenzylbutyrolactones such as 98 have been reported. The first involves diastereoselective alkylation of the esters 101 or 102 followed by reductive removal of the chiral auxiliary and oxidative cleavage of the vinyl group [reaction (lo)].’lo The second involves enantioselective C-H insertion by a carbene [reaction (ll)].”’ /LDA 98 (86%ee) Ar5CH21 C02R2 0 98 (94% ee) Ar (Ar = Ar’ AS Ar7) R 0 H+ Me0 Me0 d’ 103 104 R’ = R2 = H 8a 12 R1 = OMe; R2 = H 50 50 R1 = R2=OMe 87 13 Scheme 3 The oxidative coupling of trans-dibenzylbutyrolactonesto tetrahydrodibenzocyclooctene derivatives is now well estab-lished but can be brought about by a wide variety of reagents.73”12,’ l3 For compounds containing a para-phenolic group the sequence using hypervalent iodine reagents gives high yields (75-87%) and can be carried out in one step (Scheme 3).'13 trans-Disubstituted butyrolactones are valuable not only as precursors for tetrahydrodibenzocyclooctene derivatives but also for a wide range of other lignan types.For example the keto lactones 105-108 which have all been prepared by tandem conjugate addition reactions provide key inter- mediates for the synthesis of lignans of the aryltetralin and furofuran type [reactions (12)-(1 5)].116117 OH 105 (R' = (-)-menthyl) NaBH4 EtOH 1 M eOMe oAr5 w TFA - \ '.*#, Me0 HO OH OH 0 106 (racemic) i L-Selectride 1;.TMSCI Et3N iii. KHMDS MoOPH I OTMS ,,/ iii. H2 Pd-C-(13) HO AP Ar' OH 0 (*)-cycloolivil 0 107 (racemic) i. L-Selectride ii. LiAIH4 1 HO 108 (R' = (+)-menthyl) LiAIH4 1 OH )/+,,. OH ;y CH20H Ar" (*)-eudesmin An alternative route to trans-2,3-dibenzylbutyrolactones, in addition to alkylation or conjugate addition involves oxidat- ive coupling of optically active acyl oxazolidinones [reaction (16)]. '* i. LDA ii. TiCI4 1 i. LiOOH A r 5 x ~ ii. Ac20 I cox' iii. NaBH4 I Ar5 Ar5 0 (-)-hinokinin cis-Disubstituted butyrolactones have been investigated less extensively than their trans-isomers.They can however be prepared by hydrogenation of a,p-unsaturated lactones as illustrated above. An alternative route to such compounds involves the diastereoselective opening of a rneso-anhydride 110 [reaction (17)].1'9 The meso-anhydride was prepared by a route involving consecutive Stobbe condensations. Doubly unsaturated lactones such as taiwanin A 111 can be prepared stereoselectively by cross-coupling of vinyl stannanes with vinyl bromides [reaction (1 8)]. '20 The vinyl 0 109 I steps '0 Ar"$ I Ar" (*)-methyl piperitol Ward Lignans neolignans and related compounds stannanes which in turn are used to prepare the vinyl *'h-Ar APb-AG OH bromides are obtained by stereoselective hydrostannation of acetylenic esters.0 OH 0 OR 120 Ar=Ar7 121 R=H 126 Ar = AP 122 R = Me Ar5yc02Me + Ar5y C02MOM Aflb-Ar5 APFj'*" EtO HO HO APhsAP SnBu3 Br OMe 0 123 124 125 0 111 127 Ar = Ar5 128 2.3 Substituted tetrahydrofurans 133 Ar =Ar3 Tetrahydrofuran derivatives are a prolific group of lignans and many new examples have been reported. Compound 112 from H4 the stems of Piper wightii,'" jacpaniculine 113 and isojacpani- Ar1C02-+ ..i-Ar7 r5yAfl culine 114 from the fruits of Jacquemontia paniculata,122 115 Ar\'I"' Ar7 !\"' 0 anolignan C 117 0 and 116 and the leaves of Ocoteaf~etus,'~~ 0 0 from Anogeissus acuminata,66 118 from the leaves of Machilus 129 130 Ar = Afl; R = H 132 japoni~a,'~~ and 119 from the leaves and stems of Piper 131 Ar = Afl; R = Me ~larkii"~are all members of the 2,5-diaryltetrahydrofuran 134 Ar=A$; R=H type.Compound 120 from the roots of Pyacantha coccinea,'26 todolactol A (=isoliovil) 121 from the heartwood of Abies marie~ii,'~~ koreanol 122 from the wood of Abies koreana,'28 busaliol 124 and busalicifol 125 from the leaves Key members of each of these series are listed in Figs. of Bupleurum sali~ifolium,~~,'~~ 126 from the wood 8-10. Once again only references later than 1990 are and of Abies pinsapo' 30 are examples of the 3,4-dibenzyltetra- included. The parent members of the lariciresinol olivil and hydrofuran category. liovil series are shown together in Fig. 11. Finally parabenzoinol 127 from the leaves of Parabenzoin tril~bum,'~' sesaminone 128 which is a metabolite of Strepto-myces species,'32 129 from the wood of Salix sachalinensis,'33 bionidin B 130 and E 131 from the flower buds of Magnolia b jondjj 134,135 132 from kernels of germinated seeds of Virola-michelii,136 and 5-hydroxylariciresinol 133 and 7-hydroxy-Ar = AP (-)-shonanin Ar = Ae (-)-brassilignan lariciresinol 134 from the wood of Abies pin~apo'~~ Ar = Ar5 (-)-dehydroxycubebin (refs.137,138,139) are members of the 2-aryl-4-benzyltetrahydrofuranfamily. AFyAr5 AB-%dAr5 Ar3A,dA$ OH HO 0 0 0 (+)-cis-b u rse ran (-) -trans-bu rse ran liovil Al.4-5 Ar = Afl (-)-kusunokinol Ar = Ar5 (-)-dihydrokusukinin do: Ar5-$ 135 Ar = Afl Ar = A6 (-)-cubebin 114 116 Ar = AB (-)-clusin '15 Me0 Ar = A$ (-)-tricostin (ref.139) A$-+ Ar = A6 (-)-cubebinin do: 0 117 118 Ar=Ar5 119 Ar=Afl Fig. 8 Key members of the 3,4-dibenzyltetrahydrofuranseries 52 Natural Product Reports Ar = Arl larreatricin (ref. 140) Ar = AP zuonin C henricine 136 Ar = Ar' (ref. 141) Ar = Ar3 3',3"-dimethoxylarreatricin (chicanine) Ar = AP nectandrin B (malabaricanol) (machilin I) Ar = Afl machilusin tetrahydrofuroguaiacin A Ar = Afl ganschisandrine Ar = Afl galgravin Ar = Ar5 zuonin A Ar = Ar5 zuonin B 137 Ar = A$ (ref. 143) Ar = Ar7 fragansin B1 Ar5 i"* \tf 0 0 Ar3 A r 0 "'IIAr A$ \$". H'IttAfl Ar!!l'~'fllA$ Ar 0 Ar Ar = A6 3-epi-austrobailignan-7 nectandrin A Ar = A$ fragansin D1 Ar = AP verrucosin Ar = Ar5 (+)-austrobailignan-7 (machilin F) (ref.142) Ar = Ar7 fragansin C1 Ar = Afl veraguensin Ar = Ar7 fragansin C3a Ar = Afl machilin G (ref. 144) (machilin H) 138 Ar = Ar5 Ar = Ar7 fragansin B3 Ar7 Ar Ar = Ar3 fragansin C3b eupobennettin Ar = AP astrolignin Ar = Arl 4-epilarreatricin (ref. 140) Ar = Afl fragansin D3 (ref. 145) Ar = Ar5 (+)-calopiptin Ar = AS fragansin A2 (ref. 144) Ar = Afl (-)-galbelgin Ar = Ar5 (-)-galbacin Ar = A$ (-)-grandisin Ar = Ar7 fragansin 82 A6 &Ar fragansin C2 demethylgrandisin 3-hydroxyd-epilarreatricin saucer netin 139 Ar = A6 tetrahydrofuroguaiacin B (ref. 140) Ar = AF fragansin D2 Fig. 9 Key members of the 2,5-diaryltetrahydrofuranseries Ar = Ar3 (+)-lariciresinol Ar = A6 (+)-lariciresinol @-methyl ether Ar = A$ (+)-acuminatin 140 Ar = Ar3 (ref.147) Ar = Afl (+)-lariciresinol Ar = Afl (+)-lariciresinol dimethyl ether Ar = Ar5 (+)-dihydrosesamin 141 Ar = Afl (ref. 147) 4"-methyl ether Ar = A$ dihydroyangambin Ar = Ar5 (+)-sanshodiol 142 Ar = Arlo (ref. 147) HOWAS HOyAF HOyAr7 Ar7 \$I" Ar2 A$\$'*' A$ \\'" ""\-IAr 0 0 0 Ar = AP (+)-5'-methoxylariciresinol (justiciresinol) taxiresinol di hydrosesartemin jusglaucinol Ar = Ar7 (+)-5',5"-dimethoxylariciresinol (ref. 148) (ref. 149) HOh:--APH9 HOh:-APHq HOwAr5Hq HOsAflHO HOwAr3 HOyAr3 .*~IIOH ..~IIOH Ar7 \I"' 0 A$ \I"' 0 Ar5 \\'" 0 Afl 0 Afl \\" 0 Ar3 \$I*. 0 143 tanegool 7-hydroxydi hydrosesamin fargesol 144 (-)-olivil (ref. 150) (ref. 150) (ref. 151) (ref. 152) (-)-berchemol 2-hydroxyolivil (-)-massoniresinol (vladinol A) (ref.153) Fig. 10 Key members of the 2-aryl-4-benzyltetrahydrofuran series Ward Lignans neolignans and related compounds (+)-lariciresinol (+)-isolariciresinol (-)-secoisolariciresinol (cyclolariciresinol) ""CH20H A13 (-)-oiivil (+)-isoolivil (cycloolivil) HO-d0H A GOH HO A 6 A13xAr3 v OH '"liAr3 0 0 0 OH neoolivil (-)-iiovii isoliovil Fig. 11 Parent members of the lariciresinol olivil and liovil series A useful review of the synthesis of tetrahydrofuran lignans has been p~b1ished.l~~ Two new syntheses of lignans of the lariciresinol'dihydrosesamin type have appeared. The first involves a straightforward reduction of a dibenzylbutyrolac- tone followed by acid-catalysed cyclisation [reaction (19)I.l 55 The second involves a radical cyclisation step which proceeds with high stereoselectivity [reaction (20)].156,'57 ILiAIH4 Ar Hol;j -" O Bu3SnH VA' AIBN Art$\" Ar (Ar = Ar5 or Ar") 2.4 2,6-Diaryl-3,7-dioxabicyclo[3.3.O]octanes New lignans in this series are 145 from Festuca argentina,I5* epimagnolin A 146 from flower buds of Magnolia fargesii,'59 demethylpiperitol 147 from leaves of Apollonias barbujana 2'-hydroxyasarinin 148 from Cuscuta chinensis,16' 6'-hydroxypiperitol 149 produced by Streptomyces species,132 crellisin A which is the diangeloyl ester of 150 from Cre-manthodium ellisii,'62 and graminones A and B 151 54 Natural Product Reports 145 146 1 47 150 153 154 and 152 from rhizomes of Imperata cylindrica.'63 In addition a hydroxyisopentenyl ether of piperitol has been isolated from the stems and leaves of Zanthoxylum pet jolare.164 Epimagnolin A 146 has been converted into the 4'- and 4"-demethyl derivatives 153 and 154 by microbial oxi-dation.'65 A full analysis of the NMR spectra of sesamolin and sesangolin has been published. 166 Fig. 12 shows the symmetrically substituted members of the furofuran series while Fig. 13 lists the known unsymmetrically substituted compounds and Fig. 14 con-tains the monohydroxy and dihydroxy derivatives. Ar = Arl ligballinol ..,,,Ar Ar = A$ (+)-pinoresinol Ar = Afl (+)-eudesmin ..kIl~ Ar = Ar5 (+)-sesamin Hi188 Ar = A$ (+)-yangambin Ar\""' 0 Ar = Ar7 (+)-syringaresinol (lirioresinol 6) Ar = A@ (+) -excelsin Ar = A9 (+)-epipinoresinoi Ar Ar = Ar" (+)-epieudesmin Ar = Ar5 (+)-episesamin (asarinin) Ar = A$ (+)-epiyangambin Ar = Ar7 (+)-episyringaresinol (lirioresinol A) Ar = A@ (+)-epiexcelsin Ar Ar = Ar" (+)-diaeudesmin Ar = Ar5 (+)-diasesamin Ar = A$ (+)-diayangambin Ar = Ar7 (+)-diasyringaresinol (lirioresinol C) Fig.12 Symmetrically substituted furofurans Pinoresinol has been synthesised by oxidative coupling of the P-keto ester 160 using potassium persulfate fol-lowed by DIBAL reduction and acid-catalysed cyclisation (Scheme 4).'73 The diketo diester 161 is obtained as a 1:l mixture with the meso isomer 162. Reduction of the latter compound followed by cyclisation gives the unnatural 2,4- diary1 isomer 164. HIIO..R..*,\A@.-OIIH HIIS...**IIHA@ A$ \\"' 0A$ \\'" 0 HI,,*.$.+\A@ .*~IIH AB 0 Hfl:fl AS 0 Ar\\I"'Hl,,a:i:r5 0 AT\'>"HI8 Ig:r5 0 (+)-sesartemin (+)-episesartemin A (+)-episesartemin B (+)-diasesartemin Ar = A$ (+)-piperit01 Ar = A$ (+)-xanthoxylol (ref. 167) Ar = Ar" (+)-methyl piperitol (kobusin spinesin) Ar = Ar" (+)-methyl xanthoxylol Ar = A$ aschantin Ardo/ Ar = A$ (+)-pluviatilol magnolin epimagnolin membrin demethyl magnolin pinoresinol (+)-phillygenol Ar = A@ (+)-methyl pluviatilol (ref. 168) monomethyl ether forsythigenol (fargesin) Ar = A$ (+)-epiaschantin (+)-medioresinol demethoxypinoresinol (+)-demethoxyexcelsin horsfieldin R = H (+)-sesaminol (justisolin) (ref. 170) (ref. 171) (5'-methoxysesamin) R = Me sesangolin 155 (+)-methoxypiperitol praderin (ref.172) Fig. 13 Unsvmmetricallv substituted furofurans Ar = AP 1-hydroxypinoresinol Ar = A14 gmelinol Ar = Ar" neogmelinol 157 (+)-fraxiresinol arboreol Ar = Ar" isogmelinol Ar = Ar5 isopaulownin Ar = Ar5 neopaulownin Ar = Ar5 paulownin Ar = Ar7 1-hydroxysyringaresinol isoarboreol epiphrymarol isophrymarol lePtostachYol Ar = A$ (-)-prinsepiol 158 Ar = A$ Me0 Ar = A6 (-)-wodeshiol Ar = Ar5 (+)-4-hydroxysesamin (kigeliol) (aptosimol) Me0 Ward Lignans neolignans and related compounds Full details of the synthesis of eudesmin and sesamin 0 by a route involving selective radical fragmentation (Scheme 5) have appeared.'74 The same method has also been applied to the synthesis of yangambin and methyl piperitol.174,175 LC02Me + Ar' MeCN Arl1 Arl 160 C02Me 0 161 i. DIBAL ii. HCI MeOH ..,,\Arl Arl lot,,. 0 0 0 K2S208 Arll $C02Me Arl 3C02Me 0 i C02Me v0 (Ar = Ar" Ar5 A$) 162 Scheme 5 i. DlBAL ii. HCI MeOH (*)-pinoresin01 c-HII-. .-IIH Art 1 \I". 8 0 163 Scheme 4 An asymmetric syntheses of (+)-sesamin and ( -)-asarinin 8:;"" HIIC-.0 following the route reported earlier involving a Heck reaction (Scheme 7) has also been rep~rted.'~~ In this case the Z-vinyl 164 Syntheses of methyl piperitol and methyl xanthoxylol and the corresponding diaxial isomer have been achieved by selective reduction of the 0-keto ester 165 (Scheme 6).'76,'77 The P-keto ester 165 itself was prepared by conjugate addition of an acyl anion equivalent to dimethyl maleate.Further reaction of the anhydrides 166 and 167 under carefully controlled conditions affords the dilac- tones 168 169 and 170 reduction of which gives the parent lignans. A variation on this strategy employing a homochiral analogue of dimethyl maleate has been used to synthesise (+)-methyl pluviatilol.17' Ar5 5 C02Me Hz Pd-C Ar5 NaHMDS or AeCHO THF -100°C C02Me L-Selectrideefc. 165 167 1 Zn(BH4)2etc. Ar5 sic 0 166 (90% de) 169 KHMDS AFCHO J iodide 171 is converted into 172 which by treatment with either a titanium or a silicon Lewis acid affords 173 or 174 which are utilised as precursors for the lignans. The radical cyclisation route utilised for the synthesis of tetrahydrofuran lignans [eqn.(20) see Section 2.31 has been extended to the synthesis of sesamin and eudesmin (Scheme 8).I8O A review of the acrobatic rearrangement reactions of furofurans which attempts to rationalise the mechanisms of many of the acid-catalysed oxidative and reductive reactions they undergo has been published.18' 2.5 Arylnaphthalene derivatives The phyllamyricins A-C (175-177) from Phyllanthus myrti-folius182and koelreuterin- 1 (178) from Koelreuteria henryi' 83 i. LiAIH4 ii. H+ ii. MsCI py H02C A+ (62% de) 170 methyl xanthoxylol (73% de) 168 methyl piperitol Scheme 6 56 Natural Product Reports OMe 0 Me0 Ar5 175 OMe 171 172 TBSOTN Ti(0Pr')~Clp I * 1 77 178 ToOa /fooo I I 174 i.NaBH4 iii. NaI04 ii. Os04,NMO iv. NaOMe I Ar5.%OH \'" 0 (61Oh ee) 1 (-)-asarinin Scheme 7 i. (COC1)2 OMSO HI~,Q:~:~ ii. TBAF 4 Ar\l'" 0 (Ar = Afl or Ar5) Scheme 8 173 179 180 i. NaBH4 iii. NaI04 ii. Os04 NMO iv. NaOMe OH I HI!,.. .-,IIH Ar5 \i'" R..""" 0 (62% ee) I (-)-sesamin R = C02Et R = CH20H i. TBSCI Et3N ii. B2H6 I 181 182 0 HO Aa OH Ar' 183 184 are listed in Figs. 16 and 17 while the conidendrin and retrodendrin series are displayed in Fig. 18. Routes for the synthesis of arylnaphthalene lignans frequently involve either the Diels-Alder reaction or Michael addition even for the synthesis of the fully aromatic compounds. Two new variations on the Diels-Alder approach are shown in Schemes 9 and 10.The first is not unusual in using an isobenzofuran as the diene but is Ar\W 0 unusual in adding the pendant aryl group at a late stage in RHcHo R = CH20TBS the ~ynthesis.''~ The second also involves an isobenzofuran but uses a Pummerer reaction to generate this component (Scheme 1 0). 90 Michael addition by an acyl anion equivalent to butenolide or methyl acrylate forms the basis for routes leading to either the nonphenolic or phenolic lignan lactones [Scheme 1 l(a) and (b)].I9l The synthesis of a wide variety of lignans utilising addition by anions of cyanohydrin silyl ethers has been reviewed.192 The twin themes of Diels-Alder reactions and Michael addition also account for most of the recent developments in the syntheses of the di- and tetra-hydronaphthalene deriva-tives such as podophyllotoxin.Jones et al. have continued to probe the stereochemical aspects of the Diels-Alder reac-ti~n.'~~ They have confirmed that addition of the a-aryl-o- quinodimethane 187 to dimethyl fumarate proceeds with exo addition adjacent to the aryl group to give 188. They also provide strong evidence to suggest that addition to dimethyl maleate also proceeds with exo selectivity to give 189 (Scheme 12). Full details of their synthesis of ( -)-podophyllotoxin from the o-quinonoid pyrone 190 involving endo addition to the menthyloxy butenolide 191 have been published [Scheme 13(~)].'~~ An alternative scheme involving an endo addition of the isobenzofuran 192 with the same dienophile leads to 57 are new arylnaphthalene lactones.The latter compound shows significant cytotoxicity against human tumour cells. Five reduced arylnaphthalene lactones have been reported. 2~-Hydroxy-4'-demethyldeoxypodophyllotoxin 179 and 4'-demethyldeoxypicropodophyllin 180 have been isolated from the stems and leaves respectively of Casearia clarkii. Todolactol B 181 has been isolated from the heartwood of Abies mariesii,127 isopolygamain 182 from Haplophyllum ptilostyl~rn,'~~'~ and hyptinin 183 from Hyptis verti~illata.''~ The aryltetralin 184 has been isolated from Larrea trident at^.^^ No attempt is made here to catalogue all of the known arylnaphthalene derived lignans. However some well known groups of compounds are displayed in Figs.15-18. Some complimentary pairs of so-called 'normal' and 'retro' lactones are shown in Fig. 15. The principal members of the justicidin series and the podophyllotoxin and peltatin group Wurd Lignans neolignans and related compounds Me0 I Ar Ar Ar5 Ar = Ar" dehydrodimethylretrodendrin Ar = Ar" dehydrodimethylconidendrin R = H diphyllin R = Me justicidin C Ar = Ar5 justicidin 6 Ar = Ar5 retrojusticidin 6 R = Me justicidin A 185 Ar = A16 (ref. 186) 186 Ar = A16 (ref. 186) 0 OR OR 0 I I I 0 I I Ar Ar Ar5 Ar = Afi chinensin Ar = A14 retrochinensin R = H taiwanin E R = H retrotaiwanin E Ar = Ar5 taiwanin C Ar = Ar5 justicidin E R = Me justicidin F R = Me justicidin D Ar = A16 dehydrodeoxypodophyllotoxin 0 OH 0 0 LO Ar5 Ar retrohelioxanthin helioxanthin Ar = Afi isodiphyllin (chinensinaphthol) Ar = A16 dehydropodophyllotoxin Fig.15 Complimentary pairs of 'normal' and 'retro' arylnaphthalene lactones OMe ?Me 0 I Ar5 justicidin A justicidin B justicidin C 0 OMe I I Ar5 Ar5 justicidin D justicidin E justicidin F Fig. 16 Principal members of the justicidin series of arylnaphthalenes OH OH I 1 0 0 A16 A16 0 (-)-podophyllotoxin (-)-epipodophyllotoxin (+)-isopodophyllotoxin (+)-epiisopodophyllotoxin (+)-picropodophyllin (Om; (OqQ 0 0 0 i \\ AS A16 O AS A16 0 AB isopicropodophyllin (-)-deoxypodophyllotoxin (-)-isodeoxypodophyllotoxin deoxypicropodophyllin isodeoxypicropodophyllin (ref.187) OH OR OMe OMe OR I Ar = Ar7 (-)-a-peltatin R = H iso-p-peltatin (-)$-peltatin A methyl ether (-)$-peltatin 6 methyl ether R = H iso-a-peltatin Ar = A16 (-)$-peltatin R = Me iso-p-peltatin (ref. 188) (ref. 188) R = Me iso-a-peltatin methyl ether methyl ether Fig. 17 Principal members of the podophyllotoxin and peltatin series of arylnaphthalene derivatives 58 Natural Product Reports 0 0 (-)-a-conidendrin D-conidendrin a-retrodendrin P-retrodendrin 0 0 Af' dimethyl-a-conidendrin dimethyl-P-conidendrin (-)-dimethyl-a-retrodendrin (-)-dimethyl-P-retrodendrin (Om0 0 0 (OmQqqI AP 0 AP O AP a-apopicropodophyllin P-apopicropodophyllin y-apopicropodophyllin Fig. 18 The conidendrin and retrodendrin series of arylnaphthalene derivatives FlI <acH(oMe)2 z [(Om] ?-r1 <Go CH2s+EtAqO CH20H 0 DPAD I Ar5 L Ar5 1 OH C02Me i.Me] NaH ii. KOH C02Me 1 (qco2H :; B2H6 CH20MOM ~ (q 11. MOMCI C02Pr' iii. ArMgCl C02Pri OMe kr DPAD = P$02C=C02Pri 1 Ar = Ar5 taiwanin C Ar = Ae chinensin Scheme 9 ( -)-isopodophyllotoxin [Scheme 13(b)].lg5 Meanwhile Charlton et al. have synthesised ( -)-deoxypodophyllotoxin by reacting the a-hydroxy-a-aryl-o-quinodimethane193 with the fumarate of methyl mandelate 194 which also proceeds endo to the adjacent aryl group [Scheme 13(~)].'~~ Michael initiated ring closure reactions have been used to prepare the isopicropodophyllone analogues 195 (Scheme 14). 97 A similar strategy has been applied to the synthesis of dihydronaphthalene derivatives such as collinusin 196b which on dehydrogenation can be converted into the fully aromatic compounds such as justicidin B (Scheme 15).19* Magnoshinin 197 has been synthesised by a tandem conjugate addition sequence (Scheme 16).'99 Treatment of podophyllotoxone 198 with base converts it initially into picropodophyllone 199 which on further base treatment yields thuriferic acid 200.200-202 Indeed it has subsequently been shown that whereas treatment of 198 with base gives 199 which is converted into 200 under acidic conditions epimerisation occurs at C-3 to give isopicropodo- phyllone 201 which on treatment with base gives epithuriferic acid 202 (Scheme 17).203 Ward Lignans neolignans and related compounds A r5 Ar5 i.Ra-Ni ii. KOSiMea (q I >I' -(OqC"" LiEt3BH 0 C02Me Ar5 AP X = H taiwanin C NaH. LiBH4 I X = OH taiwanin E justicidin E Scheme 10 Reaction of 4-bromo-4'-demethyl-4-deoxypodophyllotoxin 203 with ethanol or glycerol affords the corresponding 4-0-ethyl and 4-0-(2,3-dihydroxypropyl)derivatives 204 and 205 respectively.204 Treatment of 204 with phenyliodonium dia- cetate (PIDA) in methanol gives the quinone-methide monoketal 206 which undergoes transkelalisation by ethylene glycol to give 207. Hydrolysis of the dimethyl ketal with aqueous acid gives the corresponding o-quinone 208 (Scheme 18). 59 (4 TBSO ,CN sRl0q \ R20 MeO@ S i. LHMDS iii. ArCHO Ar Me0 Me0 Ar 0 iii.ArCHO 0 TBSO CN OTBS i. LDA ArACN ii. @CO,M~ C02Me iii. ArCHO Ar 1 95 (Ar = A+ Ar5 AS Ar7) TFAI reflux Scheme 14 TBSO CN ii. HC02Me R20 NaOMe R20 . C02Me Ar /ir R1 = R2 = Me; Ar = Ar5 diphyllin R1R2= CH2; Ar = Ar5 taiwanin E R' R2 = CH2; Ar = Afl isodiphyllin Scheme 11 Me0 Meowo Ar i. LDA ii.? I liii. AKHO Ar 1 88 0 187 C02Me E = C02Me Ar 1 89 Me0 Scheme 12 Ar 196a Ar = Afl 196b Ar=Ar5 Scheme 15 (4 Omenthyl ___ * (-)-podophyllotoxin The 4-azidopodophyllotoxin derivatives 209a and 209b AS 0 undergo a photochemical ring expansion in cyclohexene to 190 191 give the azepines 210 (Scheme 19).205In dicyclopentadiene or cyclopentene the triazenes 211 and 212 were obtained.(b) Omenthyl A number of heterocyclic analogues of lignans have been prepared. These include the fully aromatic phenolic com-(0 O 1q + Q0 --+(-)-isopodophyllotoxin pounds 21S216 prepared by Diels-Alder reactions from dimethyl acetylene dicarboxylate.206 Of greater interest are AS the diaza oxaza and thiaza analogues of podophyllotoxin 192 191 (217-219) details of which have now been p~blished.~'~-~'~ (4 pqAS +R*02cl --+(-)-deoxypodophyllotoxin 2.6 Dibenzocyclooctene derivatives 0 C02R* Eight new dibenzocyclooctene derivatives have been OH reported all of which belong to previously established series. 193 194 Thus schisantherins P and Q 220 and 221 which have been Ph isolated from seeds of Kadsura coccinea are new members of A'VH the schisantherin series (Fig.19).2'0 Kadsulignans L-N R*=\ C02Me 222-224 which were isolated from the same source are Scheme 13 new members of the kadsulignan family and differ from 60 Natural Product Reports OTBS i. LDA Ar15/jCN ii. *CO2M iii. ArISCH2Br OMe a H20H TFA ~ Me0 I= OMe Ar15 i. TsCI,Et3Niii! !gBu OMe Me0 11 OMe Ar15 197 Scheme 16 0 I1 198 0 199 1 base 0 TBSO ,CN Br OTOH 1 glycerol 0 C02Me (O&o Ar7 0 Ar15 Ar157 Ar7 0 i. TBAF Iii. LiAIH4 ?H Ar153c02Me I Ar’5 0 201 1 base 0 203 205 I EtOH OEt OEt I 1 PlDA e MeOH-0 204 0 OEt 1 e&o 0 Me0Q.. Me0go 0 0 0 207 208 Scheme 18 0 Ar 0 0 209a Ar=AS 210a Ar = A6 209b Ar=ArI7 210b Ar = Ar17 h \ N% NyJ N N T*O0 Aa 0 21 1 21 2 Scheme 19 schizandrin-wuweizisu group in Fig.24.218,219 With so many separate series established it is not surprising that some compounds have been given more than one name when isolated from different sources and that close structural relationships exist between members of different series. Some examples which illustrate these points are shown in Fig. 25. A closely related series of compounds the eupodienones are shown in Fig. 26.220 An alternative synthesis of deoxyschizandrin 56 involves reductive coupling of the diketone 228 followed by 61 . C02H 0 ‘“‘C02H Ars Aa 200 202 Scheme 17 previous members of the series in that they do not contain a cyclohexadienone unit but instead contain an oxygen bridge (Fig.20).21 ’ Indeed they could equally be regarded as members of the tetrahydrofuran series of lignans (Section 2.3). Kadsulignan L is diastereoisomeric with neokadsuranin. O-Benzoylgomisin 0 225 is a new member of the gomisin series isolated from the fruits of Schizandra chinensis.212 Since members of the gomisin series were listed in an earlier report they are not included here.213 Angeloylbinankadsurin B 226 and the corresponding acetyl derivative 227 isolated from the fruits of Kadsura japoni~a~’~ are new members of the kadsurin group (Fig. 21).215 The heteroclitins are a further series of dibenzocyclooctene derivatives shown in Fig.22,2167217 while the more well known stegane series are shown in Fig. 23 and the Ward Lignans neolignans and related compounds Ar Afl Afl 213 Ar = Afl or Ar5 214 215 OH C02Me Me0 Me0 Me0 Me0 Me0 Me0 schisantherin A schisantherin B schisantherin C schisantherin D schisantherin E (gomisin C) (gomisin B) ro\ To\ roj Me0 Me0 '%/ 0 0-angel \ schisantherin L schisantherin M schisantherin N (and acetyl) Fig. 19 The schisantherin series of hydrogenation of the C-C double bond produced [reaction (21) cf reaction (5)].221 ( -)-Steganone has been formally synthesised by a palladium-catalysed cross-coupling of an arene-chromium tricarbonyl complex with an arylboronic acid [reaction (22)].222 A number of functionalised tetra-hydrodibenzocyclooctene derivatives have been prepared starting from the corresponding a,P-unsaturated lactones which are readily prepared by oxidative coupling (cf Scheme 1).'07-'09 Some examples of the further transformations which have been carried out are shown in Scheme 20.223,224 It has been suggested that the unusual spirodienone subunit present in kadsulignans C-J may arise through cyclisation of a carbon radical derived from a methoxy group.A similar subunit is present in the heteroclitins D-F (Fig. 23) and in the interiorins A-D. Circumstantial evidence in favour of this pathway has been provided by carrying out a biomimetic radical cyclisation starting from the 2,4-dinitrophenyl ether 229 [reaction (23)].225,226 Finally an aza analogue of stegane (230) has been synthesised in optically active form by oxidative coupling of a dibenzylpiperidine derivative using VOF,.227 An aryl- benzoquinolizidine 231 was unexpectedly obtained when the 62 Natural Product Reports To\ ro Me0 Me0 HO '"I/ Me0 0 OH \ Me0 schisantherin 0 220 schisantherin P dibenzocyclooctene derivatives r0\ Lcl 221 schisantherin Q corresponding a-hydroxybenzylpiperidine was treated with RuO,.2.7 Miscellaneous lignans (-)-Padocin 232 is a lignan with a most unusual structure isolated from Hapluphyllum cappadocicum a Turkish herb.228 Formally it can be related to a 3,4-dibenzyltetrahydrofuran (Section 2.3) in which an extra cyclisation has occurred.Hydrogenation leads to cleavage of the benzylic C-0 bond to give 233 [reaction (24)]. The aryl benzocyclooctadiene 234,which has been synthe- sised by arylation of the parent benzocyclooctadiene 235,can be regarded as a bis-homo analogue of either the aryltetralin lactone or dibenzocyclooctene lignan series and as such might be expected to show interesting biological properties [reaction (25)].229No naturally occurring compounds with this structure have been reported. 3 Neolignans As in previous reports there is no shortage of new neolig- nans to include. Structures 236247 show new benzofuran 216 217 X=NH 218 X=O 219 X=S Me0 Me0 Me0 Me0 Me0 0 Me0 kadsulignan A kadsulignan B kadsulignan C kadsulignan D kadsulignan E 0 Me0 Me0 Me0 Me0 0 0 Me0 Me0 Me0 kadsulignan F kadsulignan G kadsulignans HJ kadsulignan K 222 kadsulignan L R = Pr Et Bus (heteroclitinG) rO\ Me0 \ angel = angeloyl= $ -Me0 ''P tigloyl= $-co )=\ H0 Me0 223 kadsulignan M 224 kadsulignan N Fig.20 The kadsulignan family Me0 Me0 Me0 225 Me0 LO Me0 Med Me0 (-)-kadsurin kadsuranin isokadsuranin (+)-kadsutherin (-)-kadsurarin Me0 r ro\ \ Me0 Me0 \ Me0 Me0 Me0 neokadsuranin binankadsurin A (R = H) binankadsurin B (R = H) 226 R = angeloyl 227 R=acetyl Fig. 21 The kadsurin group of dibenzocyclooctene derivatives Ward Lignans neolignans and related compounds I-? Me0 0 Me0 \ Me0 Me0 Me0 Me02C’ MeO’ heteroclitin A R = isovaleryl heteroclitin D heteroclitinE heteroclitin F heteroclitinG heteroclitin B R = angeloyl heteroclitin C R = tigloyl (kadsulignan K) Fig.22 The heteroclitins series c&o Me0 ,.P2 r$o\ Me0 $o Me0 Me0 / / ‘‘Y{ Me0 \ 0 Me0 I 0 Me0 \ 0 Me0 --Me0 Me0 Me0 Me0 R1 = R2 = H (-)-stegane R’ = R2 = H (+)-isostegane R’ = R2= H (-)-picrostegane R’ = R2 = H (+)-isopicrostegane R1R2= 0 (-)-steganone R’ R2= 0 (-)-isosteganone R1= H; R2= OH (-)-picrosteganol R1 = H; R2= OH (-)-steganol R’ = H; R2= OAc isosteganacin R’ = OH; R2= H (-)-epipicrosteganol R’ = H; R2= OAc (-)-steganacin R‘ = H; R2 = O-angel steganangin R’ = OH; R2 = H (-)-episteganol R1= OAc; R2 = H (-)-episteganacin R’ = O-angel; R2= H episteganangin Fig.23 The stegane series of dibenzocyclooctenes Me0 Me0 Me0 Me0 Me0 Me0 Me0 Me0 Me0 Me0 (+)-schizandrin (+)-isoschizandrin (+)-deoxyschizandrin y-schizandrin (-)-wuweizisu C (wuweizisu A) (wuweizisu 6) Fig. 24 The schizandrin-wuweizisu group of dibenzocyclooctenes Me0 Me0 Me0 Me0 Me0 Me0 Me0 isokadsuranin kadsuranin deoxygomisin A (-)-gomisin L2 deoxygomisin S deoxyschizandrin = deoxygomisin 0 = gomisin M methyl ether = y-schizandrin methyl ether methyl ether = gomisin K3 = gomisin N = wuweizisu B deoxygomisin U methyl ether methyl ether Fig. 25 Some Examples of overlap between the different series of dibenzocyclooctene derivatives 64 Natural Product Reports Meoq<g,,,l, .11111 <g,,lil M e O g PhCOO PhCOO .11,l1 \ \ \ Me0 Me0 Me0 Me0 I Me0 I Me0 I Me0 / Me0 I Me0 Me0 Me0 Me0 Me0 OMe OMe OMe OMe 0 OMe 0 0 0 0 eupodienone-3 eupodienone-4 eupodienone-5 eupodienone-1 eupodienone-2 PhCOO q .11111 e 0 OMe 0 0 0 0 eupodienone-6 eupodienone-7 eupodienone-8 eupodienone-9 Fig.26 The eupodienone series of dibenzocyclooctene derivatives OMe R1O \ Me0 Me0 Me0 Me0 OMe Me0 228 RIR1 = CH2; R2 = Bn TiCI4 Mg-Hg R1 =Me; R2=Bn 1 Me0 Me0 Rh(PPh&I /Et3SiH 02 PhSiHAMn(acac)z J RIO H2 -Pd-C Me0 Me0 Me0 Me0 56 Me0 Me0 i. DIBAL iii. MsCl steps ii. Os04 Ivi. LiAIH4 R1O ro 0 Me0 + d+ CHO RIO MeO$cHo CH20H Me0 Me0 Me0 Me0 “‘“$jrCH20H (CO)3C; OMe (CO)3Cr OMe OH t (-)-steganone Me0 Scheme 20 Ward Lignans neolignans and related compounds 65 Me0 Me0 229 Ar = 2,4-dinitrophenyl i.Na NH3 ii. MsCI py iii. LiAIH4 R20 R20 i. LiAIH4 ii. MsCI,py * Me0 iii. LiAIH4 Me0 Me0 Me0 Me0 Me0 R1= R2 = Me (+)-schizandrin Me0 OMe Ar5 R1R2= CH2 (+)-gomisin A 230 231 Scheme 21 Meom -H2 Meo~cH20H (24) derivatives isolated from various plant sources. The structure of schmiditin isolated from Piper schmidtii has been revised to 241b (=kadsurin B).233 Woorenogenin 242 was isolated along HO 232 A13 Pd-C HO \ 233 Ar3 with a number of glycosides in which it is the aglycone from Coptis japoni~a.~~~ p-Hydroxybenzoate esters of 248a and 248b have been isolated from Chosenia arb~tifolia,~~~ and ferulic acid esters (containing cis-and trans-ferulic acid residues boehmenans B-D) of 249a and 249b have been isolated from Ochroma lagop~s.~~~ A full analysis of the NMR spectra of eupomatenoids 3-6 and 13 has been published,239 and the Me0 MeS03H Me0 I 0 (25) absolute configuration of dehydrodiconiferyl alcohol has been established.240 HO 235 Ar4 234 _CH20H 236 237a Ar = Arl (ref.231) 238a Ar = A+ (ref. 232) 239a Ar = A+ (ref. 125) 240 (ref. 230) 237b Ar = AS (ref. 231) 238b Ar = AP (ref. 125) 239b Ar = AP (ref. 234) (ref. 233) 237c Ar = A6 (ref. 231) OMe 241a Ar = AP (ref. 234) 242 243 244 245 241 b Ar = AP (ref. 233) (ref. 235) (ref. 236) (ref. 236) (ref. 236) CH20H HocH2~..u>iAr OMe OMe OMe 246 247 248a Ar = AP (ref. 237) 249a Ar = AP (ref.238) (ref. 236) (ref. 236) 248b Ar = Ar7 (ref. 237) 249b Ar = Ar7 (ref. 238) 66 Natural Product Reports M~OTCH~OH Me10CH2OH CH20H HOq'. Ar7 OMe OH "'I A6 OHHoY5OMe A$ Ar3 250 251 252 253 Me0TcH20H (ref. 241) Me;TcH20H (ref. 242) Me;* (ref. 242) 0 NH Ar' (ref. 243) HN-Ar' H O Ar A R OH H O A6 A R OH "Ag-Ar1 AS 0 0 0 -Ar1 254a Ar = A$; R = H (ref. 244) 254b Ar = Ar7; R = OMe (ref. 244) 255a R = H (ref. 238) 255b R = OMe (ref. 238) 256 (ref. 70) 257 (ref. 70) \\ P 258 259 260 261 262 (ref. 232) (ref. 125) (ref. 236) (ref. 236) (ref. 236) 0-I ? \\ 263 264 265a Ar = A+ (ref. 246) 266 (ref. 236) (ref. 245) 265b Ar = Ar5 (ref. 246) (ref. 246) Structures 250-255 show new compounds of the alkyl aryl ether type.Ehletianol D is a glucoside of 253 isolated from Ehretia o~alifolia.~~~ p-Hydroxybenzoate esters of 2541 have been isolated from Salix sachalinensis24 and ferulic acid esters (containing cis and trans residues carolignans A-F) have been isolated from Ochroma lagopu~.~~~ Cannabisins E and F 256 and 257 isolated from the fruits of Cannabis sativa contain the 4-hydroxyphenylethylamine residues which characterise other members of this series (cf 52)." Compounds 258-266 are new neolignans of the bicyclo[3.2. lloctane type. Examples include iso-ocobullenone 264 from Ocotea b~llata~~~ and puberulins A-C 265a 265b and 266 from Piper puberul~m.~~~ Compounds 267-271 con-tain a diarylethane skeleton; nitidanin 272 from Xanthoxyhm nitidum is a further example of a benzodioxin derivative;247 isomagnolone 273 from IlZicium simonsii is a biaryl ether; and biondinin A 274 from Magnolia biondii is of a unique structural type.'35 ( -)-Viriolin 276 has been synthesised by a route involving an enzyme catalysed kinetic resolution of the acetate 275 (Scheme 22).249 Magnolol 279 has been synthesised by Ward Lignans neolignans and related compounds palladium catalysed coupling of the aryl iodide 277 and the zinc reagent 278 (Scheme 23).250 It can also be prepared by treating the dibromobiphenyl derivative 280 with allyltributy ltin .Schizotenuin D 282 the parent lignan of the schizotenuins has been synthesised from the dimethyl ester of dehydrod- iferulic acid (281) which can be readily prepared by oxidative coupling of methyl ferulate (cf Section 1.3).25' The same starting material was also used in a synthesis of 3',4-di-0-methylcedrusin 284.252Both enantiomers of 284 were pre- pared by resolving 283 on a chiral column prior to reduction (Scheme 24).An eleven step synthesis of porosin 285 has also been reported.253 This was then converted into 5-demethoxy- megaphone acetate 286 [reaction (26)]. Engler and co-workers have continued their detailed study of Lewis acid catalysed reactions of arylpropenes with quinones and have used these reactions to synthesise a number of neolignans including compounds of the kad-surenone 287 burchellin 291 and guianin (cf 292 293) type (Schemes 25 and 26).254,255 Of particular note is the subtle control which can be exercised over the outcome of such II 267 268 (ref.121) (ref. 121) 272 (ref. 247) 0 OAc OH i. NaBH4 Rhizopus- ii. Ac20 py * A+* Af'* Br Br Br 275 (79% ee) 1NaOH 276 Scheme 22 MOMO MOMO i ZnCl 277 278 DIBAL HOq AoH HOqBr Br&OH 280 Scheme 23 reactions by careful choice of the Lewis acid and the reaction conditions. A number of benzodioxin derivatives of the eusiderin type have been prepared using the general method outlined in the 68 Natural Product Reports A$& Ar5&OMe \ 3 I 269 270 271 (ref. 121) (ref. 245) (ref. 236) 273 274 (ref. 248) (ref. 135) i. Ac20 py ii DDQ/ iii. BBr3 iv. aq. NH3 OH I OMe CH20H 281 Ar=AB 283 Ar=Ar" .,,IIA+ HOCH2-y$ OMe 284 Scheme 24 MeO,,,, i.DIBAL MeO,,,. ii. MsCl * .-SIIA+ iii. Et3N H20 (26) 0 ' 0 iv. Ago py 285 286 0 i. Tf20 py ii. allylSnBu3 Pdo iii. BF3.Et20 Me.$ 287 kadsurenone (a-OMe) 289 liliflol-B 288 denudatin (P-OMe) Scheme 25 last report.256 The structure of megacerotonic acid 295 has been finally clarified by an independent synthesis by Brown and co-workers (Scheme 27).257,258 Sesquipinsapols A-C 298-300 have been isolated from the wood of Abies pinsapo,' 303261 and sesquimarocanols A and B -Ariint..hOR rnarocana.262 have been isolated from isolated from of bark &OR SnC,4 301 and 302Ehletianol C 303 has been the wood theAbies A r w / 1 equiv. + 0 (R = En) (Ar = A+ or Ar5) (R = Me or Bn) 290 R=H 291 = Me (burchellin) SOR Ar 0 I OR 292 R=H 294 (R = Me or Bn) 293 R=Me Scheme 26 HO Me Ar5CH0 piperidine i.NaOH ii. MeOH H' I Ar13CH0 Ar5 Ar'3T,yzMe * NaOMe Ar5 4. Oligomeric lignans and neolignans A number of new sesquimeric and dimeric lignans and neolig- nans have been isolated. Neoarctin B 296 and diarctigenin 297 which have been isolated from the seeds of Arctiurn lappa have very symmetrical structure^.^^^^^^^ The biphenyl link in 296 is difficult to justify on biogenetic grounds and may warrant further investigation. On the basis of the NMR data provided it would be difficult to exclude a 3"-3" link as found in 297. 296 297 Ward Lignans neolignans and related compounds of Ehretiu ov~tifolia,~~~ and simonsinol 304 has been isolated from the bark of Illicium ~imonsii.~~' Finally 305 (both erytho and threo isomers) has been isolated from the wood of Choseniu arb~tifolia,~~~ and the same compound has also been isolated from the wood of SaIix ~acha1inensi.s.~~~ Ar3-0 A-o CH20H CH20H 298 299 OMe Ar3 OH OH 300 301 CH20H 0 ""CH20H Ar3 it II OH OH OH OH 302 303 ri OHil 304 Me0 Ar'CO2CH2 I OMe 305 69 5 Hybrid lignans A new flavonolignan 306 has been isolated from the heartwood of Distemonanthus benthamian~s,~~~ while iryantherins G-J (307-310) have been isolated from the fruits of Iryanthera grandi~.~~~ Brevitaxin 311 is a diterpenelignan found in the bark of Taxus brevifolia,266 while 5'-demethoxycadensin G 312 is a new xanthonolignan isolated from Cratoxylurn cochinchi- nese.267,268Maackoline 313 is a stilbenolignan isolated from the heartwood of Maackia arnunen~is.~~~ &A Me0 OMe OMe OMe OH 306 %.,F p Arl),,,, OH A0 r / '..r 't, OH 0 A r Arl Ar' 307 Ar=Arl3 309 Ar = Ar13 308 Ar=Ar5 310 Ar = Ar5 OH CH20H 311 31 2 HO I 31 3 ( -)-Monoterpenylmagnolol 318 has been synthesised in eight steps from (+)-3,9-dibromocamphor 314.250The key step involves coupling the arylzinc reagent 315 with the iodide 316 leading to the tricyclic product 317 (Scheme 28). 6 Norlignans Ailanthondol 319 and the related 2-arylbenzofurans 320 and 321 have been isolated from Zanthoxylum ailanthoides Krame- ria grayi and K.paucifolia re~pectively.~~'-~~~ Of greater interest from a structural point of view are the pyrones 322-325 which have been isolated along with 326 from cultures A of Jamesoniella aut~mnalis.~~~biosynthetic pathway accounting for the formation of 322-325 has been proposed. The diastereoisomeric glucosides curculigine and isocur-70 Natural Product Reports MoMo? I 314 I R=H 315 R = MOM MoMo~ 1 316 1 I 4 31 8 317 R = MOM R=H NPSP = K(phenylse1eno)phthalimide Scheme 28 319 Ar=A?; R=OMe 320 321 Ar = 2-HO-CMeOphenyl; R = H HOWCO2R' HOWCO2H HO '"'C02R2 HO C02H 325 Hoqco2H HO Ar2 C02H 326 327 R=H 328 R=H 329 R=Me 330 R=Me culigine 327 and 328 and their 0-methyl ethers 329 and 330 have been isolated from Curculigo recur~ata.~~~ Ailanthoidol 319 has been synthesised from the alkyne 331 which was prepared by a palladium catalysed coupling reac- tion [reaction (27)].275 Egonol 334 and machicendiol 335 have also been prepared using a palladium catalysed coupling reaction but this time on the benzofuran 336 (Scheme 29).276 I Pdo OMe 331 OMe OMe 336 OMe 333 R=H R = TBDMS BuLi ZnClp ArSBr WPPbh OR I I I OMe OMe 335 R = TBDPS or TBDMS 334 R=THP R=H R=H Scheme 29 References 1 R.S. Ward Nat. Prod. Rep. 1993 10 1. 2 R. S. Ward Nut. Prod. Rep. 1995 12 183. 3 N. G. 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