摘要:

Lignans and Neolignans D. A. Whiting Department of Chemistry The University Nottingham NG7 2RD ~ ~~ ~~ Reviewing the literature from 1976 to December 1983 1 Introduction 1.1 Definitions 1.2 Classificatiop 1.3 Numbering and Nomenclature 1.4 Scope of the Review 2 Lignans 2.1 Dibenzyltrutanes 2.2 Di benzylbutyrolactones 2.3 Substituted Furans 2.3.1 General Type (7) 2.3.2 General Type (6) 2.3.3 General Type (5) 2.4 Furofurans 2.4.1 2,6-Diaryl-3,7-di~xabicyclo[ 3.3.0Joctanes 2.4.2 Epoxylignanolides 2.5 1-Arylnaphthalenes and Relatives 2.5.1 1-Arylnaphthalenes 2.5.2 1-Aryltetralins 2.6 o,o’-Bridged Biphenyls (Dibenzocyclo-octadienes) 2.7 Trimers and Tetramers of Ar-C3 Units 2.8 Biosynthesis 3 Neolignans 3.1 (3,3’)-Neolignans 3.2 (9,9’)-Neolignans 3.3 (8,3’)-Neolignans 3.3.1 Benzofurans 3.3.2 Di hydrobenzofurans 3.4 (8.1’)-Neolignans 3.5 (8,1’.7,3‘)-Neolignans 3.6 (8,5’.7,3’)-Neolignans 3.7 (8,1’.7,9’)-Neolignans 3.8 (2,2’.5,1’)-Neolignans 3.9 (8-0-4’)-N eolignans 3.10 (3-O-.l’)-Neolignans 3.1 1 (8-0-4’.7-0-3’)-Neolignans 3.12 New Types of Neolignan 4 References 1 Introduction I .1 Definitions The lignans and neolignans are groups of natural products whose carbon skeletons are constructed by the linking of c6c3 units (l) which are formed biogenetically through the shikimate pathway.The term ‘lignan’ reflecting the woody tissue from which many examples derive was introduced by Haworth,’ and implied structures that are composed of two units (l) linked p+’ (8-8’). The frequent occurrence of this linkage can be ascribed to p+‘ coupling of radicals (2) derived by oxidation of for example a p-hydroxycinnamyl precursor. The name ‘neolignan’ was coined by Gottlieb initially for compounds containing two c6c3 fragments that are linked otherwise than p+’. More re~ently,~ neolignans were rede- fined as the products of oxidative coupling of allyl- or propenyl-phenols while lignans were regarded as the coupling products of cinnamyl alcohols etc. A distinction based thus on biosynthetic origin has attractions but these origins are chiefly matters of hypothesis at present as little experimental work has been carried out in this area.Since experience shows that 9 ca( I $C P 7c when uncovered biosynthetic pathways are sometimes more subtle than their rationalizations on paper it seems wiser to employ a classification that is based on structure rather than on speculation. Gottlieb’s former definition of neolignans will be used in this review. It should be noted that there is now confusion in the literature over the use of ‘neolignan’; this label has recently been attached to compounds belonging to traditional lignan groups (e.g. see ref. 21 below). 1.2 Classification Natural products that are included here are divided into two major groups the lignans and the neolignans.Another group the norlignans warrants inclusion. However more comprehen- sive treatment of the norlignans is required than space permits here since they have not been reviewed before. For similar reasons no account is made in this review of compounds (‘ligno’ compoucds) which derive from coupling of a c6c3unit with for example a flavonoid or a coumarin moiety. These will be dealt with in a second article by the author. Reflecting the literature covered the lignans are divided into six subgroups based on general structures (3)-( 10) (Scheme 1). The dibenzylbutanes (3) have c6c3 units linked p-0’ only; the lactones (4) furans (5)-(7) and furofurans (8) have an additional oxygen bridge and the arylnaphthalenes (9) and bridged biphenyls (10) have a second C-C link.Neolignans show very varied structures and more than fifteen subgroups can be discerned including the frameworks (1 1)-(25) (Scheme 2). These are most readily designated by specifying as shown the points of union between the C,C3 units. 1.3 Numbering and Nomenclature The current situation is decidedly unsatisfactory. Trivial names proliferate even for enantiomers and glycosides and are still being introduced even where systematic nomenclature is straightforward. Freudenberg and Weinges introduced a scheme for lignans in 19614 and this has recently been restated and e~panded.~“ Neolignans are not included although the term ‘isolignans’ is used to describe 2-aryl-benzofurans which are treated by others as a subgroup of the neolignans.It is proposed that prefixes such as ‘guaia-’ and ‘pipero-’ should indicate certain substituted aryl moieties but ‘methoxy’ and ‘methylenedioxy’ are to be employed at the same time. This is not in line with current practice and has possibly contributed to the limited usage of the system. Even within a well defined subgroup difficulties appear. Thus in the 1-arylnaphthalene and tetralin group different numbering systems are used and configurations are still 192 NATURAL PRODUCT REPORTS. 1985 specified by prefixes such as ‘iso’ and ‘picro’. AyresSb has pointed out that an agreed international system is urgently needed. Rationalization of nomenclature for the podophyllo- Ar ‘ toxin group has been suggested (see Section 2.5.2).This review Ar3( ArRArF Ar’ Ar’ which is essentially ‘updating’ retains the authors’ nomen- (3) (41 (51 clature but not necessarily the numbering. Ar’ Ar Ar@ Ar’ O@ Ar 1.4 Scope of the Review The most recent major work on lignans and neolignans (and indeed the only book dedicated to this subject) is a compilation of expert reviews edited by R~o,~ covering literature to ca. 1976. A shorter less comprehensive account by Grimshaw6 covers similar ground; this has been supplemented.’ Early (7) (8) work on lignans was described by Hearon and MacGregor.* Since 1976 a further account of neolignans has been given by Gottlieb3 and major synthetic approaches to lignans have been well reviewed by Ward9 (1982); otherwise apart from some articles on biological only short reports have appeared.’* This article sets out to cover the literature on general and structural aspects from 1976 and on synthetic work from 198 1 in order to update previous major accounts.Ar w 2 Lignans 2.1 Dibenzylbutanes [General Structure (3)] (9) (1 0) Seeds of Salviaplebeia have been shown’ 3914 to contain two new Scheme 1 Lignan types esters [(26) and (27)] of secoisolariciresinol and zuihonin D w ArriAr (12) &2 2/ ArI0L (d o3 5’ Ar Ar Ar (23) (24) (25) Scheme 2 Neolignan types showing points of union of the C,C units NATURAL PRODUCT REPORTS 1985-D. A. WHITING (28) which is an unusual enedione has been isolated15 from Machilus zuihoensis. The strategy shown in Scheme 3 has been employedI6 to prepare without stereoselectivity various dibenzylbutanes including nordihydroguaiaretic acid which is an inhibitor of the biosynthesis of thromboxane A2.(2) and meso iii,iv 1 2.2 Dibenzylbutyrolactones [General Structure (4)J Several new members of this class have been discovered and their constitutions established. Absolute configurations have been determined for the lactones (29)-(36),17 as well as for the two 5-hydroxylated epimers of a further example. Lactone (37) was isolatedI8 from Cinnamomum camphoru Sieb. and the (+)-enantiomer (38) of arctigenin from Wikstroemia indica.19 Seeds of Virofu sebijera yielded (39) while the stereoisomer (40) was found in the pericarps.20 The lactones (41),(42) and (43)(the antileukaemic wikstromol) were extracted from Chuerophylfum maculatum Trachelospermum asiaticum,22 and Wikstroemia s~p.,~~ respectively and the structure of pinopalustrin was establi~hed~~ent-(43).The arylidene lactone (44) was as obtained25 from Jatropha gossypfolia; its structure was determined by X-ray analysis. Related compounds were reported in Ant hriscus nemorosa* and Chaerop h yllum maculatum.2 Enterolactone [( +)-(45)] and the corresponding diol (*)-(46) have been discovered as sulphate or glucuronide conju- gates in body fluids (bile urine semen etc.)of humans and of monkeys and other These lignans appear to be formed by the action of intestinal micr~flora~~ dietary on vegetable fibre,33- 36 and possible connections between these Ar" Ar threo and erythro Reagents i ArMgX Ni; ii Raney nickel; iii Ar'MgX PdO; iv Ar"MgX Pd" Scheme 3 0 QJ 0 (29) R'= R2= OMe; (2RJ3R) (30) R'= H R2= OH; (2RJ3R) (31) R'= H R2=OMe; (2R,3R) RYo OA [CH2],oCHMeEt E (26) R = CH=CHAr** (27) R = [CH2Il0CHMeEt * Throughout this article (32) (33) (31) (35) (36) R' !! OOMe OMe R'= R2 = H R3= OMe ; (2R,3R) R1 = OH R2 = R3= H ; (2SJ3S) R'=OH R2= H R3= OMe;(2SJ3S) R'= R2= OH R3= H; (2SJ3R) R'= RZ= OH R3= OMe; (2S,3R) OOMe OMe .o\ (37) R'= R2= R3= OMe;(2RJ3R) (38) R'= H R2= R3 = OH; [2SJ3S) 0 M;Q--& R' \ OMe OMe OOMeOH (41) R'= H RZ= OMe (12) R'= OMe R2 = OH ;(2RJ3R) NATURAL PRODUCT REPORTS 1985 0 HO OMe OMe (44) (45) H OH HO metabolites and cancer (either as inducers or as protective agents) have been disc~ssed.~’ The very interesting question of the origin of the m-hydroxyaryl moieties of these lignans is currently unsolved.Three syntheses of enterolactone have been reported. Pelter have Ward and their co-w~rkers~~~ used the versatile approach of Ziegler and Sch~artz,~*~ with Michael addition of a dithiane anion to butenolide followed by benzylation in situ. Desulphurization of the resulting trans-lactone (47; Ar‘ = Ar” = 3-hydroxyphenyl) (see Scheme 4) gave enterolactone. Snieckus and his collaborator^^^ have shown that dianions derived from succinamides can be doubly benzylated to give amides (48) (predominantly threo) and hence lactones (49) in which Ar’ = Ar” e.g.hinokinin enterolactone and mataire- sinol dimethyl ether. A classical Stobbe approach to enterolac- tone has also been reported.40 An alternative approach to the lactones (49) uses the Stobbe reaction to generate an unsatu- rated ester (50); hydrogenation selective reduction and trans- alkylation of intermediates (52) completes the sequence. In this way ( +)-pluviatolide (49 ; Ar’ = 4-hydroxy-3-methoxypheny1 Ar” = 3,4-methylenedioxyphenyl)and ( )-isopluviatolide (49 ; Ar’ = Ar“ = 4-hydroxy-3-methoxyphenyl) have been pre- pared,41 thus confirming their structures. Chiral hydrogena- tion of the esters (50) has afforded (@-esters (51) in 23-78% optical yields.42 2.3 Substituted Furans 2.3.1 General Type (7) Various new members of this group have been characterized; chicanine (53) from a species of the genus Schisandra with the (2S,3R,4S,5S) absolute stereochemistry shown ;43 the zuihon- ins A (54) B (53 and C (56) from Machilus ~uihoensis;~~ the nectandrins A (57) and B (58) from Nectandra rigid^;^^ machilusin (59) from leaves of Machilus j~ponica;~~ the tetra- hydrofuran (60) (of incompletely determined stereochemistry) from Schisandra henr~i;~~ neo-olivil (61) from Thymus longi- ~7orus;~~ and verrucosin which is the 3,4-trans isomer of (59) from Urbanodendron verruco~um.~~ 2.3.2 General Type (6) This is a small varied and more uncommon group of tetrahydrofuranoid lignans.The members appear to be related to the dioxabicyclo-octanes (see Section 2.4.1) by the formal cleavage in the latter of a C-0 bond. Such a cleavage might in some cases be a mode of biosynthesis. Araucaria angustifolia provided the lariciresinol monomethyl ether (62) together with the corresponding secolariciresinol.sO ( -)-Dihydrosesamin [ent-(63)] was isolated from Daphne tangutica.s * Magnolia stellata yielded magnostellin A (64) (2S,3S,4S) and magnostel- . .. 0 Art’ CNMe2 f0 Ar CNMe22 (491 t Reagents:i Ar’C(SR),; ii Ar”CH,X; iii Raney nickel; iv 2ArCH,X Scheme 4 R’ R2 R3” H&;RL 5 3 3L 2 (53) R’= RL = R = H R = Ar ,R = Ar (54) R’ = R3 = RL= H RZ= R5 = Ar3 (55) R’ = R2 = RL= H R3 = R5 = Ar3 (56) R’= R3 = RL= H R2 = Ar3,R5 = Ar 1 (57) R’= R2 = R4= H R3= Ar2 R5=Ar’ (58) R’= R2= RL= H R3= R5 = Ar2 (59) R’= R3= RL= H; R2=Ar1,R5= Ar30~R2=‘Ar3,R5=Ar’ (60) R’= OH; R2 R3 = H Ar3 ;RLJ R5= H Ar2 (61) (63) R’= RZ= Ar3 (641 0Glc lin B (65);52 the latter is included here since its structure can be formally derived from a dioxabicyclo-octane by C-C cleavage.No other natural compound of this type is known to the author. Magnolia grandflora L.s3gave magnolenin-C (66) and the trio1 (67) was obtained from Ligustrum japonicum Th~nb.~~ A lignan that was isolated from nematode-infected potatoes has been identified tentatively as a lariciresinol bisglycoside.ss NATURAL PRODUCT REPORTS 1985-D.A. WHITING 2.3.3 General Type (5) New examples of this class have been isolated from Arzstolochiu triangularis [(68) and (69); both (3R,4R)],s6,s7 Piper clusii [(-)-clusin (70)];s8 Carissa edulis [carissanol (71)],s9 and Taxus wallichianu [isoliovil (72)].60 Podotoxin (73)6’ and acanthotoxin (74),62 which is an inhibitor of seed germination were found in (68) R’ = Ar’ R2= Ar3 Zanthoxylum acanthopodium. (69) R’ = Ar3,R2= Ar ’ 2.4 Furofurans [General Structure (8)] (67) (70) R’ = Ar3,R2= Arb ’ 2.4.I 2,6-Diaryl-3,7- Dioxabicyclo[ 3.3.0loctanes (75) Z Z These are one of the largest groups of lignans and are widely A A>k Ar distributed in plants. There have been a number of revisions of structure and stereochemistry in the period covered by this OH -< oft yo review and the range of known structures has increased.0 OH N.m.r. methods are of major importance in the elucidation of (73) R = Ar’ structure and a valuable general discussion of such techniques (71) R = Ar3 has appeared.63 Proton-proton coupling constants are not definitive of stereochemistry in these compounds but 3C n.m.r. shifts are of particular significance. Circular dichroism spectra can be correlated with absolute c~nfiguration.~~ The absolute stereochemistries that are shown in structures (75a) (75b) and (75c) have been assigned to (+)-pluviatol (+)-methylpluviatol (fargesin) and (+)-xanthoxylol respec- ti~ely,~~ and structures of epiaschantin and epimagnolin have been revised to (75d) and (75e) respecti~ely.~~ The roots of Arternisia absinthium have provided an unusual range of lignans (75) a; R’= Ar2,RZ= R3= H ,RL= Ar3 of this type66 (thirteen examples) including the new com- b; R’=Ar’,RZ= R3= H,Rb= Ar3 pounds (+)-sesartin (750 (+)-episesartemin A (75g) (+)-episesartemin B (75h) and (+)-diasesartemin (75i).Lanthan- c; R’=Ar3,RZ= R3= H ,RL= Ar2 ide-induced ’H n.m.r. shifts were analysed to deduce d ; R’= ArbJ RZ= R3= H ,RL= Ar3 stereochemistry. Other new members of this group are justisolin (75j) occurring in Justiciu simplex67 with simplexo- e; R’= ArL,RZ= R3= H ,RL= Ar’ side [which is a glucoside of phillygenol (75p)l; horsfieldin f ; R’= R3= H,RZ= Ar5,RL= Arb (75k) which is a desmethyl-fargesin from Horsjieldia iryagh- edhi;68 2-epi-fargesi n [en?-( 7 5I)] from Fleischmannia pycnoce- g ; R’.Ar5 RZ= R3= H ,Rb= Ar‘ the phal~;~~cytotoxic liriodendrin which is the bis-P-D-h; R’= RL= H,R2= Ar5,R3= ArL glucoside of (75m) from Penstemon deust~s;~~ the lignan (75n) from a cell culture of Vigna angularis that had been treated with i ; R’= Ar5 R2= RL= H ,R3= ArL actinomycin D;7 the P-glucoside of (+)-piperit01 (750) from j; R’=R3= H,R2=ArbJRL=Ar3 Helichrysum hra~teatum;~~ (+)-spinescin [ent-(75p)] from Aptosirnum ~pinescens;~~ and simplocosin (75q) [(-)-epipinore-k; R1=ArZ,R2= R3= H,RL= Ar3 1 z L sinol mono-P-~-glucoside] from Symplocos l~cida.~~ I ; R =R 3 = H,R=Ar3 ,R =Ar 1 An antihypertensive principle from Eucornmia ulmoides proved to be pinoresinol bis-P-D-glucoside ;7 (+)-medioresinol m; R’=R3= H,RZ=RL Ar7 bis-P-D-glucoside was also and it was also present n ; R’= R3= H Rz= RL= Are with the corresponding mono-P-D-glucoside in Liriodendron tulipver~.~~ Pinoresinol and its P-D-ghcoside inhibit CAMP o R’= R3= H RZ= Ar3 ,RL= ArZ phosph~diesterase,~~ while both sesamin and fargesin retard p ; R’= R3= HI Rz= Arz R & = Ar 3 the germination of seeds.79 The basic structure (75) is also found in various hydroxylated forms in Nature.New examples q; R’=RL= H,Rz=Arz-~-D-GI~,R3=Arz of this are kigeliol [(76) or ent-(76)] from the wood of Kigeliu pinnatu,sO and ( +)-1 -acetoxypinoresinol 4’-P-~-ghcoside (77) from Olea europaeu;s1-82 whether kigeliol is identical to or enantiomeric with wodeshiols3 is not clear.The unusual bisacetal(78) (occurring in Justicia simplex) has been character- ized.84 A possible origin for this compound would be aryl migration in a 2,6-bishydroperoxy compound arising from oxidation of sesamin. 2.4.2 Epoxylignanolides A seed-germination inhibitor that had been isolatedss from the monocotyledonous plant Aegilops ovatu was originally assigned the 2,4-diaryl-3,7-dioxabicyclo-octan-8-one structure (79). This is a most interesting compound since it inhibits the germination of lettuce achenes in the light but not in the dark. An irradiated sample inhibited germination. The grounds of the assignment of the novel 2,4-diaryl structure were questioneds6 and the (79) R’= RZ= Ar2 constitution was revised to the 2,6-diaryl isomer (80) following (781 (81) R’= RZ = Ph a biomimetic synthesis87 (although the synthesis involving cross oxidative coupling of ferulic acid and coniferyl (82) R’ = R2= Ar3 alcohol is not unambiguous).Structure (80) was confirmed after spectroscopic comparison with a synthetic lactone (8 The problems of distinguishing the 2,4- and 2,6-bisaryl lactones have been discussed ;89 synthetic models have been character- ized by X-ray analysis and their n.m.r. spectra analysed; I3C n.m.r. shifts can distinguish the two types. Aptosimone (from Aptosimum spinescens) has also been allocated73 a 2,4-diaryl structure (82) but on the evidence available this is open to question.86 Aptosimum spinescens also affords aptosimol which is the hemiacetal corresponding to the formal reduction of (80).Styraxin [(83) or ent-(83)] is an antitumour principle from Styrux oficinalis whose structure is firmly grounded in X-ray determinati~n."~ Some interesting chemistry is exhibited by lignans within this group. Thus arboreol (84) (see Scheme 5) undergoes an unusual pinacol rearrangement to yield gmelanone (85) in a biomimetic synthe~is;~' paulownin (86) rearranges when it is oxidized with dichlorodicyanoquinone to yield the 4-pyrone (87),92 and the same reagent converts gummadiol (88) into the enol lactone (89). A general synthesis of 2,6-diaryl-3,7-dioxabicyclo-octane lignans has been reportedg3 which allows for the first time two different aryl units to be introduced in a controlled manner (Scheme 6).This employs trapping of the dianion (90) with an aryl aldehyde and subsequent lactonization. One of the epimeric lactones i.e. (91) afforded a bis-lactone (92) from which the lignans (93) or (94) could be obtained. A short and stereospecific routeg4 to a 2,6-diaryl-monoepoxylignanolideis shown in Scheme 7; the trans-lactone (95) was formed from truns-cinnamyl acetate and converted into the acetal (96). Cyclization by an intramolecular aldol reaction was stereo- specific when conducted with titanium tetrachloride. No natural lignans have yet been made by this method. 2.5 1-Arylnaphthalenes and Relatives [General Structure (9)l 2.5.1 I-Arylnuphthalenrs A few new members of this class have been isolated and characterized ; 1,2,3,4-tetradehydrodeoxypodophyllotoxin(97) from seeds of Hernandia o~igera;~~ daurinol (98) from Huplophyllum d~uricum;~~ the prostalidins A (99) B (loo) and C (lol) which are mild antidepressants isolated from Justicia prostr~ta;~~ and cleist- justicinol (102),from Justicia fla~a;~~ NATURAL PRODUCT REPORTS 1985 tion and conformation of ring B.In the podophyllum series (1 R,2R,3R)-podophyllotoxone (104) has been isolated from Podophyllum hexundrum and P. peltatum,' O5 and was shown to epimerize at C-3 on heating. A rational set of names based only on 'podophyllotoxin' and 'podophyllotoxone' as roots has been Ar3 - H-@:OH DDQ OHCXYAr3Ar3 A r 3" (861 O F AAr r 3 (88) Scheme 5 MeOzC \-r-\ MeOzC\ SMe + '!-I MeS co; anthoside A (diphyllin 4-0-[P-~-glucopyranosyl-(1-+2)]-P-3,4-di-0-methyl-D-xylopyranoside),from Cleistanthus patulu~.~~ Justicidin P (from Justiciu e-utensu) has been obtained by 3-methoxylation of justicidin A (0-methyldiphyllin).loo Meyers and AvilaIo' have synthesized (Scheme 8) the model lactone (103) in a scheme which emphasizes aryl anions. Thus 2- substitution of 1-methoxynaphthalene is achieved by carboxy- lation of the 2-anion. The I-aryl fragment is introduced by displacement of methoxyl by 3,4-dimethoxyphenyl-lithium and the 3-position is carbonylated again uiu the aryl anion. 2.5.2 1-Arylretrulins Podophyllotoxin is the best known member of this group. It is now reportedIo2 that lignans of the podophyllotoxin type occur in Juniperus spp.in specialized cells in the mesophyll. Separation of members of this group by h.p.1.c. has been described.Io3 The c.d. and 0.r.d. spectra of a number of 1-aryltetralins have been measured' O4 and reflect the configura- R' H-Q:IH (92) (93) X = OMe (94) X = H Reagents i ArCHO; ii CF,CO,H; iii LiNPr'?; iv Ar'CHO Ph' Scheme 6 (951 (96) /v-vi H-Q:tr P hHO' 0xO (80) R'= R2 = Ar2 Reagents i Mn(OAc), AcOH; ii H,O+; iii LiNPr',; v Me,SiCl; vi TiCl ArCHClOEt; iv (83) R'= Ar2 R2= Ar3 Scheme 7 NATURAL PRODUCT REPORTS 1985-D. A. WHITING I97 OMe Q-OMe 09 R’ 0Me (1 07) (108) R’ RZ=OCH20,R3= OMe (110) R’ = OMe R2 = R3 = OH OH 0-Xyl OJ (99) R’ = OH R2 = OMe OH OH (100) R’ = R2= OMe (102) (101) R’ = OH R~ = H OMe I OOMe OH I Me0 b”0 (112) (113) -ii-iv FJ oMy \ 0 OMe / OMe Me Me0 Me0 I MeO\ OMe OMe (114) R = H (1 16) (115) R = OH proposed to replace the uninformative collections of trivial OOMe names.Io5 The constitutions of various new natural products in Me0 this set have been elucidated.These include the lignan (105) from Iryanthera grandis,Io6 and attenuol (106) from Knema attenuata (Wall) Warb. lo7 The structure of hypophyllanthin has been revised to ( 107)’08 and lintetralin (from Phyllanthus Li; ii BusLi TMEDA; iii DMF; iv NaBH niruri) has been assigned structure (108).log Cinnamosmu madagascariensis has the lignan (1 09). O9 Isolariciresinol 4-Me0 methyl ether (1 10) has been characterized’ lo and the structure Scheme 8 of pygeoside (from Pygeum acuminatum) elucidated as (1 1 1);l its aglycon pygeoresinol is a diastereoisomer of lyoniresinol.The structure of phyltetralin has been revised’ to (1 12). Irirolu sebijera has yielded four new compounds i.e. (1 13) and its 3- epimer (1 14) and (1 15).’13 Unusually a l-aryldihydronaph- thalene [magnoshinin (1 16)] was isolated from Magnolia salicijoliu’ and another 3,4-dihydrotaiwanin C from Cleist-anthus c01linus.~~ A set of lignan acetals (1 17)-(I 19) has been 571 extracted from Dacrydiurn intermedium,’ l I and these do not from the published data appear to be artefacts arising from the OMe (105) R’ = H R2= OH action of the solvent alcohol on natural hemiacetals. The hemiacetal (120) has been found in Olea africana.’17 The 1104) (106) R’ R2 = OCH20 biogenetically unusual lirionol (121) from the bark of NATURAL PRODUCT REPORTS 1985 R' Me0 R'O Me00 \ OMe OMe 3(1171 R'= Ac,RZ= OMe R = H; (3R) (121) [1LO/ 3 (118) R' = Ac R2= OMe R3= H; (35) Me0M e O d A.+ (119) R' =Ac RZ=OEt R3= H 1 (3s) OMe (120) R' = RZ= H ,R3= OH !! 0 (1 23) OMe OMe HO 'C H20H (125) [17°/o] OMe Reagents i CrO, HBF, MeCN OH OMe Scheme 10 Oh 0 (121) R = CH,OH (122) DDQ ). + WdoMe (1 26) (127) &(Iio CH20Me Ar Scheme 9 Liriodendron tulipijera could be derived from intramolecular substitution in a hypothetical precursor (1 22) as indicated. In chemical transformations of natural lignans it is 0;' interest that lead tetra-acetate has been shown to oxidize aryl- methylenedioxy-units to catechols' ' and dichlorodicyanoben- zoquinone (DDQ) to oxidize selectively an aliphatic ether' 2o (Scheme 9).The synthesis of lignans uia oxidative coupling of C,C3units is a constant source of interest. Non-phenolic oxidation121 of the arylpropene (1 23) was shown to give the tetralone (124) as well as the tetrahydrofuran (125) (Scheme 10). Combined oxidation-cycloaddition results in a one-step conversion (Scheme 11) of the cinnamyl cinnamate (126) into the lactone (127) albeit in only 7% yield.'22 Several applications of the Diels-Alder reaction to create ring B in aryltetralin lignans have been forthcoming. Thus (&)-epi-isopodophyllotoxin (128) has been formed123 by trapping of a photo-en01 (Scheme 12); deoxyisosikkimotoxin has been obtained via interception of a quinone methide that is generated by retro-Diels-Alder decarboxylation' 24 (Scheme 13 note the epimerization at C- 2); and pyrolysis of a sulphone125 has also provided quinone methides which react with appropriate dienophiles to generate intermediates for the synthesis of lignans (Scheme 14).A novel approach has been introduced by Murphy and his co-workers126.'27 (Scheme 15) in which ring B is closed by aromatic substitution by a C-1 cation generated from a cyclopropyl ketone. The tetralone that was thus formed was converted into ( )-picropodophyllotoxone (1 29). Pelter Reagents i CrO, HBF, MeCN Scheme II OH gqCHO A L Ar Me00 / OMe OMe MeOvOMe OMe (128) Reagents i hv MeO2CCHLCHCO2Me ii LiBHEt,; iii Me2C0 H+;iv KOH;v H,O+; vi dicyclohexylcarbodi-imide Scheme 12 Ward and Rao12* have examined a model reaction (Scheme 16) for the formation of ring B in this group using a reaction that is possibly biomimetic.The quinone methide acetal (130) cyclizes to a 1-aryltetralin on treatment with boron trifluoride although a proton acid induces only elimination. Finally the methods for synthesizing dibenzylbutyrolactones can be ex- tended to aryltetralin lactones as exemplified in Scheme 17. NATURAL PRODUCT REPORTS 1985-D. A. WHITING 199 “3 PPh Meo% OMe OMe ii-vi 8r-Qo !O MeO\ OMe 0 OMe Reagents i N-phenylmaleimide at 300°C; ii KOH; iii CH,N2; iv 0 LiAIH,; v KOH MeOH; vi HCI A voMe; Scheme 13 Reagents i BuLi; ii iii BF,; iv H+ Me0 Scheme 16 Ar Ar2 % HO -+ Ar$o iii & 0 HO HO ,C02Me Art Ar‘ Reagents i LiNR,; ii Ar’CHO; iii H+ ‘C0,Me Scheme 17 1 I Ar The C-I-aryl cyclization may be stereoselective and domi- nance of 1a-or IP-H products has been observed,I 29 according to the substitution of the aryl group.Brown and his co-workers have thus prepared ( &)-attenuol,130 (+)-podorhizol (*)-isodeoxypodophyllotoxin,’ 31 and (k)-isopeltatin.’ 2y D:) I 0 2.6 o,o’-Bridged Biphenyls (Dibenzocyclo-octadienes) Ar Ar This interesting group of lignans has been discovered relatively recently the first example being the anti-tumour compound Scheme 14 steganone.I3’ The fact that stereoisomers could arise in this series from restriction of rotation in the biphenyl unit as well as 0 0 from chiral centres was recognized early in synthetic studies e.g.on iso~teganacin.~~~ The fruits of Schisandra chinensis Bail]. which are used medicinally as for example an antitussive have proved a rich source of such lignans and the known compounds are shown in structures (131)) Ar (150).’34 IJyGomisin D with its lactone bridge is particu- larly noteworthy. Five subgroups have been distinguished,’ 3J .. ... with examples of both (S)-biphenyl (e.g. gomisin N) and (R)-II,III biphenyl (e.g. schizandrin) configurations being apparent. Molecular shape in the series has been studied by X-rays135 and (yypo 0by n.m.r.spectroscopy including 3Cand nuclear Overhauser effects.’3J.’36 The eight-membered ring can adopt a twist boat- chair (15 1a) or a twist boat (1 51b) conformation. A dibenzyl-Me06 and is butane pregomisin (152) has also been is~lated~~~~~~~ 0 _iv I presumed to be a biosynthetic precursor it has been prepared Ar 0 from guaiaretic acid. An overlapping group of compounds has been extracted / OMe from Schisandra sphenunthera Rehd. et Wils. and from S.henryi Clarke. I50 -1 52 N amed the schisantherins A-E,150,’51 com-OMe pounds A and B appear to be the same as gomisins C and B (129) while schisanheno1152 may be identical to gomisin K3. Other examples of this type are kadsurin (153) and its relatives Reagents i SnCl, MeNO,; ii hydrolysis; iii CH,O; iv H,CrO, (1 54)-( 157),’ sJ from Kadsura japonica and the lactones s331 HISO neoisosteganel 5s and araliangine (1 58),l 56 which are related to Scheme 15 steganone and both of which were obtained from Steganotaenzu 200 NATURAL PRODUCT REPORTS.1985 Me0 / "R2 Ro-:->..l Me0 \ OMe Gomisin A'36 Gomisin B'36 (131)R'= OH R2= Me R3=OMe,R'= H (132)R'= Me R2= OH R3= OMe RL= 02CCMe=CHMe Z Me@-+0 Gomisin C'36 (133) R'= Me R2= OH R3= OMe R'= 0,CPh L O Gomisin Z F'36*'37(136)R = O2CCMe=CHMe Gomisin D'3*"39 (134)R1= Me R2= OH R3RL= U0*O> OH Go m isi n G'36J'37(137)R =02CPh Gomisin ElL' (135)R'= H R2 = Me R3RL= yo-0 OH OMe ro OH OMe OMe R S~hizandrin'~~ R (138)R' = OH R2=OMe Gomisin J'L0A1L3(141) = OH Gomisin NIL1 (144)R'= R2= R3= H Gomisin Hlb2(139) R' = R2 = OH Gomisin KIlLL (142) R = OMe;(-) Gomisin 0''' (145)R'= OH R2= R3=H Gomisin K ILL (14.3) R' = H ,R2 = OH Gomisin K21LL (143) R = OMe; (+) Epigomisin OIL' (146)R'= R3 = H R2 = OH Gomisin PlL6 (147) R'= H R2= R3= OH R isogomisin 0lL5(148)R = OMe (151b) Gomisin dL7(150) (1 51a) Gomisin R'" (149)RR = OCH20 rot Me0 orb, "toqH OMe 0Me R= OAC Z OMe (153)R'= Me,R2= R3= H R = 02CCMe=CHMe Z -( 154) R1= 0H R2 = Me R3=OzCCMe -CHMe R = 02CCCH21 Me (1 58) araliacea.Of particular interest are the oxygen-bridged Elucidation of the structures of these compounds has examples (1 59) and (16O) from Clerodendron inerme.' 57 provoked considerable synthetic interest. In general strategy Finally the spirodienones (161)-( 163) (eupodienone-1 -2 and the two aryl groups may be joined before or after bridging i.e.-3) have been extracted from Eupomatia l~urina,'~* and these either inter- or intra-aryl coupling is employed. The former are biogenetically significant as possible intermediates in approach was utilized by Raphael and collaborators for their oxidative coupling (see Scheme 22). synthesis of (-)-steganone (167) (Scheme 18) full details of NATURAL PRODUCT REPORTS 1985-D. A. WHITING 20 I RL which have now appeared.' 5c) Coupling of an appropriate aryl- zinc chloride and an aryl iodide efficiently formed a biaryl aldehyde (164) which was converted into a phenanthrone enamine (165); ring-expansion resolution and lactone annela- tion gave (-)-steganone (10.3%overall) uia (+)-isosteganone (166) which was thermally epimerized.The second approach involves aryl-aryl linkage of a dibenzylbutyrolactone or a dibenzylbutane and thus has much in common with syntheses of these types discussed above. Koga and his co-workers have refined the tandem Michael addition- (159) R' R2= R3RL=OCH20 (161) R =Ac benzylation of butenolide (Scheme 4)by adding a chiral control R' R2= OCH20 R3= RL= OMe (162) R = H Scheme 19 sets out the general strategy. The element.160*161 (160) (163) R = PhCO chiral lactone (168) was dehydrogenated via cr-phenylselena-R' = R2= OMe R3 R4= OCH2O tion-elimination to form the optically active butenolide (1 69). /-0 4-OMe ZnCl (R = n -C6H,3) OMe (1611 /-0 Me0 \ C02H CO,H Me0 ' OMe OMe OMe (1651 (1671 (1661 Reagents i Ni"; ii Me0,CC-CC0,Me; iii H,O+; iv Hz; v resolution; vi CH20; vii Jones' oxidation; viii heat Scheme 18 (1 68) (1 170) (171) r o h o tIt -vl,, vt CAr= ArL Ar'; Ar3 ' Me0 Me0 OMe OMe Ar (174) (173) (172) s-7 Reagents i Ar*s> ; ii Ar'CHIX; iii LiAIH, iv NaIO,; v CrO,; vi VOF3 Scheme 19 202 NATURAL PRODUCT REPORTS 1985 I II Me0 OMe OMe 0 Me J.J. g~"oBr (2) -Steganone ++ *'C02H (175) OMe Reagents i (175) Cu; ii LiNRl Scheme 20 The latter compound can alternatively be formed from D-ribonolactone.I6' Addition-alkylation to form the lactone (1 70) then proceeded under stereochemical control.The then unwanted chiral centre in (171) was destroyed in a carbonyl- transposition sequence to give dibenzyl lactones (172) e.g. (+)-deoxypodorhizone160 and (+)-burseran. 160 A related se-quence differing essentially in the order of steps gave (-)-podorhizone.I6l Oxidative aryl coupling in (1 72) then yielded the desired bridged biaryls e.g. (-)-isostegane (1 73). (+)-Steganacin was prepared by this method with predictable absolute stereochemistry and hence that of natural (-)-steganacin was determinedI6O to be as in (174) and not as previously reported. The earlier employed a test using anomalous dispersion of X-rays by oxygen and did not afford a high confidence level. Technical improvements in the Ullmann reaction164 have enabled Brown and collaborators to design a short synthesis of ( +)-~teganone,l~~ sketched out in Scheme 20 while radical cation coupling with vanadium oxytrifluoride was exploited by Schneiders and Stevenson166 to prepare (+)-wuweizisu C (176) (Scheme 21).The spirodienone eupodienone-1 (161) was isolated from Eupomutiu luurina and could be rearranged to the o,o'-bridged biphenyl (177) with sulphuric and acetic acids as shown in Scheme 22;16' inversion of the benzylic acetoxy-group is concomitant with 1,2-alkyl migration. The alcohol(s) (178) rearrange to the biaryl (179) under mild treatment. 2.7 Trimers and Tetramers of Ar-C3 Units Structural investigations have disclosed a group of compounds in which three rather than two C6C3 fragments have been coupled.These have been referred to as 'sesquilignans' by analogy to the terpenes. Tetramers of the fragment C6C3 (dilignans?) have also been uncovered (see below) and it seems not unlikely that other oligomers await characterization. Several compounds have been extracted from fruits of Arctium luppa,168 which is a plant with edible roots and which has various uses in folk medicine. These display both 0-C-p-C links and others (0-C-aryl C and P-C-OAr) which could have been formed by oxidative phenolic coupling between C,C units and the group includes the lappaols A-E [(180)- (1 84) respectively] lappaol AL-D (1 85) and lappaol AL-F [which is a stereoisomer of (185)l as well as the two tetramers lappaol F (186) and lappaol H (187). Herpetrione (188) was isolated from Herpetospermum cuudigerum' ',and Lurix lepto- kyis Cord.yielded the trimers (1 89) (leptolepisol A) and (190) (176) Reagents i 3H,; ii VOF Scheme 21 OMe Me0 Meo% R3 (161) R' R2 = 0 (177) R' = R3= OAc R2=H (178) R' = H R2= OH (179) R' = R3= H R2=OAc Scheme 22 X Me0 LappaOl A (180) R = H ,X = 0,Y = H Lappaol 8 (181) R = Me,X= H2,Y =O Lappaol AL-D (185) R = H; X = 0,Y = H or X = H ,Y = 0 NATURAL PRODUCT REPORTS 1985-D. A. WHITING 203 X " HO' \OV0 OH " m 0Me0 H Lappaol Lappaol C (182) R = H,X = O,Y= H D (183) R= Me,X= H,,Y=O Lappaol E (184) OMe Me0 Lappaol F (186) Lappaol H (187) OMe OMe HO OH (1 9G) OMe 0Me OMe OH (193) (leptolepisol B). I 73 The toxic principles of Suururus cernuus have been characterinxi' 7-L as thz teeramers manassantins A (191) and Et (192) and saucerneol (193).The absolute configurations of lappaol A (1 80) and lappaol F (1 86) have been determined by their degradation (through ozonolysis) to reference compounds,' 7s and dehydrolappaol A dimethyl ether has been synthesized,' as indicated in Scheme 23. 2.8 Biosynthesis The biosyiithesis of iignans is a rather neglected experimental area. Studies that have been reported to date have concentrated R\ 0 0 RtJ+soQ& OMe OMe OH OH (191) R = OMe (192) R R = OCH,O CO,Me C0,Me SMe I OMe R = tetrahydropyran-2-yI Reagents i LiNPri2;ii ArCH,X; iii heat; iv (194) Bu"Li; v Raney nickel Scheme 23 on the demonstration of the incorporation of C,C3 units into lignans and on the nature of the preferred units.Little is known about the nature or the transformations of the immediate products of coupling. Carbon-14-labelled substrates phenyl- alanine substituted cinnamic acids and cinnamyl alcohols were incorporated' 77 into liriodendrin and syringaresinol in twigs of yellow poplar (Liriodendron tulipijeru) with minimal dilutions being observed for [2-'T]sinapyl alcohol (i.e.with the same oxygenation pattern of the aryl group as occurs in the lignans). The glucosides of ferulic acid and the corresponding alcohol and aldehyde were incorporated into arctiin and phillyrin (195) in shoots of Forsythia suspensu var. jortunei although 3,4-dimethoxycinnamic acid was not accepted.' 78 Phenylalanine was transformed into podophyllotoxin in Podo-phyllum ernodi,'7" and two moles were required.Both podo- phyllotoxin and 4'-demethylpodophyllotoxin were labelled by IT-labelled phenylalanine cinnamic acid and ferulic acid in Podophyllum he.uundrum. The biosynthesis of C,C3 compounds is clearly germane to the origin of lignans. It might well be assumed that the carbon skeleton of phenylalanine would be maintained intact in cinnamyl compounds in allyl- and propenyl-phenols and in other C,C3 compounds. However Manitto and Canonica and their collaborators have reported' 81 work on the biosynthesis of eugenol (196) which indicated that phenylalanine is incorporated but that C-9 of eugenol is not mainly derived from the carboxyl carbon of the amino acid.The same conclusions were drawn by Senanayake et ul.I8' (these authors also showed that phenylalanine was incorporated into cinna- maldehyde without exchange of carbon and similar observa- tions have been made by others'83)). On the other hand Zenk and co-workers'X1 have shown that both coniferyl alcohol and ferulic acid supply eugenol and methyleugenol with complete retention of carbon which is apparently in discord with the earlier result. ls1 However it has recently been reported' 85 that in rim phenylalanine is converted into caffeic acid with partial exchange of the terminal carbon of the side-chain which can be supplied by formate and S-adenosylmethionine. Thus all of the results are concordant with a pathway -t phenylalanine caffeic acid -+ ferulic acid + eugenol but further complexities probably remain to be revealed.3 Neolignans The general problem of definition has been discussed earlier. Apart from major biological activity in the group has been discussed,IXh as have the chemosystematics of species that form neolignans.'87 Carbon-1 3 n.m.r. assignments to some members of the group have been madeIXx and absolute configurations assigned to a number of members through 0.r.d. and other physical methods.'8v 3.1 (3,3')-Neolignans [General Structure (1 l)] Taiwan sassafras (Su.ssuJru.s tui~~~n~nsi.~) has been shown' to contain the known compounds magnolol (197) and randainal (198); the former has CNS-depressant activity.lc)l 3.2 (9,9')-Neolignans [General Structure (12)l Ocimin (199) is a new (E,E)-neolignan is~lated'~' from Ocinitini umericununi; two syntheses have been de-~cribed.'~~.'''~ This compound is interesting since the 9-9' linkage does not obviously arise through oxidative coupling.3.3 (8,3')-Neolignans [General Structure (1 3)) The majority of compounds in this group have an oxygen bridge between the C,C3 units to form benzofurans or dihydrobenzofurans. Compounds without such a bridge in- clude (-)-carinatone (200) carinatonol (201) and carinatol (202) from Virolu carinuta'"s*'"6 and the lancifolins A-F NATURAL PRODUCT REPORTS. 1985 (197) R = (199) (198) R = wCHo OMe R20u IR' (203) R'= H R2= Me; (3's) (201) R'= H R2= Me; (3'~) (205) R'= R2 = H ;( 3's) (200) R'= H R2R3 =O (206) R'= R2= H; (3'R) (201) R'=OH,R2R3=0 (207) R' R*= CH,; (3's) (202) R'= R2= H R3= OH (208) R' R2= CH,; (3'R) & RO' ' OMe R\&-Me0 R2 (209) R = Me (211) R' = OMe R2= OH,R3= H (210) R = H (212) R' OH R2= H R3= Me (203) (208) from Anibu Iun~rfoliu.'~~ Related dienones are also found in Piper jutokudsuru.'98 3.3.I Bwiofuruns ViroIu carititrtu also affords carinatin (209)'"h and carinatidin (210).""' Ratanhiae radix Ph. Eur. (Krumeriu spp.) has the phenols (21 1) and (212);200 the former appears to be a nor- neolignan and the latter appears to be the same as eupomaten-oid-6. Syntheses of the eupomatenoids- I -3 -4 -5 -6 -7 and -13'O' have been described,")' using an intramolecular Wittig reaction to construct the benzofuran nucleus from an aryl- phenyl ester; an example [eupomatenoid-3 (213)] is outlined in Scheme 24.3.3.2 Dih?.drobi.ti=c~irrcitis Three new neolignans from Virolu curinutu fall into this group; (2S,3S)-dihydrocarinatidin (2 14; 2,3-tr~n.s),'~'' dihydrocarina-tinol(215),"j5 and (216).Ioh An as yet unclassified speciesofthe genus Anibu afforded the 2,3-ci.r-dihydrofuran (21 7)3 and seeds of Phj*toluccu umericunu yielded americanin-D (2 18),'03 ( )-Dehydrodiisoeugenol (219) (Erdtman's compound) has been isolated from natural sources for the first time from Myristicu fragran.s'OJ and from Aristolochiu tulisc~nu.~~~ Balanophorin (from Bulunophoru japonicu) has been assigned206 the 2,3-trans- NATURAL PRODUCT REPORTS 1985 D.A. WHITING 205 (213) Reagents i N-bromosuccinimide; ii PPh,; iii NEt Scheme 24 structure (220) and the 2,3-cis dimer (221) of coniferyl acetate has been extracted from Lasiolaena morii.*07 Cedrus deodara afforded cedrusin (222) and also its 4'-gluco~ide.~~~ A new glycoside from Euphrasia rostkociana proved to be the dehydrodiconiferyl alcohol glucoside (223),*09 and other new dihydrobenzofuran glycosides have been I A new bis-tyramide grossamide from Capsicum annuurn var. grossum (bell pepper) has been allocated structure (224);2' * it has 2,3-trans geometry in common with the hordatines.' * The absolute configurations of some previously known members of this group have been demonstrated,' using X-ray determina- tions chemical correlations 0.r.d.data and lanthanide-induced n.m.r. shifts. Each of the compounds (214)-(224) apparently arises biogenetically from two 3,4-dioxygenated Ar-C units. A different substitution pattern is seen in the liliflols A (225) and B (226)?Is and in the related liliflone (227) {all from Magnolia lilzjlora Desr. [ = M. quinquepeta (Buc'hoz) Dandy]) in which a resorcinol nucleus appears as a substituted cyclohexenone. Blocked phenol tautomers also figure in the denudatins A (228) and B (229) (from Magnolia denudata),*16 in the extractive (230) from Aniba burchellii Kosterm.,217 and in mirandin-A (23 1) (from Nectandra miranda) whose structure has been confirmed by X-ray analysis.'18 Experiments on the formation of dihydrobenzofurans by oxidative coupling of phenolic monomers continue; thus (*)-dehydrodi-isoeugenol (2 19) has been obtained from isoeu- genol in 54% yield,'19 which is a high value for such an experiment.Dimerization of coniferyl alcohol by horseradish peroxidase yielding dehydrodiconiferyl alcohol (and pinore- sinol) has been carried out in the presence of asymmetric additives; it is reported that 0-cyclodextrin induces an optical yield of 100%.220 The sensitized photo-oxidation of methyl (E)-ferulate has also been examined'? and the dihydrobenzofuran (232) isolated. The acid-catalysed rearrangement (Scheme 25) of blocked cyclohexadienones to bicyclo[3.2.1 ]octanes has been de-scribed,'" and may have biogenetic significance.3.4 (8,l')-Neolignans [General Structure (14)l This group comprises a number of dihydrobenzofurans in which aromatization is blocked by an angular C unit the former aromatic ring appearing at various oxidation levels. New members of this group are the burchellin type (233) from (221) Ar = Ar2 R'= OAc R2= Me R3= -0~~ (222) Ar = Ar2 R'= OH R2=H R3= -OH (223)Ar = Ar2-P-D-glucosyl R1= OH RZ=Me R3=Zc\\/\0" (224) (227) 0Me (229) R = OMe (230) MeooOw Me0 OMe (2311 C02Me HO ( 232I a species of the genus Nectcrndr~,~~~ the porobin types (234),49 from Urhuriocl~wdron cerrucosum and (235) and (236) [or ent-(235) and enf-(236)] from the wood of Aizibaferrea.225 Licariu urmmiuca yielded (237a) and (237b),Iz5 and (238) was found in Ocotua ccrthurinc.nsis.”” Structure (239) has been elucidated for a neolignan from a species of the genus Aniba by X-ray methods.”’ An unusual oxygenation pattern is observed in the novel ‘ferrearin’ types (240) and (241) [or ent-(240) and ent-(241)] also from Anibujerreu.”‘ Dienones in this class are acid- sensitive and the rearrangement that is induced by an acidic ion-exchange resin has been shown to take two possible courses,228 dependent on the solvent (Scheme 26).Full details of the structure determination of megaphone (242) which is a cytotoxic metabolite of Aniba rneguphyflu have appeared.229 Elegant synthetic studies on megaphone and other neolignans by Buchi and his collaborators have been reviewed elsewhere.9 A further lengthy synthesis of megaphone has now been reported.230 3.5 (8,1’.7,3’)-Neolignans ]General Structure (16)l The survey of Brazilian species of plants by Gottlieb and his group has uncovered a plethora of new examples with general formula (16) with variations of stereochemistry and oxygen- ation pattern.These include (243)-(246) from a species of the genus Oc~recr,~~~ (247) and (248) from Ocoteu catharinen-byis, 2 2 6 (249) and (250) from an Amazonian species of the genus (25I) from Licuriu arr~ieniucu,~~~ Anih~,’~’ (252)-(259) from Anihu iid/iarnsii,235 and (260) from Aniba burchuliii.2’7 The last paper reports absolute configurations of various members of this class. The electrochemical oxidation of allylphenols has been ingeniously deployed23s to synthesize (260) and (261) (Scheme 27).Formal removal of a proton and two electrons from thc allylphenoi (262) afforded the cyclopentadienyi cation (263) which was effectively trapped by (E)-isosafrole to provide the neolignan (261) in good yield; (260) was obtained from similar reactions. Under more acidic conditions a small amount of the dienone (264) was isolated from which denudatin A (228) was prepared. The reaction of (263) with (Z)-isosafrole yielded the neolignan epimer (245) [epi-(261)]and futoene (266). These transformations may be genuinely biomimetic. Scheme 25 \\ ~ &;e (; R2 o+ Me0 \ Meoo’ (234) R’= R2=H OM‘ (233) (235) R’= R2=OMC (236) R’ = OMe R2=H (237b) Ft = GMe (238) NATIJRAL PRODUCT REPORTS 1985 (239) (240) R=H (241) R=OMe Ar Ar Reagents i Dowex 50W-X?.resin dioxan dt 50 60°C; ii Dowex 50M/-X2 resin benzene or CHCI Scheme 26 Me0 ArOW O M e I OMe OAc (242) 0Me (263)Ar = Ar3 R’=OH,R*=H (264)Ar = Ar5 R’ =OH R2= H (245)Ar = ArL R’ R2= 0 ‘> 3 OMe (246) R’= H R2= OH R3=Me R’R2= 0,R3= H (249) R’RZ=0,R3=OMe,RL= H (250) R’=OH,RZ=H,R3RL=0 (251) (252) R’= OMe R2= I4 (256) Fi’ = OH,R2= H (253)k’=R2= OMe (257) R’= OH R’= OMe (254) R ’= OH,R2= H (258) R’= OMe H2=H (255) R‘= OH,R2=OMt (259) R’= R2 = OMe NATURAL PRODUCT REPORTS 1985-D. A. WHITING 0Me IJ Ar 4- (267) Ar = Ar2,R1R2=0 0 (260) Ar = Ar2 (268) Ar = Arb,R1=H,R2=OH (269) (261) Ar =Ar3 Me0 OMe OMe (272) R'.H ,RZ=OH R3= 5-Me (27 3) R'= OMe ,R*=H ,R3=iw (270)R= H (274) R'= R2=H,R3= \"b' (271) R=OH (275)R = I-CHO (276)R = \-OH (277) R CHO :*-+ +(228) (264) Reagents i glassy curbon itnode; ii (E)-isosafrole,AcOH MeOH; iii Pt anode (E)-isosafrole AcOH CF,C02H; iv Pt anode (Z)-isosafrole AcOH C'F.3C02H Scheme 27 3.6 (8,5'.7,3')-Neolignans IGeneral Structure (17)1 The structure (267) has been assigned2IS to liliflodione which is an extractive of Magnolia lilfloru Desr. [ = M. quinyuepeta (Buc'hoz) Dandy]. The only other new neolignan of this type that is within the briefof this review is macrophyllin B (268).?13 3.7 (8 I '.7,9')-Neolignans IGeneral Structure (I 8)I Denudatone (from Magtzoliu cknudata) has been formulated as (269),'Ih i.e.as an analogue of futoene (266) presumably with simliar stereoc hemist ry . 3.8 (2,2'.5,1')-Neolignans IGeneral Structure (19)l Two new relatives of a~atone,~ i.e. isoasatone A (270) and isoasatone B (271) have been isolated from Heterotropa t~kcroi.'~~ This plant has provided other unusual neolignans (see Section 3.12). 3.9 (8-0-4')-Neolignans [General Structure (21)l Three new examples of these phenylalkyl ethers have been discovered in Virolu species. Virolu carinata' 99 has carinatidiol (272)(threo stereochemistry) while V. sririnamensis has surina- mtnsin (273) and virolin (274).237Three ethers (275)-(277) with low optical activity have been isolated from Larix Ieptolepis Gord. ;23p the compounds had previously been obtained from the hydrolysis of lignin.That such ethers could be formed in Nature by C-0 coupling of phenoxyl radical is supported by the biomimetic syntheses of Zanar~tti'~" (Scheme 28). Thus oxidation of the propenylphenol (278) by silver(1) oxide followed by addition of water to the quinone OH OH ( 279) (278) 9 OH OH i iv iii ( 280) Reagents i Ag,O; ii H,O; iii CH,N,; iv NaBH Scheme 28 methide product and methylation gave the stereoisomers of (279) the thrro form of which was (+)-virolin. Cross-coupling of allyl- and propenyl-phenols was also possible (280) (which is a neolignan from Mjristica jiugrans) being obtained in 80% yield. 3. I0 (3-0-4')-Neolignans [General Structure (22)] Three new diary1 ethers have recently been characterized ;they are obovatol (281) and obovatal (282) from Magnolia ohoouta Thunb.(= M. hjpdeucu Sieb. et ZUCC.),~"~ and isomagnolol (283) which is a constituent of the roots of Sassafras NATURAL PRODUCT REPORTS 1985 (281 R’=OH RZ=$4 R (282) R’= OH R2 {Wcm (284) R = OMe (283) R’= H R2=\W (285) R = H OH OH Me0 Me MeOu (288) p-H (289) a-H I (291) ( 290 1 I 1ii Meow ( 292) Reagents I heat; ii (292) Scheme 29 rant1uicw.w.’“ The ether (28 1) displayed antibacterial properties. 3.1 1 (8-0-4’.7-0-3’)-Neolignans [General Structure (23)l Two new eusiderins [-C(284) and -D (285)] have been extracted from the bark of Virolu pazionis,242 and allocated cis stereo-chemistry. Eusiderin-B a known benz~dioxan,~ has been isolated from Licariu rigida.2J3 The seeds of Phytolucca umericuna have been shown to contain the benzodioxan americanin (286)234and also the ‘sesquineolignan’ americanin-B (287),lo3 which is the first example of such a compound.Me0 OMe OMe OMe (293) Me0 (294) p-H (295) ct-H II \ OMe ,OM e 3.12 New Types of Neolignan A fascinating range of compounds has been revealed in Hotcwtropu tukuoi Maekawa including three new types of neolignan. Thus the epimers heterotropanone (288) and isoheterotropanone (289) are (8,5’.9,2‘)-neolignan~.~~~.~~~ These compounds were synthesi~ed~~~.~~’ (Scheme 29) by a Diels Alder reaction between the dienone (291) which was generated in .viru by thermolysis of asatone (290) and the allylphenyl ether (292).Another new skeleton is exhibited by heterotropan (393),24s.24h which can be produced by [2 + 21 dimerization of (E)-asarone. 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Wagner Tetruheclron Lett. 1980 21 4255. 204 K. K. Pnrushothaman and A. Sarada Indiun J. Chem. Sect. B 1980 19 236. 205 F. Ionescu S. D. Jolad and J. R. Cole J. Pharm. Sci. 1977 66 1489. 206 M. Haruna T. Koube K. Ito and H. Murata Chem. Pharm. Bull. 1982 30 1525. 207 F. Bohlmann J. Jakupovic A. Schuster R. M. King. and ti. Robinson Phj.tochemistry 1982 21 161.208 P. Agrawal S. K. Agarwal and R. P. Rastogi Phytochemistry 1980 19 1260. 209 0. Salama R. K. Chaudhuri and 0. Sticher Phytochemistry 1981 20 2603. 210 K. Miki and T. Sasaya MorluzaiGakkaishi 1979 25,437 (Chem. Ahsrr. 1979 91 105 175). 21 i T. Satake T. Murakami Y. Saiki and C-M. Chen Chem. Pharm. Bull. 1978 26 1619. 21 1 212 T. Yoshihara K. Yamaguchi S. Takamatsu and S. Sakamura Agric. Biol. Chem. 1981 45 2593. 213 T. Yoshihara K. Yamaguchi and S. Sakamura Agric. Biol. Chem. 1983 47 217. 214 0.R. Gottlieb J. C. Mourao M. Yoshida Y. P. Mascarenhas M. Rodrigues R. D. Rosenstein and K. Tomita Phytochemistry 1977 16 1003. 215 T. Iida and K. Ito Phytochemistry 1983 22 763. 216 T. lida K.Ichino and K. Ito Phytochemistry 1982 21 2939. 217 M. A. de Alvarenga U. Brocksom 0.Castro C. 0.R. Gottlieb and M. T. Magalhaes Phytochernistry 1977 16. 1797. 218 K. Tomita R. D. Rosenstein and G. A. Jeffrey Acta Crystallogr. Seer. B. 1977 33 2678. 219 Y. H. Kuo and S. T. Lin E.yperientia 1983 39 991. 220 A. Ichihara M. Kawagishi and S. Sakamura Tennen Yuki Krigobutsu Toronkai Koen Yoshishu 24th I98 I 490 (Chem. Ahstr. 1982 96 138 887). 221 Y. H. Kuo P. C. Kuo and S. T. Lin Proc. Nutl. Sci. Counc. Repuh. China Purr B 1983 7 28. 222 M. A. de Alvarenga U. Brocksom,O. R. Gottlieb M. Yoshida R. Braz Filho and R. Figliuolo J. Chem. Soc. Chem. Commun. 1978 831. 223 R. Braz Filho R. Figliuolo and 0. R. Gottlieb Phj'tochemisrrj,. 1980 19 659.224 C. H. S. Andrade R. Braz Filho. and 0. R. Gottlieb. Phytocheniisrrj. 1980 19 1 191. 225 C. J. Aiba 0.R. Gottlieb J. G. S. Maia F. M. Pagliosa and M. Yoshida Phyrochemistry 1978 17 2038. 226 M. Haraguchi M. Motidome M. Yoshida and 0. R. Gottlieb. Phj-rochemistry 1983 22 561. 227 K. Tomita Cryst. Struct. Cornmiin. 1980 9 1069. 228 0.Castro C. and 0. R. Gottlieb Ing. Cienc. Quim. 1981 5 67 (Chem. Ahstr. 1982 96 181 040). 229 S. M. Kupchan K. L. Stevens E. A. Rohlfing B. R. Sickles A. T. Sneden R. W. Miller and R. F. Bryan J. Org. Chern. 1978 43. 586. 230 P. A. Zoretic C. Bhakta and R. H. Khan Tetrahedron Lett. 1983. 24 1125. 231 M. C. C. P. Comes M. Yoshida 0.R. Gottlieb J. C. Martinet V. and H. E. Gottlieb Phi-rochemisfry,1983 22 269.232 S. M. C. Dias J. B. Fernandes J. G. S. Maia 0.R. Gottlieb and H. E. Gottlieb. Phytochemistry 1982 21 1737. 233 L. V. Alegrio R. Braz Filho 0.R. Gottlieb and J. G. S. Maia. Phj~tochentistr~~, 198I 20 1963. 234 M. A. de Alvarenga 0.Castro C. A. M. Giesbrecht and 0.R. Gottlieb Phyrochemistry 1977 16 1801 ;the misidentification oi' the source of the compounds as Aniha sinzuluns is corrected b! 0. R. Gottlieb and I(.Kubitzki Biochem. Syst. Ecol. 1951 9. 5. 235 Y. Shizuri and S. Yamamura Tetrahedron Lett. 1983 24 50i 1. 236 Y. Terada and S. Yamamura Chem. Lett. 1978 553. 237 L. E. S. Earata P. M. Baker 0. R. Gottlieb and E. A. Ruveda. Pliytochemistry 1978 17 783. 238 K. Miki T. Takehara T. Sasaya and A. Sakakibara Phj~toch~-niisrry 1980 19 449.239 A. Zanarotti J. Cheni. Res. (S) 1983 306. 240 K. Ito T. lida K. Ichino M. Tsunezuka M. Hattori and T. Namba Chem. Phurm. Bull. 1982 30 3347. 241 F. S. El-Feraly S. F. Cheatham and R. L. Breedlove J. Nut. Prod. 1983 46 493. 242 J. B. Fernandes M. N. de S. Ribeiro 0. R. Gottlieb and H. F. Gottlieb Phjmchenristry 1980 19 1523. 243 R. Braz Filho M. G. de Carvalho 0.R. Gottlieb J. G. S. Mai:]. and M. L. da Silva Phytochemistry 1981. 20 2049. 244 W. S. Woo S. S. Kang H. Wagner and V. M. Chari Tetrulirvlroii Lett. 1978 3239. 245 S. Yamamura M. Niwa M. Nonoyama and Y. Terada. Tetrahedron Lett. 1978 489 1. 246 S. Yamamura M. Niwa Y. Terada and M. Nonoyama Bid/. Chem. 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ISSN:0265-0568    

DOI:10.1039/NP9850200191

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Pyrrolizidine Alkaloids D. J. Robins Department of Chemistry University of Glasgow Glasgow G 12 8QQ Reviewing the literatare published between July 1983 and June 1984 (Continuing the coverage of literature in Natural Product Reports 1984 Vol. 1 p. 235) 1 Synthesis of Necines 2 Synthesis of Necic Acids 3 Synthesis of Macrocyclic Alkaloids 4 Alkaloids of the Boraginaceae 5 Alkaloids of the Compositae 6 Alkaloids of the Gramineae 7 Alkaloids of the Leguminosae 8 Alkaloids in the Lepidoptera 9 General Studies 10 Pharmacological and Biological Studies 1 I References (41 The highlights this year are the first synthesis of the necine base otonecine the preparation of further optically active necines Jvi from (2S,4R)-4-hydroxyproline,and the synthesis of the eleven- membered macrocyclic alkaloids crispatine and fulvine.Fif- teen new alkaloids have been isolated. The growing number of X-ray structures that is available will lead to a better SzoH understanding of the stereochemistry and conformations of dzoH pyrrolizidine alkaloids. (5) (6) Reagents i BrCH,COBr at -78 "C; ii CH,(CO,Me),; iii MeOH, 1 Synthesis of Necines anode Bu",N+ BF,-; iv AICI,; v LiCI DMSO; vi LiAIH Two related syntheses of (*)-trachelanthamidine (5)and (+)-Scheme I isoretronecanol (6) have been carried out using anodically prepared material as key intermediates. In the route of Blum et d.,' anodic alkoxylation of the tertiary amide (I) gave the a-substituted product (2) in 90% yield (Scheme 1). Under acidic conditions (2) formed an a-acyliminium ion which underwent intramolecular cyclization to afford a 4 1 mixture (under thermodynamic control) of the pyrrolizidinones (3) and (4) ii again in 90% yield.The diastereoisomeric compounds (3) and I (4) were separated by column chromatography and reduced to 4 CO2Et give ( +)-trachelanthamidine (5) and ( +)-isoretronecanol (6). In the second approach reported by Shono et ~l.,~ (Scheme 2) the a-methoxylated carbamate (8) was prepared by anodic oxidation of the benzyl carbamate (7) in 67% yield. The a-LNC02CH2Ph NC02 CH Ph acyliminium ion was generated and used to form a new carbon- (9) carbon bond in (9). A series of steps was then used to afford the (10) diester (10). Hydrogenation of (10) and distillation of the vi i product under reduced pressure gave a 3 :2 mixture of the 1 pyrrolizidinones (1 1) and (1 2).As before separation of these compounds and reduction yielded ( & )-trachelanthamidine (5) and ( +)-isoretronecanol (6). Kametani and co-workers3 have postulated the intermediacy of an aziridinium salt (13) in their synthesis of (*)-trachelanthamidine (5) and (*)-supinidine (18) (Scheme 3). 0 Opening of the aziridinium ion (1 3) gave the pyrrolidine (14) 0 (12) which underwent intramolecular alkylation to afford the (11) pyrrolizidine ester (15). This ester can be reduced to (i-)-trachelanthamidine (5). The introduction of unsaturation into Pi J..;;; (6) the pyrrolizidine was achieved by the method of Robins and (51 Sakdarat.4 This led to a mixture of selenides (16) which yielded Reagents i MeOH anode; ii Me02CCH2CH(C02Me), TiC1,; iii the up-unsaturated ester (1 7) on carrying out the oxidative NaOH; iv HCl; v AcOH heat; vi EtOH H+ heat; vii H2 Raney elimination step.The ester (17) can be converted into (+)-nickel EtOH; viii LiAIH supinidine (1 8).4 Scheme 2 214 NATURAL PRODUCT REPORTS 1985 CI CCH213CHO .1; CI C C H23 3CH=C HC02Et b (13) C02Et d2" (17) (15) 1 1 15) d20H (18) Reagents i NaH (EtO),P(O)CH2CO2Et; ii aziridine at 0 "C; iii LiNPr', THF at -78 "C; iv LiNPr', PhSeC1 at -78 "C; v m-ClC,H,CO,H CH2Cl Scheme 3 The ketene dithioacetal (19) was previously used by Chamberlin and co-workers as a terminator for cyclization of an or-acyliminium ion in their synthesis of (f)-supinidine (18) (cf ref.5a). These workers have now described a modification of this route for the synthesis of (+)-trachelanthamidine (5) (Scheme 4).' A related strategy was utilized in the preparation of (+)-heliotridine from (S)-malic acid (cf ref. 6a). Riieger and Benn previously reported the synthesis of the lactone (20),in optically active form from (2S,42?)-4-hydroxy- proline (cf ref. 5a). This lactone has now been used by these workers8 for the first synthesis of (+)-croalbinecine and for the first synthesis of retronecine (26) and platynecine (25) in optically active form. The strategy is based on the preparation of (+)-retronecine by Geissman and Wai~s,~ which was recently improved by Narasaka et al.(cf ref. 56). The lactone (20)was alkylated and the product was subjected to Dieckmann cyclization to afford the keto-ester (21). Hydrogenation of the enolizable ketone (2 1) gave a dihydroxy-ester that was formulated as (22) since it yielded (+)-croalbinecine (23)on reduction. Hydrogenation of the Ij-keto-ester (21) with a different catalyst gave the lactone (24) and reduction of the lactone afforded (-)-platynecine (25). The conversion of the dihydroxy-ester (22)into (+)-retronecine (26) was carried out in a manner similar to that described by Narasaka et al. (Scheme 5). The overall yield of (+)-retronecine (26) was 49% from the lactone (20). A new necine trio1 (28)was prepared by the treatment of the dihydroxy-ester (22)with sodium ethoxide to form the lactone (27) followed by reduction of the lactone.Kametani and co-workers have provided full details1° of their synthesis of (+)-retronecine (26)and ( )-turneforcidine utilizing a 'sulphenocycloamination' reaction (cJ ref. 6b). n P 0 v,iii 1 (5) (18) Reagents i MeS02Cl Et,N; ii HClO, H1O THF MeCN; iii LiAlH,; iv LiNPr', MeOH; v HgCl Scheme 4 vi ,vii lv n viii iv 1;. i (28) (26) Reagents i BrCH,CO,Et; ii KOEt PhMe; iii H, PtO? AcOH; iv LiAlH,; v H Rh/Al,O, AcOH; vi Ac,O pyridine 4-dimethyl- aminopyridine; vii NaH; viii HCl EtOH; ix NaOEt EtOH Scheme 5 The first synthesis of (+)-otonecine (34) has been achieved by Yamada and co-workers (Scheme 6).' The chosen starting material was the hydroxy-ester (29) which had previously been used in the synthesis of (+)-retronecine (26) by the same research group (cf ref.66). Michael-type addition of thiophen- NATURAL PRODUCT REPORTS 1985-D. J. ROBINS olate anion to (29) afforded the tricyclic lactone (30). This material was converted into the corresponding hydroxy- compound and quaternized to afford (31). Treatment of the methiodide (31) with phenylselenenyl chloride and sodium hydride served to introduce the phenylseleno-group and to (31 1 J.iv -Se Ph vii,viii IMe I Me I Me (34) (33) (321 Reagents i PhS-Li+; ii Hg(OAc), AcOH H,O; iii MeI; iv NaH PhSeCI; v Bui,AIH Et,AlCI; vi Ac,O pyridine; vii H202; viii NaOMe MeOH Scheme 6 cleave the bicyclic pyrrolizidine system.Selective reduction of the lactone (32) that was thus formed required the addition of a Lewis acid to the hydride reducing agent. The product was acetylated (for ease of handling) to give the intermediate (33). Finally oxidative elimination of the phenylseleno-group and removal of the acetyl groups gave (f)-otonecine (34). Danaidone (37) is a pheromone which is produced by several species of butterflies of the subtribe Danainae after they have ingested pyrrolizidine alkaloids. A synthesis of danaidone from monocrotaline (35) in an overall yield of 60% has been carried out by Pereira and Barreiro (Scheme 7). Dehydroretronecine HO CH20H ?I A I / 00 (26) (35) 137) Reagents i o-chloranil then NaBH,; ii TsCI pyridine; iii LiAlH Scheme 7 H2N ‘H (43) (41) /i x (42) H Y HH 0 (45)R=CN or H (46)R = CN (47)R = H Reagents i (EtO),P(0)CH,C02Et NaH; ii Bu’,AlH; iii Ti(OPr’), (+)-diethy1 L-tartrate; iv (MeO[CH2],0),A1H; v PhCOCI Et,N ; vi potassium phthalimide Ph,P EtO,CN=NCO,Et; vii K,CO, MeOH; viii HZNNH2.H20; ix HCIO,; x NaBH,CN xi DMSO (COCI),; Et,N; xii Ph,P=CH[CH,],Me; xiii H, Pt Scheme 8 (36) was prepared by alkaline hydrolysis of monocrotaline followed by oxidation of the retronecine (26) that was formed.Deoxygenation at the 9-position of dehydroretronecine afford- ed danaidone (37). Takano et a/. have synthesized the ant venom alkaloid (48) from the aldehyde (38) as outlined in Scheme 8. The key step involves an enantioselective Sharpless oxidation of the alkene (39) followed by regioselective cleavage of the epoxide (40).The primary hydroxy-group in the diol(41) was then protected and the secondary hydroxy-group was substituted by phthalimide anion with inversion of configuration to yield (42). Removal of the protecting groups gave the amino-alcohol (43). The pyrrolinium perchlorate (44) was then formed after cleavage of (43) under acidic conditions. Reduction of the pyrrolinium salt (44) afforded a mixture of pyrrolizidines (46) and (47). The stereochemical outcome is attributed to participation of the hydroxy-group in (44) which directs delivery of the hydride or cyanide ions from the si-face of the iminium ion via a boronate complex (45). Finally the side-chain was elaborated by a Wittig procedure to give the ant venom alkaloid (48).2 Synthesis of Necic Acids The synthesis of (+)-viridifloric acid (53) which is the acid component of coromandaline (73) has been achieved by Ladner.'" The reaction of the enolate (50),which was derived from the (+)-ester (49) with acetone under thermodynamic control yielded the ester (51) as the predominant isomer (Scheme 9). The isopropyl group in (52) was formed by dehydration and reduction steps and removal of the protecting groups in (52) afforded (+)-(2R,3R)-viridifloric acid (53). The more commonly occurring ( -)-(2S,3S)-viridifloric acid could be prepared by formation of the enantiomer of the ester (49) from L-threonine and then submitting this material to the sequence that is shown in Scheme 9.The nucleophilic displacement of bromide anion from the (2Z)-2-bromomethylalk-2-enoate ester (54) by attack of aceto- acetic ester derivatives (55) under basic conditions has been studied by Drewes and co-workers (Scheme The relative amounts of the two products (56) and (57) that were formed by attack on the allylic carbon and the vinylic carbon of (54) respectively depend upon the structure of the substrate and the choice of solvent system. For example with (54; R' = Me) and (55; R2 = Me) the ratio of [(56)]:[(57)] is 1OO:O with sodium ethoxide in ethanol and 30 :70 with sodium hydride in tetrahydrofuran. The products from these reactions are potential precursors for integerrinecic acid and sceleranecic acid respectively.An improved synthesis of fulvinic acid (61) has been described by Vedejs and Larsen. l6 The thermodynamically less stable (E)-enol silane (58) was prepared by the bromocarbenoid route (Scheme 11). Selective [2 + 21 cycloaddition of . .Me Me. ,Me MeXMe _,_. MeXMe Me2C H 0 0 4 = 0 0 H tf-CHMe2 )f-CMe2OH Me Me C0,Me Me C02Mc (53I (521 (51) Reagents i LiNPrl,; ii Me,CO; iii POCl, pyridine; iv H, Pt/C; v KOH; vi CF,CO,H Scheme 9 NATURAL PRODUCT REPORTS 1985 methylketene with (58) gave the meso-cyclobutanone (59). Bromocarbenoid ring-expansion of (59) followed by oxidative cleavage of the enol silane (60) yielded fulvinic acid (61). This material was used in the synthesis of (i-)-fulvine (see below).3 Synthesis of Macrocyclic Alkaloids A total synthesis of the eleven-membered macrocyclic alkaloids (+)-crispatine (70) and (f)-fulvine (71) has been achieved by Vedejs and Larsen.I6 Crispatic acid (62) was converted into its anhydride and the hydroxy-group was protected (Scheme 12). Opening of the anhydride ring in (63) generated the glutarate ester (64). Coupling of (64) via its mixed phosphoric anhydride (65) with the lithium alkoxide (66) of monoprotected (+)-retronecine gave a 1 1 mixture of (67) and a diastereoisomeric racemate. The mixture of isomers was converted into the corresponding mesylates (68). Lactonization of this material was carried out in dilute solution the yield being 73-80% after removal of the protective silyl groups. At this stage the racemates were separated and (69) was converted into (+-)-crispatine (70).An X-ray crystal structure of crispatine has recently established the mode of connection of crispatic acid to retronecine. 'Removal of the protecting group from the other diastereoisomeric racemate of (69) yielded ( f)-isocrispatine. An exactly analogous sequence of reactions (Scheme 12) from fulvinic acid (61) was used to prepare ( -t)-fulvine (71) and (I)-isofulvine. Full details are now available'* of the synthesis of integerrimine which is a twelve-membered dilactone that contains retronecine (c$ ref. 5c). I R'MCH2Br+ R2 Me CO C H C02E t H' C02Me (551 RZ= H ,Me or PhCH (541 R'= alkyl or aryl R2 R' RtHCH2-7I -COMe + MeCOA-~_C//CH2 Ill -CO,E t Et0,C H C02Mc H C02Me (561 (571 Scheme 10 Me,SiO (581 (59) 1 iii C02H -.Me-. -3 HO Me Me I Me CO,H Me,Siu we Me,SiO L J (611 (601 Reagents I BunLi Me,SiCl; ii MeHC=C=O; iii CH2Br2 LiNPr'?; iv 0,; HC0,H Scheme 11 NATURAL PRODUCT REPORTS 1985-D. J. ROBINS Me ,0CH20Me . .. Me Me rH I,II ".-A#-HO Me M e I H o+-oko (63) lii (64) R = H CO,[CH,],SiMe (65) R = P(O)(OEt) 0 0 CH20SiMeZBu' ~ iv + ! I 0-H CH20SiMe2Bu' (67) diastereoisomer + v vi * (681 + diastereoisomer @ Li+ (661 0C H20 Me To (69) biii (70) Reagents i dicyclohexylcarbodi-imide;ii PzOs (Me0)?CH2; iii MelA10CH2CH,SiMe,; iv 4-dimethylaminopyridine; v HF; vi MeSO,CI Et3N; vii; MeCN BunlN+ F-; viii BF,.EtzO EtSH Scheme 12 H CH20R S20R (72) R = R' (75) R = R' (73) R =R2 (76) R = R2 (74) R =R3 (77) R = R3 4 Alkaloids of the Boraginaceae The three major alkaloids in Heliotropium curassavicum were previously shown to be esters of trachelanthamidine namely curassavine (72) coromandaline (73) and heliovicine (74) (cf ref.54. Seven new minor alkaloids have now been isolated from this species. * Three of the new alkaloids it. heliocuras-savine (75) heliocoromandaline (76) and heliocurassavicine (77) are esters of isoretronecanol ;one heliocurassavinine (78) is an ester of laburnine; and the remaining three (obtained as a mixture) i.e. curassavinine (79) coromandalinine (80) and heliovinine (81) are esters of supinidine.The structures (75)- (8 1) were established by H n.m.r. and mass spectroscopy and by paper electrophoresis of the alkaloids and their hydrolysis products. Structure (82) which was previously assigned to a necine base named curassanecine from H. curassavicum has been revised to (83) on the basis of a 270 MHz n.m.r. spectrum and decoupling experiments. This is the first necine containing a 1-hydroxy-group. Confirmation of this structure by synthesis would be desirable. Primary calluses have been induced from various organs of Symphytum oficinale L. (comfrey).*O The production of pyrrolizidine alkaloids ceased on prolonged subculturing of cell suspension cultures that were derived from these calluses. However polyamines which may be biosynthetic precursors of the necines were still detectable and regenerated plants produced the original alkaloids.5 Alkaloids of the Compositae Senecio triangularis Hook. is believed to have been used by the Cheyenne Indians to prepare a tea that has sedative properties and which was used to treat chest pains. Two independent investigations of the alkaloidal constituents of this species have been carried out. RoitmanZ1 isolated senecionine as the major alkaloid together with small amounts of integerrimine platyphylline rosmarinine and retrorsine from material that had been collected in California U.S.A. Two new alkaloids were also identified by spectroscopic methods and named triangularine and neotriangularine.Triangularine is 7-angelyl- 9-sarracinylretronecine (84),and neotriangularine (85) con- tains the geometrical isomer of sarracinic acid. This represents the first reported isolation of this acid. The mode of attachment of the two acids in (84) and (85) was deduced from mass-spectral data (cleavage of the C-9-0 bond occurs more readily than of the C-7-0 bond). Rueger and BennZZ also obtained triangular- ine (84) from S. triangularis that was found in Alberta Canada but no senecionine was detected. They also isolated 7-angelylretronecine (86) and the two new alkaloids 7-senecioyl- retronecine (87) and 9-sarracinyl-7-senecioylretronecine(88). Young plants of Ligularia dentata are used as food in rural areas of Japan. Three new alkaloids [(91)-(93)] have been isolated from this species by Asada and Furuya together with the known compounds clivorine (89) and ligularidine (90) (cf.ref. 5e).23Neoligularidine (91) is the geometrical isomer of ligularidine because hydrogenation of clivorine (89) yielded a (78 1 R =R' R = R2 R = R3 1-co 1-co R' = EtMeCH R2 = Me2CH.*:; R3= Me$;,fOH OH H H Me Me Me 218 NATURAL PRODUCT REPORTS 1985 afH20H (83) Z z (84)R'= COCMe =CHMe R2=COC(CH20H)=CHMe z E ( 85 R' = C0C Me =CHMe ,R2 = COC(C H 2 OH)=C HMe Z (86)R'=COCMe=CHMe R2=H (87)R'=COCH=CMe2 R2=H Z (88) R'=COCH=CMe2 R2=COC(CH20H)=CHMc R' 0 Y I.V I I Me Me (89) (90) R'= H,R2=Me (91) R'= Me R2=H Me I Me (92) (93) mixture of (90) and (91).Ligularizine (92) is formulated as the P-epoxide of neoligularidine (91) from which it can be formed by the action of performic acid. Hydrolysis of ligularinine (93) afforded platynecine (25) and a necic acid which was identical to that obtained from hydrolysis of neoligularidine (91). Florosenine otosenine and floridanine are present in Senecio ~ureus.~~ Senecionine seneciphylline senkirkine and 7-angelylretronecine (86) were isolated from S. desfontainei Druce. 25 6 Alkaloids of the Gramineae The presence of loline derivatives in Festuca arundinacea Schreb. (tall fescue) may be due to an endophytic fungus since the accumulation of these loline derivatives is reduced in plants which have been treated with the systemic fungicide benomyl (cf ref.6c).26 7 Alkaloids of the Leguminosae Grantianine (94) and grantaline were isolated some time ago from Crotalaria uirgufata subsp.grantiana.27Spectroscopic data for these two alkaloids have now been presented,2s and the structure of grantaline has been revised to (95) on the basis of an X-ray crystal structure.29 Grantaline thus contains the unusual oxetane system. The epoxypyrrolizidine (96) was also present in samples of this species that were collected in Australia.28 Crotaluria gfobifera E. Mey. was previously reported to contain di~rotaline.~~ Seeds of C.gfobifera that had (97) (98) Me (99)R = CH20Ac (100) been collected from two separate locations in South Africa yielded different pyrrolizidine alkaloids. One batch gave trichodesmine and grantaline (95) while the other afforded grantianine (94) and a new pyrrolizidine alkaloid globiferine.The structure (97) was established for globiferine from spectroscopic data.3 Monocrotaline is present in seeds of Crotalaria uegyptiaca C. cephalotes C. cunninghamii C. nitens C. paufina and C. recta.32 8 Alkaloids in the Lepidoptera Ithomiine butterflies gain protection from spider predators by the presence of dehydropyrrolizidine alkaloid monoesters and their N-oxides. These compounds are sequestered by adult butterflies from flowers mainly of the Eupatorieae and from decomposing foliage mainly of the B~raginaceae.~~ The role of pyrrolizidine alkaloids in insect-plant co-evolution has been discussed.34 9 General Studies A considerable number of X-ray crystal structures of pyrrolizi- dine alkaloids have now been determined and some interesting conformational patterns have emerged.All of the natural retronecine-containing eleven-membered macrocyclic pyrroli- zidine alkaloids that have been studied (with the exception of trichodesmine) possess ester carbonyl groups that are syn-parallel. The X-ray structure of crispatine (70) conforms to this pattern.17 In the case of grantaline (95),29although the ester carbonyl groups are on the same side of the plane of the macrocyclic ring 'they are directed outwards from it with an angle between these groups of 94 '. This is presumably due to the presence of the oxetane ring system in (95). X-Ray structures of seneciphylline (98) which was isolated from Adenostyfes gfabra (Compo~itae),~ and acetylgynuramine (99)36have been determined.These twelve-membered retrone- cine-containing macrocyclic alkaloids both have ester carbonyl groups that are anti-parallel in common with other examples that had previously been studied. The X-ray structure of senecionine which was isolated from Gynuru segetum (Compo-sitae) has been established again.37 The ester carbonyl groups are also anti-parallel in platyphylline (1 00) which is a twelve- NATURAL PRODUCT REPORTS. 1985-D. J. ROBINS (102) (104) R’= Me,R2= CH,OH (105) R’= H R2= CHO (103) membered dilactone that contains the saturated pyrrolizidine base platyne~ine.~~ Doronine (10 1) has been isolated from Senecio clevelandii E.L. Greene and an X-ray analysis has established the ab- solute configuration of its acid portion.39 The transannu!ar N...C=O distance is 2.33 8 [cf. values in other pyrrolizidine alkaloids that contain otonecine clivorine (89) 1.98 A; senkirkine 2.29 A]. Dehydrosenecionine (I 02)40 and dehydromonocrotaline (103)4i are the toxic metabolites of senecionine and monocrota- line. The conformation of the macro-ring of dehydrosenecion- ine is similar to that of senecionine. In dehydromonocrotaline the flattening of the dihydropyrrolizine system changes the conformation about the primary ester system although the ester carbonyl groups remain syn-parallel. A large-scale extraction of pyrrolizidine alkaloids from Senecio jacobaea has been described.42 The isolation of 8-10 grams of alkaloids from 23 kg of plant material represents an improvement in previous yields.Chemical-ionization mass spectrometry with ammonia as the reagent gas has been used to analyse mixtures of pyrrolizidine alkaloids.43 10 Pharmacological and Biological Studies Ingestion of pyrrolizidine alkaloids constitutes a health hazard of global proportion^.^^ The toxic effects of these alkaloids have been reviewed.45 These alkaloids can enter the human food chain via contaminated foodstuffs and by the use of herbal teas. The intakes of these alkaloids by some humans have been estimated to be comparable with doses leading to a significant incidence of tumours in rats.46 The carcinogenicity of some pyrrolizidine alkaloids has been The transfer of 3H-labelled alkaloids from species of the genus Senecio into rats’ milk4* and of unlabelled alkaloids into goats’ milk49 has been observed.A weak (or zero) mutagenic response was of rats with jacobine (which is an inducer of epoxide hydrolase) caused a shift in the hepatic microsomal metabolism in citro of benz~[u]pyrene.~~ 11 References 1 Z. Blum M. Ekstrom and L.-G. Wistrand Acta Chem. Scand. Ser. B,1984 38 297. 2 T. Shono Y. Matsumura K. Uchida K. Tsubata and A. Makino J. Org. Chem. 1984 49 300. 3 T. Kametani K. Higashiyama H. Otomasu and T. Honda Heterocycles 1984 22 729. 4 D. J. Robins and S. Sakdarat J. Chem. SOC. Perkin Trans. I 1979 1734. 5 D. J. Robins in ‘The Alkaloids’ ed.M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London (a) 1983 Vol. 13 p. 70; (b) 1983 Vol. 13 p. 67; (c)1983 Vol. 13 p. 66; (d) 1978 Vol. 9 p. 58; (e) 1979 Vol. 10 p. 53. 6 D. J. Robins Nat. Prod. Rep. 1984 1 (a)p. 236; (b)p. 238; (c) p. 240. 7 A. R. Chamberlin H. D. Nguyen and J. Y. L. Chung J. Org. Chem. 1984 49 1682. 8 H. Rueger and M. Benn Heterocycles 1983 20 1331. 9 T. A. Geissman and A. C. Waiss J. Org. Chem. 1962 27 139. 10 T. Ohsawa M. Ihara K. Fukumoto and T. Kametani J. Org. Chem. 1983 48 3644. 11 H. Niwa Y. Uosaki and K. Yamada Tetrahedron Lett. 1983,24 5731. 12 A. L. Pereira and E. J. Barreiro Quim. Nova 1983 6 74. 13 S. Takano S. Otaki and K. Ogasawara J. Chem. SOC.,Chem. Commun. 1983 1172.14 W. Ladner Chem. Ber. 1983 116 3413. 15 F. Ameer S. E. Drewes N. D. Emslie P. T. Kaye and R. L. Mann J. Chem. SOC. Perkin Trans. I 1983 2293. 16 E. Vedejs and S. D. Larsen J. Am. Chem. SOC. 1984 106 3030. 26 T. A. Jones R. C. Buckner P. B. Burrus and L. P. Bush Crop Sci. 1983 23 1135. 27 L. B. Bull C. C. J. Culvenor and A. T. Dick ‘The Pyrrolizidine Alkaloids’ North-Holland Amsterdam 1968. 28 L. W. Smith and C. C. J. Culvenor Phytochernistry 1984 23,473. 29 M. F. Mackay and C. C. J. Culvenor Acta Crystallogr Sect. C 1983 39 1227. 30 J. C. S. Marais Onderstepoort J. Vet. Sci. Anim. Ind. 1944 20 61. 31 K. Brown J. A. Devlin and D. J. Robins Phytochemistry 1984,23 457. 32 D. J. Pilbcam A. J. Lyon-Joyce and E. A. Bell J. Nut. Prod. 1983 46 601.33 K. S. Brown Nature (London) 1984 309 707. 34 J. A. Edgar Toxicon 1983 Suppl. 3 p. 97. 35 H. Wiedenfeld F. Knoch E. Roder and R. Appel Arch. Pharm. ( Weinheim Ger.) 1984 317 97. 36 H. Wiedenfeld A. Kirfel E. Rider and G. Will Phytochemistry 1983 22 2065. 37 Z. Hua X. Xu X. Wei S. Tang and Y. Wu Beijing Dame Xuebuo Ziran Kexueban 1983 No. 4 p. 89 (Chem. Abstr. 1984 100 139 425). 38 H. Wiedenfeld E. Roder A. Kirfel and G. Will Arch. Pharm. (Weinheim Ger.) 1982 315 165. 39 R. Y. Wong and J. N. Roitman Acta Crystallogr. Sect. C 1984,40 163. 40 M. F. Mackay M. Sadek C. C. J. Culvenor and L. W. Smith Acta Crystallogr. Sect. C 1983 39 1230. observed in various test^.^^.^^ 41 M. F. Mackay M. Sadek C. C. J. Culvenor and L. W. Smith Acta Crystallogr.Sect. C 1984 40,473. Pyrrolizidine alkaloids are converted into the toxic pyrrolic 42 A. M. Craig G. Sheggeby and C. E. Wicks Vet. Hum. Toxicol. metabolites in the liver.’ Two dihydropyrrolizines (104) and 1984 26 108. (105) were isolated from mouse hepatic microsomes in vitr~.~~ 43 J. W. McCoy M. R. Roby and F. R. Stermitz J. Nat. Prod. 1983, The lungs were the main organs to be affected by fourteen different pyrrolic esters and similar compounds that are analogous to metabolites of pyrrolizidine alkaloids when these were injected into rats.53 The aggregation of blood platelets in rats which had been treated with dehydromonocrotaline (103) has been studied.54 The various effects of monocrotaline (35) on the liver heart and lungs of rats have been detailed.55-60 Gerbils were the most resistant of the animals that were tested towards ingestion of Senecio jacobaea.61 The effects of various additives to a diet of S.jacobaea were tested on rats,62 ponies,63 and sheep.64 The effect of heliotrine on enzymic redox processes in rat hepatocytes was studied.65 Pretreatment 46 894.44 J. N. Roitman A. C. S. Symp. Ser. 1983,234 (Xenobiotics in Foods and Feeds) 345. 45 J. E. Peterson and C. C. J. Culvenor in ‘Handbook of Natural Toxins’ ed. R. F. Keeler and A. T. Tu Marcel Dekker Basel 1983 Vol. 1 p. 637. 46 C. C. J. Culvenor J. Toxicol. Enciron. Health 1983 11 625. 47 0. Schimmer Drsch. Apoth.-Ztg 1983 123 1361. 48 J. Luethy T. Heim and C. Schlatter Toxicol. Lett. 1983 17 283.49 R. D. White P. H. Krumperman P. R. Cheeke M. L. Deinzer and D. R. Buhler J. Anim. Sci. 1984 58 1245. 50 U. Candrian J. Luethy U. Graf and C. Schlatter Food Chem. Toxicol. 1984 22 223. 51 R. A. Swick J. Anim. Sci. 1984 58 1017. 52 H. J. Segall J. L. Dallas and W. F. Haddon Drug Metah. Dispos. 1984 12 68. 53 A. R. Mattocks and H. E. Driver To.uicologj 1983 27,159. 54 K. S. Hilliker J. A. Dey T. G. Bell and R. A. Roth Thromh. Res. 1983 32 325. 55 Y. Hayashi T. Kokubo M. Takahashi F. Furukawa H. Otsuka and K. Hashimoto To.uicol. Lett. 1984 21 65. 56 A. Molteni W. F. Ward C. H. Ts'ao C. D. Port and N. H. Solliday Proc. Soc. E.p. Biol. Med. 1984 176 88. 57 I. Medugorac and R. Jacob Card. Adapt. Hemodyn. Ocerloud Train..Stress tnt. ErM7iii Riesch Symp. 1982 341 (Chem. Abstr. 1984 100 155 335). 58 W. M. Lafranconi and R. J. Huxtable Thorax 1983 38 307. 59 W. M. Lafranconi R. C. Duhamel K. Brendel and R. J. Huxtable Biochem. Pharmacol. 1984 33 191. NATURAL PRODUCT REPORTS 1985 60 T. W. Petry G. T. Bowden R. J. Huxtable and G. I. Sipes Cancer Res. 1984 44 1505. 61 P. R. Cheeke and M. L. Pierson-Goeger To.uicol. Lett. 1983 18 343. 62 B. J. Garrett and P. R. Cheeke J. Anim. Sci. 1984,58 138; R. D. White R. A. Swick and P. R. Cheeke J. To.uicol. Enciron. Health 1983 12 633. 63 B. J. Garrett D. W. Holtan P. R. Cheeke J. A. Schmitz andQ. R. Rogers Am. J. Vet. Res. 1984 45 459. 64 R. D. White R. A. Swick and P. R. Cheeke Am. J. Vet. Res. 1984 45 159. 65 ,L. M. Fesenko I. G. Savin and A. N. Aripov Med. Zh. Uzb. 1983 No. 6 p. 72 (Chem. Abstr. 1983 99 117 508). 66 D. E. Williams C. L. Miranda and D. R. Buhler Biocheni. Phurmacol. 1983 32 2443.

ISSN:0265-0568    

DOI:10.1039/NP9850200213

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Tropane Alkaloids G. Fodor and R. Dharanipragada Department of Chemistry West Virginia University Morganto wn WV 26506- 6045 USA Reviewing the literature published between July 1983 and June 1984 (Continuing the coverage of the literature in Natural Product Reports 1984 Vol. 1 p. 231) 1 Occurrence and Structure of New Alkaloids 2 Synthesis and Chemical Transformations 3 Pharmacology 3.1 Atropine 3.2 Cocaine 3.3 Scopolamine 3.4 Miscellaneous Alkaloids 4 Analytical Aspects 5 References 1 Occurrence and Structure of New Alkaloids Convoline (1) an alkaloid occurring in Convolvulus krauseanus has been isolated' and its structure determined as (the mesoid) 3a-veratroyloxy-N-hydroxynortropane.The i.r. spectrum showed hydroxyl absorption at 3245 cm-I and the absorption of an ester carbonyl group at 1705 cm-I.The IH n.m.r. spectrum was indicative of six methoxyl protons (6 3.89 p.p.m.) but there was no signal for an N-methyl group. The mass spectrum (M+ 307) was consistent with the molecular formula C,,H2,05N. Alkaline hydrolysis gave veratric acid and a product that was expected to be N-hydroxynortropan-3a-01;unfortunately this was not characterized except by a molecular peak of m/z 143 in the mass spectrum. Reduction of convoline with zinc gave convolvine (0-veratroylnortropine). On this basis convoline appears to be the first N-hydroxynortropanol ester to be found in Nature. Hyoscyamine and hyoscine were found2 to be the major alkaloids of species within the tribe Anthocercideae of the Solanaceae.2 Synthesis and Chemical Transformations Noratropine oxalate was prepared3 by oxidative N-demethyla- tion of atropine sulphate with aqueous potassium permangan- ate followed by treatment with oxalic acid. Non-glycolate esters of (+)-tropan-2a-o1 and (-)-tropan-2P-ol were pre-pared4 by known transesterification procedures. A series of N-a1 koxycarbonylal kyl-nortropane-3-spiro-5'-hydantoins (2) have been synthesized5 by treatment of the appropriate N-substi- tuted nortropinone with potassium cyanide and ammonium carbonate in aqueous ethanol. The crystal and molecular structures of (2f) were determined by X-ray diffraction. In the crystalline state the cyclohexane ring of (2f) adopts a deformed chair conformation with a flattening at C-3 (C-5').This deformation is due to the steric interaction between the ethylene bridge and the hydantoin group. The opposite puckering at N-8 and the axial position of the N-substituent make the formation of the intramolecular N(3')-H..-N(8) bond easy. Stereospecific reduction of nortropinone derivatives was achieved6 in the presence of a rhodium-phosphine catalyst. Arylphosphine ligands gave the a-isomer (nortropine) whereas complexes with trialkylphosphines as ligands gave the p-isomer (norpseudotropine). The difference in selectivity is due to the different structures of the intermediate complexes and the different co-ordination of the substrate. Derivatives of noratro- pine which have anticholinergic activity and their addition HO (2) a; R= H b; R=Me C; R= CH,Ph d ; R = CH*CH,CO,Et e; R= Pri (2)f ; R = [CH,],CO,Et 9; R= C,H,-p-CO,Et o+-f3=+H OC-CHCH20H II I 0 Ph (31 Me\ NpoF,[cH,I" NR 0 (4) salts with acids (which are useful as bronchodilators) have been prepared.Thus N-isopropylnoratropine in methanol was treated with peracetic acid at 0 "C and the mixture was stirred overnight with warming to give (3) which was subsequently converted into its hydrochloride salt. The tropan-30-01 aminoalkanoates (4; n = 1,2 or 4; R2N = morpholino Me2N Et2N pyrrolidino piperidino or pipera- zino) were prepared8 from tropine and pseudotropine by successive acylation by o-chloroalkanoyl chlorides and subse- quent amination by the corresponding dialkylamines.NATURAL PRODUCT REPORTS 1985 Br-NHR~ 0 (51 -Br R (11) a ; RR = 0 b; R=H (13) Z = alkylene or phenylene The antidepressant and anxiolytic benzamides (5; R1 = C,- alkoxy; R2 = H or alkanoyl; R3 = C1 or Br; RS = Me,C Me,CHCH, or cyclopropyl; n = 1 or 2) were ~repared.~ For examp!e 3P-amino-8-neopentyl-8-azabicy-clo[ 3.2. lloctane was treated with 4-acetamido-5-chloro-2-meth-oxybenzoic acid to give (5; R1 = OMe R2 = Ac R3 = C1 R4 = Me,C n = 1). Isopropylatropinium bromide (6) has been synthesized. Oa The configuration of the ring nitrogen is described according to a previous convention. lobThus Robinson condensation of succinic aldehyde acetonedicarboxylic acid and isopropyl- amine gave N-isopropylnortropan-3-one.Reduction of this compound with lithium aluminium hydride gave 3-epimeric alcohols which were separated by chromatography.Transes- terification of the purified tropan-3a-01 with methyl phenylace- tate and then formylation with methyl formate in the presence of sodium followed by reduction and subsequent quaterniza- tion with methyl bromide gave the desired compound (6). The norscopines (7; R1= C2-10alkyl R2 = H) which are useful as synthons for pharmaceuticals were prepared' from the corresponding esters. Thus treatment of (7b) with sodium borohydride in ethanol at 20°C gave (7a). The quaternary 0-(6,ll -dihydrodibenzo[b,e]thiepin-11-y1)-N-alkyl N-methylnorscopinium bromide (8; R = Me) which is useful as a bronchodilator was prepared' by treating scopine hydrochloride with 1 I-chloro-6,ll-dihydrodibenzo[b,e]thie-pine followed by methylation with methyl bromide.Bicyclic benzamides of the type (9) which are useful as antiemetics and as dopamine antagonists have been pre- pared. Thus 2-methoxybenzoic acid was sulphonated with chlorosulphonic acid followed by reaction with pyrrolidine to (7) a; R'= Pri,RZ= H Ph b; R'= Pr' ,R2= COCH(Ph)CH,OH (as hydrochloride) o=s=o I 0 I12) R = alkyl ,alkenyl ,aryl or heteroaryl give 2-methoxy-5-(pyrrolidinosulphonyl)benzoicacid which was treated with ethyl chloroacetate and 3P-amino-8-benzyl-8- azabicyclo[3.2. lloctane to give (9). Norscopine (10) was prepared' from norscopolamine hydrochloride by treating it with sodium borohydride in ethanol.Azabicyclo[3.3.l]nonylphthalimidines of the type (1 1b) which are usehi1 as dopamine antagonists and as antiemetics have been prepared. Thus reduction of the phthalimide (1 1a) with tin and hydrogen chloride in acetic acid gave (1 lb). Ester derivatives of scopolamine of the type (12) and (1 3) were prepared' from scopolamine hydrobromide and the corresponding carboxylic acids or diacids in the presence of 4- N-methylaminopyridine and NN'-dicyclohexylcarbodi-imide. The absolute configuration of ( -)-anisodinic acid which is the esterifying acid of anisodine (14) was determined" by chemical correlation with (-)-(R)-2-phenylpropane- 172-diol and ( -)-(R)-2-hydroxy-2-phenylpropionicacid. A biomimetic synthesis of the ladybug alkaloids (1 8) and (1 9) of the adaline series was accomplished' via intramolecular Mannich reaction of the intermediate imminium-enols (1 7) which were generated from the corresponding 2-cyanopiperi- dines (15) and (16) (Scheme 1).A short convenient synthesis of 2-tropanyl 2-granatanyl and 2-homotropanyl methyl ketones [(20) (21) and (22), respectively] has been developed,' via Mannich cyclization of the dioxo-aminobutyl ketal-acetals (23a)-(23c) (Scheme 2). The same research group has also accomplished20a the synthesis of (+)-anatoxin-a and (-)-anatoxin-a (24) of high optical purity directly from D-and L-glutamic acids. Initial formation of a carbon-carbon bond proceeding from the NATURAL PRODUCT REPORTS 985 -G.FODOR AND R. DHARANIPRAGADA Bn pyroglutamate via sulphide contraction and transfer of the I chirality of the amino-acid by catalytic hydrogenation were . .. crucial to the synthesis (Schemes 3 and 4).Sulphide contraction '1 " is a processZob by which enamino-esters could be made from thioamides. Fii Total syntheses of ( +_)-knightin01(25) and (+)-acetylknight-"BMX Bn 'u Iv vii (15) R = Me (16) R = n-C5Hll 1 R$j R 4 4v (18) R = Me (19) R = n-C5Hll (Bn = CH,Ph) Reagents i PhCH,Br; ii NaBH, MeOH; iii m-chloroperoxybenzoic acid CH,CI,; iv (CF3CO)I0 CH,CI, at -10 "C for 20 minutes KCN H+ at pH 4; v HI Pd/C 10% EtOH; vi LiNPr', THF at -2O"C RX; vii MeOH 1OM-HCI (10%). Scheme 1 k Q 0 0 0 (211 n 1 NHBn (23) a;y=2 z=1 b;y=z= 2 c; y = 3,z = 1 1 Reagents i MeOH H20 HCI at 55-6OoC for 21 hours.Scheme 2 inol (26),which are the alkaloids of Knightia strobilina and the synthesis of ( +)-2,3-dihydrodarlingine (27) which is the alkaloid of Bellendena rnontana have been achieved (Scheme 5).21 Analogous synthetic transformations have led to the synthesis of strobamine (29) via chalcostrobamine(28)(Scheme 6).22 The 3C spin-lattice relaxation times of tropine and pseudotropine have been measured,23 in CDC13 as a function of concentration; they showed these molecules to be intramole- cularly hydrogen-bonded over the whole concentration range. 3 Pharmacology 3.1 Atropine Atropine was foundZ4 to reduce the tremors that are induced by physostigmine.When it was administered to cats atropine causedZS the classical shift of the electrocorticogram from a high-frequency-low-voltage pattern to a low-frequency-high- voltage pattern. Amongst other studies investigations of the role of the sympathetic nervous system in atropine-induced tachycardia in conscious cats,26 of the effects of an electrical current on the activity of mitochondria1 monoamine oxidase and on the total protein content of the rat brain after atropine has been admini~tered,~~ and of the influenceZ8 of atropine on a-adrenoceptors in the female rabbit urethra have been described. 3.2 Cocaine Cocaine has received considerable An extensive review on the behavioural effects of cocaine in humans and in laboratory animals has appeared.29 Amongst other effects studies on the sodium-sensitive binding of cocaine30 to rat striated membrane the disadvantages of using cocaine as a neuronal blocking agent,3 the discriminative stimulus proper- ties of cocaine in the rhesus monkey,32 the effects33 of cocaine on responding (under a multiple schedule of presentation of food or nitrous oxide),33 the relationship between reinforcing and subjective effects in crab-eating monkeys,34 cortical dopaminergic involvement in cocaine reinfor~ement,~~ and the sex-dependent difference^^^ between left- and right-side rats on cocaine-induced rotation were studied.In addition studies on the effects37 of cocaine on rats under a mild water-deprivation schedule and the effects38 of cocaine on the electromechanical activity of the gastric antrum and duodenum of conscious dogs have been reported.Classical conditioning and the decay and extinction of cocaine-induced hyperactivity and ~tereotyping~~ have been studied. 3.3 Scopolamine Scopolamine is still the focus of investigation^.^^-^^ Amongst other studies the effects of scopolamine on respiration and on blood pressure in rabbits40 and on the spontaneous activity of neurons of the nucleus locus cer~leus,~' the effects of repeated administration of scopolamine on ambulatory activity in mice,42 and the effect of scopolamine on stimulus sensitivity and response bias in a visual vigilance task43 have been investigated. Other studies included an investigation of the central antimuscarinic cholinergic of scopolamine and an assessment of the chromosomal aberrations that are induced by scop~lamine.~~ NATURAL PRODUCT REPORTS 1985 B u' 0,C.I Bn Bu'0,C' Bn - r n t But 0,C" Bu'0,C'' Bn hii B nN n iv,v,iii,vb But0,C ,OkN A.,c02Me Bn ix-xiJ.H ( Bn = CH,Ph 1 A? xii,xiii Me3Si0LQ I-)-Anatoxin -a(2L) Reagents i BrCH2C0,Me; ii PPh3 Et3N at 20 "C; iii H2 Pt/C; iv LiBH4 Et,O; v Ph3h ",,-, LiNPrI2 DMSO; vi PrnOH H+; \I -vii POCl, at 95 "C; viii conc. HCI MeOH at 57 "C; ix H2 Pd/C; x di-t-butyl dicarbonate; xi Me3SiC1 KH Et,N; xii Pd(OAc), MeCN; xiii 1M-CF,CO,H. Scheme 3 o=s=o HoYph I ._ 1 n But02CAN Bn %o ... C0,Bn MeNpO -+ (+I -Anatoxin -a k,vi 0 Scheme 4 MtNwrH OAc 3.4 Miscellaneous Alkaloids Effects of intravenous administration of anisodamine on the (261 haemodynamics of unshocked and endotoxin-shocked dogs have been studied.46 Anisodamine was found4' to reduce acute Reagents i NaH THF Ph-C-CN; ii H2 PtO,; iii Ac,O BF,.Et myocardial infarction in rabbits. The anti-shock action of at r.t. ;-iv 10 equiv. Ac,O catalytic 4-dimethylaminopyridine,heat; anisodamine was studied in cats in a well-controlled model of haemorrhagic shoc k.48 The effects of 8-(2-fluoroethyl)-3a-0 hydroxy-laH,5aH-tropanium bromide benzilate (Ba598Br) '"N ;vi 1M-H2S04 at 50 "C for 3 hours. which is a new atropine derivative on the canine airway were v9NaH7 Me Me HH investigated.Inhalation of 0.01%of Ba598Br had an inhibitory effect against acetylcholine-evoked bronchoconstri~tion.~~ Scheme 5 NATURAL PRODUCT REPORTS 1985 -G. FODOR AND R. DHARANIPRAGADA 0 II Reagents i PhCH=CH-C-CN; ii 1M-H2S04 at 50 "C for 3 hours. Scheme 6 4 Analytical Aspects The development of a second-order derivative U.V. spectropho- tometric assay of atropine hyoscine and benztropine in formulations has been described.50 An oscillopolarographic titration method has been developed5 to determine hyoscine butyl bromide alone or in injections. Atropine sulphate and its preparations have been analysedS2 by the double-phase titration method. Mass spectra of (-)-cocaine and its semi- synthetic epimer pseudococaine were founds3 to be similar but significant differences in the abundance of ions of m/z 152 and 94 could be used to distinguish between the two epimers.5 References 1 S. F. Aripova E. G. Sharova U. A. Abdullaev and S. Yu. Yunusov Khim. Prir. Soedin. 1983 749 (Chem. Abstr. 1984 100 171 549). 2 W. C. Evans and K. P. A. Ramsey Phytochemistry 1983,22,2219. 3 M. J. Van der Meer and H. K. L. Hundt J. Pharm. Pharmacol. 1983 35 408.. 4 E. R. Atkinson D. McRitchie-Ficknor L. S. Harris S. Archer M. Acito J. Pearl and F. P. Luduena J. Med. Chem. 1983,26 1772. 5 E. Galvez M. Martinez J. Gonzalez G. G. Trigo P. Smith- Verdier F. Florencio and S. Garcia-Blanco J. Pharm. Sci. 1983 72 881. 6 L. Kollar and S. Toros Magy. Kem. Lapja 1983 38 223 (Chem.Abstr. 1983 99 122 721). 7 P. Chiese Ger. Offen. 3 243 820 (1983) (Chem. Abstr. 1983 99 176 126). 8 L. M. Kostochka A. P. Rodionov A. P. Skoldinov and V. V.. Zakusov Khim.-Farm. Zh. 1983 17 558 (Chem. Abstr. 1983,99 140 190). 9 M. S. Hadleyand E. A. Watts Eur. Pat. Appl. 99 194(1984) (Chem. Abstr. 1984 100 210 240). 10 (a) Instituto de Investigacion y Desarrollo Quimico y Biologic0 S.A. Span. P. 504 263 (1983) (Chem. Abstr. 1984,100,68 577); (b) G. Fodor J. Toth and I. Vincze J. Chem. SOC. 1955 3504. 11 R. Banholzer Ger. Offen. 3 215 493 (1983) (Chem. Abstr. 1984 100 68 579). 12 R. Banholzer and R. Bauer Ger. Offen. 3 21 1 185 (1983) (Chem. Abstr. 1984 100 22 862). 13 A. E. Watts Eur. Pat. Appl. 96 524(1983)(Chem. Abstr.1984,100 156 867). 14 R. Banholzer Ger. 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Rupreht B. Dworacek and R. Ducardus Acta Anaesthesiol. Belg. 1983 34 123 (Chem. Abstr. 1983 99 169 376). 26 G. E. Samonina and M. 0. K. Hakumaki Scand. J. Clin. Lab. Invest. 1983 43 389. 27 N. K. Kerimova Izv. Akad. Nauk Az. SSR. Ser. Biol. Nauk 1983 No. 5 p. 101 (Chem. Abstr. 1983 99 187 534). 28 B. Larsson K. Andersson and A. Mattiasson Acta Physiol. Scand. 1984 120 537 (Chem. Abstr. 1984 100 185650). 29 R. M. Post and N. R. Contel Stimul.Neurochem. Behav. Clin. Perspect. 1983 169. 30 L. Kennedy and I. Hanbauer J. Neurochem. 1983 41 172. 31 M.J. Lew and J. A. Angus J. Auton. Pharmacol. 1983,3,61 (Chem. Abstr. 1983 99 99 182). 32 R. De la Garza and C. E. Johanson Pharmacol. Biochem. Behav. 1983 19 145. 33 M. A. Nemeth and J. H. Woods Int. Congr. Ser.-Excerpta Med. 1982 620 275 (Chem. Abstr. 1983 99 115 886). 34 S. Kato Y. Wakasa and T. Yanagita Int. Congr. Ser.-Excerpta Med. 1982 620 294 (Chem. Abstr. 1983 99 115 887). 35 N. E. Goeders and J. E. Smith Science 1983 221 773. 36 S. D. Click P. A. Hinds and R. M. Shapiro Science 1983 221 775. 37 C. M. Franco and G. C. Wagner Drug Alcohol Depend. 1983 11 409 (Chem. Abstr. 1983 99 187 518). 38 K. Yamada and M.Iizuka Nippon Heikatsukin Gakkai Zasshi 1983 19 25 (Chem. Abstr. 1983 99 187 519). 39 G. Barr N. Sharpless S. Cooper S. Schiff W. Paredes and W. Bridger Life Sci. 1983,33 1341 (Chem. Abstr. 1983,99 152 006). 40 Z. Qian J. Xiao Y. Fan and Z. Chen Shanghai Diyi Yixueyuan Xuebao 1983 10 181 (Chem. Abstr. 1983 99 99266). 41 H. Wu L. Xie and G. Liu Nanjing Yaoxueyuan Xuebao 1982 No. 3 p. 39 (Chem. Abstr. 1983 99 115 913). 42 H. Kuribara and S. Tadokoro Jpn. J. Pharmacol. 1983 33 1041 (Chem. Abstr. 1983 99 187 619). 43 K. Wesner and D. M. Warburton Neuropsychobiology 1983,9,154. 44 J. Xu G. Jin L. Yu J. Li and A. Yu Zhongguo Yaoli Xuebao 1983 4 156 (Chem. Abstr. 1983 99 205 997). 45 J. Yu Y. Yang G. Xiong and M. Chen Zhonghua MazuixueZazhi 1983 3 3 (Chem.Abstr. 1984 100 61 626). 46 H. Guo and R. 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ISSN:0265-0568    

DOI:10.1039/NP9850200221

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Aporphinoid Alkaloids M. Shamma Department of Chemistry The Pennsylvania State University University Park Pennsylvania 7 6802 USA H. Guinaudeau Facult4 de M4decine et de Pharmacie Universith de Limoges 87032 Limoges Cedex France Reviewing the literature published between July 1983 and June 1984 (Continuing the coverage of the literature in Natural Product Reports 1984 Vol. 1 p. 20 1) 1 Introduction OH 2 Proaporphines 3 Aporphines 4 Dimeric Aporphinoids 5 Oxoaporphines 6 Dioxoaporphines 7 Oxoisoaporphines 8 Phenanthrenes 9 Chiloenamine and Chiloenine H OMe 10 Aristolochic Acids and Aristolactams (1) R=H (3) R = H 11 Miscellaneous 12 References (2) R= Me (4)R= Me Me0 A 1 Introduction A listing of the new monomeric aporphinoids that have been reported since 1979 including physical and spectral data has PMe appeared.' Similarly a tabulation of all of the dimeric OM aporphinoids that were obtained since 1979 is now available.2 (5) R = Me 2 Proaporphines (6) R = H Phoebe formosana (Lauraceae) has yielded the two new hexahydroproaporphines (+)-lauformine (1) and (+)-N-methyl-lauformine (2) which are epimeric at C-10 with the known litsericine and N-methyl-litsericine respe~tively.~~~ Known proaporphines that have been re-isolated from plants are listed in Table 1.3 Aporphines An impressive twenty-six new aporphines were isolated during (8) the past year. Significant use of 13C n.m.r. spectroscopy was (71 ::y made in the elucidation of the structure of (+)-3-hydroxy- glaucine (4) derived from Ocotea bucherii (Lauraceae).lo This alkaloid was also found in Thalictrum baicalense (Ranuncul-Me aceae) where it is accompanied by its nor-derivative (+)-thalbaicaline (3).The structures l-hydroxy-2,9-dimethoxyaporphine and 1,2,9-MeO?; trimethoxyaporphine were originally attributed to lirinine and 0-methyl-lirinine respectively which are found in species of Ho H the genus Liriodendron (Magnoliaceae). 2* At a later date (91 these assignments were corrected and the alkaloids were shown to correspond to 2-hydroxy-l,3-dimethoxyaporphine Table 1 Proaporphines that have been re-isolated and their and 1,2,3-trimethoxyaporphine,respectively.14* Presently, natural sources the 1,2,9-trioxygenated aporphines (+)-orienthe (5)16 and Alkaloid Source Ref.(+)-orientinhe (6)' and the 1,2,11-trioxygenated alkaloid (-)-N-Methylcrotsparine Isolona zenkeri 5 (+)-0-methylisothebaine (7)16 have been found in Papaver (-)-Pronuciferine Isolona pilosa 5 orientale (Papaveraceae) although they were previously known Peumus boldus 6 as synthetic racemates. Even though the biogenesis of these (-FStepharine Luurelia novae-zelandiae 7 three alkaloids was not discussed it is probable that they (-)-Mecambrine Papaver pilosum 8 originate from the diastereoisomeric tetraoxygenated proapor- Papaver trinigolium 9 phinols (8) and (9). Dienol-benzene rearrangement of (8) could yield (5) or (6) while rearangement of (9) would lead to (7). NATURAL PRODUCT REPORTS I985 OMe OMe OMe OMe (10 1 (12) (13) (14) R = CHO (15) R = Me HO Me0 OMe OH (19) (20) (21) (22) Me2 Me0 \ OR OR (23) R = Me (25) R = Me OH (21) R = H (26) R = H (29) Me0 / "'" N Me0 W Me Me.@ / Me0 OH MeoFMe Me0 ' OH AcO (30)R = Me (31) R = H (33) (35) Three newly obtained noraporphines are (+)-norbracteoline jimbrilligerum (Papaveraceae).Glaufidine was originally as- (lo) from Glaucium corniculatum (Papaveraceae),18 (-)-signed structure (20),23924 and epiglaufidine was then believed oureguattidine (1 l) from Guatteria ouregou (Ann~naceae),'~ to be represented by expression (21).25 However in the n.m.r. and (+)-norpreocoteine (1 2) from Phoebe molicella (Laur-spectrum of glaufidine the proton at C-4 falls at 6 4.46 p.p.m. aceae).2o Duguetia obouata (Annonaceae) has furnished the while the corresponding proton is at 6 4.98 p.p.m.in epi- rather unusual N-formyl derivatives (-)-N-formylxylopine glaufidine. It follows that structure (20) must represent (1 3) (-)-N-formylbuxifoline (1 4) and (-)-N-formyldugue-epiglaufidine and that glaufidine is (21). vanine (16). These are accompanied by (-)-N-methylbuxifo- Guatteria discolor (Annonaceae) has furnished the new 7- line (1 5) (-)-N-methylcalycinine (19) (-)-duguevanine (17) dimethylated aporphine guadiscidine (22) which accompanies and (-)-N-methylduguevanine (1 8).21 the known guadiscine and guadiscoline.26 Other interesting The stereochemistry of the 4-hydroxylated aporphines may be new aporphines in this plant are guacoline (23) and guacolidine determined from the sign of the specific rotation and from the (24) which are 7-hydroxylated 7-methylated compounds.n.m.r. chemical shift of the proton at C-4 which is geminal to and the noraporphines (-)-discoguattine (25) and (-)-the hydroxyl group. The configuration at C-6a follows the isocalycinine (26). 26 An accompanying and related alkaloid is normal rule for the aporphines whereby a negative rotation saxoguattine (27). 26 indicates the R configuration and a positive rotation the S Four new classical-type dehydroaporphines are 6a,7-didehy- arrangement. In the n.m.r. spectrum the absorption of the droboldine (28) from Peurnus boldus (M~nimiaceae),~~ dehy-proton at C-4 falls near 6 4.50 p.p.m. when H-4 and H-6a are dropredicentrine (29) from Polyalthia caulijlora (Annona-syn to each other and appears near 6 4.90 p.p.m.when the ceae),28 and orientidine (30)16 and dehydroisothebaine (31),l protons at C-4 and C-6a are anti.22These simple rules can only from Papauer orientale (Papaveraceae). lead to the conclusion that the original stereochemical Bulbodione (32) is an unusual blue-violet quinoidal apor- assignments for (+)-gla~fidine~~.~~ and (+)-epigla~fidine~~ phine that is found as a minor alkaloid in Corydalis bulbosa should be reversed. Both alkaloids were found in Glaucium (Fumariaceae). Its structure was confirmed by oxidation of the NATURAL PRODUCT REPORTS 1985 -M. SHAMMA AND H. GUINAUDEAU ~~ Table 2 Aporphines that have recently been re-isolated and their natural sources Alkaloid Source Ref.Alkaloid Source Ref. Caaverine Isolona zenkeri 5 Xanthoplanine Thalictrum foliolosum 38 Isolona pilosa 5 (+)-Glaucine Papaver apokrinomenon 30 Lirinidine Isolona zenkeri 5 Thalictrum foetidum 33 Nornuci ferine Isolona pilosa 5 Litsea wightiana 34 Guatteria ouregou 19 (-)-Glaucine Papaver pilosum 8 Anonaine Isolona pilosa 5 Nantenine Nandina domestica 39 (-)-Roemerine Isolona pilosa 5 Actinodaphnine Hernandia guianensis 36 Laurelia novae-zelandiae 7 Dicentrine Papaver apokrinomenon 30 Dicentra peregrina 32 Gwtteria modesta 31 (-)-Calycinine Duguetia obovata 21 (+)-Roemerine Papaver pilosum 8 I socorytu be rine Glaucium fimbrilligerum 25 Isopiline Isolona pilosa 5 Magnoflorine Glaucium jimbrilligerum 25 Guatteria ouregou 19 Thalictrum foetidum 33 0-Methylisopiline Guatteria ouregou 19 Thalictrum foliolosum 38 Thalictrum javanicum 40 (-)-Anolobine Duguetia obovata 21 Pachygone ovata 35 (-)-Isolaureline Laurelia novae-zelandiae 7 Dioscoreophyllum cumminsii 41 Duguetia obovata 21 Tinospora capillipes 42 (-)-Mecambroline Laurelia novae-zelandiae 7 Aristolochia indica 43 (+)-Isothebaine Papaver orientale 16 Norcorydine Litsea wightiana 34 (-)-Zenkerine ISO~OMzenkeri 5 Corydine Laurelia novae-zelandiae 7 Isolona pilosa 5 Glaucium fimbrilligerum 25 (-)-Laweline Laurelia novae-zelandiae 7 Dicentra spectabilis 32 (-)-Obovanine Laurelia novae-zelandiae 7 Dicentra peregrina 32 (-)-Pukateine Laurelia novae-zelandiae 7 Hernovine Hernandia guianensis 36 (-)-Pukateine N-oxide Laurelia novae-zelandiae 7 N-Methyl hernovine Hernandia guianensis 36 0-Methylpukateine Laurelia novae-zelandiae 7 Norisocorydine Peumus boldus 6 Guatteria discolor 26 Glaucium jimbrilligerum 25 Puterine Guatteria discolor 26 Isocorydine Dicentra peregrina 32 Buxi foline Duguetia obovata 21 Eschscholtzia californica 37 Tinospora capill@es 42 Isoboldine Laurelia novae-zelandiae 7 Menisperine Glauciurn jimbrilligerum 25 Cocculus laurifolius 44 Dicentra peregrina 32 Nandigerine Hernandia guianensis 36 Thalictrum foetidurn 33 N-Methylnandigerine Hernandia guianensis 36 Litsea wightiana 34 Hernandia guianensis 36 Pachygone ovata 35 Ovigerine Phoebe molicella 20 Bracteoline Papaver orientale 16 Preocoteine 20 Thaliporphine Glauciurn corniculatum 18 Norpurpureine Phoebe molicella Thalictrum foetidum 33 Thalicsimidine Phoebe molicella 20 Laurolitsine Laurelia novae-zelandiae 7 Thalictrum minus 45 Litsea wightiana 34 Norushinsunine Polyalthia nitidissima 46 Boldine Laurelia novae-zelandiae 7 Ushinsunine Polyalthia nitidissima 46 Polyalthia caulipora 28 Glaufidine Glaucium corniculatum 18 var.beccarii Dehydroroemerine Papaver pilosum 8 Predicentrine Glaucium corniculatum 18 Papaver apokrinomenon 30 Polyalthia caulipora 28 De h ydroglaucine Papaver pilosum 8 var. beccarii Dicentra peregrina 32 Papaver apokrinomenon 30 Laurotetanine Hernandia guianensis 36 Corydalis bulbosa 29 Litsea wightiana 34 Dehydrocorydine Glaucium corniculatum 18 N-Methyl-laurotetanine Peumus boldus 6 Floripavidine Papaver triniifolium 9 Papaver apokinomenon 30 Thaliadine Thalictrum minus 47 Eschscholtzia californica 37 var.majus corresponding 1 1 -hydroxylated aporphine (+)-bulbocapnine The first synthesis of leucoxylonine (40) was achieved with Fremy’s salt.29 through the thallium-trifluoroacetate-induced cyclization of Known aporphines that have been re-isolated from plants the tetrahydrobenzylisoquinoline(39).50 are listed in Table 2. Irradiation of the enamide (41) in the presence of iodine led The 1,2,10,11-tetraoxygenated aporphine N-methyl-lauro- to geometric isomerization and then to the aporphine (42). tetanine (35) was readily prepared via treatment of the Removal of the ethoxycarbonyl group from (42) with KOH quinol acetate (34) with an acid; (34) was itself obtained from gave the dehydroaporphine (43); treatment of this with the tetrahydrobenzylisoquinoline(33) by oxidation with lead aqueous formaldehyde provided the oxazine (44).The same tetra-a~etate.~* reaction sequence starting with the methylenedioxy-enamide In another use of lead tetra-acetate oxidation of the (45) provided the unusual alkaloid duguenaine (46).5 tetrahydrobenzylisoquinoline(36) with this reagent generated Finally classic Pschorr-type cyclization of the amine (47) the o-quinol acetate (37) quantitatively.Acid cyclization then supplied a small yield of the aporphine (48).52 furnished the unnatural aporphine (38).49 A high-yield conversion of apomorphine into norapo- NATURAL PRODUCT REPORTS 1985 Me MAcOe o y M e MeoFMe OH (ITk (:vk \ \ \ \ Me0 Me0 / Me0 0 Me0 0OMe Me0 ’OMe OMe OMe OMe OMe OMe (371 (41) R = Me (45) RR = CH2 (42) R = COZEt (43) R = H R2 m 0 M e M e O m FMH e NOMe o ,N Me ::p;e OM [ Me0 0 W (49) R’ = Me R2= OMe (50) R’= H R2=OMe (51) R’ = R’=H morphine has been claimed.The procedure involves treatment with phenyl chloroformate followed by reaction with a 1:l mixture of 64% and 95% hydra~ine.~~ These conclusions however are almost certainly unwarranted since Hofmann elimination was never considered. In a continuing study of the pharmacology of apomorphine and its derivatives the kinetics of solvolysis of N-(2-chloro- ethyl)norapomorphine which is an irreversible dopamine receptor antagonist have been studied.s4 Labelled N-(2-chloro- ethyl)-[8,9-2H2]norapomorphine was shown to label the D2 receptor.5s A comparative assessment of the five dopamine agonists (-)-norapomorphine hydrobromide (-)-2,10,1 l-tri- hydroxyaporphine hydrobromide (-)-lo 1 1 -methylenedioxy-N-propylnoraporphine hydrochloride N-ethyl-2,10,1 l-tri- hydroxynoraporphine hydrobromide and (- )-2,10,1 l-tri-hydroxynoraporphine hydrobromide hydrate as anti-convulsants in two models of reflex epilepsy involving mice and baboons has been carried out? The structural require- ments within the aporphine series that are required to secure inhibition of motor activity of male albino mice are best fulfilled by ( -)-N-propylnorapomorphine.57 Finally the struc- ture-activity relationships of aporphines as agonists and antagonists of dopamine receptors have been rationally summarized.* The neuromuscular blocking activity of isocorydine metho- chloride has been discussed44 and the effects of isocorydine itself on the contraction of and on the release of acetylcholine in isolated ileum of guinea pigs,s9 as well as on the cardiovascular system,60 have been studied. The inhibition of butyrylcholin- esterases by (9)-bulbocapnine (+)-isothebaine (+)-isocory- dine (-)-apomorphine (+)-glaucine and (+)-domesticine and also by other isoquinoline alkaloids has been considered. Bulbocapnine and isothebaine were the strongest inhibitors among the aporphines that were tested.6* The combination of naloxone and N-propylnorapomorphine is a potent aphrodisiac in rats.62 OMe M€Q& 0Me W (52) A simple extraction clean-up on kieselguhr micro-columns followed by h.p.l.c.has been used for the determination of glaucine in plasma and in urine.63 4 Dimeric Aporphinoids The study of a Chinese plant Thalictrum faberi (Ranuncul-aceae) has yielded ten new aporphine-benzylisoquinoline dimer~.~~,~~ (+)-Huanshanine (49) (+)-faberonine (50),(+)-faberidine (5 l) and (+)-dehydrohuanshanine (52) are fetidine- type dimers but (+)-thalifaberine (53) (+)-thalifabine (54) (+)-thalifarapine (53 (+)-thalifabatine (56) (+)-thalifasine (57) and (+)-dehydrothalifaberine (58) are members of a new group of coclaurine-reticuline dimers incorporating an ether bridge between C-8 and C-12’.65 In several of these alkaloids positions 3 or 5‘ are oxygenated.The highly oxidized aporphine dimers beccapolydione (59) and polybeccarine (60) have been isolated from Polyalthia caulifora var. beccarii (Annonaceae) where they accompany the known and related dimers beccapoline and beccapolinium cation.28 5 Oxoaporphines Two new oxoaporphines from members of the Annonaceae are oxobuxifoline (61) from Duguetiu obouata,2 and oxoisocalycin- ine (62) from Guatteria discolor.26 Known oxoaporphines which have been re-isolated are given in Table 3. A new synthesis of liriodenine (66) proceeds by irradiation of the urethane (63) to afford the agorphine urethane (64). Reduction of this with lithium aluminium hydride gives the dehydroaporphine (65) whose oxidation (using lead tetra- acetate) generated (66) in moderate yield.66 NATURAL PRODUCT REPORTS 1985 -M.SHAMMA AND H. GUINAUDEAU 23 1 ~~ ~~ Table 3 Oxoaporphines that have recently been re-isolated and their natural sources Alkaloid Source Ref. Lysicamine Guatteria ouregou 19 Polyalthia caulipora 28 var. beccarii Liriodenine Laurelia novae-zelandiae 7 Phoebe molicella 20 Polyalthia caul flora 28 var. beccarii (53) R’ = R2= R3=Me R4=H Polyalthia nitidissima 46 31 (56) R’R2= CH2,R3= Me,RL= H Guatteria modesta 35 (55) R’ = R2= Me R3= R4= H Pachygone ovata (56) R’= R2= R3= Me R4=OH 0-Methylmoschatoline Guatteria ouregou 19 Polyalthia caul flora 28 (57) R’= R2= Me R3=H,R4=OH var. beccarii At herospermidine Polyalthia caul flora 28 var.beccarii Oxostephanine Polyalthia caulflora 28 OH var. beccarii Thailandine Polyalthia caulflora 28 var. beccarii Subsessiline Guatteria ouregou 19 Oxolaureline Laurelia novae-zelandiae 7 Oxoputerine Laurelia novae-zelandiae 7 MeOV Corunnine Thalictrum foetidum 33 Me0 Thalictrum minus 45 ( 58) 0 \ “FR 0 (63) (67) R = H (69) R =OMc (66) (68) R =Me (70) R =H 6 Dioxoaporphines The photochemical approach that was used in the previously recorded synthesis of pontevedrine has now been extended to the preparation of norcepharadione B (67) and cepharadione B (601 (68).67 7 Oxoisoaporphines Dauriporphine (69) is an analogue of the known menispor- phine (70) which like the latter is found in Menispermum duuricurn (Menispermaceae).68 Details of the structural deter- mination and synthesis of menisporphine have been given.69 Me0 0 8 Phenanthrenes OMe OH A new phenanthrene alkaloid is atherosperminine N-oxide (7 I) which together with the known phenanthrenes argentin- (61) (62) ine and atherospermidine is present in Guatteria discolor.26 NATURAL PRODUCT REPORTS 1985 0- 9 Chiloenamine and Chiloenine Two completely new catabolic oxidation products from magnoflorine or other closely related 1,2,10,11-tetraoxygenated quaternary aporphines are the lactonic chiloenamine (72) and chiloenine (73) isolated from Berberis buxgolia and B.actinacantha (Berberidaceae) of Chilean origin. The formation of these two lactones must be enzyme-catalysed the enzyme being a catechol dioxygenase.The cleavage of the catechol is of the intra-diol type. It is thus apparent that a catabolic route for the aporphines involves initial quaternization through N-methylation followed by Hofmann elimination to produce the phenanthrene. This phenanthrene can then be oxidized with cleavage of the bottom ring.70 10 Aristolochic Acids and Aristolactams Aristolochia longa (of Spanish origin) has afforded aristolochic acid IV (74). This alkaloid had previously been obtained from natural sources only in the form of the methyl ester following esterification with diazomethane. Another new compound is species (79,which is a derivative of aristolochic acid 11. Aristolochic acids I 11 and I11 are also present in the plant.71 The previously known reduction of aristolochic acid I with sodium borohydride to produce the denitro-derivative aristolic a~id~*,’~ has been further ~onfirmed.’~ The post-coital antifertility activity of different fractions and constituents of Aristolochia indica in rats and hamsters has been studied.43 11 Miscellaneous A completely new approach to the synthesis of substituted isoquinolines has been extended to the preparation of the azafluoranthene (79) which is related to rufescine (76).The reaction of the azide (77) which was prepared by condensation of 9-oxofluorene-1-carbaldehydeand ethyl azidoacetate with triphenylphosphine provided the iminophosphorane (78). Melt pyrolysis of this material gave (79) in 19% yield.Higher yields could be secured through the use of 1,2,5-triphenylphosphole in lieu of triphenylph~sphine.~~ Proton and 3Cn.m.r. spectral evidence has been supplied in support of the structure assignments for eupolauramine (80) and hydroxyeupolauramine (8 l).76 12 References H. Guinaudeau M. Leboeuf and A. Cave J. Nat. Prod. 1983,46 761. 2 H. Guinaudeau M. Leboeuf and A. Cave J. Nat. Prod. 1984,41 565. (80) R =H (79) (811 R=OH 3 S.-T. Lu and I.-L. Tsai Heterocycles 1984 22 1031. 4 S.-T. Lu and I.-L. Tsai Heterocycles 1984 22 1323. 5 R. Hocquemiller P. Cabalion A. Fournet and A. Cave Planta Med. 1984 50 23. 6 A. Urzua and P. Acuna Fitoterapia 1983 54 175. 7 A. E. Adjaye R. H. Dobberstein D.L. Venton and H. H. S. Fong J. Nat. Prod. 1984 47 553. 8 R. Hocquemiller A. Oztekin F. Roblot M. Hutin and A. Cave J. Nut. Prod. 1984 47 342. 9 G. Sariyar Planta Med. 1983 49 43. 10 H. Ronsch A. Preiss K. Schreiber and H. Fernandez de Cordoba Liebigs Ann. Chem. 1983 744. II S. Kh. Maekh S. Yu. Yunusov E. V. Boiko and V. M. Starchenko Khim. Prir. Soedin. 1983 537 [Chem. Nat. Compd. (Engl. Transl.) 1983 5111. 12 R. Ziyaev A. Abdusamatov and S. Yu. Yunusov Khim. Prir. Soedin. 1973 67 [Chem. Nat. Compd. (Engl. Transl.) 1973 591. 13 R. Ziyaev A. Abdusamatov and S. Yu. Yunusov Khim. Prir. Soedin, 1973 505 [Chem. Nat. Compd. (Engl. Transl.) 1973 4751. 14 C.-L. Chen and H.-M. Chang Phytochemistry 1978 17 779. 15 H. Hara 0. Hoshino T.Ishige and B. Umezawa Chem. Pharm. Bull. 1981 29 1083 16 I. A. Israilov M. A. Manushakyan V. A. Mnatsakanyan M. S. Yunusov and S. Yu. Yunusov Khim. Prir. Soedin. 1984,81 [Chem. Nat. Compd. (Engl. Transl.) 1984 761. 17 1. A. Israilov M. A. Manushakyan V. A. Mnatsakanyan M. S. Yunusov and S. Yu. Yunusov Khim. Prir. Soedin. 1984 258 [Chem. Nat. Compd. (Engl. Transl.) 1984 2431. 18 I. A. Israilov S. U. Karimova 0. N. Denisenko M. S. Yunusov D. A. Murav’eva and S. Yu. Yunusov Khim. Prir. Soedin. 1983 751 [Chem. Nat. Compd. (Engl. Transl.) 1983 7141. 19 M. Leboeuf D. Cortes R. Hocquemiller and A. Cave Planta Med. 1983 48 234. 20 F. R. Stermitz and 0. Castro 1. Nat. Prod. 1983 46 913. 21 F. Roblot R. Hocquemiller A. Cave and C. Moretti J.Nat.Prod. 1983 46 862. 22 D. P. Allais and H. Guinaudeau Heterocycles 1983 20 2055; and references cited therein. 23 I. A. Israilov S. U. Karimova M. S. Yunusov and S. Yu. Yunusov Khim. Prir. Soedin. 1979 104 [Chem. Nat. Compd. (Engl. Transl.) 1979 911. 24 S. U. Karimova I. A. Israilov M. S. Yunusov and S. Yu. Yunusov Khim. Prir. Soedin. 1980 224 [Chem. Nat. Compd. (Engl. Transl.) 1980 1771. 25 S. U. Karimova I. A. Israilov F. Vezhnik M. S. Yunusov Yu. Slavik and S. Yu. Yunusov Khim. Prir. Soedin. 1983 493 [Chem. Nat. Compd. (Engl. Transl.) 1983 4641. 26 R. Hocquemiller C. Debitus F. Roblot A. Cave and H. Jacquemin J. Nat. Prod. 1984 47 353. 27 A. Urzua and R. Torres J. Nat. Prod. 1984 47 525. 28 A. Jossang M. Leboeuf A.Cave T. Sevenet and K. Padmawin- ata J. Nat. Prod. 1984 41 504. 29 H. G. Kiryakov and E. S. Iskrenova Planta Med. 1984 50 136 30 A. Oztekin R. Hocquemiller and A. Cave J.Nat. Prod. 1984,47 560. NATURAL PRODUCT REPORTS 1985 -M. SHAMMA AND H. GUINAUDEAU 31 H. A. Ammar P. L. Schiff Jr. and D. J. Slatkin J. Nat. Prod. 1984 47 392. 32 I. A. Israilov F. M. Melikov and D. A. Murav'eva Khim. Prir. Soedin. 1984 79 [Chem. Nat. Compd. (Engl. Transl.) 1984 741. 33 S. Mukhamedova C. Kh. Maekh and S. Yu. Yunusov Khim. Prir. Soedin. 1983 394 [Chem. Nat. Compd. (Engl. Transl.) 1983 3761. 34 D. S. Bhakuni and S. Gupta PIanta Med. 1983 48 52. 35 M. A. El-Kawi D. J. Slatkin and P. L. Schiff Jr. J. Nat. Prod. 1984 47 459. 36 P. Richomme M.Lavault H. Jacquemin and J. Bruneton Planta Med. 1984 50 20. 37 S. A. Parfeinikov and D. A. Murav'eva Khim. Prir. Soedin. 1983 242 [Chem. Nat. Compd. (Engl. Transl.) 1983 2401. 38 S. K. Chattopadhyay A. B. Ray D. J. Slatkin and P. L. Schiff Jr. Phytochemistry 1983 22 2607. 39 N. Shoji A. Umeyama T. Takemoto and Y. Ohizumi J. Pharm. Sci. 1984 73 568. 40 S. Bahadur and,A. K. Shukla J. Nat. Prod. 1983 46 454. 41 T. Furuya T. Yoshikawa and H. Kiyohara Phytochemistry 1983 22 1671. 42 H. M. Chang A. M. El-Fishawy D. J. Slatkin and P. L. Schiff Jr. Planta Med. 1984 50 88. 43 C.-T. Che M. S. Ahmed S. S. Kang D. P. Waller A. S. Bingel A. Martin P. Rajamahendran N. Bunyapraphatsara D. C. Lankin G. A. Cordell D. D. Soejarto R. 0.B. Wijesekera and H.S. Fong J. Nat. Prod. 1984 47 331. 44 K. C. Mukherjee G. K. Patnaik D. S. Bhakuni and B. N. Dhawan Indian J. Exp. Biol. 1984 22 54. 45 S. Mukhamedova S. Kh. Maekh and S. Yu. Yunusov Khim. Prir. Soedin. 1983 393 [Chem. Nat. Compd. (Engl. Transl.) 1983 3751. 46 A. Jossang M. Leboeuf P. Cabalion and A. Cavk Planta Med. 1983 49 20. 47 A. K. Sidjimov and V. S. Christov J. Nat. Prod. 1984 47 387. 48 H. Hara F. Hashimoto 0.Hoshino and B. Umezawa Tetrahedron Lett. 1984 25 3615. 49 H. Hara H. Shinoki 0. Hoshino and B. Umezawa Heterocycles 1983 20 2155. 50 A. A. Adesomoju W. A. Davis R. Rajaraman J. C. Pelletier and M. P. Cava J. Org. Chem. 1984 49 3220. 51 G. R. Lenz and F. J. Koszyk J. Chem. SOC. Perkin Trans. I 1984 1273.52 V. Sharma aild D. P. Joshi J. Indian Chem. Sect. B 1984 61 71. 53 J. C. Kim Arch. Pharmacal Res. 1983 6 137. 54 S. A. Cohen and J. L. Neumeyer J. Med. Chem. 1983 26 1348. 55 J.-H. Guan J. L. Neumeyer C. N. Filer D. G. Ahern L. Lilly M. Watanabe D. Grigoriadis and P. Seeman J. Med. Chem. 1984 27 806. 56 G. M. Anlezark D. H. R. Blackwood B. S.Meldrum V. J. Ram and J. L. Neumeyer Psychopharmacology 1983 81 135. 57 A. J. Bradbury B. Costall R. J. Naylor and J. L. Neumeyer J. Pharm. Pharmacol. 1983 35 494. 58 J. L. Neumeyer W. Dafeldecker C. N. Filer F. E. Granchelli J.-H. Guan S.-J. Law H. M. Maksoud V. J. Ram and D. Reischig Proceedings of the Phytochemical Society of Europe. The Chemistry and Biology of Isoquinoline Alkaloids 16-1 8th April 1984; Springer Verlag Berlin 1984.59 Z. Zhao and L. Chen Zhongcaoyao 1984 15 164 (Chem. Abstr. 1984 101 65822). 60 Z. Zhang A. Miao R. Xie C. Tang G. Chen Y. Shen and S. Ma Zhongcaoyao 1984 15 20 (Chem. Abstr. 1984 100 185504). 61 J. Ulrichova D. Walterova V. Preininger and V. Simanek PIanta Med. 1983 48 174. 62 F. Ferrari and G. Baggio Adv. Biosci. 1983 44 351. 63 J. P. Fels P. Lechat R. Rispe and W. Cautreels J. Chromatogr. 1984 308,273. 64 L.-Z. Lin H. Wagner and 0.Seligmann PIanta Med. 1983,49,55. 65 H. Wagner L.-Z. Lin and 0. Seligmann Tetrahedron 1984 40 2133. 66 S. Nimgirawath and W. C. Taylor Aust. J. Chem. 1983 36 1061. 67 L. Castedo J. M. Saa R. Suau and R. J. Estevez An. Quim. C 1983 79 329. 68 M. Takani Y.Takasu and K. Takahashi Chem. Pharm. Bull. 1983 31 3091. 69 J. Kunitomo M. Satoh and T. Shingu Tetrahedron 1983,39,3261. 70 M. Shamma H.-Y. Lan A. J. Freyer J. E. Leet A. Urzua and V. Fajardo J. Chem. Soc. Chem. Commun. 1983 799. 71 J. de Pascual Teresa J. G. Urones and A. Fernandez Phyto-chemistry 1983 22 2745. 72 K. Ito H. Furukawa and M. Haruna Yakugaku Zasshi 1972,92 92. 73 S. C. Pakrashi P. Ghosh-Dastidar S. Basu and B. Achari Phytochemistry 1977 16 1103. 74 S. Mukhopadhyay S. Funayama G. A. Cordell and H. H. S. Fong J. Nat. Prod. 1983 46 507. 75 D. M. B. Hickey A. R. MacKenzie C. J. Moody and C. W. Rees J. Chem. Soc. Chem. Commun. 1984 776. 76 W. C. Taylor Aust. J. Chem. 1984 37 1095.

ISSN:0265-0568    

DOI:10.1039/NP9850200227

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

lndolizidine and Quinolizidine Alkaloids M. F. Grundon Department of Chemistry The University of Ulster at Coleraine Coleraine Co. L ondonderry Northern Ireland B T52 1SA Reviewing the literature published between July 1983 and June 1984 (Continuing the coverage of literature in Natural Product Reports 1984 Vol. 1 p. 245 and p. 349) 1 Introduction 2 Elaeokanines A and C and Epilupinine 3 Furylindolizidines and Furylquinolizidines 4 Swainsonine and Castanospermine 5 Dendrobutes Alkaloids 6 Phenanthroindolizidines,Phenanthroquinolizidines,and Related Alkaloids 6.1 Occurrence and Structural Studies 6.2 Synthesis 7 The Lupinine-Cytisine-Sparteine-Matrine-Orrnosiu Group 7.1 Occurrence 7.2 Structural and Chemical Studies 7.3 Synthesis 8 Lythraceae Alkaloids 9 Myrtine 10 9b-Azaphenalene Alkaloids 11 References 1 Introduction This year the indolizidine and quinolizidine alkaloids are reviewed in one chapter; this arrangement is of particular value when a synthetic method is applicable to both groups of HO alkaloids.Outstanding achievements have been reported in the synthesis of indolizidine alkaloids including three stereo-selective routes to the a-mannosidase inhibitor swainsonine the synthesis of the related enzyme inhibitor castanospermine and new syntheses of gephyrotoxin and perhydrogephyrotoxin. In the quinolizidine group the apparently biomimetic photo- chemical transformation of rhombifoline into the cage-type alkaloids tsukushinamine-A and tsukushinamine-B is also of considerable interest.2 Elaeokanines A and C and Epilupinine A new synthesis of indolizidines and quinolizidines has been applied to elaeokanine A (4)and to epilupinine (5) (Scheme l).I The cyclization (1) + (3) is controlled by a ketene dithioacetal group which generates an S-stabilized carbo-cation only; formation of the acyliminium ion (2) from a mesylate in a non- acidic medium ensures the survival of the dithioacetal junction. 2-Methoxy-1-(methoxycarbonyl)pyrrolidine (6) is the starting point for a synthesis of elaeokanine A (4)and elaeokanine C (7) (Scheme 2).2 3 Furylindolizidines and Furylquinolizidines Ban and co-workers developed a general one-pot procedure for the synthesis of bicyclic lactams from amino-diketones ('criss- L n n YS (5) 0 Reagents 1 Ph3P TKF then EtO,CN=NCO,Et; ii NaBH, MeOH at -40 "C then aq.NaHC03 CH2C12; iii MsCl Et3N; iv LiAlH,; v LiNPr5 PrI; vi HgCl, CaC03 aq. MeCN at 50°C; vii HgCI2 aq. HClO, MeOH reflux Scheme 1 NATURAL PRODUCT REPORTS 1985 + E i * ?4 CO2 Me ii,iii f--iv \ vi (4) -(7) Reagents i TiC14 CH2C12; ii HOCH2CH20H TsOH CH(OEt), reflux; iii NH2NH2 KOH HOCH2CH20H reflux; iv BrCH2CH ,H 9 NaH DMF at 0°C; v conc. HC1; vi aq. NaOH reflux; vii 1M-HCI reflux then NaOH reflux Scheme 2 cross annulation’) which has been applied to the synthesis of an indolizidine alkaloid (Scheme 3).3Treatment of the keto-amide (8) with lithium hydroxide and then acidification gave the indolizidinone (9) which was converted into the stereoisomeric furylindolizidines (10) and (12).An alkaloid of this type (stereochemistry unknown) was shown to be a minor constitu- ent of the scent glands of the Canadian beaver; a third stereoisomer (1 1) was prepared by LaLonde et af.4 Quaternization of the nitrogen atoms of furylquinolizidine alkaloids was studied last year (cf.ref. 5) and now the Hofmann degradation has been applied to 7-eptdeoxynupharidine methiodide (13) and to deoxynupharidine methiodide (14) (Scheme 4).6 The former methiodide (1 3) gave compound (1 5) which was transformed into compound (1 7) whereas deoxy- nupharidine methiodide suffered ring inversion to give compound (16) which was converted into (18).Similar effects were observed in the Hofmann degradation of the isomeric monomethidides that were derived from thiobinupharidine (cf. ref 5). 4 Swainsonine and Castanospermine Intense interest in the potent and specific a-mannosidase inhibitor swainsonine (20) continues (cf. ref. 7a) and three chiral syntheses of the alkaloid from carbohydrate derivatives have been reported this year. Fleet and co-wc)rkers* prepared a protected 4-azidomannose (19) from D-mannose with overall retention of configuration; after a two-carbon extension reduction gave the equivalent of an amino-dialdehyde which by two intramolecular reductive aminations was converted into swainsonine (Scheme 5). Richardson’s synthesis9 of swainsonine (Scheme 6) starts with the amino-derivative (21) obtained from D-gluCOSe; a protected pyrrolidine aldehyde (22) was subjected to a Wittig reaction and after removal of the N-protecting group the ester (23) cyclized to the amide (24).A similar synthesis of swainsonine (Scheme 7) by Suami and co-workers1° also n fi,X & Fu 0 (9) \x i & J+ H’ Fu C major 1 f minor 3 ti d&R2 H H q ki? H (10) R’ = Fu R2= H (12 1 (11) R’ = H R2=FU ( Fu = 3-furyl) Reagents i H2C=CHCN KF 18-crown-6 THF reflux; ii HOCH2CH20H; iii I I ; iv H,O; v NH20Me; vi QLi LiAlH4 THF; vii (CF3C0)20 pyridine; viii aq. CF,CO,H; ix LiOH aq. MeOH at 60-65°C; x HCI in aq. MeOH; xi NaCNBH, MeOH Scheme 3 Me &Me N rc Me Me (15) R1 =Me,R 2 =H (17) R’= Me R2=H (16) R’=H R2=Me (18) R’=H R~=M~ (Fu = 3 -furyl) Reagents i Ag20 in aq.MeOH then heat with NaOH; ii H2 Pd/C MeOH; iii MeI Me2C0 at 20°C then Hofmann degradation Scheme 4 NATURAL PRODUCT REPORTS 1985 -M. F. GRUNDON (19) lv "9 Hoe*& vii vi H V HO HO BnO' li Reagents i Ph,Bu'SiCI imidazole then Me,CO Me,C(OMe) ,camphorsulphonic acid; ii pyridinium chlorochromate molecular sieve CH2C12 then NaBH, DOH; iii (CF,SO,),O (3 equiv.) pyridine CH2CI2 then NaN, DMF then Bu,N+ F-in THF; iv pyridinium chlorochromate (2 equiv.) molecular sieve CH2C12 then Ph,P=CHCHO (2.5 equiv.); v 10% Pd/C MeOH H, for 6 hours; vi H, Pd MeCO,H for 3 days; vii CF3C0,H D20 Scheme 5 OMe OH I OH (251 iv-vii 1 I BnO iii-x E t S 6 Cbz AcNH -OBn EtS '0 Ts c02 Et (26) Pxii @ -OBn xiii,xiv -OH -V (20) (27) (24) Reagents i mesylation; ii HC1 MeOH; iii aq.MeOCH2CH20H NaOAc then acetylation; iv aq. HCI reflux then acetylation; v NaOMe MeOH then HSCH,CH,SH then tritylation; vi BnBr DMF NaH then removal of trityl group; vii tosylation; viii aq. NaOH reflux; ix HgCl, CaC0 ;x diethyl ethoxycarbonylmethyl- (20) phosphonate NaH; xi H, Raney nickel; xii aq. KOH EtOH at 90 "C; xiii LiAIH, THF; xiv Pd(OH),/C cyclohexene (CbZ = PhCHzOCO-) Scheme 7 Reagents i hydrogenolysis; ii NaOAc EtOH reflux; iii PhCH20- COCl; iv H,O+; v (HSCH2)2 HCI; vi acetylation; vii HgCI2 CdCO,; viii EtO,CCH=PPh,; ix H, Pd/C; x BH,-DMSO; xi sized for the first time by Bernotas and Ganemll (Scheme 8).NaOMe Treatment of the epoxide (28) with sodium borohydride resulted in loss of the trifluoroacetyl group and attack of the Scheme 6 nitrogen nucleophile at both carbon atoms of the epoxide ring; deprotection of one of the products (29) of this reaction furnished ( +)-deoxynojirimycin (30). The piperidine deriva- involves conversion of a carbohydrate derivative (25) into a tive (31) was obtained as a 1 :1 mixture of stereoisomers and the pyrrolidine (26) which is then cyclized to an indolizidinone less polar compound was converted via the indolizidinone (32) (27). into (+)-castanospermine; this is an enantiospecific synthesis The enzyme inhibitor castanospermine (33) (cf ref. 7a) is which establishes the absolute configuration (33) of the related in structure to swainsonine and has now been synthe- alkaloid.NATURAL PRODUCT REPORTS 1985 -En0 CH20H /Bn CH2 OH CHzOH iii-v no-8BnO OH BnO CH2NBn CH2NBn OBn BnO I COCF3 OBn (28) / (29)(+ isomer) vii1 CH20H HHO O W OH (33) (32) (31) (30) Reagents i PhCH2NH2 CHCl,; ii LiAlH, THF reflux then trifluoroacetylation; iii ButMe2SiC1,imidazole; iv mesylation then deprotection; v Bu,NF THF then NaOMe MeOH; vi NaBH, EtOH at 40°C; vii hydrogenolysis; viii (C0Cl)2 DMSO; ix LiCH,C02But; x hydrogenolysis then CF,C02H HzO at 60 "C; xi Bu\AlH Scheme 8 5 Dendrobates Alkaloids Extensive H and 3C n.m.r. spectroscopic studies of pumilio- toxins A (34) and B (35) and the 7-hydroxy-derivatives (36) (37) and (38) (allopumiliotoxins) resulted in the recognition of new stereoisomers and the revision of some structural assignments*z(cJ refs.76 13a and 136). Thus allopumilio- toxins 323B' and 323B" (37) which were formerly thought to be epimeric at C-7 have now been shown to differ only in the configuration of the hydroxyl group at C-15. Two stereoisomers of pumiliotoxin A (34) epimeric at C-15 were also isolated and have been designated pumiliotoxins 307A' and 307A". The structures of allopumiliotoxins 339A (38a) and 339B (38b) were additionally assigned by the observation that only allopumilio- toxin 339B (38b) (with cis hydroxyl groups) forms a ring phenyl boronide. Another highly stereoselective synthesis of gephyrotoxin (42) has been described by OvermanI4 (cf.refs. 74 136 and 13c) (Scheme 9). An interesting feature of the synthesis is that reduction of the octahydroquinoline derivative (39) with lithium aluminium hydride apparently occurs preferentially from the more congested concave or-face of the intermediate (40; R = metal species) to give the decahydroquinoline (41) and its epimer in the ratio 12 :1. Two stereoselective syntheses of perhydrogephyrotoxin (48) were described previously by Overman (cf. refs. 13b and 13c) and now Ibuka et a1.I5 have reported a new synthesis of this compound (Scheme 10). The key decahydroquinoline deriva- tive (43) was prepared from 1,3-bis(trimethylsilyloxy)buta-1,3-diene. The keto-ester (44) was obtained almost quantitatively by reduction of compound (43a) and was equilibrated with the required stereoisomer (45); in the subsequent sequence to the tricyclic intermediate (47) efficient decarboxylative reduction of compound (46) with lithium dibutylcopper is of particular interest.6 Phenanthroindolizidines Phenanthroquinol-izidines and Related Alkaloids 6.1 Occurrence and Structural Studies A new alkaloid tylophorinicine has been obtained from the roots of Tylophora asthmatica and Pergularia pallida and assigned structure (49) on the basis of its reduction with sodium borohydride to tylophorine (50); the stereochemistry at C-14 is indicated by analogy with known trimethoxy-14-hydroxyphen-anthroindolizidines. Five new phenanthroindolizidine alkaloids (51)-(55) have been isolated from Tylophora hirsuta and are notable for the presence of a methyl group at C-13a or a C-13-C-13a double- bond.l7 The structures of the alkaloids were determined mainly by H n.m.r. and mass spectroscopy. For example retro-Diels- Me U Pumiliotoxin A C~307 A'and 307A"1(34) Me Pumiliotoxin B E323 A3 ( 35 ) OH Allopumiliotoxin 267A ( 36) U ALLopumiliotoxins 323 B' and 323 B"(37) U Allopumiliotoxin 339A 138al R'=OH R2= H Allopumiliotoxin 3398 (38b) R'=H ,R2= OH Alder reactions occur readily under electron impact and the alkaloids (53) and (54) with methyl groups at the ring junction show prominent [M-151fragment ions. In the n.m.r. spectrum of 132-methyltylohirsutine (53) the methyl protons resonate at 6 2.18 p.p.m.the unusual deshielding by the nitrogen atom NATURAL PRODUCT REPORTS 1985 -M. F. GRUNDON OMOM lY-HCozBn vii I OMOM OMOM J (411 (40) ix-xii 1 OMOM OMOM I CHO xiii xiv .H XV,XVI xvii xviii L -'1su-B"' Bu'Ph2Si0 PhzSiO (42) [MOM = CHzOMe3 Reagents i PriNEt CICH,OMe CH2CI2 at 0 "C; ii BuLi then paraformaldehyde THF reflux; iii H, Pd/BaSO, pyridine; iv pyridinium chlorochromate NaOAc CH,CI,; v at 110 "C for 1.5 hours; vi lithium hexamethyldisilylamide H? Pd/C CF,CO,H MeC0,Et; viii LiAlH4 Et,O; ix CICO,CH,CCI, 1,2,2,6,6-pentamethyIpiperidine,CCI,; x HC104 THF; xi pyridinium toluene-p-sulphonate MeOH ;xii KOH MeCH(OH)Me H,O; xiii 1M-HCI THF then NaOMe NaBH, MeOH; xiv BurPh2SiC1 NEt, 4-(dimethylamino)pyridine CH2CI,; xv HBr MeOCH,CH,OMe at 50 "C; xvi (COCI), Me,SO; xvii Pr;SiCH2C-CSiPr; BuLi THF; xviii bb VF DMF Scheme 9 indicating that the axial methyl group is cis to the lone-pair of electrons on nitrogen.13a-Methyltylohirsutinidine(54) gives a positive Gibbs test showing that the phenolic hydroxyl group is at C-4. 13a-Hydroxysepticine (55) resists acetylation but with acetic anhydride and pyridine it gives the phenanthro- indolizidine (56). The Thai plant Cissus rheifolia (Vitaceae) contains crypto- pleurine (57) but the major alkaloid kayawongine is the new diarylquinolizidine (58); its structure was established by the mass spectrum which showed fragment ions at m/z 270 [3,4-(Me0)2C,H3CH=CHc,H4-4-oMe] 164 [3,4-(MeO),C,H3CH=CH,] and 134 (100%; 4-MeOC6H4CH= CH2) and by 'H n.m.r.and 13C n.m.r. spectroscopy.18 6.2 Synthesis The arylindolizidine (59) which is a key intermediate in the synthesis of the Ipomoea alkaloid ipalbidine (60) has now been prepared by the versatile 1,3-dipolar cycloaddition reactions of nitrones (Scheme 1 l).l9 A full account has been given of the nitrone cycloaddition to the indolizidine alkaloids septicine and tylophorine (cf. ref. 7a) and to the quinolizidine alkaloids julandine and crypto- pleurine (cf ref. 20~).~' 7 The Lupinine-Cytisi ne-Sparteine-Matri ne-Ormosia Group 7.1 Occurrence Wink and co-workerst2 have examined the pattern of quinolizidine alkaloids in cell cultures and leaves of ten species of the Fabaceae by g.1.c. and g.1.c.-m.s. Lupanine was the main alkaloid in all cell suspension cultures ; a-pyridone alkaloids were major components of plants of the genera Cytisus Genista Laburnum and Sophora but were not found in cell cultures.Those alkaloids that had not previously been obtained from some of the ten species are listed in Table 1. The seeds of Lupinus mutabilis have high fat and protein content and have been used to produce edible oil in recent years; the bitter and toxic quinolizidine alkaloids (up to 3% in the seeds) are removed before consumption and a detailed study of the alkaloid composition has now been carried out by g.1.c. and m.s. technique^;,^ alkaloids that were positively identified and which had not previously been found in this species are given in 240 NATURAL PRODUCT REPORTS 1985 R + 4 cln, tiH I I-I (45) MeOzC Me 0,C (Ua) xv-xvi i xxi HO H (R = CCH2I4Me) Reagents i at 175 "C for 48hours; ii (CH,OH), p-MeC6H4S020H PhH reflux for 10 hours; iii BuiAlH (2.3 equiv.) n-hexane-PhMe (6 :I) at -73 "C for 3 hours; iv BuLi THF-HMPT (2 :l) at -73 "C then TsCl (1.2 equiv.) at -73 +0 "C; v CuCH2CN (5 equiv.) THF at -73 + -30 "C; vi 30% H,O, aq.KOH; vii 5% aq. HCl Me,CO at 56 "C; viii 5% NaOMe MeOH at 65 "C; ix (CH,SH), BF,.Et,O CHCl,; x sss il/ Raney nickel EtOH at 78°C; xi p-MeOC H P 4\s/ C,H,OMe-p xylene at 140 "C; xii BrCH,COCH,CH,CO,Me CHCl, then 'PhP(CH,CH,NMe,), at 61 "C; xiii NaBH,CN aq. HCl-MeOH; xiv Et,N MeOH at 65 "C; xv NaBH, MeOH at -20 "C then TsOH PhH reflux; xvi ClCO,Ph pyridine 4-(dimethylamino)pyridine; xvii lithium cyclohexylisopropylamide THF-HMPT at -73 "C then PhSeC1; xviii LiOH aq.MeOH then CH,N,; xix 30% Hz02 pyridine-CH,Cl, at 0 "C; xx LiBu,Cu THF at -73 "C;xxi 1% NaOMe MeOH reflux; xxii BuiAlH n-hexane-PhMe at -60 "C Scheme 10 OMe OMe OMe OMe Tylophorinicine (49) R =OH Tylohirsutinjne (51) R'=OMe R2=H 13a- Methylt y lohir sut ine (53) R'= OMe ,R2= H (50) R =H Tylohirsutin id ine (52)R'= R2= OH 13a-Methyltylohirsutinidine (54) R'= R2=OH NATURAL PRODUCT REPORTS 1985 -M. F. GRUNDON 24 1 Table 1 Isolation of alkaloids of the lupinine-cytisine-spar- teine-matrine group OMe OMe 13a -Hydroxysepticine (55) (56) ( 57) Kayawongine (58) 0-ii-iv H 1 ArOm / CHo \ C HO H b vii Ar Ar (59) Ar = a [ ] ( 0Me ) Reagents i PhMe reflux; ii 10% Pd/C H,; iii HC02H PhMe; iv NH3 MeOH; v Collins oxidation; vi AI(OBU')~ xylene; vii Li liq.NH3 Scheme 11 been studied. 24 Table 1. The alkaloid content of forty strains of L. mutabilis has Other isolation studies are summarized in Table 1. New alkaloids were obtained from Sophora chrysophyll~~~ and from S. macrocarpa.26 7.2 Structural and Chemical Studies A minor alkaloid from Sophora chrysophylla was shown to be (-)-mamanine N-oxide (61).25The reaction of the oxide with ferrous sulphate in aqueous ammonia gave mamanine which with a peroxy-acid was converted into the N-oxide; comparison with the I3C n.m.r. spectra of (+)-mamanine and the N-oxide and observations of the chemical shifts of carbon atoms CI and p to the N-oxide group indicated that the new alkaloid has a trans-quinolizidine arrangement with the N-oxide group in an axial configuration.Species Alkaloid I Ref. Baptisia australis N-Acetylc ytisine 11-Allylcytisine (trace) N-Formylcytisine 22 Cytisus canariensis 5,6-De hydrolupanine N-Formylcytisine Lupanine Rhombifoline Cytisus purpureus Anagyrine Cytisine 5,6-Dehydrolupanine Lupanine Rhom bi foline (trace) Tetrahydrorhombifoline (trace) Genista pilosa 11,12-Dehydrosparteine Lupanine 17-Oxosparteine Lupinus alpinum 1 1-Allylcytisine 5,6-Dehydrolupanine 13-Hydroxyanagyrine a-Isolupanine 22 I Lupanine 17-Oxosparteine Thermopsine Tinctorine I Lupinus luteus 1 1 12-Dehydrosparteine 17-Oxosparteine Tetra hyd rorhom bi foline Lupinus mutabilis 13-(Angeloy1oxy)lupanine Angustifoline 1 3-(Benzoy1oxy)lupanine 13-cis- and 13-trans-(cinnamoy1oxy)lupanine Tetra h ydrorhom bi foline 13-(Tigloy1oxy)lupanine Sophora japonica Luuanine 22 Sophora chrysophylla ( -)-Baptifoline 5,6-Dehydrolupanine ( -)-N-Formylcytisine Lamprolobine Epilamprolobine Epilamprolobine N-oxide 25 (-)-Lupanine *( -)-Mamanine N-oxide (61) (+)-Matrine N-oxide (-)-N-Methylcytisine 17-Oxoluuanine (-)-Rhombifoline I Sophoru macrocarpa *(+)-9a-Hydroxymatrine (63) 26 * New alkaloid HO / gJoqp H (60) (61) CHzOH The reaction of methylcytisine with MnO in 30%acetic acid furnished the dilactam (62) and cytisine; the latter was obtained from the reaction mixture by conversion into crystalline nitrosocytisine and subsequent hydrolysis of this derivative.*' a-Isolupanine and 15-oxosparteine are conveniently convert- ed into their methiodides by treatment with methyl iodide in acetone under high pressure.28 The structure of a new alkaloid ( +)-9a-hydroxymatrine (63) isolated from Sophoru macrocarpa was established by spectroscopy.26 The 13C n.m.r.spectrum of the alkaloid compared to that of matrine indicated that an equatorial hydroxyl group was at C-3 or at C-9; the latter position was favoured by IH n.m.r. n.0.e. experiments in which irradiation at the carbinyl proton caused major enhancement of the signal for the proton at C-11.A full report has appeared on the X-ray analysis of the co-crystals of the Ormosiu alkaloids (-)-podopetaline and ( -krmosanine which were isolated form Podopetufurn ormondii (cJ ref. 20b).29 7.3 Synthesis The cage-type alkaloids (-)-tsukushinamine-A (67) and (-)-tsukushinamine-B (68) which were isolated from Sophoru 0 ( 64 R = CH2CH,CH=CHZ (67) R'= H R2=CHzCH=CHz ( 65 R =Me (68) R'= CHzCH=CHz ,RZ=H 66 R = Et (69) R' = RZ=H (70) R'= H R2=Me (71) R' =M~,R~=H NATURAL PRODUCT REPORTS 1985 jianchetianu (cf ref. ~OC) have now been synthesized;30 by analogy with the photocyclization of phenylalkylamines irradiation of (-)-rhombifoline (64) in acetonitrile gave a good yield of a 1 :3 mixture of the alkaloids (67) and (68).Similar irradiation of ( -)-N-methylcytisine (65) and (-)-N-ethyl-cytisine (66) gave compound (69) and the stereoisomers (70) and (7 l) respectively. 8 Lythraceae Alkaloids The nitrone route to 4-arylquinolizidine alkaloids (cf. ref. 5) has been applied to the synthesis of lasubine I (76) lasubine I1 (78) and subcosine I (77) (cf ref. 204 (Scheme 12).31 An inseparable mixture of E-and 2-dienes (72) reacted with 2,3,4,5-tetrahydropyridine1-oxide to give addition products ;a mixture of isomers (73) and (74) was converted into lasubine I [apparently from (73)]; lasubine I1 [which would be expected from (74)] was not obtained but was synthesized by an alternative method from isopelletierine (75). The reaction of lasubine 1 with butyl-lithium and then 3,4-dimethoxycinnamic anhydride afforded the ester subcosine I (77).9 Myrtine The quinolizidine alkaloid myrtine (80) was prepared previous- ly from pelletierine (cf ref. 20e) and the application of a new synthesis of quinolizidines and indolizidines yielded epimyr- tine (79) (55%) and myrtine (20%) (Scheme 13).32 10 9b-Azaphenalene Alkaloids A detailed and interesting account has now been published33 of the synthesis of azaphenalene alkaloids of ladybird beetles by the perhydroboraphenalene method that has been developed by Mueller and Thompson (cf ref. 20f). n (73)(74)R=d-H OMe I OMe iv (75)H m(l+ OR OMe +1(72) R =P-H 'b OMe OMe (76) R = H (77) R = trons-3,4-dimethoxycinnamoyl OMe Reagents i Ph,P=CHCH=CH2 Bu"Li Et,O; ii 2,3,4,5-tetrahydropyridineI-oxide PhMe reflux; iii HCI CHCI ; iv H2 Pd/C EtOH pyridine; v aq.NaOH THF; vi NaBH, MeOH Scheme 12 NATURAL PRODUCT REPORTS 1985 -M. F. GRUNDON Me I H2N CCH23,CH(OEt)z I MeCOCH2-C-NHCCH234CH(OEt)2 I 1 (79) R1=H R2=Me (80) R'= Me R2= H Reagents i MeCH=CHCOMe EtzO; ii 2M-HCl at 100 "C Scheme 13 11 References 1 A. R. Chamberlin H. D. Nguyen and J. Y. L. Chung J. Org. Chem. 1984 49 1682. 2 T. Shono Y. Matsumura K. Uchida K. Tsubata and A. Makino J. Org. Chem. 1984 49 300. 3 T. Ohnuma M. Tabe K. Shiiya Y. Ban and T. Date Tetrahedron Lett. 1983 24 4249. 4 R. T. LaLonde N. Muhammad C. F. Wong and E. R. Sturiale J.Org. Chem. 1980 45 3664. 5 M. F. Grundon Nut. Prod. Rep. 1984 1 352. 6 J. Cybulski K. Wojtasiewicz and J. T. Wrobel Heterocycles 1983 20 1773; J. Cybulski and K. Wojtasiewicz J. Mol. Srruct. 1984 116 1. 7 J. A. Lamberton Nut. Prod. Rep. 1984 1 (a) p. 245; (b) p. 246. 8 G. W. J. Fleet M. J. Gough and P. W. Smith Tetrahedron Lett. 1984 25 1853. 9 H. A. Mezher L. Hough and A. C. Richardson J. Chem. Soc. Chem. Commun. 1984 447. 10 T. Suami K. Tadano and Y. Iimura Chem. Lett. 1984 513. 11 R. C. Bernotas and B. Ganem Tetrahedron Lett. 1984 25 165. 12 T. Tokuyama J. W. Daly and R. J. Highet Tetrahedron 1984,40 1183. 13 J. A. Lamberton in 'The Alkaloids' ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London (a) 1981 Vol.11 p. 60; (6) 1983 Vol. 13 p. 84; (c) 1982 Vol. 12 p. 71 ; (d) 1981 Vol. 11 p. 62; (e) 1982 Vol. 12 p. 72. 14 L. E. Overman D. Lesuisse and M. Hashimoto J.Am. Chem. SOC. 1983 105 5373. 15 T. Ibuka G.-N. Chu and F. Yoneda J. Chem. SOC. Chem. Commun. 1984 597. 16 N. B. Mulchandani and S. R. Venkatachalam Phytochemistry 1984 23 1206. 17 K. K. Bhutani M. Ali and C. K. Atal Phytochemistry 1984 23 1765. 18 E. Saifah G. J. Kelley and J. D. Leary J.Nat. Prod. 1983,46,353. 19 H. Iida Y. Watanabe and C. Kibayashi Chem. Lett. 1983 1195. 20 M. F. Grundon in 'The Alkaloids' ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London (a) 1982 Vol. 12 p. 82; (b) 1982 Vol. 12 p. 76; (c) 1981 Vol. 10 p. 68 and 1983 Vol.13 p. 89; (d) 1981 Vol. 10 p. 71; (e) 1979 Vol. 9 p. 71 and 1981 Vol. 11 p. 68; (1')1981 Vol. 10 p. 72 and 1982 Vol. 12 p. 80. 21 €3. Iida Y. Watanabe M. Tanaka and C. Kibayashi J. Org. Chem. 1984 49 2412. 22 M. Wink L. Witte T. Hartmann C. Theuring and V. Volz Plunta Med. 1983 48 253. 23 T. Hatzold I. Elmadfa R. Gross M. Wink T. Hartmann and L. Witte J. Agric. Food Chem. 1983 31 934. 24 E. von Baer and R. Gross 2. Ppanzenzuecht. 1983 91 334. 25 I. Murakoshi M. Ito J. Haginiwa,S. Ohmiya H.Otomasu and R. T. Hirano Phytochemistry 1984 23 887. 26 R. Negrete B. K. Cassels and G. Eckhardt Phytochemistry 1983 22,2069. 27 T. K. Kasymov A. I. Ishbaev D. N. Danil'chuk and Sh. Yusupov Uzb. Khim. Zh 1983 No. 5 p. 43 (Chem. Abstr. 1984,100 175 111).28 J. Jurczak and T. Tkacz Synthesis 1983 920. 29 W. Wong-Ng P.-T. Cheng and S. C. Nyburg Acta Crystallogr. Sect. B 1984 40 151. 30 S. Ohmiya H. Otomasu and I. Murakoshi Chem. Pharm. Bull. 1984 32,815. 31 H. Iida M. Tanaka and C. Kibayashi J. Chem. Soc. Chem. Commun. 1983 1143; J. Org. Chem. 1984 49 1909. 32 F. D. King Tetrahedron Lett. 1983 24 3281. 33 R. H. Mueller H. E. Thompson and R. M. DiPardo J.Org. Chem. 1984 49 22 17.

ISSN:0265-0568    

DOI:10.1039/NP9850200235

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Muscarine Imidazole and Peptide Alkaloids and Other Miscellaneous Alkaloids J. R. Lewis Department of Chemistry University of Aberdeen Meston Walk Old Aberdeen A89 2UE Reviewing the literature published between July 1983 and June 1984 (Continuing the coverage of literature in Natural Product Reports 1984 Vol. 1 p. 387) 1 Muscarine Alkaloids 2 Imidazole Alkaloids 3 Peptide Alkaloids 4 Miscellaneous Alkaloids 5 References 1 Muscarine Alkaloids A synthesis of (&)-allomuscarine (2) has been reported whereby the treatment of butyl4,5-epoxy-2-hydroxyhexanoate with stannic chloride induced ring-opening which was followed by cyclization to give the furan (1). Subsequent amidation reduction and quaternization gave (2). 2 lmidazole Alkaloids A review of imidazole alkaloids covering the period 1953-1982 has been published.The aerial parts of Nitraria sibirica con-tain nitrabirine3 [5',6'-dihydrospiro(cyclohexane-1,8'-7'H-imidazo[ 1,2-a]pyridine)-2-01] (3). A new sulphur-containing amino acid has been obtained from the aqueous extract of unfertilized eggs of the sea urchin Paracentrotus lividus; this compound is novel4 in that the thiol group is to be found at position 5 on the histidine ring (4). Its dimer the disulphide was also present in the extract. CHz NMe (1) (2) 1-PhCONHCH(CH2Ph) C02CH2CH(CH2Ph 1 NHCOPh R10@CHCH2NHCOCH=CHPh -R* I (6) M e 0 CHzCHNHCOC H=C HPh (6a) 3 Peptide Alkaloids Asjanin (5) was obtained from the acetone extract of Aspergillus janus and its structure confirmed5 by a synthesis involving condensation of N-benzoyl-L-phenylalaninewith N-benzoyl-L- phenylalaninol in the presence of 2-chloro-1 -methylpyridinium bromide.The dried leaves of the Indian plant Aegle marmelos have yielded the four new aegeline-type alkaloids (6; R1 = CH,CH=CMe2 R2 = H) (6; R1= CH,CH=CMe2 R2 = OH) (6; R1= H R2 = OH) and (6a). A purple compound was also isolated but not identified.6 The structure of sylvamide (7) has been confirmed by total synthesis,' the ( )-erythro stereochemistry being obtained by selective epoxidation of the 2,4-diene (8) at its more reactive (A4) site whence mild hydrolysis gave (7). X-Ray crystallo- graphy and synthesis [by condensation of (E)-3,4,5-trimethoxy-cinnamic anhydride with 5,6-dihydro-2( 1H)-pyridone] have confirmed (9) as the structure for piplartine.8 A new inhibitor of leucine amin~peptidase,~ produced by Bacillus circulans has structure (10).Tabtoxin (12) which is the exotoxin of Pseudomonas tabaci has been synthesized stereospecifically' O through simultaneous formation of the C(2)-C(5) stereoche- mistry via a Diels-Alder reaction of ethyl cyclohexa-l,3- dienecarboxylate with PhCH,C(O)NO to give the bicyclic compound (1 l) which was subsequently converted into (12). A review outlining new approaches to the synthesis of spermine and spermidine alkaloids has appeared' and the same author has described the use of P-lactams in the synthesis of homaline (14).12 The strategy involved an intramolecular SH (7) MeCCH214CH=CHCH= CHCONHBui 4 2 (8) C02Et CO2H Ho&CONHCH(MeICONHCHCH(Me)OH I (10) rn (14) NATURAL PRODUCT REPORTS 1985 Ph n NH N Me2NCHCONH H I R’ R2 (15) (16) (17) OMe Et CH I 0t%;pcHMeEt NH Pri (26) Me 0 (28) ring-opening of the P-lactam [as (13)] to give the NN-demethyl compound.The full paper describing the synthesis of parabac- tin (19 using the thiazolidinethione procedure (cf.ref. 13) has a~peared.~ A novel spermidine alkaloid caesalpinine A obtained from Cuesulpiniu digyna has been characterized by X-ray crystallog- (27) (29) Me0 H raphyI5 and the structure (16) has been proposed. Verbaskine (17) has been found together with (a-cinnamamide in a Bulgarian specimen of Verbascum pseudonobile.16 Two new peptide alkaloids have been obtained from Discaria febri- fuga;” discarine C is (18; R1= R2 = Bui) and discarine D is (18; R1 = Bu’,R2 = CH2Ph).NATURAL PRODUCT REPORTS 1985 -J. R. LEWIS The total synthesis of (+)-verbascenine (19) using the type of imino-ether derivative (20) to couple with 4-phenylazetidin- 2-one has been achievedI8 and the same imino-ether (20) has been used to synthesize (f)-chaenorhine (21) using in this case the diphenyl ether (22).19 A synthesis of dihydromauritine A (23) has been reported.20 The macrocyclic antibiotic M-230B obtained from the gliding bacterium Myxococcus xanthus turns out to be dehydromyxovirescin A (24),21 and a mycotoxin that was obtained from Phomopsis leptostromiformis22 has the novel hexapeptide structure (25).A cyclic peptide that was obtained from a tunicate of the genus Ascidia has some novel features (26) and it also possesses antitumour properties but only sparse patent information is available for this compound.23 An antibiotic A47934 (27) is produced by Streptomyces toyocaen- sis24and a structure for virustomycin A (28) has been proposed based on the comparison of its spectral properties with those of related compound^.^^ A review of the total synthesis and the stereochemical control that is achieved in the synthesis of maytansine has appeared26 and Meyers and co-workers have synthesized maysine (29) by a convergent approach.27 A new and easily available source of maytansine maytanprine and maytanbutine namely May-tenus uariabilis has been found in China.28 4 Miscellaneous Alkaloids The seeds of Brassica elongata contain a number of glucosino- lates; the first to be identified unambiguously was 4-hydroxy-3- methoxybenzylglucosinolate (30; R = 4-OH-3-MeOC6H,) H02C OH %S7 (37) Bz Me0 lsoa and also present are its 4-hydroxybenzyl- and 3,4dimethoxy- benzyl analogues.29 Care must be taken in the extraction process because an endogenous enzyme which is capable of releasing the aglycon as the thiocyanate (31) or as the nitrile (32) (Scheme l) is present.The above-ground parts of Diptychocarpus stri~tus~~ contain diptamine which is N-isopropyl-N'-(7-methylsulphinyl-n-heptyl)urea(33). A phyto- toxin tagetitoxin is produced by Pseudomonas syringae pv.tagelis when it is grown under liquid culture conditions; the toxin has been identified31 as (34). An inoculum from the basidiomycete Leucoagaricus naucina has produced a new antibiotic basidalin (35); it also possesses weak antibacterial and antitumour proper tie^.^^ The use of H-shift-correlated two-dimensional n.m.r. spectroscopy has enabled an assignment to be made for all of the positions of the protons in the chlorinated 1,4-benzoxazin- 3-one that has been found in the young roots of Zea mays; the structure that has been proposed33 is (36). The two novel chromone alkaloids schumannificine (37 ; R = H) and its N-methyl derivative (37; R = Me) have been obtained from the root bark of Schumanniophyton magnlficum.34 A revised structure has been proposed for the bitter substance picroroccellin first isolated in 1877 from the lichen Roccellafucijormis; based on the formal synthesis of the natural product the trans structure (38) has been suggested,35 although the substitution on the nitrogen atoms may be reversed.Several novel compounds have been isolated from the African shrub Ucaria ajzelii; the latest ~yncarpurea,,~ has structure (39). Starting with hydroxyproline the 2-and E-isomers of the antitumour antibiotic tomaymycin (40; R = OMe) have been synthesi~ed,~ and the related antibiotic SEN-215 (40; R = H) has also been synthesized; in this latter case the novel step is the palladium-catalysed carbonylation of (41).38 After several unsuccessful attempts perloline (U),which is the alkaloid that is found in Lolium perenne has been synthesized by a biomimetic route39 starting with the phen- anthridine (42).Its treatment with m-chloroperoxybenzoic acid gave the N-oxide; upon irradiation in ethanol at longer wavelengths this gave dehydroperloline (43) and thence (44). The leaves of Kopsia dasyrachis contain a new type of alkaloid kopsirachine (45); its structure was elucidated by pyrolysis and oxidative cleavage.40 (36) H ,'R Me 0 OAc (41) 248 5 References I M. Chmielewski and P. Guzik Heterocycles 1984 22 7. 2 L. Maat and C. H. Beyerman in ‘The Alkaloids’ ed. A. Brossi Academic Press New York 1983 Vol. 22 p. 281. 3 A. A. Ibragimov Z.Osmanov M. R. Yagudaev and S. Yu. Yunusov Khim. Prir. Soedin. 1983 213 (Chem. Abstr. 1983 99 67 491). 4 A. Palumbo M. d’Ischia G. Misuraca and G. Prota Tetrahedron Lett. 1982 23 3207. 5 R. Nakashima H. Hara Y. Shigemasa N. Uedo Y. Kimura and T. Hamazaki Tottori Daigaku Kogakubu Kenkyu Hokoku 1983,14 179 (Chem. Abstr. 1984 100 188 459). 6 T. R. Govindachari and M. S. Premila Phytochemistry 1983 22 755. 7 A. Banerji and S. C. Pal Phytochemistry 1983 22 1028. 8 P. M. Boll J. Hansen and 0.Simonsen Tetrahedron 1984,40 171. 9 S. Kobaru M. Tsunakawa M. Hanada M. Konishi K. Tomita and H. Kawaguchi J. Antibiot. 1983 36 1396. 10 J. E. Baldwin P. D. Bailey G. Gallacher K. A. Singleton and P. M. Wallace J. Chem. Soc. Chem. Commun..1983 1049. 11 H. H. Wasserman Heterocycles 1984 21 279. 12 H. H. Wasserman and G. D. Berger Tetrahedron 1983 39 2459. 13 J. R. Lewis in ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London 1983 Vol. 13 p. 326. 14 Y. Nagao T. Miyasaka Y. Hagiwara and E. Fujita J. Chem. SOC. Perkin Trans. I 1984 183. 15 S. B. Mahato P. N. Sahu and P. Luger J. Am. Chem. Soc. 1983 105 4441. 16 Z. Koblicova F. Turecek P. Ninova J. Trojanek and K. Blaha Tetrahedron Lett. 1983 24 4381. 17 M. Digel A. Morel H. Layer J. Biermann and W. Voelter Hoppe-Seyler’s 2. Physiol. Chem. 1983 364,1641. 18 H. H. Wasserman and R. P. Robinson Tetrahedron Lett. 1983,24 3669. 19 H. H. Wasserman R. P. Robinson and C. G.Carter J.Am. Chem. Soc. 1983 105 1697. 20 R. F. Nutt K.-M. Chen and M. M. Jouillie J. Org. Chem. 1984 49 1013. NATURAL PRODUCT REPORTS 1985 21 N. Onishi K. Izaki and H. Takahashi J. Antibiot. 1984 37 13. 22 C. C. J. Culvenor P. A. Cockrum J. A. Edgar J. L. Frahn C. P. Gorst-Allman A. J. Jones W. F. 0.Marasas K. E. Murray L. W. Smith P. S. Steyn R. Vleggaar and P. C. Wessels J. Chem. Soc. Chem. Commun. 1983 1259. 23 Suntory Ltd. Jpn. Kokai Tokkyo Koho 59 05 193 [1984 05 1931 (Chem. Abstr. 1984 100 215498). 24 R. L. Hamill and R. E. Kastner Eur. Pat. Appl. 100605 (Chem Abstr. 1984 100 207 871). 25 S. Omura N. Imamura K. Hinotozawa K. Otoguro G. Lukacs R. Faghih R. Tolmann B. H. Arison and J. L. Smith J. Antibiot. 1983 36 1783. 26’ M.Isobe Kagaku (Kyoto) 1983 38 445 (Chem. Abstr. 1983 99 122 091). 27 A. I. Meyers K. A. Babiak A. L. Campbell D. L. Comins M. P. Fleming R. Henning M. Heuschmann J. P. Hudspeth J. M. Kane P. J. Reider D. M. Roland K. Shimizu K. Tomioka and R. D. Walkup J. Am. Chem. SOC. 1983 105 5015. 28 B. Li X.Xu Y. Zhou and L. Huang Zhiwu Xuebao 1983,25 142 (Chem. Abstr. 1983 99 67 532). 29 W. P. Schroeder M. E. Daxenbichler G. F. Spencer D. Weisleder and H. L. Tookey J. Nat. Prod. 1983 46 667. 30 S. F. Aripova and 0.Abdilalimov Khim. Prir. Soedin. 1983 660 (Chem. Abstr. 1984 100 99 891). 31 R. E. Mitchell and P. A. Hart Phytochemistry 1983 22 1425. 32 H. Iinuma H. Nakamura; H. Naganawa T. Masuda S. Takano T. Takeuchi H. Umezawa Y. Iitaka and A.Obayashi J.Antibiot. 1983 36 448. 33 N. Le-Van and S. J. Wratten Tetrahedron Lett. 1984 25 145. 34 J. I. Okogun J. 0.Adeboye and D. A. Okorie Planta Med. 1983 49 95. 35 S. M. Marcuccio and J. A. Elix Tetrahedron Lett. 1983 24 1445. 36 C. D. Hufford B. Oguntimein M. Martin and J. Clardy Tetrahedron Lett. 1984 25 371. 37 Z. Tozuka H. Takasugi and T. Takaya J. Antibiot. 1983,36,376. 38 M. Mori M. Ishikura T. Ikeda and Y. Ban Heterocycles 1984,22 253. 39 T. Duong R. A. Prager and S. T. Were Aust. J. Chem. 1983,36 1431. 40 K. Homberger and M. Hesse Helu. Chim. Acta 1984 67 237.

ISSN:0265-0568    

DOI:10.1039/NP9850200245

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Amaryllidaceae Alkaloids M. F. Grundon Department of Chemistry The University of Ulster at Coleraine Coleraine Co. Londonderry Northern Ireland BT52 7SA Reviewing the literature published between July 1983 and June 1984 (Continuing the coverage of literature in Natural Product Reports 1984 Vol. 1 p. 247) 1 Isolation and Structural Studies 2 Synthesis 3 References Although eight new Amaryllidaceae alkaloids have been identified stereoselective synthesis continues to provide challenging problems and perhaps the greatest achievements of the year are the efficient syntheses of elwesine oxocrinine and lycoramine by the Sinchez group. 1 Isolation and Structural Studies A study of the flower stems and bulbs of Puncrutium blflorum resulted in the isolation of lycorine pseudolycorine pretazet- tine and tazettine and the new alkaloids lycorine-1-0-P-D- glucoside (1) and pseudolycorine- 1-0-P-D-glucoside(4).Enzy-mic hydrolysis of the glucoside (1) gave lycorine and D- glucose and since the IH n.m.r. spectrum of the penta-acetate showed a singlet at 62.10 p.p.m. which is normal for the acetate group at C-2 of lycorine the glucose residue is apparently attached to the hydroxyl group at C-1; this was confirmed by hydrolysis of the permethyl ether followed by acetylation to give compound (2) the n.m.r. spectrum of which showed a singlet at 61.92 p.p.m. (acetate at C-1). The other glucoside (4) was hydrolysed to pseudolycorine (5) and gave a hexa-acetate which was shown from its n.m.r. spectrum to contain an 0-acetyl group at C-2.Further investigation of the alkaloids of Cliviu miniutu (cf ref. 2) furnished another new lycorine alkaloid cliviasindhine which was identified as 1-01-acetyl-2-02-(a-hydroxyethyl)ly-corine (3) by means of i.r. IH n.m.r. and mass spectro~copy.~ A new improved process for the extraction and isolation of lycorine from bulbs of Sternbergiu Zutea has been rep~rted.~ Lactam alkaloids from two species of the genus Crinum were studied during the year. The structure of the new alkaloid narcicrinine (6) which was obtained from Crinum oliganthum was determined by spectroscopic methods especially mass spectr~metry.~ Crinum lutijiolium was shown to contain lycorine and the three alkaloids ambelline hippadine (7),and pratorin- ine (8) that were recently isolated from C.pratense (cf ref. 6a). Two new alkaloids i.e. pratorimine (9) and its 0-methyl ether pratosine (lo) were also obtained from this species and their structures were determined by spectroscopy by the conversion of pratorimine into pratorine with diazomethane and by synthesis (Scheme l).’ A further study of the constituents of C. lutijiolium showed that the amine latisodine (1 l) which was prepared by the reaction of tyramine and veratraldehyde in ethanol and reduction of the resultant Schiffs base with sodium borohydride is present in all parts of the plant during the flowering period ;the glycoside latisoline (1 2) was isolated from the flower stem and on hydrolysis with emulsin it gave latisodine (1 1).8 A new X-ray study of hemanthamine (13) has been published .9 (1) R’= glucosyl R2= H (4)R = glucosyl (Z)R’= Ac,R2= Me (5)R = H Cliviasindhine (3)R1= Ac,RZ= CH (0H)Me OH Me0 HO 0 Narcicrinine (6) (7) nl 0 ii-l iv 0 0 Pratorinine (8) R’= Me,RZ= H Pratosine (10) Pratorimine (91 R1= H,R2= Me Reagents i indoline Et,O; ii H2 Pd/C EtOH; iii NaNO? HzS04 AcOH at -5°C then 100 “C; iv DDQ PhH; v aq.piperidine reflux Scheme 1 OR Q Latisodine (11)R = H Latisoline (12)R =p-o-glucosyl (13) NATURAL PRODUCT REPORTS 1985 OMe U;Methyl-lycorenine (14) I II At-At-wCN,+ (15) I Ill-v [ do] Ar= \/ ICN n n 0 N N/co2cH2Ph \ COZCHzPh CH20H vii 0 J \ \ (16) \CO2CH2Ph / (17) CO 2 CHZPh (18) (Major product) 3-epi-ELwesine(19) R1= OH,R2= H Jxiii Oxocrinine (21 ) Elwesine (20)R1 = H,RL Reagents i MeNO, MeCN Triton B reflux; ii MeOH H,SO,; iii HS(CH,],SH BF,.Et,O CH,CI,; iv LiAlH,-AlCl3 THF then C1CO2CH2Ph Et3N CH,Cl,; v aq.HCHO NaOH dioxane; vi TsOH PhH reflux; vii HgO BF,.Et,O THF; viii MeCOCH=CH2 DBN THF; ix NaOEt EtOH reflux; x Me$ BF,-Et,O CHzClz; xi NaBH, MeOH; xii EtO,CN=NCO,Et Ph3P HC02H THF; xiii 53-dibromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, CC14 reflux ;xiv LiBr Li2C03 DMF at 120-125 "C Scheme 2 NATURAL PRODUCT REPORTS. 1985 -M. F. GRUNDON 25 1 0 work a new alkaloid was isolated and shown to be the acetal0- methyl-lycorenine (14) by spectroscopy and by its hydrolysis by acid to produce lycorenine.10 (22) CO Et ‘co Et (23) (24) ‘Me Reagents i AlCl, Et,S CHzClz; ii LiAIH4 MeOCH,CH,OMe at -78 “C then reflux Scheme 3 Br I (25) (+ isomer ) Reagents i aziridine K2C03 PhH; ii Me2C0 reflux iii LiNPr’* THF Scheme 4 R’ 0 (28) In a search for insect antifeedants the constituents of the bulbs of Lycoris radiata were tested against the larvae of the yellow butterfly Eurema hecabe mandarina.The main anti- feedants were a flavan and the three alkaloids demethylhomo- lycorine lycoricidinol and lycoricidine. In the course of this 2 Synthesis Sanchez and co-workers’ have described a highly efficient synthesis of the alkaloids elwesine (20) [30%overall yield in twelve stages from the nitrile (1 5)] 3-epi-elwesine (1 9) and oxocrinine (21) (Scheme 2).Intermediate (16) which was obtained by aromatic amidoalkylation was subjected to Robinson annelation to give the spirocyclic enone (17); removal of the protecting group and intramolecular 1,4-addition occurred in one step to give the ethanophenanthridine derivative (18) which was converted into elwesine (20) oia 3-epi-elwesine (19). Oxocrinine (21) could also be obtained from the spirocyclic enone (1 7). The benzazepine approach was also adapted to a new synthesis of lycoramine (24) (in 22% overall yield from 2,3-dimethoxycinnamonitrile)(Scheme 3) (cf ref. 6b). The dimeth- oxybenzazepine derivative (22) was prepared by a route similar to that employed in the synthesis of the elwesine intermediate [(17) in Scheme 21; specific cleavage of the more hindered methoxy-group at C-6 then led to the tetracyclic compound (23).The bromo-derivative (25) which was an intermediate in earlier syntheses of y-lycorane (26) and a-dihydrocaranone (27) (cf ref. 6c) has now been prepared by Kametani and co-workers using aziridine (Scheme 4). A full account has appeared of Umezawa’s synthesis14 of the lycorine intermediate A2-or-lycoren-7-one (28) (cf. ref. 6d). 3 References 1 S. Ghosal Y. Kumar and S. Singh Phytochemistry 1984,23 1167. 2 M.F. Grundon Nut. Prod. Rep. 1984 1 247. 3 W. Dopke and R. S. Ali 2. Chem. 1984 24 209. 4 A. Evidente I. Iasiello and G. Randazzo Chem. Ind. (London) 1984 348. 5 W. Dopke Z. Trimino I. Spengler and C. Gutierrez Z.Chem. 1984 24 184. 6 M. F. Grundon in ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Royal Society of Chemistry London (a) 1983 Vol. 13 p. 188; (b) 1983 Vol. 13 p. 194; (c) 1981 Vol. 10 p. 137; (d) 1981 Vol. 11 p. 133. 7 S.Ghosal K. S.Saini and A. W. Frahm Phytochemistry 1983,22 2305. 8 S. Ghosal K. S.Saini and V. K. Arora J. Chem. Res. (S) 1983 238. 9 W. H. Watson J. Galby and M.Silva Acta Crystallogr. Sect. C Cryst. Struct. Commun. 1984 40,156. 10 A. Numata T. Takemura H. Ohbayashi T. Katsuno K. Yamamoto K. Sato and S. Kobayashi Chem. Pharm. Bull. 1983 31 2146. 11 I. H. Sanchez F. J. Lbpez J. J. Soria M. I. Larraza and H. J. Flores J. Am. Chem. Soc. 1983 105 7640. 12 I. H. Sanchez J. J. Soria F. J. Lopez M. I. Larraza and H. J. Flores J. Org. Chem. 1984 49 157. 13 H. Higashiyama T. Honda H. Otomasu and T. Kametani Plunta Med. 1983 48 268. 14 B. Umezawa 0. Hoshino S. Sawaki H. Sashida K. Mori Y. Hamada K. Kotera and Y. Iitaka Tetrahedron 1984 40,1783.

ISSN:0265-0568    

DOI:10.1039/NP9850200249

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Camphor A Chiral Starting Material in Natural Product Synthesis T. Money Department of Chemistry University of British Columbia Vancouver Canada V6T 1Y6 1 Introduction 2 C( 10)-Functionalization of Camphor and its Derivatives 3 C(9)-Functionalization of Camphor and its Derivatives 4 C(8)-Functionalization of Camphor and its Derivatives 5 C( 10)-Functionalization of C(9)- and C(8)-Substituted Camphor Derivatives 6 C(5)-Functionalization of Camphor and its Derivatives 6.1 Chemical Methods 6.2 Biological Methods 7 C(3)-Functionalization of Camphor and its Derivatives 7.1 C(3)-Hydrogen Exchange 7.2 C(3)-Monobromination 7.3 C( 3)-Met h ylat ion 7.4 Enol Derivatives of Camphor and their Reactions 8 Ring-cleavage Reactions of Camphor and its Derivatives 8.1 Cleavage of the C(l)-C(2) Bond 8.2 Cleavage of the C(2)-C(3) Bond 8.3 Cleavage of the C(ltC(7) Bond 9 Rearrangement of Camphor and its Derivatives 10 The Use of Derivatives of Camphor in Natural Product Synthesis 11 References 'No substance known to us suffers rearrangement of its parts and undergoes a complete change of type more readily than doescamphor.. .'[H. E. Armstrong and T. M. Lowry J.Chem. SOC.,1902 81 14411 1 Introduction Interest in the chemistry of camphor and its has been continuous throughout the history of natural product chemistry. This interest is largely associated with the fact that (+)-or (-)-camphor is readily available and undergoes a wide variety of transformations which often involve fascinating rearrangement processes.Much of this chemistry has had a considerable impact on theoretical and mechanistic organic chemistry and various compounds that are derived from camphor have been used as key intermediates in organic synthesis. H@ 3 H 4 X (5) X = H (6)X = Br The versatility and importance of camphor as a chiral starting material in the enantiospecific synthesis of natural products is primarily due to the availability of methods for the direct or indirect introduction of functionality at C-3 C-5 C-8 C-9 and C-10 (see Figure 1). Inaddition cleavage of the C(1)- C(2) and C(2)-C(3) bonds in camphor and its derivatives can be accomplished by a variety of methods to provide useful synthetic intermediates.A description of the methods that have been used to functionalize camphor and the use of these derivatives in the synthesis of natural products is provided in this review. 2 C(10)-Functionalization of Camphor and its Derivatives Regiospecific and stereospecific functionalization of camphor at C-10 (which in early literature is described as a-or p-substitution)'-' can be accomplished by sulphonating (+)-camphor (1)697 or (+)-3-endo-bromocamphor (2)899 with sulphuric acid and acetate anhydride. The mechanism' of C( I 0)-sulphonation probably involves Wagner-Meerwein rearrangement of protonated camphor followed by sulphona- tion and regeneration of the camphor framework (cf. Scheme 1). In contrast the direct stereospecific C( 10)-bromination of camphor has not been reported and 10-bromocamphor (8) is normally prepared by thermolysis of camphor-1 0-sulphonyl bromide (7)' 3,14 or less efficiently by brominative rearrange- ment of camphene (9)15 or 1-hydroxycamphene (1 1)16 (Scheme 2).If the mechanism'* that is illustrated in Scheme 1 is operating during C(10)-sulphonation it is conceivable that interception of the intermediate (3) with electrophilic bromine 27 34 5 Figure 1 The numbering system that is used for the camphor molecule in this review @SO3H u (4) Reagents i H2S04 Ac,O; ii SO3 scheme 1 NATURAL PRODUCT REPORTS 1985 Reagents i KOH MeOH; ii PBr,; iii heat in xylene; iv MeCONHBr H30+; v Cr03 H+; vi Br2 HOAc; vii Br2 H2S04-Ac20; viii Zn HOAc Scheme 2 Table 1 Derivatives of camphor that have been synthesized and for which the structure is 25 R References CH2S03H 1-3 6-11 CH2S02Cl 18 19 CH2S02Br 13 14 C(Cl)=S==o CH2S02Me 21 25 32 34 20 CH2SH 11 20 CH2CI 11 13 CH2Br 11 13-17 CH2I 11 CHZOAC 1 22 CHzOH CH ,OCOPh 1 2 23 CH=CH2 24 CH=CHPh 14 CH*D CDZH CD3 C02H (ketopinic acid) 1-3 10 25-28 20 21 30 31 33 CH2S02H 11 Br 27 33 CHO 1 C H 2 COZH 1 29 CH2S02N MePh 19 could lead to the direct formation of 10-bromocamphor.As a result of this speculation 3,3-dibromocamphor (1 2)* was treated with bromine (3 moles) in acetic anhydride-sulphuric acid (2:1) followed by selective debromination (by zinc and acetic acid) and a low yield (-10%) of 10-bromocamphor (8) was obtained.I7 It is probable that further work on this approach could lead to a viable synthesis of this compound.Camphor-10-sulphonic acid is the synthetic precursor of a great variety of C(10)-derivatives of camphor and these are listed in Table 1. 3 C(9)-Functionalization of Camphor and its Derivatives Regiospecific sulphonation of (+)-camphor (1) at C-97 is a well-known reaction which can be accomplished by using The useof camphor or 3-endo-bromocamphor under these conditions resulted in C(3)-bromination and a minor amount of C(10)-bromination. t In the literature this is often described as the n position. The term was used originally36b to describe chlore or bromo-camphor that was produced by thermal decomposition ('pyrogenic formation') of the corresponding camphorsulphonyl halide (subsequently named camphor-n-sulphonyl bromide or chloride).SO3H I Jo3" Iii so3w I Br Br (2) (14) Reagents i ClS03H or HZS04-S03;ii Br2 HOAc; iii Zn NH3 Scheme 3 chlorosulphonic acid or fuming sulphuric acid as However the product of these reactions is a mixture of (+)-and (-)-camphor-9-sulphonic acid [(13a) and (13b)] and this diminishes their synthetic potential. Fortunately this problem can be solved in a simple fashion by using (+)-3-endo- bromocamphor (2) [which is obtained by treating (+)-camphor with bromine in acetic acid4'] in the sulphonation reac-ti~n.~'-~O The product 3-endo-bromocamphor-9-sulphonic acid (14) is debrominated to provide (+)-camphor-9-sulphonic acid (1 3a) with the same absolute configuration as the original (+)-camphor (1) (Scheme 3).Probable mechanisms' 2*42-43 for the production of partially racemic camphor-9-sulphonic acid (1 3a 13b) from (+)-camphor (1) and of (+)-3-endo-bromocam-phor-9-sulphonic acid (14) from (+)-3-endo-bromocamphor (2) are shown in Scheme 4. In essence these mechanisms involve Wagner-Meerwein rearrangement of camphor followed by a NATURAL PRODUCT REPORTS. 1985 -T. MONEY 255 x (1) X 3; H I x \Y v (13a) X = H Y = SO3H 18) 17) (21) (14) X=Br,Y =SO3H (19a) X=H,Y = Br I2,6 -ti 1 (20) X=Y=Br I Y (13b) X = H,Y = S03H (25) X = Br Y = SO3H (19b) X = H Y = Br (26) X=Y=Br [W M = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl .shift; 2,6-H = 2,b-hydride shift] Scheme 4 Nametkin shift of the exo-methyl group to produce an intermediate (16) which can follow two pathways [(A) and (B)].In the shorter pathway (A) sulphonation of (16) followed by reversal of the rearrangement processes that are outlined above provides (+)-camphor-9-sulphonic acid (13a) having the same absolute configuration as that of the original camphor. Alternatively intermediate (1 7) can undergo Wag- ner-Meerwein rearrangement 2,6-hydride shift and Wagner- Meerwein rearrangement [pathway (B)] to provide the enantio- meric intermediate (23) and hence (-)-camphor-9-sulphonic acid (13b). Evidence for this mechanistic scheme was obtained when [8-14C]camphor (1; A = 14C) was used in the sulphonation reaction.43 The results that were obtained were consistent with the mechanism that is outlined in Scheme 4 i.e.the methyl groups C-8 and C-10 were interchanged while the methyl group C-9 was transformed into the methylenesul- phony1 group. When (+)-3-endo-bromocamphor (2) is used as substrate the operation of the alternative pathways (A) and (B) that are shown in Scheme 4 would involve structurally different intermediates and result in the formation of (+)-3-endo-bromocamphor-9-sulphonic acid (14) (which is the actual product of the reaction) and 6-endo-bromocamphor-9-sul-phonic acid (25) with a configuration that is enantiomeric to that of the original camphor. The absence of the latter compound in the reaction product indicates that only the shorter pathway (A) is operating when 3-endo-bromocamphor is used in the sulphonation reaction.Appropriate modification of the conditions for C(9)-sulphonation has led to pro~edures~~,~~,~~ for the stereospecific bromination of camphor at C-9.$ Thus treatment of (+)-camphor (1) with bromine and chlorosulphonic acid provides a mixture of (+)-9-bromocamphor (19a) and (-)-9-bromocam- phor (19b) while similar treatment of (+)-3-endo-bromocam-phor (2) provides (+)-3-endo,9-dibromocamphor (20) and a small amount of (+)-3-endo,9,9-tribromocamphor(27)47-48 (Scheme 5). Selective removal (by zinc and acetic acid or by zinc and hydrobromic acid) of the bromine substituent at C-3 converts (+)-3-endo,9-dibromocamphor (20) into optically pure (+)-9-bromocamphor (19a).The mechani~m~~,~'.~~ of C(9)-bromination of (+)-camphor (1) and of (+)-3-endo-bromocamphor (2) is similar to that which has been pro- posed' 2,42.43 for the corresponding sulphonation processes (see Scheme 4) with the distinguishing feature being the reaction of the intermediates (16; X = H) and (16; X = Br) with bromine rather than with sulphur trioxide (or its equivalent). Although the formation of (-)-6-endo,9-dibromocamphor(26) from (+)-3-endo-bromocamphor (2) by the operation of path (B) in Scheme 4 is not observed in the bromination process the acid- catalysed (H2S04 or C1SO3H) rearrangement of (+)-3-endo,9-dibromocamphor (20) to ( -)-6-endo,9-dibromocamphor(26) 1Early literature reports'12 describing n-substituted camphor derivatives can give the impression that these compounds have their substituents in the C(8) position.More recent reports36te.43.45b.45c have clearly established that the n-substituted camphor derivatives that were obtained by the well-known sulphonation and bromination processes that are described in this Section have their functional groups (S03Hand Br) at C-9. The structure that was assigned to x-substituted compounds in the early literature'.2 should therefore be regarded with caution. As far as we are aware the only method that is available for the direct functionalization of the methyl group C-8 was developed recently by Money and ~o-workers.~~.~~ (cf. p. 257). NATURAL PRODUCT REPORTS 1985 er Bt R Br Br (2) (10) (27) Reagents i Bt2 CIS0,H; ii Brz HOAc; iii Zn HBr or Zn HOAc Scheme 5 (28a) Ccf.(17) in Scheme k] Br Br ABr (27) (28d) j Scheme 6 has been rep~rted.~~*~~*~~ (cf. p. 275). It has recently been shown 224b that this rearrangement can also be accomplished in -55% yield when 3-endo,9-dibromocamphor is heated in chlorosulphonic acid for 1 hour at 50 "C. As shown in Scheme 4 this transformation presumably involves the reversal of path (A) followed by the sequence of rearrangements that is embodied in path (B) (cf. also p. 275 and Scheme 31 Confirmation for the mechanism of bromination at C-9 that is shown in Scheme 4 has been obtained by using 8-deuteriocamphor (1; A = 2H) (see Scheme 4) and 3-endo- bromo-8-deuteriocamphor (2; A = 2H) in the bromination reaction.49 The former compound provided (+)-9-bromocam-phor (19a) and (-)-9-bromocamphor (19b) in which deuterium atoms were located at C-8 and at C-10 respectively while (2; A = 2H) provided (+)-3-endo,9-dibromocamphor (20) with deuterium located only at C-8.(+)-3-endo,9,9-Tribromocam-phor (27) is probably formed by further bromination of the intermediate (28b) (Scheme 6) followed by reversion to the camphor framework. 9-Bromocamphor (19) and 3-endo,9-dibromocamphor (20) can also be prepared in high yield by thermal decomposition of camphor-9-sulphonyl bromide and 3- endo-bromocamphor-9-sulphonyl bromide [cf. (14)], respec ti vely . 9 6*43 9 9 According to the mechanistic proposals that are shown in Scheme 4 the presence of an endo-bromo-substituent at C-3 in camphor ensures that C(9)-sulp hona tion and C(9)- bromination provides 3,9-disubstituted derivatives with retention of confi- guration.However it seems reasonable to suggest that other endo-substituents at C-3 would produce a similar result [the assumptions being (a) that the reactivity of the camphor derivative is not drastically reduced by the substituent and (b) that the 3-end0 configuration is stable under the reaction conditions for example 3-endo-bromocamphor is much more readily brominated than camphor and is also much more stable than its 3-exo-isomer]; consistent with this proposal is the observation that bromination (by Br2 and C1SO3H for 48 hours) of 3-endo-methylcamphor (33) (Scheme 4) provides (+)-9-bromo-3-endo-methylcamphor(34) in 50% yield.5 3-endo-Methylcamphor (33) is prepared by methylation (by LiNPrj and MeI at 0 "C) of camphor (see p.266 and Scheme 23) followed by equilibration (by NaOMe and MeOH) of the mixture (4 :1) of 3-exo- and 3-endo-methyl isomers [(32) and (33)] that is obtained. The final mixture contains -90% of 3-endo-methylcamphor which is readily isolated by crystallization. A minor isomeric product in the bromination of (33) is (+)-9-bromo-6-endo-meth ylisofenc hone (3 5a),5 and the formation of this compound from 3-endo-methylcamphor (33) or by rearrangement of 9-bromo-3-endo-methylcamphor (34) can be rationalized by the sequence of transformations that is shown in Scheme 7 [cf.path (B) in Scheme 41.Thus intermediate (3Oc) [derived from (33) or from (34)] could undergo 2,bhydride shift and subsequent rearrangement to produce (35a) (Scheme 7). An alternative Wagner-Meerwein rearrangement of intermediate (30c) [cf. (24) Scheme 41 could provide 9-bromo-6-endo- methylcamphor (31) but no evidence was found for the formation of this product. It is interesting to note that 9-bromo- 3-endo-methylcamphor (34) partially rearranges to 9-bromo-6- endo-methylisofenchone (35a) when treated with chloro-sulphonic acid for 8 hours.51 NATURAL PRODUCT REPORTS 1985 -T. MONEY 257 V (341 (35a) R = H (35b) R = Br + [2,3-Me](em) Br Br (294 ( 29 b) (29~1) (30d1 [cf. (17) in Scheme 41 [cf.(iB) in Scheme L] 4*p+@H,&*B& Br Br Br (30d (30b) (30~) (31) [cf.(ZL)in Scheme&] [WM = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl shift; 2,6-H = 2,Ghydride shift] Reagents i LiNPrj THF at 0 "C; ii MeI at 0 "C; iii HCl HOAc heat; iv Br2 CIS03H for 48 hours; v ClS03H for 8 hours Scheme 7 A selection of C(9)-substituted camphor derivatives is listed Table 2 Derivatives of camphor that have been synthesized in Table 2.4 C(8)-Functionalization of Camphor and its and for which the structure is & Derivatives Camphor derivatives in which functional groups are attached to C-846.47.62.64,65 have become much more accessible since stereospecific conversion of 3,3-dibromo- R the rep~rted~~.~~ References camphor (12) into 8-bromocamphor (37)69a that is shown in CHZSO3H 1-4 12 35-40 43 Scheme 8.[However the original authors have been unable to CH2Br 41 44,45 35 36 43 repeat the yield that is quoted in ref. 46 and consistently find CH 2S02Br 21 that 8-bromocamphor (37) can be obtained from 3,3-dibromo- CH 2S02C1 21 camphor (1 2) in -40% overall yield.]$ Previous twelve-step C(CI)=S=o CH~OAC 41a 43 456 53-56 synthetic ro~tes~~,~~ (cf Scheme 9) from camphor to optically CH2OH 1 2 41a 43 45b 53 54 active 8-bromocamphor were based on transformations that C02H (trans-isoketopinic acid) 1 2 21 41a 43 456 53 54 had been reported by various research gro~ps.~~*~~~-~~ 54 55 57 58 Routes CH2I 67 or from CHzCN 45b 55 58 59 to racemic 8-bromocamphor from cy~lopentadiene~~* 8,9,10-trinorcamphoP have also been described (Scheme 10).CHzCOzH 59 An attempted synthesis of 8-bromocamphor by ring-opening of CH2CH2OH 59 has been shown to provide a bicyclo- CH2CH3 3P,8-~yclocamphof'~b 59 [3.3.0]octane derivative.68 CHzOCOPh 60 CH2CH2CH=CMe2 54 It has been s~ggested~~,~~ that the direct C(8)-bromination CH2SH 21 55 process occurs by a mechanism (Scheme 11) which is similar to CH2CH2C02Me 58 that involved in the C(9)-bromination of 3-endo-bromocam- CH2D 19 21 41a 61-63 phor (2) (cf Scheme 4). The crucial difference between the two CHO 1 2 mechanisms is the postulated occurrence of 2,3-endo-methyl CD3 31 41a shifts in the C(8)-bromination reaction and of 2,3-exo-methyl CH2F 55 shifts in the C(9)-bromination reacti~n.~~~~~?~~ CH2N3 Results that are 55 55 consistent with the C(8)-bromination mechanism that is CH2OCOCFj CH20COCMe 55 8 A dibromeketone (62yL6~69band a tetrabromo-ketone (66yL'~~~~ have been CH~SBU' 55 identified as additional products in this reaction; their formation can be CH~SO~BU' 55 explained by the mechanism that is shown in Scheme 12.NATURAL PRODUCT REPORTS 1985 b Br& (19a) X (1) X = H (2) X = Br iv-vii 1;; Br Br I I ... Br (37) (36) liV v vi HO a5 xi;; or xiv (39) . & &-m (43) R = Ts (45) X = Br vii -0 I441 R = COPh (46) X = I 7 Reagents i Br, HOAc; ii Br, CIS0,H; iii Zn HOAc or Zn HBr; iv KOAc HOAc; v KOH EtOH; vi CrO, MnO, H,SO,; vii NaBH,; viii CF,CO,H H2S04; ix LiAlH,; x TsC1 pyridine; xi Reagents i Br,; ii Br, ClS0,H; iii Zn HOAc; iv Mg THF; v PhCOCl pyridine; xii CrO, H2S04 or Cr03 pyridine; xiii PBr, Me3COK Me,COD; vi Me,COK Me,COH; vii Me3COK quinoline PhBr; xiv NaI HMPA or NaI DMSO Me,COH at 250 "C in a sealed tube Scheme 8 Scheme 9 ... 0A:yNi (48) J eOlH (47) (50) (51) CH3 Jvi U (5b) Reagents i Ph,CNa Me]; ii 180 "C; iii KOH EtOH H,O; iv H, Pd/C; v Ph,CNa CO,; vi MeMgBr; vii 85% H2S04; viii LiAlH,; ix CrO, HISO, Me,CO; x PBr, quinoline PhBr; xi TsCl pyridine; xii CrO, pyridine; xiii NaI DMSO Scheme 10 NATURAL PRODUCT REPORTS. 1985 -T. MONEY outlined in Scheme 11 have been obtained by using 3,3- A selection of optically active C(8)-substituted camphor dibromo-8- and -9-deuteriocamphor as substrate^.^^ 8-Bromo-derivatives which have been synthesized from camphor is camphor (37) that was derived from these deuterium-labelled listed in Table 3.precursors had deuterium located at C-8 and C-9 respectively [cf. (60a) and (60b) in Scheme 111. Reductive cyclization of 8-bromocamphor (37) provides 5 C( 10)-Functionalization of C(9)- and C(8)- camphor-y-homoenol (38) (see Scheme 8) in high yield Substituted Camphor Derivatives (-90%).70 This compound can be reconverted into the The reaction of 3-endo,9-dichlorocamphor(67) with fuming camphor system (Scheme 8) and is potentially useful as a sulphuric acid or with bromine in chlorosulphonic acid has precursor of other C(8)-derivatives of camphor. The corre- been reported75 to yield the corresponding 3,9,10-trisubstituted sponding anion (40) has been invoked to explain the exchange camphor derivatives (68) and (69).The synthetic potential of of the protons at C-8 of camphor in strong base.15 8,lO- and 9,lO-disubstituted camphor derivatives in the CWMI C 2,3 -Me 1 Br Br (561 ( 57) (55a) A ='H (55b) A = 'H CWMI L2,3-Mc 3 -Br r Br (59) (58) (60al (60b) [ WM = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl shift] Scheme 11 \Br [2,3-B~] .& [WM] Br + (exo) 4 Br Br Br Br Br (64) (65) (66) [ W M = Wagner-Meerwein rearrangement; 2,3-Br = 2,3-bromine shift] %heme 12 NATURAL PRODUCT REPORTS 1985 Br Br Br I I I Br (70) (71) i ii,iv ( c f. Scheme 8) 8r (72) Br (73) Reagents i Br2; ii Br2 ClS03H for 4 hours; iii Br, CIS03H for 5 days; iv Zn HOAc for 30 minutes at 5 "C; v Br, HOAc Scheme 13 Table 3 Derivatives of camphor that have been synthesized and for which the structure is 23 R References CH2Br 46 54 62 CH2I 54 66 CHZOH CD2OH 1 2 62 71 CHZD CHD2 CD3 31 62 65 CHZOCOPh CD2OCOPh 62 71 CH~OAC 62 71 CHZCN 64,224a CHZCECH 64 CH,C=CCMe,OH 64 CH2COCH=CMe 64 CH2CH2CH=CMe2 (campherenone) 54 224a CH2CH=CHCHMel 64 CH 2C02H 71 CHzCHO 64 C02H (cis-isoketopinic acid) 1 2 43 456 72 CHO 1 2 71 CH(OH)CH2CH=CMe2 71 CH(CN)CH2CH=CMe 73 224a CH (C N )COCH=C Me 73 CH=CH 71 COMe 71 CH 2CH zC02 H 74 CI CI 61 CI (67) (68) X = SO3H (69) X = Br synthesis of terpenoids and steroids has stimulated recent investigation^'^ which have shown that treatment of (+)-3-endo,9-dibromocamphor (20) with bromine in chlorosulphonic acid for 5 days provides (+)-3-endo,9,10-tribromocamphor (70).Selective monodebromination of (70) with zinc and acetic acid produces (+)-9,lO-dibromocamphor (71)51*76 in 50% overall yield (see Scheme 13) although the published76 yield (-60%) for the conversion of 3-endo,9,10-tribromocamphor into 9,lO-dibromocamphor has been increased to 90% by conducting the selective debromination (using Zn HOAc and Et,O) at 0-5°C for 30 minutes. Using identical procedures (+)-3-endo,8-dibromocamphor (72) [derived from (+)-8-bromocamphor (37) by treatment with bromine in acetic acid] can be converted into (+)-8,lO-dibromocamphor (74).52-76 Bromination of (+)-3-endo,9-dibromocamphor(20) and of (+)-3-endo,8-dibromocarnphor(72) at C-10 presumably occurs by a mechanism (Scheme 14) which is similar to that which has been proposed to explain C(10)-sulphonation of camphor (cf.Scheme 1). Thus we can assume that Wagner-Meerwein rearrangement of (20) or (72) provides an intermediate camphene derivative (75a b; X or Y = Br) which can react with bromine and subsequently revert to the camphor framework. It is interesting to note that related investigations have shown that 3-end0 1 0-dibromocamphor and 10-benzoyl- oxy-3-endo-bromocamphor are not readily brominated when treated with bromine in chlorosulphonic acid.77 In these cases the substituent at C-10 may inhibit the formation of carbonium ion intermediates similar to (75a b; X = Y = H)(see Scheme 14) and hence C(9)-bromination does not occur to any significant extent.q Dibromofenchones (76a) and (76b) as shown in Scheme 15 are produced in -10% yield during the C(10)-bromination of 3-endo,9-di bromocamp hor (20) and 3-endo,8-di bromocamphor (72) respectively.It seems reasonable to assume that these fenchone derivatives are produced by a mechanism (double Wagner-Meerwein rearrangement) which is identical to that which has been proposed for the acid-catalysed interconversion of camphor and fenchone (cf. Scheme 35). Recent studies have shown that treatment of 9-bromo-3- endo-methylcamphor (34) with bromine in chlorosulphonic acid does not provide 3-endo-methyl-9 lO-dibromocamph~r.~ Instead acid-catalysed rearrangement as described previously (see p.256 and Scheme 7) provides 9-bromo-6-endo-methyliso-fenchone (35a),52 which undergoes bromination to furnish an additional product syn-7,9dibromo-6-endo-methylisofen-chone (35b) as shown in Scheme 15. The structure of the latter compound although based on excellent n.m.r. evidence has yet to be confirmed by X-ray analysis. Other 8,lO- and 9,lO-disubstituted camphor derivatives (77)-(80) have been synthesized from (71) and (74) as shown in 7 C(10)-Brominationof 8-bromocamphor and of 9-bromocamphor can also be accomplished but these reactions are less efficient and much slower than C(10)- bromination of the corresponding 3-bromoderivatives (20) and (72).'8 NATURAL PRODUCT REPORTS 1985 -T.MONEY 26 1 XY U ti@ Br (2) X tYtH (20) X =H,Y = Br (72) X -Br,Y =H X Y -"Q&Br Br (70) X = H Y = Br (73) X = Br,Y = H Reagents i ClSO,H; ii Br2 Scheme 14 XY X OH Br Br (20) X = H,Y = Br (ma) X = H,Y = Br (72) X = Br,Y= H (76b) X = Br,Y = H Br '& '& (cf. Scheme 7) Br2,CISOjH teBr, + I Br (34) (35a) (35b) Scheme 15 $02Me - 0&Br I-III. ... O&CN ,, o&WMe V vi ,vii 1 Br CN I er Me (79) Reagents:i (CH,OH), H+; ii NaCN DMSO; iii HOAc H20; iv MeOH HCl; v LiNPt2 at 0 "C;vi MeI at 0 "C for 30 minutes; vii HCl HOAc Scbeme 16 Scheme 16 and these compounds are currently being evaluated as intermediates in steroid ~ynthesis.'~ 6 C(5)-Functionalization of Camphor and its Derivatives Direct functionalization of (+)-camphor (l) (-)-bornyl acetate (81) and (+)-isobornyl acetate (82) at C-5 an be accomplished in variable yield by using various chemical or biological techniques.6.1 Chemical Methods Oxidation of (-)-bornyl acetate (81) with CrO and or with CrO, HOAc and Ac2081-86 provides a mixture of 5-oxobornyl acetate (83) [24-40% yield] 6-oxobornyl acetate (84) [5-15% yield] and other minor products86 (Scheme 17). Remote oxidation (i.e. oxidation at a position that is remote from the activating functionality) of (+)-isobornyl acetate (82) with CrO, HOAc and Ac20 provides a mixture of (4 :1) of 5-oxoisobornyl acetate (87) and its 6-0x0-isomer (88) in 55% yield87-90 (Scheme 17).The one-step transformation of (+)-isobornyl acetate (82) into ( -)-5-oxoisobornyl acetate (87) is the most efficient way to prepare this compound and has been NATURAL PRODUCT REPORTS 1985 Remote oxidation of (+)-camphor (1) with CrO and Ac20 provides a low yield (6%) of a mixture containing approximate- ly equal amounts of bornane-2,Sdione (89) and the 2,6-isomer (90)91 (Scheme 17). Although the yield in this oxidation is synthetically useless the process provides authentic samples of bornanediones which assist86 in the identification of the products that are obtained in the remote oxidation of (-)-bornyl acetate (81) and (+)-isobornyl acetate (82).Other indirect routes to C(5)-substituted derivatives of camphor [e.g. (93)-(95)] involve ring-cleavage of 3,5-cyclo- camphanone (91),21*83,92-97 which can readily be prepared from 3-diazocamphor (92) or 3,3-dibromocamphor (12) (cf Scheme 18). 6.2 Biological Methods Administration of (+)-camphor (1) to dogs 98 and to rabbits99 results in the formation of 5-endo-hydroxycamphor (96) and variable amounts of 3-endo-hydroxy- 8-hydroxy- and 9-hydroxy-camphor [(97)-(99); see Scheme 191. Bacterial degra- dation of camphor by strains of Pseudomonasputida100-106 has been shown to involve sequential formation of 5-exo-hydroxy- camphor (100) and the products (89) (96) and (101)-(106) used in various synthetic st~dies~~*~~*~~~~~ (see Table 9).that are formed by enzymic oxidation reduction and 'Baeyer- (83) '&:Ac -t AcO &:Ac &ic+ 1 (84) H (86) + o&:Ac &F0:. (81) (82) (87) (88) (891 " (90) Reagents i CrO, HOAc Ac20; ii CrO, HOAc Scheme 17 (95) (93) (94) Reagents i EtzZn benzene; ii Ag+ THFor Cu; iii HBr; iv AgOAc HOAc; v aluminium amalgam D20 Scheme 18 NATURAL PRODUCT REPORTS 1985 -T. MONEY Villiger’ ring-cleavage of the C( 1)-C(2) and C(4)-C(5) bonds (Scheme 19). Microbiological hydroxylation of (->bornyl acetate (81) by cultures of Helminthosporium satioum (syn. Bipolaris sorokin- iana) provides a mixture of (-)-5-exo-hydroxyborneol (107) (-)-5-endo-hydroxyborneol (1OS) (->6-exo-hydroxyborneol (109) and (-)-3-exo-hydroxyborneol (1 10)lo7 (Scheme 20).The overall yield of diols is -50% and the relative proportion of2,5-,2,6- and 2,3-isomers is 5 :2 :1. When (+>bornyl acetate (1 11) is used as substrate the regiospecificity of hydroxylation increases considerably and the only major products i.e. (+>5-exo-hydroxyborneol (1 12) and its 5-endo-isomer (1 13) are produced in 3545% yield (Scheme 20). Microbiological hydroxylation of (->bornyl acetate (81) by cultures of Fusarium culmorum provides 5-exo-hydroxybornyl acetate (115) as the only major product in 12% yield.lo7 An (96) OH OH (97) + + +o + L& odRl@ R2 R’ H02C C02ti (89) R’ R2=0 (101) R’ = R2= H (1 05) (106) (96) R’ = H R~=OH (102) R’ = OH R2=H (100) R1 = OH R2= H (103) R’= H,R2= OH (104) R’ R2=0 Organism i dog; ii rabbit; iii Pseudomonas putida Scheme 19 OAc OH + Ho&H OH + & (81) R~ (107) R’=OH,R~=H (109) (110) H OH (108) R’= H R2=OH J.‘; H 1115) (113) R’= H R’= OH Organism ; i Helminthosporium sativum ;ii Fusarium culmorum scheme 20 264 almost identical result was obtained when (+)-bornyl acetate (1 11) was used as the substratell (Scheme 20).The ability of cultures of I;.culmorum to hydroxylate bornyl acetate exclusive- ly at C-5 while leaving the acetate group at C-2 intact could be of value in synthetic studies. It has been suggestedlo7 that the remarkable similarity between the regiospecificity of chemical and microbiological functionalization of bornyl acetate and isobornyl acetate is probably due to the greater accessibility of C-5 to interaction with chemical reagents and enzymic systems.7 C(3)-Functionalization of Camphor and its Derivatives Position 3 in camphor (1) displays a degree of reactivity that would normally be expected for active methylene groups and a large number of C(3)-substituted camphor derivatives have been reported1-5 (cf. Tables 4 and 5). However the stereoselec- tivity of many C(3)-monosubstitution reactions has not been clearly established; in the few examples (hydrogen exchange bromination methylation) where this information is available the observed stereoselectivity has not been adequately explained. 7.1 C(3)-Hydrogen Exchange Various investigationslog have established that base-catalysed hydrogen-deuterium exchange in (+)-camphor (1) (see 11 Preliminary studies indicate that I;.culmorum also converts isobornyl acetate into the 5-hydroxy-derivative.108 Table 4 C(3)-Substituted camphor derivatives of structure R& R References D 109 110 NO2 1-3~ NH2 NHR Or NR2 1 3a 144 OH or OAc 1-3~ 98 99 145 146 OSiMe 136 OSiMe2Bu1 126 OOSiMe 136 SO3 H 1 2 SOC,H,Me 145 SiMe 130a c1 1-3~ Br 1-5 41 113-115 I 1-3~ N3 1 CN 1-3~ Me 1 2 117-119 147 Et 1 2 144 R'CH2 R2CH PhCH2 or PhCHR 1 2 COMe or COPh 1 2 COBu' 148 CH2COMe 1 2 CH2CO2R 1 2 C(OH)Me2 131 CH 2N Me2 1 2 135 144 CH2CH2NMe2 144 COR (R = alkyl) 1 CS2H 1 C02Me C02Et C02H 1-3 COCO2Et 1 CH2CH2CMe (exo and endo) 229g COCF3 237 NATURAL PRODUCT REPORTS 1985 Scheme 21) and in other rigid bicyclic ketones (121)-(126) involves exclusive removal of the 3-exo-hydrogen and exo- protonation of the intermediate enolate ion (cf.Scheme 21). In addition debromination of 3-endo-bromocamphor (2) also involves exclusive exo-protonation of the intermediate enolate system' lo (cf. Scheme 21). Although explanations that are based on stericlll and torsional11z effects have been proposed to account for the exo-selectivity of enolization and enolate (enol) protonation of bicyclo[2.2.l]heptan-2-onederivatives a c'onsiderable amount of experimental effort has provided resultslogb-f which are not consistent with these explanations. 7.2 C(3)-Monobromination Treatment of (+)-camphor (1) with bromine in acetic acid,41 ethanol -3 or provides 3-endo-bromocamphor (2) as the major product (-92%) (Scheme 22).This is also the most stable derivative since treatment with a base (NaOMe or KOBu') does not change the relative proportions of C(3)- epimers ([endo]:[exo] = 92 :8).** Bromination of camphor (1) with pyridinium bromide perbromidett or of camphor enol ** This ratio was estimated from values of optical rotation. A value of 55 :45 calculated from n.m.r. data has also been reported." Treatment of 3-edo-bromocamphor with NaOMe in MeOH for 24 hours under reflux has yielded a mixture (92 :8) whose composition was determined from the 400MHz n.m.r. spectrum. tt In contrast kinetic C(3>bromination of 8,9,1@trinorcamphor (1 24) (Scheme 22) with this reagent produces a mixture (95 :5) of 3-exo-bromo-8,9,10-trinorcamphor (1 33) and 3-endo-bromo-8,9,10-trinorcamphor(134) which on treatment with base (KOBu') is converted into an equimolar mixture.116 .Table 5 C(3)-Substituted camphor derivatives of structure R References D&D 45 149 N2 1-3~ 96 150 152 0 1-3 41~ 153 F&F 150 Br & F 1-3 46 47 95 155 NNH2 1 2 NOH 1-3~ 157 CHOH 1-3~ CHOMe 1 61a CHCl 1 CHSH 1 CHR CHPh or CH2 1-3 CHCOMe 1 CHC02Me 1 154 CH[CH2],C02Me(n = 1 or 2) 1 CHCH~BU' 229g C( Ph)C02 H 1 C02Me & CH2C02Me 1 CPh2 151 CH2 154 Me & Me 1 2 147 Me & Br 115 CH & CD 119 Me & OH 1 61 CHO & CHZCH--CHz 154 CHO & CH2CH2CH3 154 alkyl & OH 1 Ph & OH 1 PhCH2 & OH 1 OH & CH2N02 1 -OCH2CH2+ 61 156 OEt & OEt 1 -CH 2CH 2-238 NATURAL PRODUCT REPORTS 1985 -T.MONEY D (118) D (119) Br (120) Reagents i D20 DO-; ii BuLi; iii CD,CO,D; iv EtOD EtO-; v HzO HO-; vi HOAc; vii Zn DOAc; viii Zn HOAc Scheme 21 o& i wiii + ii iv or v T\ Vi Me3si0& -fi + Br & i or iii Me Me C( 32) + (3313 Br (129) Me (130) Me (34) Br (131) Me (132) (124) Reagents:i Br2 HOAc; ii NaOMe MeOH; iii C5H,NHBr3 HOAc; iv KOBu' HOBu'; v HCl HOAc heat; vi Br2 dioxane-pyridine Scheme 22 trimethylsilyl ether (128) with bromine in dioxane-pyridine leads to approximately equal amounts of 3-exo-bromocamphor (1 27) and 3-endo-bromocamphor (2).Subsequent equilibra- tion of this mixture with base (NaOMe in MeOH) provides the thermodynamic mixture ([endo]:[exo] = 92 :8). In contrast bromination of 3-exo-methylcamphor (32) and its epimer (33) with bromine in acetic acid or with pyridinium bromide perbromide in acetic acid occurs with endo stereoselectivity and the product is a mixture (-4:1) of 3-endo-bromo-3-exo-methylcamphor(1 29) and its epimer (1 30). A similar result is obtained when 9-bromo-3-endo-methyl- camphor (34) is brominated with these reagents.l15 7.3 C(3)-Methylation The literature' -3 indicates that C(3)-monomethylation of camphor is readily accomplished but the stereochemistry of the methyl group that is introduced has not been clearly established.1-3 I 7 * Recent investigations however have shown that sequential treatment of (+)-camphor (1) in THF with lithium di-isopropylamide (1 mole equivalent) and with methyl iodide (excess) at 0 "C provides a product (-75% yield) which was shown by n.m.r. (400 MHz) and capillary g.1.c. to be a mixture ( -4 :1) of 3-exo-methylcamphor (32) and 3-endo- vii,vi,ix Br I NATURAL PRODUCT REPORTS 1985 methylcamphor (33)' (Scheme 23). Subsequent treatment of this mixture with NaOMe in MeOH or with HCl and HOAc provides a mixture ( -9 :1) in which the major component is 3- endo-methylcamphor (33). Similarly protonation of 3-methyl- camphor enolate results in the formation of 3-endo-methyl-camphor (33) and a small amount of the 3-exo-methyl epimer (32) ([endo]:[exo] i= 9 :l).51 C(3)-Methylation of (+)-9-bromocamphor (19a) and of (+)-9,lO-dibromocamphor (71) can be accomplished similarly in yields of 80% and SO% respective1y.ll9 In each case n.m.r.(400 MHz) evidence established that the ratio of exo-methyl to endo-methyl epimers was 1.8 :1 (Scheme 23). Subsequent equilibration with acid (HCl and HOAc) provided the corresponding 3-endo-methyl derivatives [(34) and (79)] in -90% yield. In contrast to the results described above C(3)- methylation of the 3-methylcamphors displays endo stereo- selectivity. For example addition of excess CD31 to 3-methylcamphor enolate yields a product whose lH and *H n.m.r. spectra indicate that it is a mixture (3.4 1) of 3-exo-methyl-3-endo-trideuteriomethylcamphor(1 37) and its C(3)- epimer (1 38).Other investigators have reported that 8,9,10-trinorcamphor (124)120 and the 5,6-didehydro-ketones (140a) and (140b)12' undergo kinetic exo-methylation while the related 5,6-didehy- vi ( cf. Scheme 7 1 Br Br I vii-lX 1 0ABr i,;i V+ Me aBr (71) H (136) Me (79) Reagents i LiNPr,' THF-HMPA (20 :1) at 0 "C; ii MeI at 0 "C; iii CD31 at 0 "C; iv NaOMe MeOH heat; v HCI HOAc heat; vi Br, C1SO3H,for 4 hours; vii Br2 HOAc; viii Br2 C1S03H for 6 days; ix Zn HOAc Scheme 23 NATURAL PRODUCT REPORTS 1985 -T. MONEY dro-ketones (142a-e) 121.122 having a syn methyl group at C- 7 undergo exclusive endo-methylation (Scheme 24). In addi- tion it has been reported that 5-oxobornyl methyl ether (143) can be converted exclusively into the corresponding 6-0x0-ally1 derivative.' 23 [Recent investigation^^^^ have shown that kinetic methylation of 5,6-didehydrocamphor also occurs with almost complete endo stereoselectivity.] 7.4 Enol Derivatives of Camphor and their Reactions Consistent with current trends in synthetic methodology camphor has been converted into various enol derivatives (Schemes 25-27).These include the end trimethylsilyl ether (128),l249125 the enol t-butyldimethylsilyl ether (144),l26 the enol triethylsilyl ether (147),' 27 the enol triethylgermyl. ether (148),'*' the enol acetate (146),128 and the enol triflate (145)129 ( t24) (139) H (140a) R = CH3 (14la) H (140b) R = CH2CH20CH2Ph (141 b) (142a) R = CH,OThp (l42b) R CH2CHZCH2OThp (142~)R = CH20CHzPh H&Me0 0 (l42d) R = CHMeOThp Me0 '0 (142e) R =CH3 (143) (Thp = tetrahydropyran -2-yl ) Scheme 24 (145) %"e3si0& (128) +R3si0& Bu'MezSiO (148) Aco& -v;,vii (1461 Reagents i LiNPri DME Tf2NPh (Tf = CF,SO,); ii LiNPri Me,SiCl DME; iii TfOSiMe, benzene; iv MeLi THF Tf2NPh; v LiNPri THF ButMe2SiC1; vi BuLi THF; vii Ac20 at -50°C; viii Br2 HOAc; ix Zn Et20 Me,SiCl; x Hg(SiEt,),; xi Hg(GeEt3)2 Scheme 25 (Scheme 25).In addition the dilithio-dianion (149) and the corresponding disilylated enol ether (150) have been pre- paredI3O from 3-endo-bromocamphor (2) (Scheme 26) and converted respectively into 3-benzylidenecamphor (1 51)130a and a mixture of 3-exo-and 3-endo-trimethylsilylcamphor (152).l 30b The diethylaluminium enolate (1 53)' 31 has recently NATURAL PRODUCT REPORTS 1985 been proposed as an intermediate in the conversion of 3-endo-bromocamphor (2) into the aldol product (1 54) (Scheme 26).A recent reportI3* indicates that the morpholine enamine (156) the pyrrolidine enamine (1 57) and the piperidine enamine (1 58) of camphor can be prepared by treating camphor nitrimine (1 55) with the appropriate cyclic amine (Scheme 27). v;; (153) HO (154) Reagents i LiN(SiMe,),; ii Bu'Li; iii Me,SiCl; iv MeOH; v PhCHO; vi Et,AlCl Zn CuBr THF; vii Me,CO Scheme 26 (155) (157) (158) Reagents i morpholine benzene 5A molecular sieves; ii pyrrolidine benzene 5A molecular sieves; iii piperidine MeCN 5A molecular sieves; iv PhSCH,NMe, HCl EtOH Scheme 27 NATURAL PRODUCT REPORTS 1985 -T.MONEY Ro&-(128) R = SiMe3 ... (144) R = SiMeZBu' fi(Cexol:Cendo3=56:bt) (1611 R =SiMeJBut (162) R = SiMe3 (1141 (1 64) + Reagents i Br2 dioxane pyridine; ii Me,N=CH I- CH2C12;iii .03,CH,CI, MeOH; iv lo2,CCI,; v BH,; vi H,O, HO- Scheme 28 The morpholine enamine (1 56) has also been used to prepare the 3-(phenylthiomethy1)amphor (1 59). 33 Bromination of camphor enol trimethylsilyl ether (128) provides a mixture (1 :1) of 3-endo-bromocamphor (2) and 3- exo-bromocamphor (127) in 90% yield' 34 and similarly alkylation with Eschenmoser's salt yields the Mannich base (160) as a mixture of epimers135 (Scheme 28).Ozonization of the t-butyldimethylsilyl enol ether (144)' 26 or of the enol trimethylsilyl enol ether (128)' 36 does not result in ring- cleavage and the product has been identified as a mixture of 3-exo-and 3-endo-t-butyldimethylsilyloxycamphor(1 61) or the i;; corresponding trimethylsilyloxy-compounds(162) ([endo] :[em] = 56 :a).In contrast the reaction of the enol trimethylsilyl ether (I 28) with singlet oxygen (lo2) provides a mixture (6 :94) of 3-exo- and 3-endo-trimethylsilylperoxycamphor(163)' 36 (Scheme 28). Hydroboration-oxidation of the enol trimethylsilyl ether (128) has been reportedI3' to provide a mixture (-1 :2) of " (167) (166a) R = Me isomerictrans-camphane-2,3-diols(1 14) and (164) (Scheme 28).(166b) R = Et Since it was assumed that hydroboration occurred preferential- Reagents P,S,, diglyme; ii HC(OMe), MeOH HCI H2S; iii, ly on the eQdo face of the enolate system the major product of Me,SO NaH RI (R = Me or Et); iv 03,pyridine-dichloromethane the trans-diol mixture was assigned the 2-exo-3-endo-diol structure (164). However the known stereoselectivity of Scheme 29 reactions involving camphor enolate and camphor enol derivatives coupled with other chemical and n.m.r. evidence has led to the proposal138 that the major product in the above hydroboration-xidation reaction is the known 2-endo-3-exo- diol (1 14) (cf. Scheme 20). Ozonization of the alkenyl sulphides (1 66a) and (1 66b) 39 which were each derived from thiocamphor (165),14* also results in retention of the camphane framework and produces the camphorquinone (1 67) (Scheme 29).Recent reports have described the conversion of camphor hydrazone (1 68) cam-phor tosylhydrazone (1 69) and camphor trisylhydrazone (1 70) into the alkenyl iodide (l7l),l4' the alkenylsilane (172),142 and the alkenyl bromide (1 73),143 respectively (Scheme 30). 8 Ring-cleavage Reactions of Camphor and its Derivatives 8.1 Cleavage of the C(l)-C(2) Bond Cleavage of the C(ltC(2) bond in camphor and in various derivatives has been accomplished by the variety of methods illustrated in Table 6. It is worth noting that Baeyer-Villiger- type cleavage of the C(l)-C(2) bond in camphor also occurs microbiologically (cf. p. 262). NATURAL PRODUCT REPORTS 1985 MeC6H,NHN ..... 11 111 (170) "' (173) Reagents i 12 Bu'N=C(NMe,) or 12 HN=C(NMe2)2; ii BuLi TMEDA; iii Me,SiCl; ivy BusLi THF; v BuI; vi BrCH2CH2Br Scheme 30 Table 6 Cleavage of the C(l)-C(2) bond in camphor and its derivatives Reaction'5MQCO~H,N~OACOf Phs103H References 158 -163 (1) ( 174) (1 75) 164 (1 76) (177) 165 (179a) (179b) McCOCl or TsCI CgHgN or H2SO4 166-170 or hV (1801 Ii CN -,N-OH TsCl C5H5N7 V 58 CN (183) NATURAL PRODUCT REPORTS 1985 -T. MONEY 271 Table 6 Cleavage of the C(l)-C(2) bond in camphor and its derivatives Reaction References 222 (184) 171 -175 CHO (179b) 02N-N zb hJ 171 (186) CN H02C (187a),( 187b) KOH EtOH heat or NaOEt ,EtOH,hcat 178,239 o@Br x ROzC (8) X = H (189a) X = H R = H or Et (188) X = Br (189b) X = Br,R = H or Et NaOMc MeOH 179.232 or KOH,THF H20 ’ y?3 x3 OX f l B rOr KOH DMSO H20 u (701 X = 8r ROzC I (71) X = H (190a) X = Br,R = Me Y = Br (190b) X = H R = Me Y = Br (190~)X = R = H Y I Br (190d) X = R = H Y = OH NATURAL PRODUCT REPORTS 1985 Table 6 Cleavage of the C(l)-C(2) bond in camphor and its derivatives (continued) Reaction References Br 179 R 221 1 I (192a) R = H \CHO (192b) R = CN (193a) R = H (193b) R = CN Table 7 Cleavage of the C(2tC(3) bond in camphor and its derivatives Reaction References HNO3 1 -3~) 1230 180 or HN03,Hg2SO& KOH ButOH 181 CCI 4 CI HC 162 163 182 R HOzC (198) (196) R = CN (1971 R =COz H ~ 1 -3183 ~ NATURAL PRODUCT REPORTS 1985 -T.MONEY Table 7 Cleavage of the C(2)-C(3) bond in camphor and its derivatives Reaction References 0. Ad HO-N w lr2,l8L 185 186 HO-N w (ii) 187 188 189 Br Br 190 8.2 Cleavage of the C(2)-C(3) Bond A summary of the methods that are available for cleavage of the Table 8 Cleavage of the c(1)-c(7) bond in camphor and its C(2)-C(3) bond in camphor and its derivatives is given in Table derivatives 7. Reaction References 8.3 Cleavage of the C(l)-C(7) Bond 191 Cleavage of the C(ltC(7) bond in 9-bromocamphor can be No-K Et2O accomplished in high yield (96%) by using sodium-potassium 61a,191 alloy.lgl Other less efficient processes for cleavage of the C(lt C(7) bond610p192 are also shown in Table 8.(19a) (209) 9 Rearrangement of Camphor and its Deriv-atives wm I Rearrangements*-5*58 93-203 of camphor under acid condi- KOBU~,OMSO ~ "'"m 2 192 tions form the mechanistic basis for those reactions in which camphor is brominated or sulphonated at C-8 C-9 and C-10 (CJ pp. 253-262). In addition (+)-camphor (1) can be racemized in concentrated sulphuric acid ; the mechanism42 (210) that has been proposed (Scheme 31) involving a combination (211) of Wagner-Meerwein rearrangements 2,3-exo-methyl shifts NATURAL PRODUCT REPORTS 1985 &H+- CWMI +C2,3-MeIL CWMI (ex01 ~ Y (212b) Y (213b) (215) X =Y =H (211b) (216) X=Br,Y = H (26) X=Y= Br ( A = 14c or 0 = 2~) [WM = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl shift; 2,6-H = 2,6-hydride shift] Scheme 31 + (refs.198,199) (217a) (21%) oc0ccI3 ( refs.1970,200) (218) Oh-L& ... & (ref. 19%) (219) ' C02Et (ref. 203) C02Et (220) (2 210) Reagents i Tf20 (Tf = CF3S03);ii (Cl3CC0),O; iii PC15 PC13; iv N,CHCO,Et BF3-Et20; v Zn HOAc Scheme 32 NATURAL PRODUCT REPORTS 1985 -T. MONEY and 2,6-hydride shifts is supported by 14C-labelling evi-recently been shown224bthat this rearrangement can be A similar mechanism can be proposed for the accomplished in -55% yield by heating a solution of (+)-3-den~e.~~ conversion of (+)-3-endo,9-dibromocamphor (20) in concen-endo,9-dibromocamphor (20) in chlorosulphonic acid for 1 hour trated sulphuric acid into ( -)-6-endo,9-dibromocamphor at 50"C.An analogous rearrangement (Scheme 31) of (+)-3-(Scheme 31) (cf. p. 256 and Scheme 4). It has endo-bromocamphor (2) to ( -)-6-endo-bromocamphor (216) (26)30~42750 HF SbFg OZb (+I -Camphor (1) v+ "O? I ;i' I (-1 -Camphor ( 215) It O-eL (224) \ (223) Scheme 33 (229) (225) (209) ( cf. Scheme 331 J O&eHO&' Scheme 34 has also been shown to wcur in chlorosulphonic The mechanism (Scheme 3 1) of this transformation is supported by the observation that (+)-3-endo-bromo-lO-deuteriocamphor rearranges in chlorosulphonic acid to (-)-6-endo-bromo-8-deuteriocamphor.During the initial stages of the racemization of camphor (Scheme 3 l) it is assumed that Wagner-Meerwein rearrange- ment produces a protonated 1-hydroxycamphene (21 2a) which undergoes a 2,3-exo-methyl shift to provide a protonated 4- hydroxycamphene intermediate (21 3a). Other investigations have established that camphor can be converted into stable 1- substituted and 4-substituted camphene derivatives197-200~203 (Scheme 32). Camphor also undergoes racemization and rearrangement in the presence of HF-SbFS to provide a mixture of a cyclohexenone derivative (223) and a bicyclo- [2.2.2]octanone derivative (224)lg3 (Scheme 33). Related to this + 1-camphor (1) C 2,6 -hydride shift 3 1 0 Coxidation 1 NATURAL PRODUCT REPORTS 1985 result is the observation that thermolysis of dihydrocarvone (209) produces (+)-camphor (l) toluene and m-xylene2O4 (Scheme 34).It has been suggested that the aromatic products in this reaction are formed from a bi~yclo[2.2.2]octanone intermediate (222) by retro-Diels-Alder reactions. 204 The remarkable oxidative rearrangement of (+)-camphor (1) or (+)-fenchone (23 1) to 3,4-dimethylacetophenone(233) has been studied in detail by the use of 14C-labelled substrates. 94-1 96 Camphor and fenchone are interconverted under these reaction conditions (conc. H2S04) and two complex mechanisms which occur to different extents [Mecha- nism A (90%) is shown in Scheme 35; Mechanism B (10%) is shown in Scheme 361 have been proposed to account for the labelling pattern in 3,4-dimethylacetophenone.195*Ig6 Photolysis of camphor benzenesulphonylhydrazone(234) in methanolic sodium methoxide results in rearrangement to ,& HO I a C76'1.3 / I I T (232) ( 233) (0 ,'kc1 Scheme 35 NATURAL PRODUCT REPORTS 1985 -T. MONEY C2,3-hydride shift 3 1 \ 1 Cox idat ionI (232) 9 (235a) 02 (240) (241) (242) Reagents i hv NaOMe MeOH; ii N,H4,benzene Scheme 37 278 NATURAL PRODUCT REPORTS 1985 (167) 0& (167) 0FF II CO H (249) 0 (248) Reagents i PhMgBr; ii H2S04 Scheme 39 heat SO3H SO3' & -4? I (251a) (251b) [WM = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl shift; 2,6-H = 2,6-hydride shift] Scheme 40 NATURAL PRODUCT REPORTS 1985 -T.MONEY camphene (236),P-pinene (238),and the derivatives (237)and (239)2020*b (cf. Scheme 37). A similar reaction carried out on the cyclic sulphonylhydrazone (241)[which was derived from (+)-camphor-1 0-sulphonyl chloride (240)]-,provides higher yields (-80%) of camphene and P-pinene202' (Scheme 37). Camphorquinone (1 67) undergoes interesting rearrange- ments when treated with strong acid.3a For example in concentrated sulphuric acid the major product is 2,2,3-trimethyl-4-oxocyclohexanecarboxy~c while acid (244)205-209 in fuming sulphuric acid a mixture of this acid (244) and isocamphorquinone(245)is produced205* 209 (Scheme 38). The structure of isocamphorquinone (245)was finally established by careful degradative studies21° and by its synthesis,21 and a which accounts for the formation of these products from a common intermediate (243) is shown in Scheme 38.Related investigations2 have shown that the alcohol (246)(derived from camphorquinone) rearranges to the bicyclic lactone (249)when treated with concentrated sulphuric acid at 0°C (Scheme 39). The unsaturated carboxylic acid (248) which has been proposed212 as an intermediate in this transformation is presumably formed by rearrangement processes (Scheme 39)similar to these described above for the conversion of camphorquinone into the acid (244). Thermal rearrangement of 10-isobornyl sultone (250) which can be derived from (+)-camphor-10-sulphonic acid (S) results in formation of (f)-em-camphene sultone (251 a 251b),2 and the mechanism that has been suggested for this transformation (Scheme 40) is supported indirectly by labelling studies.2 3b Table 9 Natural products and intermediates for natural products that have been synthesized from camphor derivatives From C(10)-derivatives of camphor (4-tizanoic acid 177b (-) -2-epi-Zizanoic acid177u From C(9)-derivatives of camphor HO-(+) -Isoepi~ampherenol~~ (+)-a-Santalene (X = H)2'582'6 (+)-a-Santalo( (x= OH)217-220 (+I -€pi-p-santa~ene~~*~~~ steroid steroid intermediotez2l vitamin 6,+nter med iates Vitamin B12int ermed iate 222 (X = H or CNIz2' From C(9),C( 10)-derivatives of camphor (-1 -Oest rone '79,232 ent-Pseudoguaianolide intermediates 223a [(+I -0estrone from (-)-camphor] steroid intermediate 234 [enantiomers from (-1-camphor I I A California Red Scale pheromone 233 280 NATURAL PRODUCT REPORTS 1985 Table 9 Natural products and intermediates for natural products that have been synthesized from camphor derivatives (continued) From C(8)-derivatives of camphor JzyqcJ OH (-1 -~ampbrenot~~ Y Y (+I-Copacamphor54 Longicamphor intermediates 64g223be224a Vitamin B, intermediate185 From C(5)-derivatives of camphor OH ( +I -Nojigiku alcohol 88 carot en0 id inter med iat e From C(3)-derivatives of camphor or from camphoric acid etc.Vitamin B12intermediates carotenoid intermediatezz5- 227 t erpenoid intermediates 123 f erpenoid intermediates '23 NATURAL PRODUCT REPORTS 1985 -T.MONEY 28 1 10 The Use of Derivatives of Camphor in Natu- products is illustrated by the examples in Table 9. In addition ral Product Synthesis derivatives of (+)-and of (-)-camphor have also been used as chiral auxiliaries in the enantiospecific synthesis of natural The versatility of camphor derivatives in the synthesis of prod~cts.~~*-~~ * Some representative syntheses using a variety natural products and of synthetic intermediates for natural of camphor derivatives are outlined in Schemes 41-51. v,v i I 'Cl (-1 -Khusimone (-1-2-epi-fizanoic acid (R1= H R2= C02H) (+) -2izanoic acid ( R1= C02H,F$= H1 Reagents i KOH heat; ii K2C03 MeI; iii 0,; iv H+ benzene; v H,C==C(OEt), hv;vi H30+; vii butan-2-one ethylene acetal; viii NaOH MeOH; ix NaH; x MeMgBr; xi CH,N,; xii SOCl, pyridine; xiii LiAlH,; xiv POCl, pyridine; xv N,CHCO,Et BF3; xvi NaOH; xvii Me,SOCH,; xviii BF3.Et,0; xix Cr03 Me,CO H+ Scheme 41"' iv 4 (+I -a-Santalem f Reagents i N2H4; ii HgO heat; iii Mg Me2C=CHC02C6H2Me3; iv NaI DMSO; v [Me,C=CHCH,NiBr], DMF Scheme 42 282 NATURAL PRODUCT REPORTS 1985 /vi,vii $ -Yi (+) -a-Santalol Reagents i N,H,; ii HgO heat; iii LiCH2CrCSiMe3; iv AgN03 EtOH; v KCN H,O; vi BuLi; vii CH,O; viii Bu\AlH; ix I,; x MsCl; xi LiBr Et,O; xii NaBH, DMSO; xiii Ni(CO), NaOMe MeOH; xiv LiAlH Scheme 43 H (+I -Epicamphereno ne (+I -lsoepi campherenol (+I-€pi-P-santalene Reagents i NaI HMPA; ii (CH20H), H+; iii [Me,C=CHCH,NiBr], DMF; iv Me,CO HCl; v LiAl(OMe),H THF vi TsCl pyridine Scheme qqS4 CN I CN CN Iviii,ix 5-a x-xii k ~ &A 0 I steroid intermediate Reagents i KI DMF at 110"C; ii NaCH(CO,Me), DMF; iii NH,OH.HCl; iv TsCl pyridine; v CF,C02H CH,Cl,; vi CF3C02H (CF,CO),O; vii KOBu' THF; viii H2C=CHCOMe NEt, MeOH THF; ix Me2C(CH20H), TsOH; x K A1,0,; xi HOAc H,O; xii NaOMe MeOH Scheme 4Sa NATURAL PRODUCT REPORTS 1985 -T.MONEY I i i,v iii,iv I ICNI vi-viii iv -(-) -Campherenone (-1 -eSantalene (+) -Isocampherenol (-1 -Campherenot Reagents i NaI HMPA; ii (CH,OH), H+; iii [Me,C=CHCH,NiBr], DMF; iv Me,CO HCI; v NaCN HMPA; vi LiNPr', THF; vii Me,C=CHCH,Br THF; viii K HMPA Bu'OH; ix LiAIH(OMe), THF; x TsCl pyridine; xi Na propanol Scheme 4654,224a I (-1-Campherenone I (+I-Copacamphor (+I-Ylangocamphor v,v i v,viI I v I (-1 -Copacamphene (-) -Sat ivene Reagents i CIC,H,C03H benzene; ii ButOK Bu'OH; iii SOCI, pyridine; iv H2 Pt; v LiAlH,; vi MeSO,CI pyridine Scheme 4754 284 NATURAL PRODUCT REPORTS 1985 \ii Ace yJ$(4&& OH iv,v oti iii 0 0 1 vi,vii Ho& viii,ix 'OsimzBut I Nojigiku alcohol Reagents i CrO, Ac,O HOAc; ii SeO,; iii Zn HOAc; iv (CH,SH), BF3.Et20; v Raney nickel; vi ButMe2SiC1 imidazole; vii KOH EtOH; viii MsCl pyridine; ix Bu4N+ F-Scheme W8 i-iii (cf.Scheme 13) Br (2) H02C v-vii HO f----o~ viii-xi xii ~ 0 IH H \NMe x iii & xiv 0 ~ __+ H xv,xvi 0 Me0 \ Me0 IH lxvii $.0 00.. xviii,xix (-1 -Oest rone Reagents i Br, C1SO3H for 1 hour; ii Br, C1SO3H for 5 days; iii Zn HOAc Et20 at 0 "C; iv KOH DMSO H20 for 24 hours; v MeLi THF; vi Me3SiC1; vii 1M-HCl; viii pyridinium dichromate CH2C12 at 20 "C for 24 hours; ix 2M-NaOH MeOH at 0 "C for 5 minutes; x MsCl Et,N DMAP; xi DBU; xii (Me2N),CHOBut heat; xiii rn-MeOC,H,CH2MgC1 Et,O; xiv Li NH, Et,O; xv 03,CH2Clz; xvi Me,S; xvii HCl HOAc; xviii H, Pd; xix BBr, CHZCl2 Scheme 49' 79,232 NATURAL PRODUCT REPORTS 1985 -T. MONEY 285 i-iii iv tviii +Me02cw RO v,x,xi RO J (ref.235) (ref. 236) ( R = SiMepBut) J done A California Red Scale Pheromone Reagents i Br, CIS03H for 1 hour; ii Br, ClS03H 5 days; iii Zn HOAc Et,O at 0°C; iv KOH DMSO H20; v LiAlH, THF; vi Bu1Me2SiC1 4dimethylaminopyridine CH2C12 ;vii O, MeOH ;viii Me,S; ix NaOMe MeOH; x pyridinium dichromate CH2C12 ;xi H2C= PPh, THF; xii Bu,N+ F- THF; xiii H,C=C(Me)MgBr THF Scheme i-iii i iv-vi 1 viii,ix 1 (-1 -9-Santalene Reagents i L-Selectride@; ii NaH Bu1CH2Br; iii H30+;iv BrCH2COBr AgCN; v PPh,; vi MeCOCl NEt, CH,Cl,; vii cyclopentadiene TiCl,(OPr), at -20 "C; viii NaBH, Ni(OAc), H,; ix LiNPr, Me2C=CHCH2CH21; x LiAlH,; xi pyridinium chlorochromate CH2C12; xii NtH4 KOH Scheme 51229d 11 References 1 ‘Elsevier’s Encyclopaedia of Organic Chemistry’ Vol.12A ed. E. Josephy and F. Radt Elsevier Amsterdam 1948. 2 J. L. Simonsen and L. N. Owen ‘The Terpenes’ Vol.11 2nd edn.,Cambridge University Press 1949. 3 (a)A. Pelter and S. H. Harper in “Rodd’s Chemistry of Carbon Compounds” Vol. IIc ed. S. Coffey Elsevier Amsterdam 1969 p. 136; (b) R. T. Brown in “Rodd’s Chemistry of Carbon Compounds” Suppl. Vol. IIc ed. M. F. Ansell Elsevier Amsterdam 1974 p. 53. 4 P. de Mayo ‘Mono- and Sesquiterpenoids’ Vol. 11 Interscience New York 1959 p. 132. 5 ‘Terpenoids and Steroids’ ed. K. H. Overton [Vols. 1-61 or J. R. Hanson [Vols. 7-1 21 (Specialist Periodical Reports) Vols. 1-9 and 1 1 12 The Chemical Society/The Royal Society of Chemistry London 1969-1983. 6 A. Reychler Bull. SOC.Chim. Paris 1898 19 120. 7 (a)P. D. Bartlett and L. H. Knox Org. Synth. 1965 45 12; (6) G. R. Brubaker and L. E. Webb J. Am. Chem. Soc.1969 91 7199; (c) C. Couldwell K. Prout D. Robey R. Taylor and F. J. C. Rossotti Acta Crystallogr. Sect. B 1978 34 1491. 8 H. E. Armstrong and T. M. Lowry J. Chem. Soc. 1902,81,1441. 9 W. J. Pope and J. Read J. Chem. Soc. 1914 105 800. 10 E. Wedekind D. Schenk and R. Stusser Ber. Dtsch. Chem. Ges. 1923 56 633. 11 J. 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Thesis University of British Columbia 1980 Vancouver B.C. 24 N. Fischer and G. Opitz Org. Synth. 1968 48 106. 25 M. F. Haslanger and J. Heikes Synthesis 1981 801. 26 P. D. Bartlett and L. H. Knox Org.Synth. 1965 45 55; Org. Synth. Coll. Vol. V 1973 689; J. Am. Chem. Soc. 1939,61 3184. 27 W. C. M. C. Kokke and F. A. Varkevisser J. Org. Chem. 1974 39 1653. 28 T. Polonski J. Chem. Soc. Perkin Trans. I 1983 303. 29 (a)J. P. Bain A. H. Best B. L. Hampton G. A. Hawkins and J. L. Kitchen J. Am. Chem. Soc. 1950 72 3124; (6) W. R. Vaughan J. Wolinsky R. R. Dueltgen S. Grey and F. S. Seichter J. Org. Chem. 1970 35 400. 30 (a)J. D. Connolly and R. McCrindle Chem. Znd. (London) 1965 379; (b)A. Heumann and B. Waegell Nout.. J.Chim. 1977,1,275. 31 D. R. Dimmel and J. Wolinsky J. Org. Chem. 1967 32 410. 32 J. F. King and T. Durst Tetrahedron Lett. 1963 585. 33 W. C. Fong R. Thomas and K. V. Scherer Tetrahedron Lett. 1971 3789. 34 P. A. T. W. Porrskamp R.C. Haltiwanger and B. Zwanenberg Tetrahedron L.ett. 1983 24 2035. 35 F. S. Kipping and W. J. Pope J. Chem. Soc. 1893 63 548. 36 (a)F. S. Kipping and W. J. Pope J. Chem. SOC.,1895,67,354; (6) ibid.,p. 371 ;(c) J. A. Wunderlich Acta Crystallogr. 1967,23,846; (d)W. H. Pirkle R. L. Muntz and I. C. Paul J. Am. Chem. Soc. 1971,93 2817; (e)S. M. Johnson I. C. Paul K. L. Rinehart Jr. and R. Srinivasan ibid. 1968 90,136. 37 W. J. Pope and J. Read J. Chem. SOC.,1910 97 2199. 38 A. W. Ingersoll and S. H. Babcock J. Am. Chem. Soc. 1933,55 541. 39 H. Regler and F. Hein J. Prakt. Chem. 1937 148 1. 40 G. B. Kauffman J. Prukt. Chem. 1966 33 295. 41 (a)W. L. Meyer A. P. Lobo and R. N. McCarty J. Org. Chem. 1967,32,1754; (b)cf. F. H. Allen and D.Rogers J. Chem. SOC.B 1971 632. NATURAL PRODUCT REPORTS 1985 42 T. Miki M. Nishikawa and H. Hagiwara Proc. Jpn. Acad. 1955 31 718 and references cited therein (Chem. Abstr. 1956 50 13 819d). 43 A. M. T. Finch Jr. and W. R. Vaughan J.Am. Chem. SOC.,1969 91 1416. 44 H. Nishimitsu M. 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Roelofs M. Gieselmann A. Carde H. Tashiro D. S. Moreno C. A. Henrick and R. 'J. Anderson J. Chem. Ecol. 1978 4 21 1. 236 W. C. Still and A. Mitra J. Am. Chem. SOC.,1978 100 1927. 237 H. L. Goering J. N. Eikenberry and G. S. Koermer J.Am. Chem. Soc. 1971 93 5913. 238 M. Shimizu and I. Kuwajima J. Org. Chem. 1980 45 2921. 239 In contrast to previous reports,178 it has been shown that treatment of 10-bromocamphor (8) with KOH in DMSO-H20 (10 1) at 65 "Cfor one hour produces the exo-methylene acid ent- (187a) in 77% yield.115 Other conditions (e.g. KOH HzO and THF or NaOMe and MeOH) for cleavage of the ring also produced this compound in 50-65% yield. Similar treatment of (-)-6-endo-bromocamphor (216) produces ent-(187b).240 240 G.Antoniadis J. H. Hutchinson and T. Money unpublished results.

ISSN:0265-0568    

DOI:10.1039/NP9850200253

出版商:RSC    

年代:1985

数据来源: RSC

摘要:

Book Review Natural Products and Drug Development (Proceedings of the Alfred Benzon Symposium 20)ed. P. Krogsgaard-Larsen S. B. Christensen and H. Kofod; 1984;Munksgaard Copenhagen; 559 pp; D. kr. 375.00(US $42.35 f28-10 DM 110.60);ISBN 87- 16-09563-4 This book represents the conference proceedings of the 20th Alfred Benzon Symposium held in Copenhagen Denmark during August 1983. The symposium was attended by thirty- seven invited participants from both academia and industry and some fourteen countries were represented although the USA and the host country accounted for over half of these participants. Virtually all those attending presented papers and a casual glance down the list of speakers which included researchers of such repute as Cassady Djerassi Farnsworth Kutney Nakanishi Rapoport Wagner Wall and Witkop leads one to expect contributions of particularly high quality.After reading the book I was not disappointed and the organizers of the symposium should be congratulated on gathering together such a distinguished group of speakers and turning the conference proceedings into a useful readable and stimulating book. As the editors outline in the preface the object of the symposium was to focus on examples of successful conversion of natural products into therapeutic agents and on areas in this research field at present under development. All aspects of the multidisciplinary approach to the production of new or established drugs via natural products are illustrated in the articles from the screening of organisms for biological activity through structure determination synthetic modifications and on to detailed pharmacological and medicinal chemical investigations.Although many different types of chemicals and activities are covered in the articles and the emphasis given in each reflects the contributor’s own research effort one still acquires a satisfactory overview of the philosophy approach and difficulties associated with transforming a natural product into a useful drug. For convenience the papers are grouped into five main divisions beginning with ‘Terrestial Sources for Active Constituents and Lead Structures’. The eight papers in this section cover materials of plant origin and include several discussions of screening for biologically active compounds especially approaches based on folk-lore usage and traditional herbal medicine.There is continued enthusiasm for the potential of plants as sources of new drugs or lead compounds from these authors but their comments on reluctant attitudes shown by drug manufacturers and the termination of the National Cancer Institute’s plant-screening programme are far from encouraging. The production of anticancer agents via plant cell cultures and applications of genetic engineering restricted at the moment to micro-organisms are further topics discussed which give a little more hope for exploitation of the plant kingdom. ‘Marine Sources for Active Constituents and Lead Struc- tures’ forms the topic for the second section and three papers here illustrate the structural novelty of compounds derived from marine organisms.A fascinating description of the poten- tial wealth the sea offers for biologically active compounds is however marred when one learns that the screening programme described had also been terminated through lack of financial support. The third section focusses on two types of activities ‘Antimicrobial and Antitumour Compounds’. The six papers cover aspects of the screening of micro-organisms and plants for such agents together with more detailed chemical and biochemical investigations of specific materials danomy- cin bleomycin camptothecin and anthracyclines. Eight papers in the fourth section of the book are grouped together under the heading ‘Natural Products as Experimental Tools and Leads in Drug Design’.Emphasis in this section is on the toxic effects of various groups of natural products from plants animals and fungi the study of the toxicity mechan- isms and the possible utilization of this knowledge in the design or modification of drug agents. A wide variety of topics is covered including neurotoxins cardiac glycosides anti hepa- totoxics immunostimulants and antifertility agents the character of the articles moving away from natural products chemistry to medicinal chemistry and pharmacology. The last section contains seven papers covering ‘CNS-Active Natural Products in Drug Development’. These papers describe medicinal chemistry relating to natural products such as opiates ergot alkaloids cannabinoids and Amanita muscaria constituents and structural modifications resulting from these templates.The individual papers in this book range from really fascinating and most readable review articles to a few rather shallow research papers that one expects will be published again elsewhere in greater detail. A miscellany like this is to be expected from any conference and it is a valuable aspect of this book that the more general review treatment predominates and the reader will find a variety of stimulating material. With few exceptions the papers are very well presented (another tribute to the editors) are accompanied by comprehensive reference lists and are surprisingly free of typographical errors. Structural formulae are obviously taken from the presenters’ own diagrams and are thus correct but the quality varies. An unusual aspect of the book is to include the discussions which took place immediately after the presentation. I found this a useful addendum. Certain points raised by the article in the reader’s mind may be clarified by this discussion and it becomes possible to appreciate how various research groups inter-relate with respect to interests approaches and techni- ques. Finally the book contains an extensive subject index and for light relief some poetry from Carl Djerassi. P. M. Dewick

ISSN:0265-0568    

DOI:10.1039/NP9850200291

出版商:RSC    

年代:1985

数据来源: RSC