12 TERPENOIDS AND STEROIDS By A. B. Turner (Department of Chemistry University of Aberdeen Aberdeen AB9 2UE) Biogenetic-type Syntheses. -Chemical simulations of further stages in the build-up and cyclisation of acyclic polyenes are reported this year. The total synthesis of a steroid has been achieved by conversion of the tetraenol (1) into the tetracyclic diene (2) in the presence of trifluoroacetic acid. This transformation which involves the stereospecific formation of five asymmetric centres provides the closest non-enzymic analogy so far for the biological formation of the steroid nucleus. The stereoselectivity of the process is confirmed by oxidative ring-opening of the crude olefin (2) to the triketo-aldehyde (3) followed by double ring closure to ( +)-16-dehydro-progesterone (4) in an overall yield of 29%.[The trisubstituted double bond of the tetraene (1)was introduced by means of a new stereoselective synthesis exemplified by conversion of the alcohol (5) into the trans-olefin (6),in 85% yield using anhydrous zinc bromide.21 In an extension of this type of process cyclisation of the tetraenic acetal (7) with tin (IV) chloride gives the tetracyclic alcohol (8) in 30% yield.3" Both C4 isomers are obtained. A high degree of asymmetric induction attends the cyclisation of the related acetal(9; R = Me) with the same ~atalyst,~' while its optically inactive derivative (9; R = H) is known to give racemic mixtures. Studies in this area of bio-organic chemistry have been re~iewed,~" as have those on the cyclisation of terminal ep~xides.~' Details of the olefinic cyclisations promoted by the generation of allylic carbonium ions have appeared.' ' W.S. Johnson M. F. Semmelhack M. U. S. Sultanbawa and L. A. Dolak J. Amer. Chem. SOC. 1968,90,2994. S. F. Brady M. A. Ilton and W. S. Johnson J. Amer. Chem. SOC. 1968,90,2882. (a)W. S. Johnson K. Wiedhaup S. F. Brady and G. L. Olson J. Amer. Chem. SOC.,1968.90 5277; (b)W. S. Johnson C. A. Harbert and R. D. Stipanovic ihid.. p. 5279. '(a)W. S. Johnson Accounts Chem. Res. 1968 1. 1;(b) E. E. van Tamelen. ibid. p. 111. W. S. Johnson N. P.Jensen J. Hooz and E. J. Leopold J. Amer. Chem. SOC. 1968,90 5872. 0'& A. B. Turner HH IH OCH;CH,OH (9) (7) (8 ) Stereospecific cyclisation of methyl trans,trans-farnesate (10) on cation-exchange resins is reported to give methyl monocyclofarnesate (12; R = Me) and the bicyclic products (13; R = Me) in better yields than those obtained using Lewis acid catalysts.ti Addition of benzoyloxy-radicals to the corres- ponding acetate (11)gives the bicyclic product ( 14).7 This free-radical pathway is also remarkably specific. Monocyclofarnesic acid (12; R = H) gives the rearranged bicyclic acid (15) along with the normal products (13; R = H) on treatment with boron trifluoride.* I (14) (15) The possibility that the interfarnesyl bond of squalene is formed with the aid of a thiol grouping of the enzyme has led to a new understanding of the mechanism and scope of the sigmatropic rearrangements of allylic sulphonium H.Moriyama Y. Sugihara and K. Nakanishi Tetrahedron Letters 1968,2851. ' R. Breslow S. S. Oh and J. T. Groves Tetrahedron Letters 1968 1837. * Y. Kitahara T. Kato and S. Kanno J. Chem. SOC.(C),1968,2397. Terpenoids and Steroids 411 ylides and related compounds. Studies in a number of laboratories have shown that carbon-carbon bond formation occurs readily in these systems under mild condition^.^ The process involves concerted rearrangement of six electrons in a five-membered transition state by virtue of the capacity of the sulphur atom to undergo conversion from the formally quadrivalent into the divalent state The reaction is illustrated by the conversion of the dimethylallylsulphonium fluoroborate (16) into the rearranged sulphide (17) which occurs almost quantitatively at room temperature with a variety of ba~es.'~?~ Conversion of the unsymmetrical diallylsulphonium salt (18) into the rearranged sulphide (19) provides chemical analogy for the enzymic coupling of farnesol as well as a simple procedure for tail-to-tail coupling of allyl units.'O In an alternative method for the coupling reaction benzyne-promoted rearrangement of digeranyl sulphide (20) gives the phenyl sulphides (21) and (23) while geranyl linalyl sulphide (22) gives mainly (21).la Similarly unsymmetrical coupling of geraniol can be achieved by conversion of the sulphide (20) into its ethyl- sulphonium salt which rearranges in the presence of potassium t-butoxide to the ethyl analogue of (23).'lb The transformation (20) -+(23) provides analogy for the biogenesis of skeletal features of artemesia alcohol and bakuchiol.Another convenient method for tail-to-tail coupling of allyl units involves (a)G. M. Blackburn W. D. Ollis J. D. Plackett C. Smith and I. 0.Sutherland Chem. Comm. 1968 186; (6) J. E. Baldwin R. E. Hackler and D. P. Kelly ibid..pp. 537 538; (c)R. B. Bates and D. Feld Tetrahedron Letters 1968 417; (d)B. M. Trost and R. La Rochelle ibid ,p 3327 lo J. E. Baldwin R. E. Hackler and D. P. Kelly J. Amer. Chem. Soc. 1968,90 4758; cf ref. 12. l1 (a) G. M. Blackburn and W. D. Ollis Chem. Comm. 1968 1261; (b)J. E. Baldwin and D. P. Kelly ibid.,p. 899. 412 A. B. Turner the combined action of titanium trichloride and alkyl- or aryl-lithium on ally1 alcohols.This procedure allows reductive coupling of geraniol to the 1,5-diene in good yield.12 Monoterpenoids.-Conflicting results for the addition of maleic anhydride to the allo-ocimenes (24) and (25) are explained by a competing cis-trans- isomerisation which is catalysed by the anhydride. This isomerisation of (24) to (25) occurs with a variety of x-acids. Steric inhibition of the s-cis-form of the triene (24) accounts for the concerted addition-abstraction reaction with azodicarboxylates while addition to the 2,4diene system readily occurs to the s-cis-form of the isomer (25) both with azodicarboxylates and maleic anhydride. In the latter reactions the cis-relationship of the two methyl groups rules out the competing addition-abstraction process.Syntheses of the alcohols (26 and its 2,3-dihydro-derivative) and (_+)-cis-verbenol are reported. l4 These are the principal components of the sex attract- ant produced by the male bark beetle Ips confusus boring in ponderosa pine. The alcohol (27) of a new skeletal type has been isolated from the oil of Arternisiafeddei growing in the suburbs of Hiroshima.' Sensitized photo-oxygenation of methyl homosafranate (28) gives the spiroperoxy-lactone (29) as well as the expected endo-peroxide (30). Further l2 K. B. Sharpless R. P. Hanzlik and E. E. van Tamelen J. Amer. Chem. Soc. 1968,90,209. l3 E. Koerner von Gustorff and J. Leitich Tetrahedron Letters 1968,4689; 4693. l4 C. A. Reece J. 0.Rodin R. G. Brownlee W. G. Duncan and R. M. Silverstein Tetrahedron 1968,24,4249.S. Hayashi. K. Yano. and T. Matsuura. Tetrahedron Letters 1968 6241. Terpenoih and Steroids 41 3 transformations of these intermediates lead to (4)-loliolide and related compounds. Transformations of several types of epoxide have been studied. The ct-hydroxy-epoxide (31) is converted into pinocarvone (32) in basic solution :I7 The a-keto-epoxide pulegone oxide (33) gives the products of ring opening (34) methyl migration (35) and ring enlargement (36) upon treatment with electrophilic catalysts or pyrolysis in the liquid or gas phase.18 The behaviour of a-cyclopropyl epoxides in the presence of acids has been examined using various epoxy~aranes.'~ Opening of the epoxide ring is controlled by the adjacent cyclopropane ring giving the pseudoallylic carbonium ion and the cyclopropane ring itself is then cleaved to give the tertiary carbonium ion e.g.A similar mechanism is probable for the deamination of caran-2- and -5-amines leading to menthadienes and menthenols.20 Concerted processes may operate in these cases as the geometry is favourable. Details of thermal and acid- catalysed rearrangements of (+)-carene,2'" and further work on the stereo- l6 E. Demole and P. Enggist Helv. Chim. Acta 1968 51,481. l7 J. M. Coxon E. Danstead M. P. Hartshorn and K. E. Richards Chem. Comm. 1968 1076. '* W. Reusch D. F. Anderson and C. K. Johnson J. Amer. Chem. SOC.,1968,90,4988. l9 G. Ohloff and W. Giersch Helv. Chim. Acta 1968,51 1328. 2o W. Cocker D. P. Hanna and P.V. R. Shannon Tetrahedron Letters 1968,4217; W. Cocker A. C. Pratt and P. V. R. Shannon J. Chem. SOC.(C),1968,484. (a)W. Cocker D. P. Hanna and P. V. R. Shannon,J. Chem.SOC.(C),1968,489; (b)P. J. Kropp D. C. Heckert and T. J. Flautt Tetrahedron 1968 24 1385; (c) M. S. Carson W. Cocker D. H. Grayson A. C. Pratt and P. V. R. Shannon J. Chem. SOC.(B) 1968 1136. 414 A. B. Turner chemistry of its electrophilic substitution,2 lb have been published The con- formational preferences of the cis-caranols have been deduced using a combina- tion of n.m.r. data relative rates of oxidation and esterification and hydrolysis of their dinitrobenzoates.21c The effect of primary amines on cis-and trans-carbone tribromides shows that a-axial halogeno-ketones can in fact undergo Favorskii rearrangement.22 The importance of solvent polarity in controlling the course of such reactions is again apparent.The natural tropone nezukone (37),has been synthesised by the action of silver fluoroborate on the adduct (38) of dichlorocarbene and the Birch reduc- tion product of 4-i~opropylanisole.~~ The co-occurrence of this tropone with pinenes and thujanes in a Thuja spp. reinforces the suggestion that tropones arise from the latter by ring expansion. The glucoside loganin which is of some importance in the biogenesis of indole alkaloids is present in plants of the Rubiaceae family.24a Loganic acid co-occurs with gentiopicroside in Gentianuceue spp.24b Sesquiterpen0ids.-Identification of substances active in the communicative systems of insects continues.2,3-Dihydro-6-trans-farnesolis the main com- ponent of the marking perfume of male bumble bees.25 The acid (39),containing a degraded sesquiterpene skeleton is secreted during courtship by the male monarch butterfly.26 Its structure has been confirmed by synthesis. 22 J. Wolinsky R. 0.Hutchins and T. W. Gibson J. Org. Chem. 1968,33,407. 23 A. J. Birch and R. Keeton J. Chem. SOC.(C),1968 109. 24 (a)D. S. Bhakuni and R. S. Kapil Experientia 1968,24,1185 ;(b)C. J. Coscia and R. Guarnaccia Chem. Comm. 1968 138. 25 G. Bergstrom B. Kullenberg S. Stallberg-Stenhagen and E. Stenhagen Arkiu Kemi 1968,28 543. J. Meinwald,A. M. Chalmers T. E. Pliske and T. Eisner Tetrahedron Letters 1968,4893. Terpenozds and Steroids 415 Total syntheses are announced of the racemic juvenile hormone (40) responsible for arresting development of Hyalaphora cecropia at the pupa The high yields and stereoselectivity of these make the hormone readily accessible.One ~ynthesis,’~“ which starts from p-methoxytoluene makes use of a number of novel procedures. These include the stereospecific conversion of prop-2-ynyl alcohols into trisubstituted olefinic alcohols using organometallic reagents selective propynylation and a novel conversion of ally1 alcohols into esters under mild conditions by the following sequence :2 -(!d-CO-CN A&-CO,R + HCN The reactions are carried through without isolation of intermediates. The a-and fJ-sinensals which form the flavour constituents of the Chinese orange have been prepared from myrcene.” They exist in the all-trans- configuration being aldehydes derived from D-and a-farnesene respectively.A new three-stage route to abscisic acid (abscissin) is de~cribed.~’ The first stage makes use of t-butyl chromate to oxidise both allylic positions of a-ionone. A stereospecific synthesis of natural (+)-juvabione (41) is reported and the absolute configurations of the two asymmetric centres are established by chemical correlation. 31 The allene (42) forms part of the repellent secretion emitted by grasshoppers when di~turbed.~’ Its structure resembles the end-groups of the recently isolated carotenoid pigments fucoxanthin and neoxanthin. 27 (a)E. J. Corey J. A. Katzenellenbogen N. W.Gilman S. Roman and B. W. Erickson J. Amer. Chem. SOC. 1968,90,5618;(b)W. S. Johnson T. Li D. J. Faulkner and S. F. Campbell ibid. p. 6225; cf R. Zurfliih E. N. Wall J. B. Siddall and J. A. Edwards ibid. p. 6224. ’* E. J. Corey N. W. Gilman and B. E. Ganem J. Amer. Chem. SOC.,1968,90 5616. 29 G. Buchi and H. Wuest Helv. Chim. Acta 1967 50 2440; E. Bertele and P. Schudel ibid. p. 2445; CJ R. Teranishi A. F. Thomson,P. Schudel and G. Buchi Chem. Comm. 1968,928. 30 D. L. Roberts R. A. Heckman B. P. Hege and S. A. Bellin J. Org. Chem. 1968,33 3566. 31 B. A. Pawson H.-C. Cheung S. Gurbaxam and G. Saucy Chem. Comm. 1968 1057. 32 J. Meinwald K. Erikson M. Hartshorn Y. C. Meinwald and T. Eisner Tetrahedron Letters 1968 2959. 416 A. B. Turner 0 GQo (43) (44) (4 7) (48) AcO oc-0 oc- 0 (49) (50) (51) .=\ HO 02) (5 3) (5 4) Chemical support is provided for hypotheses concerning the biogenesis of various classes of bicyclic and tricyclic sesquiterpenes from cyclodecadienes.Photocyclisation of the dienone (43) yields ketones (44) and (45) containing the copaene and bourbonene ring system.33 Whereas cyclisation of the 1,2- epoxide of the germacrane (46) with electrophilic catalysts gives the expected trans-decalin the 5,6-epoxide yields the guaiane (47). 34 The only analogous cyclisation is that of the germacranolide parthenolide which is also a 5,6-epoxide. It is therefore possible that biochemical control of cyclisation to the guaiane ring system is achieved via monoepoxide formation.It is suggested3’ that cis-fused eudesmanes could arise from cyclodeca-l,5-dienes by dehydro- 33 C. H. Heathcock and R. A. Badger Chem. Cornm. 1968 1510. 34 E. D. Brown and J. K. Sutherland Chem. Comm. 1968 1060. ” A. G. Hortmann Tetrahedron Letters 1968 5785. Terpenoich and Steroich 417 genation to the triene (48).Thermal (disrotatory) cyclisation would then lead to the cis-ring-fusion. Another explanation involves cyclisation of alternative conformers of the 1,5-dienes. Furanodiene (49) the likely precursor of many mono- and bi-cyclic sesquiterpenes has been isolated. 36 N.m.r. studies show that the germacranolide dilactone (50) exists in two distinct conformers at room temperat~re.~~ The conformations of the related lactone (51) have been investigated using nuclear Overhauser effects,38 and the absolute configura- tions of derived epoxides have been e~tablished.~~ The essential oil of Hedycarya augustifolia is a rich source of elemol(52) but this compound has now been shown to be an artifact.When the leaves are extracted at room temperature the major product is its precursor hedycaryol (53) and only a trace of elemol is ~btained.~' This confirms earlier doubts about the natural occurrence of some elemanes. By contrast the dilactone vernolepin (54) can be isolated along with the isomeric lactone by hot or cold extraction of Vernonia hymen ole pi^.^' A germacranolid. occurs in the same species.42 More furanoid elemanes are reported,43 as well as their thermal rearrangement through germacranes to cad inane^.^^ The alternative mode of cyclisation to those described above reflects the influence of the carbonyl group in the ten-membered ring and leads to the aromatic structure (55) The structure of eremophilene has been revised to (56) following synthetic in which the stereospecific introduction of the angular methyl group is achieved by the action of lithium dimethyl copper on an ap-unsaturated ketone.This method of reductive methylation originally used by House provides an efficient entry into the vicinal dimethyl system of the eremophilanes 36 H. Hikino K. Agatsuma and T. Takemoto Tetrahedron Letters 1968,931. 37 H. Yoshioka T. J. Mabry and H. E. Miller Chem. Comm. 1968 1679. 38 K. Takeda I. Horibe M. Teraoka and H.Minato Chem. Comm. 1968,940. 39 K. Takeda I. Horibe and H. Minato Chem. Comm. 1968. 1168. 40 R. V. H. Jones and M. D. Sutherland Chem Comm. 1968 1229. 41 S. M. Kupchan R. J. Hemingway D. Werner A. Karim A. T. McPhail and G. A. Sim J. Amer. Chem. SOC.,1968,!MJ 3596. 42 R. Toubiana and A. Gaudemer Tetrahedron Letters 1967 1333. 43 H. Hikino K. Agatsuma and T. Takemoto Tetrahedron Letters 1968 2855; S. Hayashi N. Hayashi and T. Matsuura ibid. p. 2647. 44 H. Hikino K. Agatsuma C. Konno and T. Takemoto Tetrahedron Letters 1968 4417. 45 E. Piers and R. J. Keziere Tetrahedron Letters 1968 583 ;R. M. Coates and J. E. Shaw ibid. p. 405 cf J. Krtpinsky' 0.Mtol L. DolejS L. Novotnf V. Herout and R. B. Bates ibid. p. 3315. 418 A. B. Turner and has also been used in the total synthesis of (+)-nootkatone from 4-acetyl-l- e thox ycycl ohexene.46 P-Gorgonene (57) from Pseudopterogorgia ~rnericana,~~ is an analogue of the intriguing monoterpene sylvestrene.The cyclopropane (58) is a minor component from the same species Sirenin (59) the sperm attractant of the water mould AIlomyces is an isoprene homologue of ~arane.~’ Syntheses of a-and P-agarofurans (a),“’ and routes to various aristolones (e.g. 61),” are reported. Several spirolactones having the bicyclononane structure (62) have been isolated.51 This new skeletal type appears to be biogenetically related to the eremophilanes. Details of the extensive chemical work on anisatin (63)52 and coriamyrtin (64),’ and their hydroxy-derivatives have appeared.Microbiological oxidation has been useds4‘ in the structural elucidation of guaioxide (65) which can be prepared from guaiol by lead tetra-acetate oxidation followed by catalytic hydrogenation. 54b Liguloxide has finally been shown to be 4-epi-g~aioxide.’~ Further natural examples of the rare fulvene system have been found in the guaiane class (e.g. 66).” The total 46 M. Pesaro G. Bozzato and P. Schudel Chem. Comm. 1968 1152. 47 A. J. Weinheimer P. H. Washecheck D. van der Helm and M. B. Hossain Chem. Comm. 1968 1070. 48 W. H. Nutting H. Rapoport and L. Machlis J. Amer. Chem. SOC. 1968,90,6434. 49 H. C. Barrett and G. Buchi J. Amer. Chem. SOC. 1967,89 5665; J. A. Marshall and M. T. Pike J. Org. Chem. 1968 33 435; A. Asselin M.Mongrain and P. Deslongshamps Canud. J. Chem. 1968,46,2817. 50 E. Piers W. de Waal and R. W. Britton Chem Comm. 1968 188; R. M. Coates and J. E. Shaw ibid. p. 515 ; C. Berger M. Franck-Neumann and G. Ourisson Tetrahedron Letters 1968,3451. N. Abe R. Onoda K. Shirahata T. Kato M. C. Woods and Y. Kitahara Tetrahedron Letters 1968,369; N. Abe R. Onoda K. Ro and T. Kurihara ibid. p. 1993; K. Naya I. Takagi M. Hayashi S. Nakamura M. Kobayashi and S. Katsumura Chem. and Ind. 1968 3 18. 52 L. K. Yamada S. Takada S. Nakamura and Y. Hirata Tetrahedron 1968,24,199. 53 T. Okuda and T. Yoshida Chem. and Pharm. Bull. (Japan),1967,15 1687 1697 1955. ’‘ (a) H. Ishii T. Tozyo and H. Minato Chem. Comm. 1968 649; (b)C. Ehret and G. Ourisson Bull. SOC.chim. France 1968,2629 ;(c)H.Ishii,T. Tozyo and H. Minato Chem. Comm. 1968,106,1534. 55 D. J. Bertelli and J. H. Crabtree Tetrahedron 1968 24 2079. Terpenoids and Steroids 419 synthesis of racemic bulnesol is reported. 56 Pseudoguaianolides have been reviewed,57aand syntheticapproaches to the ring system made from ~antonin.~~' Full papers are now available on the structural elucidation of the himacha- lenes and related products.58 P-Himachalene (67) can be converted directly into cuparene (68) in 40% yield by pyroly~is.'~ The high yield is apparently due to the ready formation of a biallylic diradical which recyclises to the easily oxidised dihydro-derivative of (68). However incomplete racemization suggests the partial operation of a concerted mechanism which the authors claim conflicts with theoretical predictions concerning [1,3]-sigmatropic rearrangements in this type of system.A total synthesis of sativene (69) is reported.60a This makes use of a general route to the tricyclic carbon skeleton involving intramolecular alkylation in a cisdecalone a process which is similar to that used to prepare copaene.60b Cyclosativine (70) is related to sativine (69) as longicyclene is to longifolene. Prolonged treatment with copper(@ acetate in refluxing acetic acid gave the same equilibrium mixture from both compounds (69 and 70) indicative of a common carbonium-ion intermediate. 61 The mould metabolite culrnorin (71) is the first longifolene-based product isolated from a micro-organism. 62 Its J. A. Marshall and J.J. Partridge J. Amer. Chem SOC. 1968,90 1090. 57 (a)J. Romo and A. Romo de Vivar Fortschr. Chem. org. Naturstoffe 1967 25 90; (6) J. B. Hendnckson C. Ganter D. Dorman and H. Link Tetrahedron Letters 1968 2235. T. C. Joseph and S. Dev Tetrahedron 1968,24 3809 et seq. '' H. N. Subba Rao N. P. Damodaran and S. Dev Tetrahedron Letters 1968,2213. 6o (a) J. E. McMurry J. Amer. Chem. SOC. 1968 90 6821; (6) cf Ann. Reports 1966 63 447; C. H. Heathcock R. A. Badger and J. W. Patterson J. Amer. Chem. SOC.,1967,89 4133. 61 L. Smedman and E. Zavarin Tetrahedron Letters 1968 3833; J. E. McMurry ibid. 1969 55. 62 D. H. R. Barton and N. H. Werstiuk J. Chem. SOC.(C),1968 148. 420 A. B. Turner structure was established by degradation to tetrahydroeucarvone and con- version into enantio-longiborneol.Its absolute configuration is thus the inverse of that of the plant metabolite longifolene (72). Studies on stable carbonium ions obtained by dissolving longifolene in fluorosulphonic acid reveal that the normal acid-catalysed rearrangement to iso-longifolene (73) is by-passed in favour of other useful intermediate^.^^ At temperatures below -3O" n.m.r. data indicate that the cation (74) is formed both from (72) and (73); quenching with sodium carbonate at this stage gives the diene (75) in high yield. Similar combination of physical and chemical evidence demon- strates the further rearrangement of the carbonium ion (74) into the ions (76) and (77) as the temperature of the fluorosulphonic acid solution rises.The transformation (76) +(77) probably involves spiro-intermediates analogous to those in the dienone-phenol and anthrasteroid rearrangements. I (71) (72) (73) Hydroboration of longifolene (69) followed by oxidation with hydrogen peroxide gives the expected longifolol (78) whereas the isomeric alcohol (80) formed by transannular transfer is also obtained when silver oxide is used as the oxidising agent. 64a Lead tetra-acetate oxidation of longifolol (78) gives the tetrahydrofuran (81) and the longicyclenes (82; R = H and CHO).64b The epimeric alcohol (79) also gives the cyclopropane hydrocarbon but not its aldehyde derivative. Tricyclenes are not produced by oxidation of endo- and em-camphanols with lead tetra-acetate cyclic ethers only being formed.64c 63 D.G. Farnum and G. Mehta Chem. Comm. 1968 1643. 64 J. Lhomme and G. Ourisson (a) Tetrahedron 1968,24 3167; (b) ibid. p. 3177; (c)ibid. p. 3201. Terpenoids and Steroids 421 Details of the structual elucidation of longicyclene (82; R = Me) have been p~blished,~~" and \Ir-longifolic acid is shown to have structure (82; R = C0,H). 65b (78;R = CH,OH R1= H) (80) (81) (82) (79; R = H R1= CH,OH) Tricyclovetivene (83; R = Me) and various oxidised forms (e.g. 83; R = CH,OH and C02H)occur in vetiver oils.66 The revised structure of p-vetivone has been confirmed by synthesis of its ra~emate.~~ A total synthesis of illudin-M (84) is remarkable for the sequence used to protect and expose particular carbonyl groups.68 Michael addition of the fl-keto-sulphoxide (85) to the cyclopentenone (86) gives exclusively the product (87).This adduct undergoes Pummerer rearrangement to the ketone (88) which on heating in ethanol yields a single methyl ketone (89). Base treatment of (89) affords the enedione (go) the new keto-group of which is selectively attacked by methylmagnesium iodide to give an intermediate readily con- vertible to (+)-illudin-M (84). Details of the photochemical syntheses of a-and P-bourbonenes are avail- able,69 and a new route to the a-isomer involves photolysis of 1,6-dienes of type (91)'' Syntheses of isoiresin (92) and dihydroiresin (93) from the ketone (94) have been reported.71 0 + 0 (83) (84) (85 1 (86) 65 (a) V. R. Nayak and S. Dev Tetrahedron 1968 24 4099; (b) G.Mahta V. R. Nayak and S. Dev ibid. p. 4105 c$ ref. 64b. 66 R. Sakuma and A. Yoshikoshi Chem Comm. 1968,41; H. Komae and I. C. Nigam J. Org. Chem. 1968,33 1771; F. Kido H. Uda and A. Yoshikoshi Tetrahedron Letters. 1968 1247; 6099; I. C. Nigam H. Komae G. A. Neville C. Radecka and S. K. Paknikar ibid. p. 2497. 67 J. A. Marshall and P. C. Johnson Chem Comm. 1968,391. 68 T. Matsumoto H. Shirabama A. Ichihara H. Shin S. Kagawa F. Sakan S. Matsumoto and S. Nishida J. Amer. Chem. Soc. 1968 90 3280. 69 J. D. White and D. N. Gupta J. Amer. Chem SOC.,1968,90,6171. 70 M. Brown J. Org. Chem. 1968,33,162. 71 S. W. Pelletier and S. Prabhakar J. Amer. Chem. SOC.,1968,90 5318. 422 A. B. Turner HO HO (90) (91) (92) 0 Ac 0 (93) (94) Diterpenoids.-Re-examination of the acid-catalysed dehydration of various labdadienol progenitors of the mesomeric cation (95)has shown that rosadienes (96) are formed as well as pimaradienes by a process akin to the biogenetic one.72 Hibane derivatives such as the tetracyclic alcohol (97) can also be isolated.This alcohol is thought to arise by coupling at the terminal methylene groups to give the cyclo-octene cation (98) which rearranges uia the cyclo- butane (99) to the bridged alcohol (97). This suggested mechanism is sub- stantiated by solvolysis of a model cyclo-octene tosylate. 72b Ruzicka's hydro- carbon now shown to have structure (lOO) is also obtained in good yield from manool and related compounds under more vigorous conditions.Ozonolysis of cis-abienol(101) gives the alkoxy-hydroperoxide (102'), the cleavage probably being initiated by intramolecular attack of the hydroxy-group on the ozonide linkage.74 Opening of ring B or of rings A and B occurs with concurrent aromatization of ring c when methyl levopimarate is treated with base at 72 (a)0. E. Edwards and R. S. Rosich Canad. J. Chem. 1968,46 1113; (b)E. Wenkert and Z. Kumazawa Chem. Comm. 1968 140; (c)T. McCreadie and K. H. Overton ibid. p. 288. 73 R. M. Carman and N. Dennis Tetrahedron Letters 1968,4127. 7* R. M. Carman and D. E. Cowley Tetrahedron Letters 1968,2723. Terpenoih and Steroih 200°.75 The first synthesis of a member of the trachylobane class (+)-methyl- trachylobanate (103) is described.76 The pentacyclic system is constructed from the major adduct of methyl levopimarate and n-butyl crotonate by successive oxidations and reductions leading to the bridged alcohol (104; R = H). The final stage involves borohydride reduction of the bridged cation from (104),to give directly the enantiomer of the natural acid. Details of the studies on hibaene and related compounds from the trunkwood of E. monogynum have been published. (98) do-oH@‘ HO (102) k7\/ C0,Me (101) (103) Two synthetic approaches to the tanshinones (e.g. 105) have been made. One7 involves condensation of a 2-hydroxy-lY4-naphthaquinonewith a P-chloropropionyl peroxide to give a dihydrofurano-o-quinone which is 75 H. Takeda W. H. Schuller and R. V. Lawrence J. Org.Chem. 1968,33,3718. 76 W. Herz R. N. Mirrington H. Young and Y. Y. Lin J. Org. Chem. 1968,33,4210. 77 R.McCrindle A. Martin and R. D. H. Murray J. Chem. SOC.(C),1968 2349; cf A. Martin and R. D. H. Murray ibid. p. 2529. 78 (a)A. C. Baillie and R. H. Thomson,J. Chem. SOC. (C) 1968,48;(b)H. Kakisawa M. Tateishi and T. Kusumi Tetrahedron Letters 1968 3783. 424 A. B. Turner dehydrogenated with dichlorodicyanobenzoquinone. The other starts from a trimethoxy-a-tetralone. 8b Various new syntheses of ring-c-aromatic diterpenes are reported. Isoxazole annelation has been employed to prepare ferruginol.79 The fact that quaternary salts of isoxazole derivatives are readily converted into acyl phenols makes this a convenient route. A method for constructing the 11,12-dihydroxylated ring c of carnosic acid derivatives makes effective use of P-keto-sulphoxides.80 The sequence can be adapted to produce ferruginol derivatives.In work on podocarpic acid and methyl dehydroabietate,81 the 1,3-diaxial shielding effect of a carbonyl group was useful for distinguishing stereoisomers at (2-4. Taxodione (106) and taxodone (107) are tumour inhibitors isolated from Taxodium distichurn.82a The anti-tumour activity of quinone methides has been noted previously. The extended quinone chromophore of taxodione is similar to that of fuscin but the stability of the quinone methide (107) is remarkable in a fused-ring system. (On treatment with acid it isomerises to dihydrotaxo- dione.) Both molecules possess the stabilizing feature of a hydroxyl group ortho to the 0x0-group and their structures have been confirmed by conversion into 11-methoxyferruginol methyl ether.The natural occurrence of these compounds is of interest in connection with the formation of artifacts derived from carnosic acid.82b Quinone methides analogous to taxodone (107) are likely intermediates in the formation of carnosol rosmaricine and other ferruginoid products isolated from plants of the Labiatae family and the extended quinone methide fuerstion also occurs in this group. 82c (106; X = 0) (105) (107; X = AH --OH) A novel fragmentation occurs on treatment of the totarol derivative (108) with sodium hydrogen carbonate. 83 Elimination of hydrogen bromide involves 79 M. Ohashi T. Maruishi and H.Kakisawa Tetrahedron Letters 1968 719. D. C. Shew and W. L. Meyer Tetrahedron Letters 1968,2693; W. L.Meyer R. W. Huffman I$ and P. G. Schroeder Tetrahedron 1968,24,5959. T. A. Spencer T. D. Weaver R. M. Villafica R. J. Friary J. Posler and M. A. Schwartq J. Org. Chem. 1968,33,712;T.A.Spencer R. J. Friary W. W. Schmiegel J. F. Simeone and D. S. Watt ibid. p. 719. 82 (a) S. M. Kupchan A. Karim and C. Marcks J. Amer. Chem. SOC.,1968,90 5923;c$ Ann. Reports 1965,62,336;(c)D.Karanatsios J. S. Scarpa and C. H. Eugster Helv. Chim. Act6 1966,49 1151. 83 R. C. Cambie and R. T. Gallagher Tetrahedron 1968,24,4631. Terpenoids and Steroids cleavage of the bond common to rings A and B and leads via the quinone methide (109) to the cyclodecanone (110) in 80% yield.This reaction is a modification of the classical method for the preparation of quinone methides and the fragmentation is favoured by the antiperiplanar configuration of the ring-a bonds involved. Inumakilactone (1 11) and related a-pyrones have been isolated from Podocarpus rnacropyllus. 84 Hydroxytotarol which occurs in the same plant may be their biogenetic precursor as catechols are known to yield a-pyrones by oxidative cleavage. The cyclopropanes (112) and (113) are formed along with the ether (114; R = Et) when abietic acid is photolysed in ethan01.’~ When methanol is the solvent only products of type (114; R = Me) are formed. The cyclopropanes could be formed from a bicyclobutane intermediate but the reason for the change to a carbonium-ion mechanism leading to the ether (1 14) in methanol is not clear.Br (10 8) (109) (1 10) 0 H COzH COzH (114) 84 S. Ito M. Kodama M. Sunagawa T. Takahashi H. Imamura and 0.Honda Tetrahedron Letters 1968,2065; Y. Hayashi S. Takahashi H. On& and T. Sakan ibid. p. 2071. 85 J. C. Sircar and G. S. Fisher Tefrahedron Letters 1968,5811. 426 A. B. Turner Total syntheses of (+)-gibberellins A, A, A, and A, have been achieved.86 Conclusion proof of the stereochemistry of atractylogenin has been provided by correlation with kaurenolides of proven stereochemistry at C-9. 87 Details of the chemical work on phorbol are reported.88 Its highly reactive hydroxy- cyclopropyl carbinol system leads to various reactions resulting from cation formation c1 to the cyclopropane ring Several interesting intramolecular oxidations with lead tetra-acetate are also encountered.Sesterterpen0ids.-Acyclic members of this group are reported this year. The alcohols moenocinol (115) and its allylic isomer (116) form the lipid portion of the antibiotic moenomycin. 89a The all-trans-alcohol geranyl nerolidol has been isolated from the fungus responsible for leaf spot disease in maize.89b The same organism also produces the ophiobolin (117) which is of biogenetic interest. 89b Ceroplasteric acid (1 18) and the corresponding alcohol are present in the waxy coating secreted by Ceroplastes alboline~tus.~~ Their structures were determined by X-ray analysis. These are the first of the ophiobolins to be isolated from an insect source.The fungal metabolite (117) F:Hrco2H H... (118) (119) OH 86 K. Mori M. Shiozaki N. Itaya T. Ogawa M. Matsui and Y. Sumiki Tetrahedron Letters 1968 2183; T. Ogawa K. Mori M. Matsui and Y. Sumiki ibid. pp. 125 2551. 87 E. L. Ghisalberti P. R. Jefferies S. Passannanti and F. Piozzi Austral. J. Chem. 1968 21 459; J. R. Hanson and A. F. White Tetrahedron 1968,24,2533. L. Crombie M. L. Games and D. J. Pointer J. Chem. SOC.(C) 1968 1347. 89 (a) R. Tschesche F.-X. Brock and I. Duphorn Tetrahedron Letters 1968 2905; (b)S. Nozoe M. Morisaki K. Fukushima and S. Okuda ibid. p. 4457. 90 Y. Iitaka. I. Watanabe I. T. Harrison and S. Harrison J. Amer. Chem. SOC.,1968 90 1092. Terpenoids and Steroids 427 fusicoccin (119)’ has the ophiobolin ring system.” An intriguing feature of this diterpene is the presence of a fifth isoprene unit attached to the glucose moiety.Triterpenoids.-The stereochemistry of the carbocyclic nucleus of ( +)-malabaricol has been established by correlation with ( +)-ambrein~lide.~~ The related tricyclic alcohol (120) is produced by enzymic cyclisation of 18J9-dihydrosqualene 2,3-0xide.’~” Analogous products were reported last year from the non-enzymic cyclisation of squalene 2,3-oxide but this is the first demonstration that the enzyme can produce structures different from lanosterol. The possibility that lanosterol biosynthesis could proceed via this tricyclic intermediate is discussed. The squalene derivative was obtained by reductive coupling of appropriate ally1 alcohols using a combination of titanium trichloride and alkyl- or aryl-lithi~m.’~~ This is a general synthesis of 1,Sdienes which can be carried out without isolation of intermediates.Limonoid bitter principles have been re~iewed.’~ Details of structural work on the tetranortriterpenoids mexicanolideg5” and grandif~lione’~~ have been published. The parent alcohol of a series of limonoids from the timber of Trichilia heudelotii is shown96a to be 14P,lSP-epoxy-7a,ll p,12a- trihydroxymeliac-1 -en-3-one (121)’ related to hirtin. The nomenclature is based on the 17-furylgonane system (122) of these limonoids for which the name ‘meliacan’ is proposed. Odoratol (123) and related tirucallols are ob- tained from various Cedrela specie^.'^ (120) (121) 91 A.Ballio M. Brufani C. G. Casinovi S. Cerrini W. Fedeli R. Pellicciani B. Santurbano and A. Vaciago Experientia 1968 24 631; K. D. Barrow D. H. R. Barton E. B. Chain C. Conlay T. V. Smale R. Thomas and E. S. Waight Chem. Comm. 1968 1195; K. D. Barrow D. H. R. Barton E. B. Chain U. F. W. Ohnsorge and R. Thomas ibid. p. 1198; E. Hough M. B. Hursthouse S. Neidle and D. Rogers ibid. p. 1197. 92 R. R. Sobti and S. Dev Tetrahedron Letters 1968,2215. 93 (a) E. E. van Tamelen K. B. Sharpless R. Hamlik R. B. Clayton A. L. Burlinghame and P. C. Wszolek J. Amer. Chem. Soc. 1967,89 7150; (b)cf ref. 12. 94 D. L. Dreyer Fortschr. Chem. org. NatwstojJie 1968,26 190. 9s (a) J. D. Connolly R. McCrindle and K. H.Overton Tetrahedron 1968 24 1489 et seq.; (b)J. D. Connolly K. L. Handa R. McCrindle and K. H. Overton J. Chem. SOC.(C) 1968 2227. 96 D. A. Okorie and D. A. H. Taylor J. Chem. SOC.(C) 1968 1828; cf E. K. Adesogan and D. A. H. Taylor ibid. p. 1974. 97 J. D. Connolly K. L. Handa R. McCrindle and K. H. Overton J. Chem. SOC. (C) 1968,2230; W. R. Chan N. L. Holder D. R. Taylor G. Snatzke and H.-W. Fehlhaber ibid. p. 2485. 428 A. B. Turner (122) (123) (124) (12 5) Fusidic and helvolic acids have been correlated using a combination of chemical and microbiological transformation^.^^ Autoxidation of lanostenyl acetate has been re-e~amined.~' The major products are the 7p-and 1lP-hydroperoxides and several minor peroxides are also formed. Further oxida- tion of these primary products has been studied.Cycloartenol has been synthesised from lanosterol. loo Functionalization at C-19 was achieved by photolysis of the 11 p-nitrite in the presence of iodine. The resulting 19-iodo- 11-alcohol was oxidised to the 11-ketone and treatment of this y-iodo-ketone with base gave the 9~,1Oj3-cyclopropyl-l1 -ketone which was finally reduced with lithium aluminium hydride. Actein (124)"' and ambonic acid (125)'02 are related compounds with differing degrees of side-chain oxidation. The (R)-configuration at C-25 of the latter is established by Baeyer-Villiger oxida- tion of the derived 24-ketone and 0.r.d. determinations on the resulting propane-l,2-diol. '02 Factors affecting the reactivity of olefins towards epoxidation are dis-cussed.'03 Euphol or euphorbol can be selectively attacked at the side-chain double bond particularly in ether.A synthesis of P-amyrin has been rep~rted."~ Olean-l2-ene is converted 98 W. von Daehne H. Lorch and W. 0. Godtfredsen Tetrahedron Letters 1968 4843; cf s. Okuda,Y. Sato T. Hattori and M. Wakabayashi ibid. p. 4841. 99 J. Scotney and E. V. Truter J. Chem. SOC.(C) 1968 1911; 2184; 2516. loo D. H. R. Barton D. Kumari P. Welzel L. J. Danks and J. F. McGhie Chem. Comm. 1968 643; J. Chem. SOC.(C) 1969,332. lo' H. Linde Arch. Pharm. 1967,300,982; 1968,301 120. lo' S. Corsano and E. Mincione Chem. Comm. 1968 738. G. Possinet G. Ourisson and G. Charles Bull. SOC.chim. France 1967,4453. Io4 D. H. R. Barton E. F. Lier and J.F. McGhie J. Chem. SOC.(C) 1968 1031. Terpenoids and Steroidr into olean-12-en-1-one by a sequence involving photolysis of its 1la-nitrite and several methods are developed for transformation of the 1 -oxo-compound into the 3-ketone. Acetyl migration between the 16a-and 28-hydroxy-groups of primulagenin A (126) is catalysed by acids and bases.lo5" The rearrangement occurs only when ring D is in the twist-boat form. Similar acetyl migrations reported earlier105b for compounds having an additional 22a-hydroxy-group may not therefore involve prior acetyl migration from the 16a- to the 22a-hydroxy- group. (126) Photo-oxidation of oleanic acid in acid medialo6" leads to the lla,l2a- epoxy-13,28-lactone system of eupteleogenin (127) (127) A similar reaction occurs with the derived alcohol (126; 16deoxy) and the competing reaction in which epoxide formation is accompanied by methyl migration is also observed.106b This latter reaction predominates in the absence of an oxygen function at C-28.'06' Serratenediol derivatives are present as methyl ethers in Sitka spruce.lo' Apetalactone (128) co-occurs in Calophyllurn spp. with canophyllol (129) from which it can be obtained by Baeyer-Villiger oxidation.lo8 It is the first lactone of the friedelin group to be found in Nature. lo' (a)0.D. Hensens and K. G. Lewis Tetrahedron Letters 1968 3213; (b) R. Tschesche B. T. Tjoa and G. Wulff ibid. p. 183; I. Yosioka T. Nishimura N. Watani and I. Kitagawa ibid. 1967 5343. lo6 (a)I. Kitagawa K.Kitazawa and I. Yosioka Tetrahedron Letters 1968 509; (b) ibid. p. 2643; (c) cf Ann. Reports 1965 62 342. lo' J. P. Kutney and I. H. Rogers Tetrahedron Letters 1968,761. T. R. Govindachari. D. Prakash. and N. Viswanathan. J. Chem. SOC.(C). 1968. 1323. 430 A. B. Turner H (128) (129) An intramolecular hydride transfer accompanies base-catalysed epimerisa- tion at C-19 in certain norlupanes:loga A related redox reaction between C-19 and C-3 occurs in the steroid series under ketalization conditions. '09* Rearrangement of 7P-hydroxyhopanes on dehydration with phosphorus pentachloride gives a number of B-nor-c-homohopenes. 'lo In the 7a-isomers dehydration is accompanied by migration of the C-8 methyl group. A series of isoprenoid ketones has been isolated from lipid extracts of human tubercle bacilli,'" The major components have structure (130 n = 6 or 7) with one of the double bonds reduced The minor constituents have n = 2 to 5.Steroids.-Oestrogen synthesis and biosynthesis '' and recent advances in the synthesis of heterocyclic steroids' 12' 'l3 have been reviewed. Synthesis of oestrones by coupling of vinyl carbinols with 2-methyl-cyclopentane-1,3-Io9 (a)A. VystrEil and M. Budesinsky Tetrahedron Letters 1968,4173;(b)J. Wicha and E. Caspi J.Chem. SOC.(C) 1968 1740. R. E. Corbett R. A. J. Smith and H. Young J.Chem. SOC.(C) 1968 1823. L. Coles and N. Polgar J. Chem. SOC.(C) 1968 2376. (a) P. Morand and J. Lyall Chem. Rev. 1968,68 85;(b)L. Starka Chem. listy 1968,62 1220. H.0.Huisman Bull. Soc. chirn. France 1968 13. Terpenoids and Steroids 431 dione is facilitated by use of the intermediate crystalline isothiourorlium salt (131).l14 The resulting dione (132) undergoes selective as well as stereo- specific reduction of the 17-keto-group with lithium tri-t-butoxyaluminium hydride. Bis-annelation of cyclohexanone enamines with 6-vinyl-2-picoline promises to be a useful method for steroid total synthesis."' Further routes to anthrasteroids have been described. l6 18-Hydroxyoestrone has been preparedl l7 from oestrone by a sequence involving photolytic oxidation of the amide (133) with iodine and lead tetra- acetate to the 18,20-anhydride (134). A re-examinationllEa of chromium trioxide oxidations of oestrone methyl ethers shows that 9P-hydroxy-11- ketones are formed as well as the 6-oxoderivatives the latter being the normal oxidation products of 3-acetoxyoestrones.Aerial oxidation of 3-methyl ethers also occurs at C-9 in the presence of soluble catalysts.'lEb Oestrone methyl ether can be obtained by removing the methyl group from its 1-methyl deriva- tive,' l9 thereby providing a new route from 1,4,6-triene-3-ones to 19-nor- steroids. The aromatic methyl group is first oxidised with ceric ammonium nitrate to an aldehyde which is then decarbonylated with tristriphenyl- phosphinerhodium chloride. (131) (132) (13 3) 'I4 C. H. Kuo D. Taub and N. L. Wendler J. Org. Chem. 1968,33,3126. 115 S. Danishefsky and R. Cavanaugh J. Amer. Chem. SOC.,1968,90 520.116 K. Wiedhaup A. J. H. Nollet,J. G. Korsloof and H. 0. Huisman Tetrahedron 1968 24 771; K. Wiedhaup F. H. Kesselaar and H. 0.Huisman ibid. p. 779. J. E. Baldwin D. H. R. Barton I. Dainis and J. L. C. Pereira J. ChPm. SOC.(0,1968,2283. (a) R. C. Cambie and T. D. R. Manning J. Chem. SOC.(C),1968,2603; (b)A. J. Birch and G. S. R. Subba Rao Tetrahedron Letters 1968 2917. '19 S. B. Laing and P. J. Sykes J. Chem. SOC.(C) 1968,2915. 432 A. B. Turner A remarkable dehydrogenation of oestrone to its A9(l')-derivative occurs with the adamantyl carbonium ion.12oo A similar oxidation takes place with dichlorodicyanobenzoquinone.'20b It is likely that both of these reactions involve the quinonoid intermediate (135),l2OC although the mechanism of the two oxidations may differ.In contrast dehydrogenation of the D-seco- compound (136) with the high-potential quinone does not give the 9,ll- dehydroderivative.' 21 Instead the A8-isomer with the tetrasubstituted double bond is formed. This transformation has been used in the synthesis of 8a,9P-oestrone methyl ether (137) which has ring C in the boat form. Details of the dehydrogenation of steroidal 6-lactones to ap-unsaturated lactones with dichlorodicyanobenzoquinonehave appeared. '22 Ring A a-pyrones have been prepared using the same reagent. Studies on the in vitro methylation of 2-hydroxyoestrone suggest that selective formation of the 2-methyl ether is achiev'ed by protection of the 3-hydroxy-group through sulphate conjugation. 123 It appears that both a methyl transferase and a sulphatase act in concert in the transformation of these catechol substrates.0 ~CH,CH~CO~H Me0 (135) (138; R = H or CH,OH) (139) (137) Treatment of the 4,6dien-3-ones (138) with sodium methoxide in dimethyl sulphoxide followed by acidification with aqueous acetic acid gives pre- cipitates of the free enols (139).124 Addition of acetic anhydride to the basic (a)W. H. W. Lunn and E. Farkas Tetrahedron 1968,24,6773 ;(b)W. Brown J. W. A. Findlay and A. B. Turner Chem. Comm. 1968 10; (c) CJ Ann. Reports 1963,60,418. ''I W. S. Johnson. S. G. Boots and E. R. Habicht. J. Org. Chem. 1968.33 1754. 12' B. Berkoq L. Cuellar R. Grezemkovsky N. V. Avila J. A. Edwards and A. D. Cross Tetra-hedron 1968,24,2851.J. Fishman M. Miyazaki and J. Yoshizawa J. Amer. Chem. SOC.,1967,89,7147; M. Miyazaki and J. Fishman J. Org. Chem. 1968,33 662. G. Kruger J. Org. Chem. 1968,33 1750. Terpenoids and Steroids mixtures produces the corresponding trienol acetates. Transformation pro- ducts of these intermediates include various ring B aromatic steroids. Autoxida- tion of enamines of ap-unsaturated ketones occurs at the y-po~ition,'~' leading to the corresponding 1,4diones on hydrolysis (i)air (ii) H,O@ 0 This contrasts with autoxidation of the enolate anions which gives a-keto- derivatives. The corresponding Schiff bases are also oxidised at the y-position probably by radical attack upon their enamine tautomers. Sensitized photo- oxygenation of the enamine (140) which is stable to ground-state oxygen gives progesterone.126 The mechanism is thought to involve 1,2-addition of singlet oxygen to the double bond with subsequent decomposition of the adduct to two carbonyl fragments. Eniminium salt formation is useful for protection of ap-unsaturated ketones during electrophilic reactions. 12' Thus the eniminium perchlorate (141) from progesterone can be converted into 17-hydroxyprogesterone in 48 % overall yield by epoxidation of its 17,20-enol acetate. Final mild alkali treatment regenerates both the keto- groups. The preferred conformation (142) of the side-chain in cortisol has been revealed by i.r. and n.m.r. studies'28o and by molecular orbital calculations.'28b These agree that the 20-keto-group projects towards the p-face of the molecule and the C-2042-21 bond eclipses the C-17-0(17a) bond.A weak intramolecular hydrogen bond is formed between the 20-carbonyl group and the 21-hydroxy- group but no such bond is formed between the 20-carbonyl and a 17a-hydroxy- group in the presence of a substituent at C-21. H 125 S. K. Malhotra J. J. Hostynek and A. F. Lundin J. Amer. Cheni. SOC.,1968,90 6565. J. E. Huber Tetrahedron Letters 1968 3271. 12' B. Gadsby and M. R. G. Leeming Chem. Comm. 1968,596. 128 W. G. Cole and D. H. Williams J. Chem. SOC.(C) 1968 1849; L. B. Kier J. Medicin. Chem. 1968 11 915. 434 A. B. Turner Details are available of the synthesis and conformational analysis of A-homo- B-nor- and A-nor-B-homo-steroids prepared by the stereospecific rearrangement of 1,2-cisdiol monotosylates.12' New syntheses of ~-homo-19-norsteroids involve incorporation or elimination of the C-19.In the former 19-mesyloxy-1,4-diene-3-onesand their 19-chloroanalogues are reduced with lithium and biphenyl in tetrahydrofuran and the latter' 30b involves decarbonylation or decarboxylation of the cyclopropanes (143) to the triene (144). The fragmentations occur with base and acid respectively with con- current cleavage of the cyclopropane ring. The synthesis of la,2a-methylene 19-nor pregnanes is best achieved by ring opening of (143) to the la-chloro- methyl derivative followed by acid-catalysed elimination of the C-10 carboxyl group and final regeneration of the cyclopropane ring.'30b A long-range directing effect which manifests itself in terms of changes in product ratio rather than in rate differences is exerted by the cholestane side-chain in the formation of A-homosteroid ketones.' 3'0 The direction of the ring enlargement of 3-ketones having a variety of substituents at C-17 is markedly influenced by the C8Hl side-chain. The effect may be due to micelle formation. Other abnormal effects have been observed in reactions of choles- tanes in aqueous solution. 31 Photochemical ring-contraction of A-homosteroids of type (145) gives the A-nor-derivatives (146).' 32 An efficient synthesis of A-nortestosterones involves photolysis of the epoxy-ketone (147) to give the hydroxymethylene compound (148).133 (146) (147) (148) lZ9 M.Nussim and Y. Mazur Tetrahedron 1968,24,5337; cf Ann. Reports 1961,58 328. lJo (a)P. Wieland and G. Anner Helu. Chim. Acta 1968 51 1932; (b)R. Wiechert Chem. Ber. 1968,101,2388. lJ1 (a) J. B.Jones and J. M. Zander Canad. J. Chem. 1968 46 1913; (b) J. B. Jones and D. C. Wigfield ibid. p. 1459. lJ2 M. Fischer and B. Zeeh Chem Ber. 1968,101,2360. 133 J. Pfister C.Lehmann and H. Wehrli Helu. Chim. Acta 1968,51 1505. Terpenoidrs and Steroids 435 12~-Mesyloxycholane is now found' 34 to rearrange in refluxing collidine to the c-nor-D-homoderivative (149) as do the epimeric 12P-mesylate and derivatives of the 12-oxo-compounds. The name 'cholajervine' is proposed for the parent hydrocarbon of these C, products to accompany the trivial names jervane and etiojervane commonly associated with the C27 and C, series.A13-Isomers of A12-5P-cholajervene (149) are also formed in the above rearrangement ;these have the usual C/D-C~Sring-junction. When 14P-hydroxy- 12P-tosyloxy-steroids are solvolysed the resulting c-nor-D-homo alcohols have the c/~-truns ring-junction.' 35 c-Nor-D-homo-analogues of oestrone and progesterone have been prepared from jervine. '36 Deamination of the amine (150; R = NH,) and attempted tosylation of the alcohol (150; R = OH) give c-homo-D-bisnor-steroidssuch as (151). 137 These results confirm the known tendency of some bicyclohexanes to rearrange with participation of a cyclobutyl C-C bond. Boron trifluoride-catalysed cleavage of 5P,6-epoxy-4-ketones and 4P,5- epoxy-6-ketones of the cholestane series leads to the corresponding fluoro- hydrins without skeletal rearrangement.13* The nucleophile attacks P to the carbonyl group and the C-5-0 bond remains intact; development of carbonium-ion character at C-5 in the co-ordinated complex is inhibited by the adjacent carbonyl group and there are no rearrangements of the type commonly observed with similar epoxides lacking a-keto-groups. A novel fragmentation occurs when the epoxy-cholestane (152) is kept for a short time in refluxing ~ollidine.'~~ The ether (153) is obtained along with the aromatic product (154). 18 I I H HA :Base (153) (154) (152) 134 F. C. Chang and R. C. Ebersole Tetrahedron Letters 1968 1985; 3521. 135 Y. Shimizu and T. Mitsuhashi Tetrahedron 1968,24,4207.136 S. M. Kupchan and M. J. A. El-Haj J. Org.Chem. 1968 33 647; S. M. Kupchan A. W. By and M. S. Flow ibid. p. 911. 13' J. Meinwald and J.-L. Ripoll J. Amer. Chem. Soc. 1967,89 7075. J. R. Bull Tetrahedron Letters 1968 5959. 13' J. M. Coxon R. P. Garland M. P. Hartshorn and G. A. Lane Chem. Comm. 1968 1506. 436 A. B. Turner Epoxidation of 19-hydroxy-As-androstenes and -cholestenes gives exclusively the Sp-epoxides in spite of p-face steric hindrance.14' The rate of the reaction is much reduced with the 19-acetoxy- and 10-methyl derivatives. The specificity of epoxidation is explained by formation of the complex (155) which is stabilized by hydrogen bonding. The orienting effect of an llp-hydroxy-group in the epoxidation of a 7,8-double bond is less marked although still sufficient to partially counteract the steric effects of the angular methyl groups on the p-face.The product mixture contains 25 % of the 7P,8P-epoxide and 70 % of the 7a,8a-isomer. Acid-catalysed rearrangement of the B-nor-lactone (156) gives the acid (157).I4l Lead tetra-acetate oxidation of a derivative (158) of Westphalen's diol gives the ether (159) thereby providing direct chemical evidence for the p-configuration at C-5 in the di01.l~~ Tracer studies'43 establish the following mechanism for the oxidative cyanohydrin<yanoketone rearrange-ment Details of the Baeyer-Villiger oxidation of A4-3-ketones and derived epoxides leading to A-norsteroids have appeared. 144 M. Mousseron-Canet B.Labeeuw and J.-C. Lanet Bull. SOC. chim. France 1968 2125; M. Mousseron-Canet and B. Labeeuw ibid. pp. 4165,4171. 141 M. S. Ahmad R P. Sharma H. Siddiqui and Shafiullah Austral. J. Chem. 1968 21 1867. 14* M. J. Harrington and B. A. Marples Tetrahedron Letters 1968,484. 14' J. Kalvoda Helv.Chim. Ada 1968,51,267. Terpenoids and Steroids Reduction of cholesteryl chloride with triphenyltin hydride or the sodium biphenyl radical anion gives only cholest-5-ene whereas 3,5-cyclocholestan-6-yl chloride gives mixtures of 3,5-cyclocholestane and the cholestene. 145a These and other results can be interpreted in terms of the formation of intermediate radicals which can rearrange or capture hydrogen. They show that the choles- teryl radical is significantly more stable than the cyclocholestanyl radical.Members of a new class of cyclo-steroids 5P,7P-cyclocholestanes have been obtained by addition of methylene to B-norcholesterol acetate or by irradiation of cholesta4,6diene. 145b The photochemical reaction could involve a bicyclo- butane intermediate. A transannular hydrogen transfer from C-5a to C-3a is shown by deuterium labelling to be involved in the formation of la,5-cyclo- k-cholest-2-ene (160)during attempted tosylation of the ally1 alcohol (161).145c The mechanism of photolysis of the keto-aldehyde (162) which shows strong conjugation between its aldehyde and enone systems has been discussed. 146 The products include the ketones (163) and (164) and the photochemistry differs markedly from that of the 19-deoxy-analogue.H (160) OAc 0& o@ CHO CHOH (1 6 2) (16 3) (164) 144 J. T. Pinhey and K. Schaffner,Austral. J. Chem. 1968,21 1873. 14’ (a) S. J. Cristol and R. V. Barbour J. Amer. Chem. SOC.,1968,90,2832; (b)P. G. Gassman and W. E. Hymans Tetrahedron 1968 24 4437 cf ref. 85; (c)S. B. Laing and P. J. Sykes J. Chem. SOC. (0,1968,421; 653; 937. 146 E. Pfenninger D. E. Poel C. Berse H. Wehrli K. Schaffner and 0.Jeger Helu. Chim. Act4 1968,51 772. 438 A. B. Turner The isomeric cyclobutenes (165) undergo thermal rearrangement to the bicyclohexene (166) possibly via a diradical intermediate. 14' The recent clarification of the role of steroid hormones in the metamorphosis of insects has been followed by recognition of the wide distribution of active substances in the plant kingdom.Among many reports this year there are further examples (167; hydroxylated at C-25 26 or 29) of moulting hormones based on the p-sitosterol ~ke1eton.l~~ Another C,,-hormone the lactone (168) is the probable precursor of cyasterone. Whereas all previous steroids exhibiting moulting-hormone activity have been 2P,3pdiols ponasterones B and c (171; R = H and OH respectively) have 2a,3a-hydroxy-group~.~~~~ Their companion in the leaves of Podocarpus Nakaii,ponasterone A (169) has the usual 2P,3Pdiol system. Further evidence for the structure of the latter has been obtained by degradati~n"'~ and synthesis. It occurs as the 3P-glucoside in Pteridiurn aquilinurn.150dThe isolation of rubrosterone 26 I II OH HOW H 11 0 0 147 P.H. Nelson J. W. Murphy J. A. Edwards and J. H. Fried J. Amer. Chem. SOC. 1968 90 1307; 5572. 148 M. N. Galbraith D. H. S. Horn Q. N. Porter and R. J. Hackney Chem. Comm. 1968 971; T. Takemoto K. Nomoto and H. Hikino Tetrahedron Letters 1968,4953. 149 T. Takemoto K. Nomoto Y. Hikino and H. Hikino Tetrahedron Letters 1968 4929; cf Ann. Reports 1967,64 371. 50 (a)K. Nakanishi M. Koreeda M. L. Chang and H. Y. Hsy Tetrahedron Letters 1968 1105 ; (b) H. Moriyama and K. Nakanishi ibid. p. 1111; (c) G. Huppi and J. B. Siddall ibid p. 1113; (d) T. Takemoto S. Arihara and H. Hikino ibid. p. 4199. Terpenoids and Steroids 439 (170) from Achyranthes rubrofuscasuggests that a metabolic pathway analogous to that from cholesterol to dehydroepiandrosterone exists for moulting hormones in plants.51 Several syntheses of rubrosterone are reported,'52"* as well as new routes to e~dysone'~~' and 20-hydroxyecdysone. 152d In two of these' 52a*d the 14a-hydroxy-group is introduced via epoxidation of 6- acetoxy-6,8( 14)-dienes. An alternative method of generating the 14a-hydroxy-7- en-6-one system which is a feature of all moulting hormones so far isolated involves photo-oxygenation of Py-unsaturated ketones :' {Q-# 0-OH @L pLg! 0 0 0 0 Deuterium work indicates a concerted cycloaddition mechanism for this reaction. A trimethylsilyl ether is used to protect a hydroxy-group in the synthesis of an isomer of ecdysone.'54 This may presage wide application of silyl ethers as protective groups in chemical synthesis. The fungal metabolite wortmannin (172) is related to viridin. lS5Cleavage of ring A does not appear to have involved p-elimination. The spirostan ring system can be readily constructed by Michael addition of l-acetoxy-5-nitro-2-methylpentane The adducts to A' 7(20)-pregnene-16-ones. cyclise directly to sapogenins on reduction and the method has been used to prepare kryptogenin diosgenin and yamogenin. ' Treatment of 21-acyloxy- 20-ketones of type (173) with alkali produces cardenolides (1 74). ' A survey of the Zimmermann reaction of various steroidal ketones has allowed correlations to be drawn between their structure and reactivity.' l8 Interactions between ketone functions at C-1 and C-11 in androstanes and pregnanes are responsible for various anomalous reactions.lS9 The degree of enolization of 1,3-diketones is markedly inhibited by an 11-0x0-substituent while 1,ll-diketones are resistant to metal hydride or catalytic reduction. The presence of an 11-keto-group inhibits oxidation of 1P-hydroxy-groups by chromium trioxide. lS1 T. Takemoto Y. Hikino H. Hikino S. Ogawa and N. Nishimoto Tetrahedron Letters 1968 3053. (a)K. Shibata and H. Mori Chem.and Pharm. Bull. (Japan),1968,16,1404;H. Mori K. Shibata K. Tsuneda and M. Sawai ibid. p. 1593; (b) H. Mori K. Shibata K. Tsuneda and M. Sawai ibid. p. 563; (c) P. Hocks U. Kerb R Wiechert A. Furlenmeier and A. Fiirst Tetrahedron Letters 1968 4281 ;H.Hikino Y. Hikino and T. Takemoto ibid. p. 4255 ;(d)U. Kerb R. Wiechert A. Furlenmeier and A. Fiirst ibid. p. 4277. 153 N. Furutachi Y. Nakadaira and K. Nakanishi Chem. Comm. 1968 1625. 154 M. N. Galbraith D. H. S. Horn E. J. Middleton and R. J. Hackney Chem. Comm. 1968,466. 155 J. MacMillan A. E. Vanstone and S. K. Yeboah Chem. Comm. 1968,613. lS6 S. V. Kessar and A. L. Rampal Tetrahedron 1968 24 887 et seq. 15' H.-G. Lehmann and R. Wiechert Angew. Chem. Internat. Edn. 1968,7,300. D. N. Kirk W. Klyne and A. Mudd J. Chem. SOC.(C),1968,2269. lS9 J. J. Schneider P. Crabbe and N. S. BhaccaJ. Org. Chem. 1968,33 3118. 440 A. B. Turner HO. HO" (171) O-0 0& COCH-1R R' [173; R' = PPh,P or PO(OEt),] (174)