10. TERPENOIDS AND STEROIDS By A. B. Turner (Department of Chemistry University of Aberdeen) BIOGENETIC-TYPE syntheses continue to attract attention. Cyclisation of the terminal epoxides of simpler terpenes gives polyclic systems. Of particular interest is the terminal epoxide (1) of geranylgeranyl acetate,' which on brief treatment with stannic chloride in benzene gives the tricyclic product (2) with six asymmetric centres all having the stereochemistry of the natural diter- penoids. Mechanisms involving either a concerted cyclisation or a stepwise process via mono- and bi-cyclic carbonium ions are proposed. The non-enzymic cyclisation of squalene 2,3-epoxide leads to the tricyclic compounds (3) and (7; R = c~H) (8;R = PH) E. E. van Tamelen and R.G.Nadeau J. Amer. Chem. SOC., 1967,89 I76 350 A. B. Turner (4) under similar The former product (3) clearly arises more directly from squalene oxide while the latter (4) is formed either from the inter- mediate carbonium ion or by further reaction of (3). These results underline the need for enzymic control in the formation of ring c in Nature in order to counteract the purely chemical tendency for this ring to become five-membered. (The natural configuration of the A/B ring system is obtained by non-enzymic cyclisation of terpene terminal epoxides2‘) The selectivity of the terminal oxidation of polyolefins has been ascribed to both steric and conformational factors3 The stereochemical course of the cyclisation of the olefinic acetals (5) and (6) is dictated by the configuration of the central olefinic bonds in the substrate^,^" as previously noted for the acid-induced cyclisation of acyclic p~lyenes.~* The trans-acetal(5) gives the trans-octalin (7)whereas the cis-isomer (6)gives the cis-octalin (8).The stereospecificity again demands either a syn- chronous mechanism or cationic intermediates which maintain their stereo- chemical integrity. The chemistry of anthropod defensive substances among which the terpenes form a major group is the subject of an interesting review.’ The compounds concerned are mainly monoterpenes with some sesquiterpenes. Testosterone as well as several pregnane derivatives is present in the protective glands of water beetles6 Grasshoppers which feed on milkweeds contain cardenolides similar to those in the plant.’ These toxic materials are found in the insect’s body tissues and can also be ejected in solution from its defensive glands.The terpene constituents of the Cupressaceae have been reviewed.’ Monoterpenoids.-New examples are reported’ of the hydrolysis of phos-phate esters as model reactions for the biogenesis of monoterpenes. Acid hydro!ysis of geranyl neryl linaloyl and a-terpinyl phosphates and pyro- phosphates leads to a number of naturally occurring acyclic and monocyclic systems. Fission of the cyclopropane ring of various chrysanthemic acid derivatives (9) by generation of the appropriate carbonium ions allows rupture of each of the three ring bonds (A+) to give compounds with the santolinyl (lo) artemisyl (1 l) and lavandulyl skeltons (1 2).’ On heating linalool(l3) all four possible diastereoisomeric plinols are formed (a)E.E. van Tarnelen J. Willet M. Schwartz and R. Nadeau J. Amer. Chem. Soc. 1966 88 5937; M. Kishi T. Kato and Y. Kitahara Chem. and Pharm. WIN (Japan) 196;7,15 1071. (6)cf Ann. Reports 1966,63 443. (c) cf Ref. 65. E. E. van Tarnelen and K. B. Sharpless Tetrahedron Letters 1967 2655. (a)W. S. Johnson A. van der Gen and J. J. Swoboda J. Amer. Chem. SOC.,1967,89 170. (b)I. G. Mursakulov A. V. Sernenovsky W. A. Smit and V. F. Kucherov Tetrahedron 1967 23 1621. ’ J. Weatherston Quart. Reo. 1967 21 287. H. Schildknecht H. Birninger and U. Maschwitz Angew. Chem. 1967,79,579; H. Schildknecht R. Siewerdt and U.Maschwitz Annalen 1967,703 182. ’ J. v. Euw L. Fishelson J. A. Parsons T. Reichstein and M. Rothschild Nature 1967,214 35. H. Erdtrnan and T. Norin Fortschr. Chem. org. Naturstofle 1966 24 206. F. Crarner and W. Rittersdorf Tetrahedron 1967 23,3015 3023. lo L. Crombie R. P. Houghton and D. K. Woods Tetrahedron Letters 1967 4553. Terpenoids and Steroids 351 via an intramolecular Alder ‘ene’ synthesis’ The name ‘iridane’ is proposed for the carbon skeleton (14) of these substances which is of widespread occur- rence. Conflicting assignments of configuration to the isomeric pulegone epoxides on the basis of physical measurements have now been resolved by their stereospecific Favorskii rearrangement. l2 Abnormal opening of the cyclo- propane intermediates predominates and subsequent protonation proceeds with retention of configuration.Chemical transformation’ to diols of known configuration gives the same results (+)-and (-)-pulegone oxides are the cis-and trans-isomers (1 5)and (16) respectively. ( -)-Piperitenone dioxide has the cis-configuration (17).’ PoH q-,Q 0; (13) 9 10 (15) (14) (17) (18) (19) ‘I H. Strickler G. Ohloff and E. Kovats Helti. Chim. Acta 1967 50 759. G. W. K. Cavil1 and C. D. Hall Tetrahedron 1967 23 1119; W. Reusch and P. Mattison ibid. p. 1953. J. Katsuhara J. Org. Chem. 1967. 32 797. 352 A. B. Turner Syntheses of ( f)-genipin,14 and (i-)-bakuchiol” and its methyl ether16 have been achieved. The novel oxetone (18) and its dihydro-derivative have been obtained from hop 0i1.l~ Hydrogenation of the diene (18) in ether gives the tetrahydro- derivative whereas hydrogenation in acetic acid is accompanied by hydro- genolysis of the spiroketal linkage.The bicyclo[3,2,0] heptane ring system is recognised in the D-and L-filifolones (19) and its mirror image from Zieria and Arternisia species. ’* Sesquiterpenoids.-The chemistry of picrotoxinin and related substances has been reviewed,’ and physical data on sesquiterpenoids collected.z0 New stereospecific synthesis of farnesol” and humulene (20)” are reported from Harvard. Germacratriene is foundz3 to have the all-trans-configuration (21) by X-ray analysis of its silver nitrate adduct. The ready conversion of this triene (2 l) a possible biosynthetic intermediate into bicyclic selinane deriva- tives is ascribed to the reactivity of the 6,7-double bond towards electrophilic reagents.24“ A detailed thermodynamic argument suggests spz-spz torsional strain contributes significantly to the high reactivity of such medium-ring trans-olefins and that in the case of germacratriene this contribution may be much larger than that from the familiar sp3-spz torsional strain.24b P-Elemene (22) and elemol (23) have been synthesised from a-santonin.” The thermal interconversion of this transdivinylcyclohexane system and a cyclodeca-1,5-diene has been observedz6 in the derivatives (25) and (26) of the germacranolide (24).Increased attention has been paid to the action of juvenile hormones which regulate larval development or reproduction in insects.Methyl farnesoate dihydrochloride (27) shows lo4 times the activity of farnesyl methyl ether the most active compound previously rep~rted.’~ Work on such compounds may therefore have important implications for insect control. The ester (28) is the juvenile hormone of the giant silkworm moth.z8 In the bisabolene group dehydrojuvabione (29) which shows high juvenile hormone activity has been l4 G. Biichi B. Gubler R. S. Schneider and J. Wild J. Amer. Chem. Soc. 1967 89 2776. Is J. Carnduff and J. A. Miller Chem. Comm. 1967,606. l6 N. P. Damodaran and S. Dev Tetrahedron Letters 1967 2897. l7 Y. Naya and M. Kotake Tetrahedron Letters 1967 1715. lS R. B. Bates M. J. Onore S. K. Paknikar C. Steelink and E.P. Blanchard Chem. Comm. 1967 1037. l9 LA. Porter Chem Rev. 1967,67,441. 2o Tables of Constants and Numerical Data. 15 Sesquiterpenoids by G. Ourisson S. Munavalli and C. Ehret Pergamon Press 1966. 21 E. J. Corey J. A. Katzenellenbogen. and G. H. Posner J. Amer. Chem. SOC.,1967,89,4245. 22 E. J. Corey and E. Hamanaka J. Amer. Chem. SOC. 1967,89 2758. ” F. H. Allen and D. Rogers Chem. Comm. 1967 588. 24 (a) E. D. Brown M. D. Solomon J. K. Sutherland and A. Torre Chern. Comm. 1967 11 1. (b)F. H. Allen E. D. Brown D. Rogers and J. K. Sutherland ibid. p. 11 16. 25 L. J. Patil and A. S. Rao Tetrahedron Letters 1967 2273. N. H. Fischer and J. J. Mabry Chem. Comm. 1967 1235. 27 M. Romanuk K. Skima and F. Sorm Proc. Nat. Acad. Sci. U.S.A.,1967,57 349.28 H. Roller K. H. Dahm C. C. Sweely and B. M. Trost Angew. Chem. 1967,79 190. Terpenoids and Steroids (22; R = H) (20) (2 1) (23; R = OH) p RO c1 COzMe (24; R = H X = CHJ (27) H (25; R = Ac X = '--_Me 1 0,Me CozH isolated from the Balsam fir.29 Syntheses of both the racemic compound (29) and ( f)-juvabione are rep~rted.~' (+)-Abscissin I1 has been shown31 to have the absolute stereochemistry in (30). a-and p-Vetivone have long been regarded as the hydroazulenones (31) differing only in stereochemistry at C-6. Both structures have been drastically modified this year. a-Vetivone the less thoroughly investigated of the twe it had never in fact been chemically inter-related with its supposed epimeric counterpart-has now been shown32 to have structure (32) after its n.m.r.spectrum had been found to indicate the presence of an angular methyl group. The Canadian group related the new structure with an eremophilone deriva- ti~e,~~" while the Americans showed that dehydro-or-vetivone was identical to i~odehydronootkatone,~~~and later confirmed the structure by total ~ynthesis.~ 29 V. Cerny L. DolejS L. Labler F. Sorm and K. Slrima Coll. Czech. Chem. Comm. 1967 32 3926. 30 K. Mon and M. Matsui Tetrahedron Letters 1967,2515,4853; K. S. Agyar and G. S. Krishna Rao ibid. p. 4677. 31 J. W. Cornforth W. Draber B. V. Milborrow and G. Ryback Chem. Comm. 1967 114. 32 (a)K. Endo and P. de Mayo Chem. Comm. 1967 89. (b)J. A. Marshall and N. H. Andersen Tetrahedron Letters 1967 161 1.33 J. A. Marshall H. Faubl and T. M. Warne Chm Comm.. 1967.753. 354 A. B. Turner The synthetic studies of Marshall and his co-w~rkers~~' then surprisingly in- validated the accepted structure for p-vetivone and with it the proposed framework(3 1)of the entire class of bicyclic vetivane sesquiterpenes. The wealth of chemical and physical data on p-vetivone the n.m.r. spectrum of which was not in conflict with the old structure was then reinterpreted34b in terms of the spiro[4,5]decane structure (33). The nature of the ring system was confirmed by degradation to the known spirodecane (34).A choice between structure (33) and its mirror image was possible because of the known34c conversion of hinesol now reformulated as (39 into ( +)-p-vetivone.(The absolute configuration of hinesol is already established. 35) The group of sesquiterpenes containing the spiro[4,5]decane system which previously contained only the acorones and the agaro~pirols,~~ must now be expanded to include p-vetivone hinesol and several other ~etivanes.~~~ These results underline the caution required in interpreting the results of dehydrogenation experiments. 36 Chamigrene (36) from the leaves of Charmaecyparis taiwmensis is the Me I 0m (33) (34) (35) CH,OH I (36) (37) (3 8) 34 (a)J. A. Marshall N. H. Andersen and P. C. Johnson J.Amer. Chem. SOC.,1967,89 2748. (b)J. A. Marshall and P. C. Johnson ibid.,p. 2750. (c)cf Ann. Reports 1965 62 335. 3s cJ Ann. Reports 1962. 59.292. 36 cf M. Holub Z. Samek V. Herout and F. Sorm,CoZZ. Czech. Chem. Comm. 1967,32 591. Terpenoids and Steroids 355 first sesquiterpenoid spiro[5,5]undecane to be found in Nat~re.~'" Its occur- rence is significant since it corresponds to a probable link in the biogenesis of thujopsene cuparene and the cuprenes. It is a known isomerisation product of thujop~ene,~~' and is also formed by acid-catalysed dehydration of widdrol. Both of these compounds are also found in the leaf oil. A synthesis of (+)-chamigrene (36) is recorded,37c as well as a biogenetic-type synthesis of (+)-a-chamigrene (37) by dehydration of both the cis-and trans-monocyclofarnesols (38)? 7d The tumour inhibitor euparotin acetate (39) is the most highly oxygenated guaianolide yet discovered and the first recognised to contain a ~piro-epoxide.~~ Its epoxide and a,P-unsaturated lactone functions are common to other tumour inhibitors such as withaferin A and elephantin.In the solid state santonene exists in the keto form (40) whereas the dihydro- santonene produced by catalytic hydrogenation of the 1,2-double bond exists as the enol (41). In solution a tautomeric equilibrium is set up between keto and enol forms in both corn pound^.^^ The position of equilibrium can be de- termined using n.m.r. spectroscopy and specific rotations. Perezinone the cyclodehydration product from hydroxyperezone has the quinone methide structure (42). The highly hindered terminus of the chromophore is reflected in its slow rate of hydrogenation and its failure to add hydrogen ~hloride.~' 0 H '0 (41) (42) 37 (a)S.Ito K. Endo T. Yoshida M. Yatagai and M. Kodama Chem. Comm.. 1967 186 (b)cf Ann. Reports 1964 61 360. (c) A. Tanaka H. Uda and A. Yoshikoshi Chem. Comm. 1967 188. (4S. Kanno T. Kato and Y. Kitahara ibid.,p. 1257 ;cf A. Tanaka H. Uda and A. Yoshikoshi ibid. 1968 56. 38 S. M. Kupchan J. C. Hemingway J. M. Cassady J. R. Knox A. T. McPhail and G. A. Sim Sim J. Amer. Chem. SOC.,1967,89 465. 39 T. B. H. McMurry and R. C. Mollan J. Chem. SOC.(C),1967 1813. 40 D. A. Archer and R. H. Thomson J. Chem. SOC.(C),1967 1710. 356 A. B. Turner . CHzOH Illudol (43) a third metabolite of Clitocybe ill~dens,~~" has the carbon skeleton of a postulated biogenetic precursor of the illudins S and M.41b The cyclobutene moiety appears in the fungal metabolite fomannosin (44) the structure of which was determined by X-ray analysis of a dihydro-deriva- tive.* A preliminary report43 on the characterisation of 1,2-and 1,3-diols by gas chromatography-mass spectrometry of the derived cyclic n-butyl and phenyl- boronate esters suggests that the method may have important applications in the terpenoid and steroid fields. Diterpenoids.-The cis-configuration for abienol (45) has been confirmed by conversion into its trans-isomer (46) with mercuric acetate.44 This novel HOH2C H OH (49) 41 (a)T. C. McMorris M. S. R. Nau and M. Anchel J. Amer. Chem. SOC.,1967,89 4562. (b)cJ Ann. Reports 1965 62 332. 42 J.A. Kepler M. E. Wall J. E. Mason C. Basset A. T. McPhail and G. A. Sim J. Amer. Chem. SOC. 1967 89 1260. 43 C. J. W. Brooks and J. Watson Chem. Comm. 1967 952; c$ S. Hara T. Watabe and Y. Ike Chem. and Pharm. &U. (Japan). 1966.14. 131 1. 44 J. S. Mills J. Chem. SOC.(C) 1967 2514. Terpenoids and Steroids 357 isomerisation is thought to proceed via the intermediate acetoxymercuri- compound (47) formed by participation of the hydroxyl group. Mercuration of dihydroabienols also involves hydroxyl participation and leads to five- and six-membered ring ethers. The dust of protracted battles over the stereochemistry of marrubiin has finally settled and structure (48)has emerged.45 The common 13(R)-configura- tion in eperuic and labdanolic acids is inferred from differing behaviour of derived diketones under alkaline condition^.^^ Acids of the eperuane and labdane series co-occur in Oxystigrna oxyphyll~rn.~’ The structure of phorbol (49) for which several incorrect proposals have been made,48b is now settled by X-ray work on a bromofuroate deri~ative.~~” Details of the work of the Leeds school on taxicins I and I1 have a~peared.~’ Preferential oxidation of the vinyl group of methyl pimarate (50)with per- manganate-buffered periodate gives” the epoxy-ketoacid (52)along with the expected acid (51).The epoxide probably arises by an intramolecular process perhaps taking place in the initial permanganate-olefin complex. (50;R = CH4H2) (53;R = Me) (51 ;R = C02H) (56; R = CH21) &O H fil R *,.H HO (54;R= CH,I) (57) (58 R = Me) (55; R = Me) (59;R = CH2I) ” D. M. S. Wheeler M. M. Wheeler M. Fetizon and W. H. Castine Tetrahedron 1967,23 3909; R. A. Appleton J. W. B. Fulke M. S. Henderson and R. McCrindle J. Chem SOC.(C) 1967,931. 46 K. H. Overton and A. J. Renfrew J. Chem. SOC.(C),1967,931. 47 D. E. U. Ekong and J. I. Okogun Chem Comm. 1967 72. ‘’(a) R. C. Pettersen G. Ferguson L. Crombie M. L. Games and D. J. Pointer Chem. Comm. 716 cf E. Hecker H. Bartsch. H. Bresch. M. Gschwendt. F Harle. G Kreihich. H. Kubinyi. H. U. Schairer C. Szczepanski and H. W. Thielmann Tetrahedron Letters 1967 3 165. (b)ct Ann. Reports 1965. 62 336. 49 M. Dukes D. H. Eyre J. W. Harrison R. M. Scrowston and B. Lythgoe J. Chem. SOC. (C) 1967,448; D.H. Eyre J. W. Harrison and B. Lythgoe ibid. p. 452. J. W. ApSimon A. S. Y.Chaw W. G. Craig and H. Krehm Canad. J. Chem. 1967,45 1439. 358 A. B. Turner COzH The range of intramolecular radical reactions at saturated carbon atoms has been extended to include functionalisation of methyl groups some distance from a hydroxyl group.” Thus hypoiodite oxidation of the ketol (53) gives the iodo-derivative (54) as well as the expected ketoxide (55). The unstable iodohydrin (56)is an intermediate in the formation of (54) which arises by two oxidations of the original alcohol (53). The novel long-range oxidation which occurs in the iodohydrin (56) involves two consecutive 1,Shydrogen shifts the second of which represents the rare intramolecular abstraction of a hydrogen atom by a carbon radical.(Overoxidation in hypohalite reactions has previously been observed only at the site of initial attack of the alkoxy radical.) The double 1,5-hydrogen shift in the oxidation of the iodohydrin (56) probably reflects the steric congestion at the 10P-iodomethyl group. A second example of this type is the lead tetraacetate-iodine oxidation of friedelan-3P-01 (57) in which the major product (58) is accompanied by its iodo-derivative (59). The configuration of the secondary methyl group in vinhaticoic acid (60) is assigned as shown on the basis of a total synthesis of the (&)-methyl The final assembly of the furan ring involves 1,4-addition of carbethoxy carbene to an a-methoxy methylene ketone:52b Combined gas chromatography-mass spectrometry promises to be useful for the rapid identification of gibberellins in plants.53 Bamboo gibberellin (61) has been identified in Phaseoh rnultifurus by this method.54 The corresponding ” E.Wenkert and B. L. Mylari J. Amer. Chem. SOC. 1967,89 174. 52 (a)T. A. Spencer R. M. Villarica D. L. Storm T. D. Weaver R. J. Friary J. Posler and P. R. Shafer J. Amer. Chem. SOC.,1967 89 5497; cf D. L. Storm and T. A. Spencer Tetrahedron Letters 1967 1865. (b)cJ Ann. Reports 1966,63 456. 53 J. MacMillan; R. J. Pryce G. Eglinton and A. McCormick Tetrahedron Letters 1967 2241. 54 K.J. Pryce J. MacMillan and A. McCormick Tetrahedron Letters 1967 5009. Terpenoids and Steroids tribasic acid (62) was obtained from seeds of the same species without the guidance of bioassay.55 The three C-20 gibberellins now isolated from green plants all have a 7-hydroxy group unlike the fungal C-20 gibberellins AI2-Al5 and this suggests that 7-hydroxylation may occur at a much earlier stage of biosynthesis in the plant.The gibberellin-A,-glucopyranoside (63) is the first gibberellin glycoside isolated from natural sources. 56 Mechanisms involving fission of the C-H or C-0 bonds are ruled out for the base-catalysed epimeri- sation at position 2 in 2-hydroxygibbane 1 -+4a lactones.” There is no (61 ; R = CHO) (63) C02H (62; R = C0,H) incorporation of deuterium and the 2-methoxy derivatives are not epimerised. This leaves the possibility of proton abstraction from the 2-hydroxy group in a retro-aldol mechanism although the ring-opened intermediate could not be trapped.2-Ketogibberellins readily undergo retro-Claisen cleavage in ring A,~* with the lactone bridge remaining intact. Atractyloside the toxic glucoside from the root of Atractylis gummqera has the ( -)-kaurene structure (64).59 Sesterterpen0ids.-Agreement has been reached on the nomenclature of this group.60 The fundamental hydrocarbon of the series is named ophiobolane with the numbering and steric configuration shown in (65). Ophiobolin D ’’ R. J. Pryce and J. MacMillan Tetrahedron Letters 1967 4173. s6 K. Schreiber. J. Weiland and G. Sembdner Terrahedron Letters 1967 4285. ” J. MacMillan and R. J. Pryce J. Chem. SOC.(C‘) 1967 740. 58 I. A. Gurvich I.M. Milstein and V. F. Kucherov Tetrahedron Letters 1967 4293. ” F. Piozzi A. Quilico C. Fuganti T. Ajello and V. Sprio Gazzetta 1967 97 935. 6o K. Tsuda S. Nozoe M. Morisaki H. Hirai A. Itai S. Okuda L. Canonica A. Fiecchi M. G. Kienle and A. Scala Tetrahedron Letters 1967 3369; cf Ann. Reports 1966,63 451. 360 A. B. Turner has the structure (66),6'"and has been correlated616 with ophiobolin C. The oxygen atom at C-3 in ophiobolin A does not originate from molecular oxygen,62 unlike that at C-14. Triterpenoids-There is evidence for the presence of squalene 2,3-epoxide in tobacco tissues cultured in vitr~.~~ Lansic acid (67) from the fruit peel of Lansium domesticum is a unique onocerin variant in which both rings A and E are cleaved.64 Malabaricol (68)6' has the carbon skeleton of one of the products of the non-enzymic cyclisation of squalene epoxide (vide supra).New evidence66" is adduced for the structure of shionone which has also been correlated with friedelin.66b Full details are now available of the work on methyl angolen~ate,~~ turraeanthin 68a and melianone.68b The related melian- trio1 is the substance responsible for making certain M elia species unpalatable to the desert locust.69 Acid-catalysed rearrangement7' of the C-14 methyl group in 7a,8a-epoxy- tirucallols of type (69) gives the 7a-hydroxyapo-derivatives (70). This is an interesting model for a possible step in the biogenesis of tetranortriterpenes all of which are oxygenated at C-7. In grandifoliolenone (71) this methyl migration and C-7 oxygenation have occurred but the side-chain is not degraded.71 The tetranortriterpenes (72) (73) and (74) occur together in the same Melia H 61 (a)A.Itai S. Nozoe K. Tsuda S. Okuda Y. Iitaka and Y. Nakayama Tetrahedron Letters 1967,4111. (b)S. Nozoe A. Itai K. Tsuda and S. Okuda ibid. p. 4113. 62 S. Nozoe M. Morisaki K. Tsuda and S. Okuda Tetrahedron Letters 1967,3365; L. Canonica A. Fiecchi M. G. Kienle B. M. Ranzi A. Scala T. Salvatori and E. Pella ibid. p. 3371. 63 P. Benveniste and R. A. Massy-Westropp Tetrahedron Letters 1967 3553. 64 A. K. Kiang E. L. Tan F. Y. Lim K. Habaguchi K. Nakanishi L. Fachan and G. Ourisson Tetrahedron Letters 1967 3571. 65 A. Chawla and S. Dev Tetrahedron Letters 1967,4837; cf Ref.2. 66 (a)T. Takahashi,Y. Moriyama,T. Tanahashi and G. Ourisson Tetrahedron Letters 1967,2991. (b)T. Takahashi T. Tsuyuki T. Hoshino and M. Ito ibid. p. 2997; cf Ann. Reports 1964,61 366. 67 C. W. L. Bevan J. W. Powell D. A. H. Taylor T. G. Halsall P. Toft and M. Welford J. Chern. SOC.(C) 1967 163; W. R. Chan K. E. Magnus and B. S. Mootoo ibid. p. 171. (a) C. W. L. Bevan D. E. U. Ekong T. G. Halsall and P. Toft J. Chem. SOC.(C) 1967 820. (b)D. Lavie M. K. Jain and I. Kirson J. Chern. SOC.(C), 1967 1347. 69 D. Lavie M. K. Jain and S. R. Shpan-Gabrielith Chern. Comm. 1967 910. 'O G. P. Cotterrell T. G. Halsall and M. J. Wriglesworth Chem. Comm. 1967 1121. J. D. Connolly and R. McCrindle Chem. Comm. 1967 1193. Terpenoids and Steroids 36 1 p (69) 'YOH I "OAc (72; R = 0) (73; R = H2) species.72 This supports a proposed scheme for the biogenesis of the ring D epoxylactone system in limonin involving Baeyer-Villiger oxidation of the 14,15-epoxy- 16-ketone.Triterpenoid saponins and sapogenins have been re~iewed.'~ It is noted that hydroxylation is mainly confined to one edge of the carbon skeleton in these compounds particularly in rings D and E. Many new members of this group have been noted this year. 72 D. Lavie and M. K. Jain Chem. Comm. 1967,278; cf C. R. Nakhyanan P. V. Pachapurkar and B. M. Sawant Tetrahedron Letters 1967 3563. '' N. Basu and R. P. Rastogi Phytochemistry 1967 6 1249. 362 A. B. Turner The sapogenin (75) is a component of the defensive secretion of the sea cucumber.74 Revised structures for the cactus lactones stellatogenin (76) and thurberogenin (77) were required when their n.m.r.spectra were found to indicate that the hydroxylic terminus of the lactone bridge was secondary rather than tertiary.75 The new structures are substantiated by the appearance of a new secondary hydroxyl group after metal hydride reduction of the lactone function. The total synthesis of hydroxyhopanone has been completed.76 Serratene (76; R = CH,) (77; R = OH Me) (78; R = H) (79; R = OH) Ac 0 @I7 (82; R' = R2= H2) (83; R' = 0,R2 = H,) (85; R' = H2 R2= 0) 74 B. Tursch,I. S. S. Guimaraes B. Gibert R. T. Aplin A. M. Duffield and C. Djerassi Tetrahedron 1967 23 761. '' M. Marx J.Leclercq B. Tursch and C. Djerassi J. Org. Chem. 1967,32 3150. 76 Y. Tsuda and M. Hattori Chem and Pharm. all.(Japan) 1967 15 1073. Terpenoids and Steroids 363 (78) has now been obtained from a natural source Polypodium uulgare and is the first triterpene hydrocarbon from a fern which does not contain a hopane or rearranged hopane The detailed paper7' on serratenediol (79) includes a retro-pinacol rearrangement which establishes the identical structure ofthe terminal rings and aclassical proofthat the central ring is seven-membered. 19w79a and 20P-Hydroxyursolic and ursonic are present in apple peel which is a common source of ursolic acid. Nitration of glycyrrhetic acid and the corresponding 3-ketone gives the a-gem-dinitroketone (80) in good yield.80 Few such a,a-dinitro-ketones have been described.Although quite stable towards acids the dinitroketone (80) is instantly hydrolysed by cold aqueous bicarbonate to the ring-opened acid (8 1).Rearrange-ments of 32-oxygenated lanostanes under a variety of conditions leads to 4,4- dimet hylcholestanes." Cycloartenyl acetate (82) is much more susceptible to attack by chromic acid at C-1 1 than at C-1. The 11-ketone (83) is obtained in 25 %yield.82 The derived epoxide (84) isomerises to the 12-ketone (85) under mild conditions in accor- dance with the remarkable tendency of the cyclopropyl group to stabilize a positive charge a to the ring. Until recently the only reported fungal triterpene conjugates were acetates. This situation which resulted from the once prevalent practice of saponi- fying the extracted material has been altered b$ a re-examination of the fungus Piptoporus betulinus under conditions favourable to the isolation of conjugates.Polyporenic acid A the major triterpene constituent is present in the sporo- phores mainly in the form of conjugate^.'^ Its 3a-hydroxyl group is esterified by acetic malonic caproic and P-hydroxy-P-methylglutaric acids. The dibasic acid conjugates occur partly as mixed esters with methanol. Such combination with biologically important acids suggests that these conjugates may play a significant role in the sporophore. Steroids.-The last few years have seen the rapid acceptance of steroid hormones as oral contraceptives. The existence of an already large and potentially enormous market for 19-nor-steroids has directed more attention towards total synthesis particularly in view of the possible limitation of natural precursors.The major obstacle to the efficient large-scale operation of existing total syntheses is the formation of unwanted enantiomers and current work is aimed at circumventing this pr~blem.'~ The most promising approach appears 77 G. Berti F. Bottari A. Marsili I. Morelli and A. Mandelbaum Chem. Comm. 1967. 50. " Y. Inubushi Y. Tsuda T. Sano T. Konita S. Suzuki H. Ageta and Y. Otake Chem. and Pharm. Bull. (Japan),1967 15 1153. 79 (a)C. H. Brieskorn and H. Wunderer. Chem. Ber.. 1967. 100. 1352 (b)W. Laurie J. McLean and M. El-Garby Younes J. Chem. SOC. (C),1967. 851. J. C. Turner Chem.Comm. 1967. 396. J. Fried and J. W. Brown Tetrahedron Letters 1967 925. S. Corsano and G. Nicita Ricerca Sci. 1967,37,351;cf:R. Beugelmans and R. Toubiana Compt. rend. 1967 264C 343. 83 T. A. Bryce I. M. Campbell and N. J. McCorkindale Tetrahedron 1367,23 3427. 84 L. Velluz J. Valls and J. Mathieu Angew. Chem. 1967,79 774; L. Velluz J. Mathieu and G. Nomink Tetrahedron 1966. Suppl. 8. p. 495. 364 A. B. Turner to be that of asymmetric synthesis which avoids the difficulties of optical resolution although this has only been successful in a few cases. One is the reaction of a tartramic hydrazide with a carbonyl group of the prochiral inter- mediate (86)leading to preferential formation of one of the two compounds (87). Cyclisation and hydrolysis of this product gives the derivative (88) which has the configuration of the natural steroids at C-13 and is readily converted into ~estradiol.~’ In another approach86 involving early chemical resolution the prochiral dione (89; R = CH2CH2C0,Et) is transformed into its racemic monoacetal (90) thereby allowing resolution of the derived acid by standard methods.The unwanted isomer can be reconverted to the original dione by hydrolysis. The synthesis is completed by cyclisation of the optically active monoacetal to the lactone (91),which is used to construct the ketone (88).Other purely chemical procedures include resolution of steroidal alcohols by salt formation between the derived hemisuccinate esters and various optically active bases.87 An elegant asymmetric reduction of one carbonyl group of the dione (86) by micro-organisms allows exclusive formation of natural oestradiol 3-methyl ether.88 Related reductions of the D-homo analogue of the dione (86) by yeast fermentation lead to the corresponding ketol and di01.~~ These are very unstable and readily rearrange to the’spiro ethers (92; R,R’ = 0and R = OH R’ = H).R. Bucourt L. NMdClec J-C. Gasc and J. Weill-Raynal Bull. SOC. chim. France 1967,561. 86 R. Bucourt M. Vignau and J. Weill-Raynal Compt. rend. 1967 2692 834. G. C.Buzby D. Hartley. G. A. Hughes H. Smith B. W. Gadsby and A. B. A. Jansen J. Medicin. Chem. 1967,10 199. C. Rufer E. Schroder and H. Gibian Annafen 1967,701 206. 89 L. M. Kogan V. E. Gulaya and I. V. Torgov Tetrahedron Letters 1967 4673.Terpenoids and Steroids Mechanistic features of the condensation of vinylcyclenols with cyclic 1,3-diketones to give structures of the type (86) have been discussed.90 Several new and convenient syntheses make 2-methylcyclopentan-1,3-dione (89;R = H) readily acce~sible.~' A new annelation reaction involving isoxazoles has been developed in Stork's laboratory for the construction of cyclohexanone rings in polycyclic system^.'^ This allows a simple and efficient synthesis of steroids in which the elements of rings A and B are added at once to a bicyclic system and is illustrated by syntheses of ( )-D-homo-testosterone and ( f)-progesterone which also include stereospecific introduction of the C,,-methyl group.Alkylation of the enolate anion from 10-methyl-1(9)-octalin-2,5-dione (93) with the chloromethyl-isoxazole (94) gives the dione (99 which is converted by a series of steps into the tricyclic ketol (96). The subsequent conversion of this ketol into the pure 10P-methyl compound (97)' in almost quantitative yield by the alkylation- trapping method solves an old and troublesome problem. Conventional methylations of the ketol(96) lead to the usual mixture of lop-and 10a-A9(")-epimers. The intermediate (97) was readily converted into ( f)-~-homo-testosterone and a sequence was devised for the further transformation of this material into ( +)-progesterone. Details are publishedg3 of Johnson's total syntheses of racemic conessine progesterone and cholesterol by the hydrochrysene route.ClH,C 0dl (93) (94) 0 A. V. Zakharychev D. R. Lagidze and S. N. Ananchenko Tetrahedron Letters 1967 803. 91 H. Schick G. Lehmann and G. Hilgetag Angew. Chem. 1967 79 97; T. Miki K. Hiraga, T. Asako and H. Masuya Chem. and Pharm. Bull. (Japan),1967,15,670; V. J. Grenda G. W. Lindberg N. L. Wendler and S. H. Pines J. Org. Chem. 1967,32 1236. 92 G. Stork S. Danishefsky and M. Ohashi J. Amer. Chem. SOC. 1967 89 5459; G. Stork and J. E. McMurry ibid. pp. 5463 5464. 93 W. S. Johnson J. A. Marshall J. F. W. Keana R. W. Franck D. G. Martin and V. J. Bauer Tetrahedron 1966 Suppl. 8 p. 541. 366 A. B. Turner Elegant manipulation of metal-ammonia reductions to avoid hydrogeno- lysis of oxygen functions allows the ketone (99) to be obtained from the readily available phenanthrene (98).94uThe precursor of this phenanthrene can be converted into ( +)-equilenin methyl ether.94b The ionic A/B-aromatisation of 901,ll P-dichloro- and related derivatives of 1,4-dien-3-ones involves expulsion ofthe angular methyl group as the methyl halide.95a The 1,4,8-trien-l lp-ol(100) gives equilenin with acid under particularly mild conditions.Metal-ammonia reduction of equilenin methyl ether gives the trienol (101) which is readily transformed into equilin and 19-norte~tosterone.~~~ Birch reduction of free phenols can be achievedg6 by increasing the metal concentration thereby overcoming the high potential energy barrier to electron addition to the phenolate anion. Rate differences between the reduction of oestrone and its ethylene acetal may be due to a long-range electrostatic effect.In both cases 94 (a) A. J. Birch and G. S. R. Subba Rao Tetrahedron Letters 1967 857. (b)A. J. Birch and G. S. R. Subba Rao ibid. p. 2763 95 (a)M. Heller R. H. Lenhard and S. Bernstein J. Amer. Chem. SOC.,1967,89 1911 1919. (b)E. J. Bailey A. Gale G. H. Phillipps P. T. Siddons and G. Smith Chem. Comm. 1967 1253. 96 J. Fried N. A. Abraham and T. S. Santhanakrishnan J. Amer. Chem. SOC. 1967 89 1044; cf Ref. 94a. Terpenoids and Steroids 367 the major product is a A5('O)-3a-01 (102) and fully reduced derivatives are also formed. These products also result from solvent-dependent photoreductions of oe~tradiol.~' Use of sodium borohydride in ethanol gives the diol(lO2) and its A/B cis-fused dihydro derivative whereas photoreduction with sodium sulphite yields the corresponding A/B trans-fused oestrane.The 2- and 4-isomers of oestradiol have been prepared.'* Both are very weak oestrogens. A double iso- tope method99 for the simultaneous determination of testosterone and 17- keto-steroids in human plasma involves enzymatic aromatisation to oestradiol followed by bromination with bromine-82. The rate of acetolysis of 3P-toluene-p-sulphonates reflects the distortions produced in ring A by the introduction of double bonds into rings B or c and is correlated with changes in the C-14-4 dihedral angle.looa In 3-ketones the chemical shift of the C-19 methyl protons is affected by similar changes and in addition is proportional to the rate of benzylidene condensation at c-2.1OOb Studies on the directive effects of remote substituents show that whereas A4-3-ketones lacking polar substituents react with alkaline hydrogen peroxide to give exclusively the 4P,SP-epoxides up to 30 "/ of the a-epoxyketone results when the steroid contains a polar group at C-17 or beyond.Polar substituents at C-11 show even stronger directive effects. These results are discussed in terms of electrostatic interactions between the substituents and the anionic transition states. O1 The stereochemistry of hydrogenation of the 4,5-double bond in these ketones is also influenced by the nature of the substituent at C-17.lo2 The geometry of the perhydrophenanthrene skeleton in several steroids has been discussed along with torsional angles at ring junctions and conformational transmission effects.lo3 The dipole moment of SP-cholane-3,12- dione shows that ring A is in the chair form.lo4 This finding invalidates an earlier interpretation of the dipole moment of SP-androstan-3,17-dione in terms of an equilibrium mixture of boat and chair forms-this compound now appears to have a deformed ring D. Spectacular chemical proof of the structure of the backbone rearranged product (103) of androst-5-en-3P,17P-diol (105) is provided'05 by synthesis of the corresponding dione (104) from the ketol (106) by contraction of ring A and expansion of ring D. The 4a,Sa-epoxycholestane (107; R = Me) gives only the backbone rearranged product (108 ;R = Me) on treatment with boron 97 J.A. Waters and B. Witkop J. Amer. Chem. SOC.,1967,89 1022. 98 H. Dannenberg D. Meier and H. J. Gross Z. physiol. Chem. 1967,348 775. 99 J. Saroff R. E. Keenan A. A. Sandberg and W. R. Slaunwhite Steroids 1967 10 15. loo (a)R. Baker and J. Hudec Chem. Comm. 1967,479. (b) R. Baker and J. Hudec ibid. p. 891. lo' H. B. Henbest and W. R. Jackson J. Chem. SOC.(C),1967,2459; H. B. Henbest W. R Jackson and I. Malunowicz ibid. p. 2469; cf. J-C. Guilleux and M. Mousseron-Canet Bull. SOC.chim. France 1967 24. lo2 M. G. Combe H. B. Henbest and W. R.Jackson. J. Chern. SOC.(C) 1967,2467. lo' H. J. Geise C. Altona and C. Romers Tetrahedron 1967,23,439. lo4 N. L. Allinger and C. L. Neumann Tetrahedron 1967,23 1279.J. C. Jacquesy. J. Levisalles and J. Wagnon Chem Comm. 1967 25. 368 A. B. Turner trifluoride. A similar rearrangement occurs with the corresponding epoxide (107; R = H) but in this case hydrogen migration to C-5 is competitive and the product (108; R = H) is accompanied by the normal 4-ketone. A new example of backbone rearrangement of steroids involves the ether (109) which gives the unsaturated alcohol (1 10) with boron trichloride."' When gaseous boron trifluoride is bubbled into a solution of the epoxide (1 11) in benzene OH (103;R=(H ) (104;R = 0) OH 78H17 Ace*@ OH (105;R = H,X =<OH XdPACOaY H (106; R = Me.X = 0;-(108) R I 'CH20H -0 (109) (111) 0 0 (113) J. W. Blunt J. M. Coxon M. P.Hartshorn and D. N. Kirk Tetrahedron 1967,23 1811. lo' M. Fetizon and P. Foy Chem. Comm. 1967 1005. Terpenoids and Steroids the 9P-methyl phenol (1 12) and the 1 la-alcohol (1 13) are formed."* Migration of the angular methyl group to the cationic site generated at C-9 probably becomes competitive owing to the additional driving force derived from aromatisation of ring A. No 11-ketones are formed under these conditions in contrast to the results with boron trifluroide-etherate. The role of the solvent in this reaction remains to be clarified. Kinetic studies on the Westphalen rearrangement of 5a-hydroxycholestanes now reveal a marked dependence on the nature of the 3P-substituent as well as on the 6P-substituent. '09 A number of related rearrangements involving migration of the angular C-18 methyl group to C-17 with concomitant formation of a 13,14-double bond are reported.' lo Some,' la* and conceivably all of these proceed via a A' 7(20)-intermediate.The reaction paths followed in the dehydrogenation of various steroidal 3-ketones by high-potential quinones are rationalised by hydride abstractions from alternative enolic forms of the substrates. '' The mechanism accommo- dates the normal 1,2-dehydrogenation of A4-3-ketones by 2,3-dichloro-5,6-dicyanobenzoquinone and the change to 6,7-dehydrogenation observed in the presence of strong acids. It also allows a simple explanation of the differing effects of chloranil and dichlorodicyanobenzoquinone upon A4-3-ketones in uncatalysed reactions," lb based on the difference in oxidation potential be- tween these two quinones.These reactions involve predominant trans-diaxial elimination of hydrogen as is the case with microbiological 1,2-dehydrogena- tions. '' While hydrogen chloride-catalysed dehydrogenation of A4-3-ketones by high-potential quinones gives 4,6-dienones in good yield Michael addition of the acid to the 6-dehydro derivatives is observed in the analogous reaction with A-nor ketones.' The corresponding 7a-chloro derivatives are formed. Di- unsaturated alcohols of type (1 14) are readily oxidised to the ketones (115) by dichlorodicyanobenzoquinone at room temperature.' l4 The unusual ease of this reaction may reflect the stability of the intermediate carbonium ion; A5~'0~-3-alcohols are not attacked under these conditions.R J. W. ApSimon and R R. King Chem. Comm. 1967. 1214. A. Fischer M. J. Hardman M. P. Hartshorn D. N. Kirk and A. R. Thawley Tetrahedron 1967 23 159. B. Krieger and E. Kaspar Chem. Ber. 1967,100 1169; H. Laurent H. Miiller and R. Wiechert ibid. 1966,99 3836; H. L. Herzog 0.Gnoj L. Mandell G. G. Nathansohn and A. Vigevani J. Org. Chem. 1967,32 2906; E. A. Brown J. Medicin. Chem. 1967 10 546; F. Kohen R. A. Mallory and I. Scheer Chem. Comm. 1967 1019. (a)A. B. Turner and H. J. Ringold J. Chem. SOC.(C) 1967 1720. (b) Ann. Reports 1960 57 201 306. cf H. J. Brodie and P. A. Warg Tetrahedron 1967,23 535. P. A. Diassi S. D. Levine and R. M. Palmere J. Medicin. Chem. 1967 10 551. M. Heller R. H. Lenhard and S.Bernstein Steroids 1967 10 21 1. 3 70 A. B. Turner P (115) The stability of isolated double bonds generated by dehydration of various 14a-hydroxyandrostanes is discussed."' Dienes of type (116) obtained by acid-catalysed rearrangement of the corresponding 5,7-dienes are stable in the cholestrol series. In the progesterone series cleavage of the C,,-C, bond occurs with acid and the aromatic product (1 17) is formed."" Further examples of the dual enolization of 50-3-ketones have appeared in brominations' and dehydrogenations,' lo and the directing effect of an 110-hydroxyl group on enol acetylation in this system has been studied."7b The mechanism of formation of steroidal dithianes has been clarified."* Reaction of ethane dithiol with 6a-chloro-4-en-3-ones under mild conditions gives 3-ethylene-thioacetals (1 18) which rearrange in pyridine to the dithianes (1 19).These dithianes are also formed directly from the original chloro com- pounds and have previously been obtained from 6P-acetoxy-4-en-3-ones. It now appears that initial attack is at C-3 with rearrailgement of the inter- mediate thioacetal rather than at C-4 as suggested earlier. The chirality of the sulphur atom in steroidal sulphoxides influences the direction of pyrolytic elimination to form olefins.llg The absolute configuration of the sulphoxides is assigned from product ratios and the relative stability of transition states in which the incipent double bonds are well-developed. 4-Chloro-pregna-1,4,6-trien-3,20-dione adds two equivalents of diazo-methane.Cleavage of the crude his-pyrazoline with perchloric acid gives the 'I5 L. Mamlok hll. Soc. chim. France 1967 3827. 'I6 J. Lakeman W. N. Speckamp and H. 0.Huisman Tetrahedron Letters 1967 3699. (a)R. Jacquesy and J. Levisalles &ll. SOC.chim. France 1967 1642. (b)A. J. Liston and M. Howarth J. Org. Chem. 1907,32 1034. 'I8 G. Karmas J. Org. Chem. 1967 32 3147 cJ M. Tomoeda A Ishida and T. Koga Chem. and Pharm. Rull. (Japan),1967 15 887. D. N. Jones and M. J. Green J. Chem. Soc. (C) 1967 532. Terpenoids and Steroids 37 1 bis-methylene derivative (12O)l2O Only the 1,2-double bond is attacked in unsubstituted 1,4,6-trienones. Addition to the 6.7-double bond is made possible by the added electron-withdrawing effect of the 4-chloro substituent.The same bis-methylene compound (1 20) results from direct methylenation using dimethyl sulphoxonium methylide. An ionic mechanism is proposed for pyrolysis of nitrites in the molten phase where hydrogen atom transfer typical of photolytic reactions does not occur. Vapour-phase pyrolysis on the other hand does involve alkoxy radicals which rearrange via the usual six-membered transition states. Tracer work shows that benzylic rearrangements of cholestane-2,3-diones occur mainly after attack at C-3 and proceed predominantly through quasi- chair intermediates. 122 New natural steroids include cyasterone a novel C2 insect moulting sub-stance from Cyathda capitata. This is biogenetically related to sitosterol whereas all previously isolated compounds having this type of activity are cholesterol derivatives.3a The identity of 20-hydroxyecdysone from various crustaceans and plants has been established. '23b The presence of this compound along with its 50-hydroxy derivative in the fern P. uulgare indicates that com- pounds of this character may be exogenous factors which an insect receives with its food.L23c This assumption is indirectly borne out by the isolation of compounds having moulting hormone activity from adult insects in which the phoracic glands have degenerated. 20,25-Dihydroxyecdysone has been iso- lated from tobacco h~rnworm.'~~ Comparative experiments with ruscogenin have revealed inconsistencies between its behaviour and that of digacetigenin thereby casting doubt on the presence of an lp-acetoxy group in the latter.'25a This has led to a new lZo R.Wiechert Angew. Chem. 1967.78 815. D. H. R. Barton G. C. Ramsey and D. Wege J. Chem. Soc. 1967 1915; c$ B. W. Finucane J. B. Thomson and J. S. Mills Chem. and Id., 1967 1747. J. Levisalles and I. Tkatchenko Wtll. Soc. chim. France 1967 3125 3131. 123 (a) T. Takemoto Y. Hikino K. Nomoto and H. Hikino Tetrahedron Letters 1967 3191. (b) M. N. Galbraith D. H. S. Horn P. Hocks G. Schulz and H. Hoffmeister Naturwiss. 1967 54,47 1. (c)J. Jizha. V. Herout. and F. Sorm Tetrahedron Letters. 1967. lfiX9. 51 39. lZ4 M. J Thompson J. N. Kaplanis. W. E. Robbins. and R T Yarnamoto Chem. Comni.. 1967. 650. 125 (a)C. W. Shoppee R. E. Lack and B.C. Newman J. Chem. Soc. (C) 1967 339. (b) C. W. Shoppee N. W. Hughes R. E. Lack and B. C. Newman Tetrahedron Letters 1967 3171; R. Tschesche H. G. Berscheid H-W. Fehlhaber and G. Snatzke Chem Ber. 1967 100 3289. (c) cf D. Satoh and S. Kobayashi Chem. and Pharm. Wtll. (Jcpan) 1967. 15,248; Ann. Reports 1966 63 458. 372 A. B. Turner formulation (121)'25b which accommodates a novel mechanism for the acid-catalysed elimination of water in ring D :12" Details have appeared'26 of the synthesis of tachysterol and of a partial synthesis of aldosterone from adrenosterone.' 27 Renewed interest in steroid conjugates stems partly from their probable direct involvement as intermediates in metabolic processes rather than simply as end products. A number of oestrogen monoglucuronides have been syn-thesised,12* as well as some novel double conjugates.The latter include oestradiol-3-sulphate-17-glucuronide (l22)lZ9 and oestriol-3-sulphate-16-glucuronide (123),'30 both isolated as their dipotassium salts. The synthesis of cardenolides has been reviewed.' 31 Details of a method for converting the cardenolide to the corticoid side-chain are reported.' 32 Oxida-tion of digitoxigenin acetate with selenium dioxide gives the corresponding ,.R2 OH HOjS (122; R' = G R2 = -H)Y 'WH (123; R' = H R2= OG) C02H lZ6 R. S. Davidson S. M. Waddington-Feather D. H. Williams and B. Lythgoe J. Chem. Sod. (C) 1967 2534. W. Nagata M. Narisada and T. Sugasawa J. Chem. SOC.(C) 1967 648. lZ8 J. S. Elce J. G. D. Carpenter and A.E. Kellie J. Chem. Soc. (C) 1967 542; T. Nambara and K. Imai Chem. and Pharm. Bull. (Japan) 1967,15 1232. lZ9 E. W. Cantrall M. G. McGrath and S. Bernstein Steroids 1966,8 967. 130 J. P. Joseph J. P. Dusza and S. Bernstein J. Amer. Chem. SOC. 1967,89 5078. 13' W. W. Zorbach and K. V. Bhat Adv. Carbohydrate Chem. 1966,21 273. 13' N. Danieli Y. Mazur and F. Sondheimer Tetrahedron 1967,23 715. Terpenoids and Steroids 17whydroxy compound which on ozonolysis and saponification yields a deri- vative of cortisone. Acid-catalysed rearrangement of isodigitoxigenin (124) and derived acetals (125) lead to the novel spiro-c-nor-cardanolide (1 26) and -cardenolide (127).' 33 The remarkable ease of this C-12 -+ C-14 methylene migration contrasts with the usual methyl group migration in Westphalen rearrangements (cf.Ref. 109). Progress towards the synthesis of the natural bufadienolides continues' 34 with the conversion of digitoxigenin into 3p- acetoxyisobufalin methyl ester (1 28) via one of the isomeric acetals (1 25). Microbiological degradation of the cholestrol side-chain involves carbon- carbon bond fission at 24-25 22-23 and 17-20 with elimination of two molecules of propionic acid and one of acetic acid.'35 Although the initial cleavage finds a parallel in the conversion ofcholesterol to bile acids in mammals this mode of formation of 17-ketosteroids from cholesterol differs from the mammalian pathway which involves initial cleavage at Czo-C22 to give pregnenolone and isocaproic aldehyde.133 T. R. Kasturi. G. R. Pettit,and J. Occolowitz,Cham. Comm.. 1967,334:G.R. Pettit,J. C. Knight and T. R. Kasturi ibid. p. 688. 134 T. R. Kasturi G. R. Pettit and K. A. Jaeggi Chem. Comm. 1967,644. 13' C. J. Sih K. C. Wang and H. H. Tai J. Amer. Chem. SOC.,1967,89 1956; C. J. Sih H. H. Tai and Y. Y. Tsong ibid. p. 1957.