Synthetic study on zizaane-type sesquiterpenoids

摘要

1972 1755Synthetic Study on Zizaane-type SesquiterpenoidsBy Fusao Kido, Hisashi Uda, and Akira Yoshikoshi,' Chemical Research Institute of Non-Aqueous Solutions,Tohoku University, Sendai, JapanThe total synthesis of epizizanoic acid (7.7-dimethyl-6-methylenetricyclo r6.2.1 ,0195 undecane-2a-carboxylic acid)from (+)-3,3-dimethyl-2-methylenenorbornan-l -ylmethanol ( X I I I ) is described. Hydrocyanation of 4- (3.3-di-methyl-2-methylenenorbornan-1 -yl)but-3-en-2-one ( X V ) derived from the alcohol ( X I I I ) , followed byozonolysis and cyclisation, gave 7.7-dimethyl-4-oxotricyclo 6,2,1 ,01~6undec-5-ene-2-carbonitriie ( X V I I ) ,which was converted into methyl 5,6-dihydroxy-7,7-dimethyltricyclo6,2,1,01~8undecane-2-carboxylate( X X I I I ) . The monomethanesulphonate of ( X X I I I ) was submitted to solvolytic rearrangement to afford the5-epimers of methyl 7,7-dimethyl-6-oxotricyclo6,2,1 ,01*5 undecane-2-carboxylate, ( X X I V ) and (XXVa),which have the desired zizaane skeleton. Finally, the epimer (XXVa) was converted into epizizanoic acid (Ib).IN recent years a new class of sesquiterpenoids, thezizaane group, has been isolated from vetiver oil.Thesesesquiterpenoids contain a tricyclo6,2,1 ,01*5undecanesystem with four one-carbon substituents situated a t theC-7 (as a geminal dimethyl group), C-6, and C-2.Zizanoic acid 2-4 (Ia), epizizanoic acid (Ib), isokhusenicacid (11), and zizanol (111), inter alia, have been re-corded as members belonging to this group. Formulaepreviously proposed for tricyclovetivene (zizaene) andkhusimol (also vetiver constituents) have been revisedto the zizaane structures (Ic and d).27899a; R1=C02H,R2=Hc; R 1 =Me,R2=Hb; R'=H.R2=C02Hd; R ' = CHyOH,R2= HIn our study on the structure of zizanoic acid (Ia),the stereochemistry was investigated chiefly by rotatorydispersion of the norketones (IV) and (V), derived from(Ia).3 Lack of suitable model compounds, however,left some uncertainty as to the stereochemistry.? ThusThe crystal structure of khusimyl p-bromobenzoate wasrecently analysed, and the stereoformula proposed by us wasconfirmed.loPreliminary report, F. Kido, H. Uda, and A. Poshikoshi,Chem. Comm., 1969, 1336.* F. Kido, H. Uda, and A. Yoshikoshi, Tetrahedron Letters,1967, 2815.F.Kido, H. Uda, and A. Yoshikoshi, Tetrahedron Letters,1968, 1247.I. C . Nigam, H. Komae, G. A. Neville, C . Redecka, andS. K. Paknikar, Tetrahedron Letters, 1968, 2497, and referencescited therein.we set about the stereoselective total synthesis of thezizaane sesquiterpenoids.Our first project was the ring expansion of suitablysubstituted camphene derivatives, which would lead tobicyclo3,2, lloctane systems corresponding to rings Band c in the zizaane skeleton. Two methods have beenrecorded for such ring expansion of camphene (VIa).Matsubara obtained the homo-ketone (VIII) from (VIa)in good yield on treatment with lead tetra-acetate.llSeveral derivatives of camphene, substituted at thebridgehead, were submitted to this oxidative rearrange-ment, but all the compounds examined (VIb-e),however, were recovered unchanged. Probably thebridgehead substituents sterically retard the reaction.The 3-bromomethylene-norbornane (VIIa) has beenreported to be transformed into a mixture of the ketones(VIII) and (IX) on treatment with base followed byhydrolysis of the vinyl ethers (Xa) so formed,12 and acarbene mechanism has been proposed for the rearrange-ment (VIIa) __t (Xa).13 Bromination of the ester(VIc) gave the dibromide (XI), which was dehydro-brominated to the bromomethylene-ester (VIIb).Thelatter was heated with potassium t-butoxide in toluenegiving a mixture, which showed four peaks in the ratioof 8 : 10: 3 : 12 on g.1.c. The four compounds wereseparated by preparative g.l.c., and their structures wereexamined.The compound eluted most quickly wasidentified as the t-butyl ester (VIf) by comparison withan authentic sample. The product corresponding to thesecond peak showed two olefinic proton signals of anAB-type in the n.m.r. spectrum. This and otherevidence seemed to support the ring-expanded structure(XII) for the product. Since the third product, formedin the least amount, indicated the presence of an olefinicproton and two t-butyl groups in the n.m.r. spectrum, itwas tentatively identified as the desired vinyl ether (Xb).N. Hanayama, I;. Kido, R. Sakuma, H. Uda, and A. Yoshi-koshi, Tetrahedron Letters, 1968, 6099.H. Komae and I. C. Nigam, J . Org. Chem., 1968, 33, 1771.A. Homma, M. Kato, M.-D.Wu, and A. Poshikoshi,R. Sakuma and A. Yoshikoshi, Chem. Comm., 1968, 41.* D. C . Umarani, K. G. Gore, and K. K. Chakravarti, Perf-lo R. M. Coates, R. F. Farney, S. M. Johnson, and I. C. Paul,l1 P. Matsubara, Nippon Kagaktc Zasshi, 1955, 76, 1088,l2 J . Wolinsky, J. Org. Chem., 1961, 26, 704.l3 K. L. Erickson and J. Wolinsky, J . Amev. Chem. Soc.,Tetrahedron Letters, 1970, 231; N. H. Andersen, ibid., p. 1755.umery Essent. Oil Record, 1969, 60, 307.Chem. Comm., 1969, 999.1965, 87, 11421756 J.C.S. Perkin IThe last fraction was a mixture, as its n.m.r. spectrumindicated.Although the structures of the products and themechanism had been insufficiently investigated, we dis-continued further elaboration of this scheme because ofthe poor yields.R R(YI) a; R = H (uII1 a; R = Hb; R = C02Hc; R = C02Meb; R = COzMec; R =C02Butd; R = CH~*OACe; R = C lf ; R =C02ButWe adopted, as the second scheme, base-inducedrearrangement of the monosulphonate of a suitablysubstituted tricyclo6,2,1,01~6undecanediol, such as(XXIII) .Judging from the well-documented stereo-selective course of this rearrangement,14 one maypresume that the monosulphonate of the diol (XXIII),for example, rearranges to a tricycl06,2,1,0~*~un-decanone with the stereochemistry shown in (XXIV).Although the 7-hydrogen atom of the predicted re-arrangement product is epimeric with that of zizaane,it has been found that the product may equilibrate withits 7-epimer in base, as experienced with the keto-ester(XXVa), a degradation product of epizizanoic acid (Ib).5Thus, we decided to examine the base-induced rearrange-ment of the a-hydroxy-sulphonate.The alcohol (XIII), which was obtained from (+)-carboxylic acid (VIb) via the methyl ester (VIc), affordedthe aldehyde (XIV) on treatment with dicyclohexyl-carbodi-imide and phosphoric acid in dimet hyl sulph-oxide15 in 80 yield.The aldehyde was condensedwith acetone in the presence of sodium ethoxide to givethe trans-enone (XV), which was hydrocyanated l6 andthe resulting keto-nitrile, without purification, wasozonised to the diketo-nitrile (XVI) in 44 yield. The* The stereochemical assignment based on n.m.r. spectra wasderived from an examination of molecular models and the Karplusrelationship between coupling constants and dihedral angles.1' C.D. Gutsche and D. Redmore, ' Carbocyclic Ring Ex-pansion Reactions,' Academic Press, New York and London,1968, pp. 101-103, and references therein.fact that the product was homogeneous (t.1.c. andn.m.r.) demonstrated stereoselective introduction of thenitrile group into the enone (XV), although its orientationcould not be established. In order to cyclise the diketo-nitrile without elimination of hydrogen cyanide, severalcatalysts (e.g., benzoic acid-pyrrolidine, acetic acid-pyrrolidine, benzoic acid-piperidine, etc.) were examinedwith a variety of reaction times and molar ratios. Thehighest yield (62) of the cyclisation product (XVII)was obtained when the diketo-nitrile was heated inbenzene with 2 mol.equiv. of benzoic acid and piperidine,with azeotropic removal of the water formed during thereaction. The n.m.r. spectrum of the product (XVII)showed a doublet at 6 2.66 p.p.m. indicating that thenitrile group was quasi-equatorial."We attempted to prepare the unsaturated ester(XXII) from the keto-nitrile (XVII). Desulphurisationof the thioacetal (XVIII), derived from (XVII), gavepoor and variable yields of the unsaturated nitrile (XIX),depending upon the activity of the Raney nickel used,while hydrolysis of the nitrile group of (XVIII), prior todesulphurisation, resulted in the formation of a complexmixture. The keto-nitrile (XVII) was treated withsodium borohydride, and the resulting hydroxy-nitrilewas hydrolysed with potassium hydroxide.The crudeproduct was treated with diazomethane followed byJones oxidation giving the keto-ester (XX) in 74overall yield. The thioacetal (XXI), obtained from(XX) without purification, was smoothly desulphurisedwith Raney nickel to the desired unsaturated ester(XXII) in 73 yield.We now considered the configuration of the methoxy-carbonyl group of the unsaturated ester (XXII) becausethis determined whether the final product of the syn-thesis is zizanoic acid (Ia) or epizizanoic acid (Ib). Inthe n.m.r. spectrum of (XXII), the proton Q to the estergroup was observed as a quartet ( J 4 and 10 Hz) at6 2-63 p.p.m. thus demonstrating a quasi-axial con-figuration.* Two conformations (XXVIa) and (XXVIb)are possible for the cyclohexene ring of the unsaturatedester.In both cases, the groups attached to C-1 and-2 are staggered or nearly eclipsed with respect to eachother, as seen in (XXVIa) and (XXVIb). Hence weconcluded that the more stable conformation of thecyclohexene ring must be the former and, consequently,that the configuration of the methoxycarbonyl group isa. We thus expected to obtain epizizanoic acid as thefinal product of this synthesis.Oxidation of (XXII) with osmium tetroxide affordeda diol, believed to be (XXIII), by oxidation on the less-hindered exo-face. Assuming that the dihydroxy-cyclo-hexane ring of (XXIII) adopts a chair conformation, the5-hydroxy-group is equatorial. This configuration isfavourable for the simple rearrangement of the central1,6-bond, in terms of an anticoplanar steric relationship.In fact, the monomethanesulphonate of the diol (XXIII)15 K. E.Pfitzner and H. G. Moffat, J . Amer. Chem. Soc., 1963,85, 3207.16 W. Nagata, S. Hirai, H. Itazaki, and I. Takeda, J . Org.Chem., 1968, 30, 23071972 1757smoothly yielded, on treatment with potassium t-butoxide, the keto-ester (XXIV) as the sole product12Me -aco 0 o L 3 2 C NI 1under mild conditions, while prolonged exposure to thebase gave not only (XXIV) but its epimerisation product(XXVa). The keto-ester (XXVa) was separated fromthe mixture and identified by comparison with anauthentic sample previously prepared from epizizanoicacid.5Ramage and McSweeney have recently described thetotal synthesis of zizanoic acid.17 These authors alsoutilised the diol (XXIII) and its epimer (XXVII) as thekey intermediates in their synthesis. They usedpyridine-triethylamine to effect rearrangement of the* Professor Ramage is now investigating the stereo-chemistry of these diols (personal communication).monomethanesulphonates of the diols into the keto-esters (XXVa) and (XXVIII), respectively.Sincepyridine-triethylamine is not sufficiently strong tocause isomerisation of the keto-esters,17 * how theisomeric keto-esters (XXVa) and (XXVIII) were formedin contrast to our results remains unexplained.The final step of the synthesis was introduction of anexo-methylene group at the 6-position of the keto-carboxylic acid (XXVb) by a Wittig reaction.In orderto obtain (XXVb) without isomerisation at epimerisablecentres, the ester (XXVa) was reduced with lithiumaluminium hydride and then oxidised with Jonesreagent. The sodium salt of the keto-acid (XXVb) wastreated with methylenetriphenylphosphorane in di-methyl sulphoxide. Although the carbonyl group wasunreactive, a large excess of the reagent and prolongedtreatment afforded epizizanoic acid (Ib) in 10 yield.Since the transformations of epizizanoic acid intozizanoic acid (Ia), khusimol (Id), and zizaene 2,8 (Ic)have been reported, the synthesis of epizizanoic acidamounts to the synthesis of these zizaane sesquiter-penoids.EXPERIMENTALAll m.p.s and b.p.s axe uncorrected. U.V. spectra weretaken on a Cary Model 14 spectrophotometer. 1.r.spectrawere run on a Hitachi EPI-S2 or G-2 spectrophotometer.N.m.r. spectra of carbon tetrachloride solutions (unlessotherwise stated) were recorded on a Varian A-60 spectro-meter with tetramethylsilane as an internal standard, andcoupling constants are given in Hz. Optical rotatorydispersions of methanolic solutions and mass spectra wereobtained on JASCO Model ORD/UV-5 and HitachiRMU-6D instruments, respectively.3,3-Dirnethyl-2-methyZenenorbornane-l-carboxylic Acid(VIb).-This was prepared according to the method ofHouben l8 from (+)- or (5)-bornan-2-one (camphor) in ca.70 yield: the (+)-acid, m.p. 75-78', aD22 +83*2"(G 1-9) (1it.,l8 m.p. 83-44', oiIDla +95.5"), vmax. (KBr) 1697,1650, and 896 cm-l, 6 (CDCl,) 1.10 (6H, s ) and 4.68 and4.98 p.p.m.(lH, s, each) (Found: C, 73.45; H. 9.0.CllHL6O2 requires C, 73.3; H, 8.95); the (*)-acid, m.p.107-5-108-5' (lit.,l* 109-1 10").Methyl 3,3-Dimethyl-2-rnethylenenorbornane-l-carboxylate(VIc).-The (+)- or (amp;)-acid (VIb) was esterified with anexcess of ethereal diazomethane to give methyl ester (VIc),b.p. 79-83" a t 4 mmHg, vmax. (film) 1735 cm-l, 6 1.10 16H,s), 3.67 (3H, s), and 4-62 and 4.80 (lH, s, each) (Found: C,74.45; H, 9-55.Methyl 2-Bromo-2-bromomethyZ-3,3-dimethylnorbmnane-1-carboxylate (XI) .-Bromine (8-2 g) was added dropwise to17 D. F. McSweeney and R. Ramage, Tetrahedron, 1971, 27,1481.l* J. Houben and E. Pfankuch, Annalen, 1930, 485, 271.C12H1802 requires C, 74.2; H, 9.35)1758 J.C.S.Perkin Ia stirred solution of the foregoing ester * (VIc) (10 g) in dryether (50 ml) at ice-bath temperature during 1-5 h. Thesolution was washed with aqueous sodium thiosulphatesolution, water, and brine. Removal of the ether leftcrystals (5.55 g) of the dibromo-ester (XI), m.p. 102-102.5"(from methanol), vmX. (KBr) 1710 cm-l, 6 1.32 (6H, s), 3-67(3H, s), and 3.94 p.p.m. (lH, d, J 12) (Found: C, 40.5; H,5.05; Br, 44-75. CI2H1,Br20, requires C, 40.75; H, 5.1;Br, 45.15).Methyl 2-BromomethyZene-3,3-dirnethylnorbornane-l-carb-oxylate (VIIb) .-The dibromo-ester (XI) (5.55 g) was heatedwith a solution of potassium t-butoxide prepared frompotassium (0.55 g ) and dry t-butyl alcohol (40 ml) for 3-5 h.The solution was poured into water and extracted withether. The extracts were washed with water and brine.Removal of the solvent left an oil (4.0 g), which waschromatographed on a silica gel column.Chloroform-n-hexane eluted the bromomethylene-ester (VIIb), an oil(2.41 g), vmZ (film) 1734 and 1634 cm-l, 6 1-31, 1-35, 3.67(3H, s, each), and 5.95 p.p.m. (lH, s) (Found: C, 53.05;H, 6.05.Reaction o/ the Bromomethylene-ester (VIIb) with Potass-ium t-Butoxide.-A solution of the ester (VIIb) (1-5 g) indry toluene (8 ml) was added dropwise to a suspension ofpotassium t-butoxide prepared from potassium (1 g)) indry toluene (120 ml) at room temperature over 20 min, thenthe solution was heated under reflux for an additional 4 h.The mixture was washed with water and brine.Evapor-ation gave an oil (1.05 g), which showed four major peakson g.1.c. (column: Carbowax 20M, 3 mm x 3 m; columntemp. 213"; helium press. 1.5 kg cm-2) with retention timesof 3.8, 4-3, 5.6, and 6.2 min (designated as A, B, C, and D).The compounds were separated by preparative g.1.c.This was identified as t-butyl 3,3-dimethyl-2-methylenenorbornane-1-carboxylate (VIf) by comparison(i.r. and n.m.r.) with an authentic sample, whose prepar-ation is described later.Fraction B. This may be designated as t-butyl 4,4-dimethylbicycZo3,2,loct-2-ene-l-carboxylate (XII) from thefollowing data: vmx. (film) 1725 cm-l, 6 0.99 and 1.02 (3H,s, each), 1-25 (9H, s), 5.08br (lH, d, J lo), and 5-90 p.p.m.(lH, dd, J 10 and 1) (Found: C, 76.5; H, 10.0.C15H24O2requires C, 76.2; H, 10.25).This fraction was tentatively identified ast-butyl 4,4-dimethyZ-2 (or 3) -t-butoxybicyclo 3,2,1 oct-2-ene-1-carboxylate, vmx. (film) 1730 and 1665 cm-l, 6 (CDCl,)1-00 and 1.07 (3H, s, each), 1-37 and 1.47 (9H, s, each),and 5.12br p.p.m. (lH, s).Fraction D. The n.m.r. spectrum showed this fraction tobe a mixture.t-Butyl 3,3-Dimethyl-2-methylenenorbo~nane-l-carboxylateWIf).-A mixture of the methyl ester (VIc) (60 mg),potassium t-butoxide (25 mg), and dry toluene (2 ml) washeated under reflux for 3.5 h. Toluene (0-5 ml) wasdistilled from the mixture, and the heating was continuedfor an additional 2 h. The mixture was poured into water,and the organic layer was washed with brine and dried.Removal of the solvent left an oil (56 mg), vmx.(film) 3050,1723, 1660, and 885 cm-l, 6 1.08 (6H, s ) , 1.45 (9H, s), and4-58 and 4-85 p.p.m. (lH, s, each) (Found: C, 76.55; H,10.2. C,,H,,O, requires C, 76-2 ; H, 10.25).3,3-Dimethyl-2-methylenenorbornan-l-ylmethanol (XIII) .-A solution of the methyl (+)-ester f (VIc) (20 g) in dry* In this series of preparations, the (amp;)-ester (VIc) was usedas the starting material.C12H17Br02 requires C, 52.75; H, 6.25).Fraction A.Fraction C.ether (80 ml) was added dropwise to a stirred suspensionof lithium aluminium hydride (7 g) in dry ether (300 ml)during 45 min, and the solution was heated under reflux for4 h. Sufficient water to destroy the excess of reagent wasadded with cooling (an ice-bath), and the resulting sus-pension was filtered.The filtrate was washed with waterand dried (MgSO,). The ether was evaporated to leave aresidue, which solidified. An analytical sample of theaZcoho2 (XIII), m.p. 31', v,~,, (CCl,) 3400, 1655, and885 cm-l, 6 1.03 and 1-06 (3H, s, each), 3.69 (2H, d, J 3),and 6.26 p.p.m. (2H, s), was obtained on sublimationin vacuo (Found: C, 78.1; H, 10.95. CllHl,O requires C,79-45; H, 10-9yo).3,3-Dimethyl-2-methylenenorbornane- 1-carbaldehyde (XIV) .-A solution of the alcohol (XIII) (16-4 g) and dicyclo-hexylcarbodi-imide (61.8 g) in dimethyl sulphoside (200 ml)was cooled in an ice-bath, and lOOyo phosphoric acid (5 g)was added.15 The solution was stirred a t room tem-perature overnight. Dilute hydrochloric acid (100 ml) wasadded to the solution at ice-bath temperature, and thesolution was stirred for 1 h.The precipitated dicyclo-hexylurea was filtered off and washed with light petroleumthree times. Water was added into the combined filtrates,and the mixture was extracted with ether-light petroleum(1 : 1) three times. The combined extracts were washedwith water and brine. Evaporation gave the crudeproduct, which was distilled in vacuo to obtain the aldehyde(XIV) (13.1 g, 8l), b.p. 81-85' a t 5 mmHg, v,, (film)2700, 1717, 1650, and 888 cm-l, 6 1.13 (6H, s ) , 4-73 (2H, s),and 9.83 p.p.m. (lH, s). The 2,4-dinitrophenyZhydrazone,yellowish orange crystals, melted at 140-142' (Found : C,59.1; H, 5.7; N, 16.2. C,,H,,N,O, requires C, 59.3; H,5.85; N, 16.25).4- (3,3-DimethyZ-2-methyZenenorbornan- 1-y1) but-3-en-2-one(XV).-A solution of the aldehyde (XIV) (10.5 g) in ethanol(30 ml) was added to a stirred mixture of acetone (20 ml)and ethanolic sodium ethoxide prepared from sodium(1.0 g) and ethanol (200 ml).After 19h at roomtemperature , water was added, and the solution wasconcentrated by evaporation. The residue was pouredinto water and extracted with ether. The ether extractswere washed and evaporated to leave an oily product(16.2 g ) . A fraction (10.0 g, 76), b.p. 134-136' at5 mmHg, of the Ketone (XV) was collected, Amax. (MeOH)230 nm (E 9900), vmx. (film) 1670 and 1625 cm-l, 6 1-08, 1-12,and 2-18 (3H, s, each), 4.57 and 4.60 (lH, s, each), and 6.00and 6-93 p.p.m, (lH, d, J 17 each) (Found: C, 82.1; H, 9.9.C,,H,,O requires C, 82.3; H, 9.85).2- (3 , 3-Dimethyl-2-oxonorbornan- 1 -yZ) -4-oxopentanonitrile(XVI).-A solution of the unsaturated ketone (XV) (14.0 g)in dimethylformamide (20 ml) was added to a stirredsuspension of potassium cyanide (9.1 g) and ammoniumchloride (5.6 g) in a mixture of water (45 ml) and dimethyl-formamide (350 rn1),l6 and the mixture was stirred for 10 hat 76-81'.The mixture was diluted with water andextracted with ether. The ether extracts were combinedand washed with dilute hydrochloric acid, water, and brine.Evaporation gave the oily crude hydrocyanation product(13 g), v,, (film) 2230, 1722, 1653, and 880 cm-l.Ozonised air was passed through a solution of the crudeproduct (13 g) in ethyl acetate (400 ml) at -70 to --50deg;,and the resulting ozonide solution was treated withhydrogen over palladium-carbon (10 ; 100 mg) at roomt The (+)-isomer was used in this series1759 1972temperature.The catalyst was filtered off, and the filtratewas washed with aqueous sodium hydrogen carbonate.The ethyl acetate was evaporated to leave an oil, whichwas chromatographed on a silica gel column. Chloroform-ether (4 : 1) eluted the diketo-nitrile (XVI) (7.05 g), vm,(film) 2240, 1723, and 1714 cm-1, 6 (CDC1,) 1.07 (6H, s),2.22 (3H, s), and 3-44 p.p.m. (lH, q, J 4 and 10) (Found:C, 71-75; H, 8-2; N, 5.95. C,,H,,NO, requires C, 72.0;H, 8.2; N, 6.0).Cyclisation of the Diketo-nitrile (XVI) .-A solution of thediketo-nitrile (XVI) (3.43 g), piperidine (2.5 g), and benzoicacid (3-59 g) in dry benzene was heated under reflux undernitrogen for 96 h, while azeotropically removing the waterformed during the reaction with a Dean-Stark head.Thesolution was washed with dilute hydrochloric acid, 5aqueous potassium hydroxide, and water. Removal of thesolvent gave an oil (4 g), which was distilled in vacuo toremove a non-volatile portion. The distillate was pouredonto an active alumina column and eluted with ether togive 7,7-dimethyl-4-oxotr~cyclo6,2,l,O1~6undec-5-ene-2-carbo-nitrile (XVII) 1.68 g, 62 on the basis of the (XVI)consumed and the unchanged diketo-nitrile (XVI) (0.47 g).The nitrile (XVII) was recrystallised from light petroleumto give crystals, m.p.62-62-5", Amx. (MeOH) 240 nm (E13,300), vmax. (CHC1,) 2250 and 1665 cm-1, 6 (CDCl,) 1.18(6H, s), 2.64 (lH, d, J ll), 2-66 (1H, d, J 8), 3.44 (lH, 9,J 8 and ll), and 5.75 p.p.m. (lH, s) (Found: C, 77.8; H,8-25; N, 6.65. C,,H,,NO requires C, 78.1; H, 7.95; N,6.5).3,3-Ethylenedithio-7,7-dinzethyltricyc106,2,1 , O 1 y sundec-5-ene-2-carbonitrile (XVIII) ,-To a solution of the nitrile(XVII) (1.68 g) in acetic acid (33 ml) were added ethanedithiol(4.5 ml) and boron trifluoride-ether (4 ml), and the mixturewas stirred for 16 h at room temperature. The mixturewas diluted with ether and washed with 5 potassiumhydroxide, water, and brine. Evaporation left crystals,which gave, on recrystallisation from methanol, the purethioacetal (XVIII) (1.73 g , 76) as needles, m.p.118-119deg;,vm, (CHC1,) 2230, 1662, and 860 cm-l (Found: C, 66-15;H, 7.05; N, 4.8. Cl,HZ1NS2 requires C, 65-95; H, 7-25;N, 4.8).7,7-Divnethyltricyclo6,2,1 ,0f~su~zdec-5-ene-2-carbon~tr~le(XIX).-An excess of Raney nickel (W-2) was deactivatedby heating in acetone. The thioacetal (XVIII) (60 mg)was added to the above suspension and heated underreflux for 18 h. The Raney nickel was filtered off, and thefiltrate was diluted with water. The product was extractedwith ether. Removal of the ether gave an oil (30 mg),which was chromatographed on a silica gel column. Chloro-form eluted the unsaturated nitrile (XIX) (24 mg), v,,2230 and 800 cm-l (Found: C, 83.35; H, 9.3; N, 7.2.C14Hl,N requires C, 83-55; H, 9.5; N, 6.95).Methyl 7,7-Dirnethyl-4-oxotricy~lo6,2,1 ,01, sundec-5-ene-2-carboxylate (XX) .-A solution of the nitrile (XVII) (470mg) and sodium borohydride (150 mg) in methanol (15 ml)was stirred and heated under reflux for 5 h.Water wasadded, and the product was extracted with ether. Theextracts were combined and washed with water and brine.Evaporation of the ether gave an alcohol (480 mg), v,,(film) 3380, 3020, and 2230 cm-1. The alcohol was dissolvedin a 50 methanol solution (10 ml) of potassium hydroxide(5 g) and heated under reflux for 40 h under nitrogen. Thesolution was cooled to room temperature and diluted withwater. A neutral portion of the product was removed byextracting with ether, and the aqueous layer was acidifiedwith dilute hydrochloric acid.The liberated acid wascollected in ether. The ether extracts were washed withwater and evaporated to give an oily acid. The crude acidwas treated with ethereal diazomethane giving an oilyester (470 mg), v,, (film) 3390, 1732, and 786 cm-l.An excess of Jones reagent (SN) was added to a solutionof the above-mentioned ester in acetone (10 ml), and thesolution was shaken at room temperature for 5 min. Usualwork-up afforded crystalline product (400 mg, 74).Recrystallisation from light petroleum gave the pureketo-ester (XX), m.p. 90-91", A,, (MeOH) 241 nm (E15,400), vmx. (CHC1,) 1730 cm-l, 6 (CDCl,) 1.13 (BH, s),2-64 (lH, d, J 8), 2-67 (lH, d, J lo), 3-33 (lH, q, J 8 and lo),and 5-80 p.p.m. (lH, s) (Found: C, 72.7; H, 7.9.C1,Hz0O,requires C, 72-55; H, 8*ly0).Methyl 7,7-Dimethyltricyclo6,2,1 ,01- 6undec-5-ene-2a-carb-oxylate (XXII) .-A solution of the keto-ester (XX)(230 mg), ethanedithiol (0.3 ml), and boron trifluoride-ether(0.5 ml) in acetic acid (6 ml) was left at room temperaturefor 40 h. The mixture was worked-up in the usual mannerto give the crystalline thio-acetal (XXI) (290 mg). The crudethio-acetal (200 mg) was added to a stirred ethanolicsuspension of Raney nickel (W-2), deactivated by heatingwith boiling acetone, and heated under reflux for 20 h.The nickel was filtered off, and the filtrate was diluted withwater. Extraction of the product with ether gave the oilyunsaturated ester (XXII) (83 mg), v,, (film) 1735 cm-l,6 (CDCl,) 1.05br (6H, s), 2-63 (lH, q, J 4and lo), 3.70 (3H, s),and 5-20 p.p.m. (lH, d, J 4) (Found: C, 77.0; H, 9.4.C15H22O2 requires C, 76.9; H, 9.45).Methyl 5~,6~-Dihydroxy-7,7-d~vnethyltr~cycl06,2, 1,015 6 -u~ecane-2u-carboxylate (XXIII) .-A solution of the un-saturated ester (XXII) (80 mg) and osmium tetroxide(98 mg) in pyridine (2 ml) was stored at room temperaturefor 5 days.A saturated aqueous solution of sodiumhydrogen sulphite (1 g) was added to the stirred mixture,and the stirring was continued at the same temperature for3 h. Water was added, and the product was extracted withether. The extracts were washed with dilute hydrochloricacid, water, and brine. The ether was evaporated to leavea crystalline residue (88 mg), which upon recrystallisationfrom n-hexane gave the dihydroxy-ester (XXIII), m.p.109-llO", v,, (CHC1,) 3600, 3400, and 1728 cm-l, 6(CDCl,) 1.03 and 1-12 (3H, s, each), 3.10 (lH, m), 3.67(3H, s), and 4.20 p.p.m.(lH, m) (Found: C, 67.3; H, 9.0.C15H,404 requires C, 67.15; H, 9.0yo).Solvolysis of the Monomethanesulphonate of the Dihydroxy-ester (XXIII) .-A solution of the dihydroxy-ester (XXIII)(88 mg) and methanesulphonyl chloride (75 mg) in pyridine(2 ml) was left at room temperature overnight. The oilymethanesulphonate (90 mg), v,, 3530, 1728, 1350, 1175,and 930 cm-l, was obtained on addition of water followed byextraction with ether. The crude methanesulphonate(20 mg) was dissolved in t-butyl alcohol (0.5 ml), andthereto t-butyl alcohol (2 ml) containing potassium t-butoxide (7 mg) was added.The solution was left a troom temperature for 10 min, then water was added. Work-up gave a crystalline residue (1 2 mg) , which was shown to bealmost homogeneous on t.1.c. Recrystallisation from lightpetroleum gave pure methyl 7,7-dimethy1-6-oxo-5aH-tri-cyc~06,2,1,0~~~undecarte-2a-carboxylate (XXIV), m.p. 92-93", v,, (CClJ 1735 and 1697 cm-1, 8 (CDC1,) 1-07, 1.17, and3.67 p.p.m. (3H, s, each), amp;lo -639" (Found: C, 71.8;H, 8.9.The mesylate (90 mg) was treated also with potassiumC1,H,,O, requires C, 71.95; H, 8.85y0)1760t-butoxide (30 mg) in t-butyl alcohol (4 ml) in a similarmanner, except for a longer time (45 min), giving an oilyproduct (70 mg). G.1.c. (Carbowax 20M, 3 mm x 3 m)showed the product to be a 2 : 3 mixture of the 5-epimers(XXIV) and (XXVa).The product was poured onto asilica gel column and eluted with chloroform to afford theBPH-esler (XXVa) (16 mg), the epimeric mixture of (XXVa)and (XXIV), and the keto-ester (XXIV) (5 mg) in thatorder. The keto-ester (XXVa) was recrystallised fromlight petroleum to give crystals, m.p. 78-78-5' (lit.,577-5-78.5'), aD23 3-33-3" (c 0.6), v,, (CC1,) 1738 and1712 cm-l, 6 1.00, 1.17, and 3.64 p.p.m. (3H, s, each),The spectra wereidentical with those of an authentic sample derivedfrom epizizanoic acid,5 and no depression of the m.p. wasobserved on admixture.Epizizanoic Acid (7,7-Dimethyl-6-methylene-5PH-tricyclo-6,2,1,01,5undecane-2a-carboxylic Acid) (Ib) ,-A mixture ofthe keto-ester (XXVa) (78 mg) and lithium aluminiumhydride (30 mg) in anhydrous ether (4 ml) was heatedunder reflux for 4 h. The mixture was worked-up in ausual manner to give a diol, an acetone solution of whichwas treated with an excess of Jones reagent (SN) a t roomtemperature for 7 min. Work-up as before afforded the+6900deg;, C$I2,, -9400" (a +164).J.C.S. Perkin Iketo-carboxylic acid (XXVb) (60 mg). A methanolicsolution of the keto-carboxylic acid was neutralised with0-1~-aqueous sodium hydroxide (with phenolphthalein asan indicator), then the solvent was removed in vucuo. Theresidue was dissolved in water, and some insoluble sub-stances were filtered off. The filtrate was evaporated togive a sodium salt. Methylenetriphenylphosphorane solu-tion prepared from triphenylphosphonium bromide (900mg) and sodium hydride (60 mg) in dimethyl sulphoxide(2.5 ml) was added to the sodium salt in dimethyl sulphoxide( 1 ml), The mixture was heated a t 58" under nitrogen for 7days and diluted with water. After extracting with etherto remove a neutral portion, the aqueous layer was acidifiedwith dilute hydrochloric acid. Extraction with ether gavean oily product (72 mg), which was chromatographed on asilica gel column. Chloroform-ether (1 : 1) eluted eei-zizanoic acid (Ib) (6 rng), m.p. 108~5-110deg; (from aqueousmethanol) (lit.,5 109-110~5'), vmx. 2600, 1700, 1640, and898 cm-1 (Found: C, 76-65; H, 9-5. C15H22O2 requires C,76.9; H, 9.45). The i.r. spectrum was identical with thatof natural epizizanoic acid.We thank Mrs. R. Tanaka for the 0.r.d. measurements.1/2311 Received, 6th December, 1971