A total synthesis of an antibacterial clerodane, 16-hydroxycleroda-3,13(14)Z-dien-15,16-olide

摘要

757J. CHEM. SOC. PERKIN TRANS. I 1995 A total synthesis of an antibacterial clerodane, 16-hydroxycleroda- 3,13( 14)Z-dien-l5,16=0lide Hisahiro Hagiwara,* Kazuhiro Inome and Hisashi Uda Institute for Chemical Reaction Science, Tohoku University, Katahira, Aoba-ku, Sendai 980-77, Japan The total synthesis of an antibacterial clerodane, 16-hydroxycleroda-3,13( 14)Z-dien- 15,16-olide, has been achieved and its absolute stereochemistry has been determined. The wide distribution of clerodane diterpenoids amongst plants and microorganisms makes them an important group of natural products, particularly so since of the 800 known clerodanes' a number have significant bioactivity, e.g. insect antifeedant, antibiotic or antitumour; nevertheless, the bioactivity of most clerodanes has yet to be explored.In spite of much synthetic effort, there have been only two successful total syntheses of optically active clerodanes so far. 16-Hydroxycleroda-3,13( 14)Z-dien-l5,16-olidet 1was first isolated by Bohlman et al. from Acritopappus longifolius3a and then from several sources such as Polyalthia longifolia,3b,3d Polyalthia viridis3' or Premna ~ligotricha.~ Although, at the time when Tayur isolated compound 1, only its antifeedant activity towards casterlooper was known,3b Waterman found that it had antibacterial activity comparable to that of streptomycin against a number of Gram- positive ba~teria.~ It is of note that thin twigs of plants containing the compound have been used as chewing sticks while the smoke formed from burning such plants has been used to sterilise milk containers in southern Ethi~pia.~ Although the relative stereochemistry of the acetate 2 was determined by 0 Ro,q513 ' 19 18 lR=H 2R=Ac X-ray ~rystallography,~~ the absolute stereochemistry has not been rigorously established.In view of significance of its biological activity, it was considered of importance to determine the absolute stereostructure of the clerodane 1, since two enantiomeric series, those arising from clerodane and ent-clerodane, occur in natural products. Biologically active compounds from plant sources are attractive targets for total synthesis in view of the difficulty in culturing plant cells. The intriguing bioactivity and lack of assignment of absolute stereochemistry stimulated us to investigate a total synthesis of 1; herein we delineate such a first total synthesis of 1,5 starting from (5R,9R,10R)-(-)-5 (99 optically pure).Results and discussion Our retrosynthetic analysis is described in Scheme 1. There were t Non-systematic numbering is used in this text, except in the Experimental section. 1 3 n Fs-amp;.*-I 0'e'0 4 Scheme 1 two major problems in the total synthesis of 1: the first was the construction of the y-hydroxybutenolide moiety and the second the introduction of four contiguous asymmetric centres in the decalin portion. We envisioned that the y-hydroxybutenolide moiety of 1 could be generated by photooxygenation of the furan 3 which, in turn, could be derived from the ketal 4 via addition of 3-furyllithium. The ketal4 would be obtained after transposition of the carbonyl group of the decalone (-)-5 whose enantiomer has been synthesised in stereochemically defined manner and used as a starting point for some biologically active terpenoids in this laboratory.6 Although we had no information about the absolute stereochemistry of 1, (5R,9R,lOR)-(-)-5 was chosen as the starting material in view of what was known about the absolute stereochemistry of other clerodanes and the sign of the optical rotation of 1.The decalone (-)-5 (99 optically pure 6a) has already three asymmetric centres in line with the four contiguous asymmetric centres of 1. The fourth asymmetric centre at C-8 was introduced by reduction with lithium in liquid ammonia of the enone 14 formed by enone transposition of the enone 12.For introduction of the butenolide moiety at the end of the synthetic pathway, removal of one carbon unit from the side chain was required. Although osmium tetroxide oxidation of the olefin 5 followed by metaperiodate cleavage gave unsatisfactory results, ozonolysis of 5 provided the ozonide 6 which was stable in the presence of dimethyl sulfide, zinc or hot water. However, the ozonide 6 could be reduced with lithium aluminium hydride (LAH) to afford the diol7 (Scheme 2). The 758 J. CHEM. SOC. PERKIN TRANS. I 1995 i c5 6 1' IOTIPS OH I OU0' 7 iv OTIPS OTIPS V 1vi 1OTIPS OTIPS I Scheme 2 Reagents and conditions: i, 0,,CH,Cl,, -78 "C; ii, LAH, Et,O, -78 "C to room temp.; iii, TIPSOTf, 2,6-dimethylpyridine, CH,Cl,, -8 "C; iv, Jones reagent, acetone, -35 to -20 "C, 30 min; v, LDA; HMPA, Me,SiCl, THF, -78 "C, 5 min; vi, PhSeC1, CH,Cl,, -78 "C, 5 min; vii, H,O,; pyridine, CH,Cl, diol7 was a mixture of epimers (3.5 :1)and the configuration of the secondary hydroxyl group at C-8 of the major epimer was assigned as equatorial from the half height width of 8-H (~3~3.5, wljZ 16 Hz), Selective protection of the diol 7 was successful and gave the silyl ether 8 in 79 overall yield upon treatment with triisopropylsilyl trifluoromethanesulfonate (TIPSOTf) at -8 "C. The reactivity of the primary hydroxy group at C-12 was low and attempts to protect it with tert-butyldimethylsilyl chloride (TBDMSCI), triethylsilyl chloride (TESCl) or pivaloyl chloride led to recovery of the starting diol7. Jones oxidation of the silyl ether 8 at -20 "C gave the ketone 9 in 94 yield. In contrast, pyridinium chlorochromate (PCC) oxidation was slow (38 yield, with recovery of the starting alcohol 8) probably because C-8 was a neopentyl position.In order to introduce the 6,7-double bond, the ketone 9 was transformed into the silyl enol ether 10 in 92 yield. Palladium-catalysed oxidation of this to give the enone 12 was slow, a large amount of the ketone 9 being recovered. In turn, the silyl enol ether 10 was transformed with phenylselanyl chloride into the selenide 11 in 80 yield, the oxidative elimination of which with hydrogen peroxide gave the enone 12 in 74 yield.Selanylation of the silyl enol ether 10 was clean and instantaneous, in contrast to direct selanylation of the enolate of the ketone 9 which led to large amounts of the starting ketone 9 being recovered. Introduction of the methyl group at C-8 was accomplished by addition of methyllithium (MeLi) to the enone 12 to afford an epimeric mixture (10: 1) of the allylic alcohol 13 (98 yield) (Scheme 3). Oxidative rearrangement of the allylic alcohol 13 was performed by employing a large excess of chromium oxide and 3,5-dimethylpyrazole to provide the A7*8-enone 14 in 62 yield accompanied by a small amount of the diene 15. Dissolving metal reduction of the A7v8-enone 14 with lithium in liquid ammonia furnished the desired a-methyl decalone 4 and the P-methyl decalone 16 in 65 yield (9: 1)9 along with recovery of the enone 14 (29).Introduction of a proton source after addition of the enone 14 improved the selectivity of the reduction. The relative stereochemistry of the a-methyl group at C-8 of 4 was determined by the coupling constants of 7P-H (6, 2.2, dd, J 14.4 and 2.8 Hz), 8P-H (6, 2.28, dd, J 12 and 2.8 Hz) and 7a-H (6,2.46, dd, J 14.4 and 12 Hz) in the NMR spectrum. The remaining problem in this series of transformations was removal of carbonyl oxygen at C-6 of the ketone 4. Since C-6 was a neopentyl position, it was expected to have low reactivity. Thus, the carbonyl group at C-6 was removed by radical deoxygenation.lo After reduction of the carbonyl group at C-6 of the ketone 4 (9373, the resulting hydroxy group was converted into an S-methyldithiocarbonate to give the xanthate 18 which was treated with tributyltin hydride and azoisobutyro- nitrile (AIBN) to afford the ketal 19 in 89 yield.Hydrolysis of the ketal 19 gave the keto alcohol 20 whose primary alcohol function was reprotected to provide the ketone 21 in 91 overall yield (Scheme 4). Selective deprotection of the ketal moiety of the ketal 19 could not be achieved even by pyridinium toluene-p-sulfonate. Addition of MeLi gave a diastereoisomeric mixture (4 :I) of the alcohol 22 quantitatively which was dehydrated with thionyl chloride to give an inseparable mixture of the exo-olefin 24 (6,4.51, d, J 2 Hz) and the endo-olefin (6, 5.2, br) 23 (1 :2) in 74 yield. Refluxing a solution of a mixture of the exo-olefin 24 and the endo-olefin 23 with a catalytic amount of iodine" in xylene completed isomerization of the exo-olefin 24 into the endo-olefin 23 in 91 yield.According to a molecular mechanics calculation, the endo-olefin 23 would be more stable (AE 1.27 kcal-' mol-' $) than the exo-olefin 24. After several attempts to introduce the y-hydroxybutenolide moiety of 1, including alkylation of maleic anhydride de- rivatives, success was achieved by singlet oxygen oxidation of the furan 3 (Scheme 5). To this end, deprotection of the TIPS ether followed by Swern oxidation provided the aldehyde 26 quantitatively.Addition of 3-furyllithium l3 to the aldehyde 26 gave an epimeric mixture (1 :1) of the alcohol 27 (97 yield), acetylation (92) of which followed by reductive removal of the acetate 28 with lithium in liquid ammonia afforded the furan 3 in 89 yield. Finally, photosensitised oxidation of the furan moiety in the presence of Rose Bengal gave a dioxetane precursor which was regioselectively opened by Hunig base l4 to provide 63 yield a total synthesis of the title compound 1. The spectral data of synthetic 1 were in good agreement with those of the natural product 1 including its optical rotation value (a,, -43 x lo-' deg cm2 g-' (c 0.21, CHCl,), lit.,, .ID-42 x lo-' deg cm2 g-' (c 0.42, CHCI,)).The 'H NMR 11 cal = 4.184J. J. CHEM. SOC. PERKIN TRANS. 1 1995 fJlWS I i 12 0 0 0:L/ 13 OTIPS + 15 iii OTIPS + 14 OTIPSI V c 18 19 Scheme 3 Reagents and conditions: i, MeLi, Et,O, 0 "C, 15 min; ii, CrO,, 2,3-dimethylpyrazole,CH,CI,; iii, Li, liq. NH,, THF, EtOH, -78 "C to reflux, 1 h; iv, LAH, Et,O, -78 to -70 "C, 1.5 h; v, BuLi, CS,, MeI, THF, 0 "C; vi, Bu,SnH, ATBN, xylene, 150 "C, 15 min spectra of both natural and synthetic 1indicated the presence of two C-16 epimers in equal ratio.15 Thus, the absolute stereochemistry of 1 was established as 5R,8R,9R,10R. 759 OH I i 19 0 u 22 21 iv 23 24 V It Scheme 4 Reagents and conditions: i, PTSA, 80 aq. acetone, reflux, 3 h; ii, TIPSOTf, 2,6-dimethylpyridine, CH,Cl,, 0 "C, 1 h; iii, MeLi, Et,O, 0 OC, 10min; iv, SOCl,, pyridine, 0 "C, 1.5 h; v, I,, xylene, reflux, 2h Experimental All mps were determined with a Mitamura Riken hot-stage apparatus and are uncorrected.IR spectra were recorded on a JASCO A-3 or FT/IR-8300 spectrophotometer for solutions in carbon tetrachloride unless otherwise indicated. 'H NMR spectra were obtained for solutions in deuteriochloroform with JEOL-FX 90Q (90 MHz) and JEOL-GX 400 (400 MHz) instruments with tetramethylsilane as internal standard. J Values are given in Hz. Mass spectra were run on a JEOL JMS- DX300 spectrometer with a JMA-3500 data system. Specific rotations, aID, were determined on a JASCO DIP-370 polarimeter for solutions in chloroform, and are given in 10-1 deg cm2 g-l.Medium-pressure liquid chromatography (MPLC) was carried out on a JASCO PRC-50 instrument with a silica gel packed column. Microanalyses were carried out in the microanalytical laboratory of this Institute. Ether refers to diethyl ether. Anhydrous sodium sulfate was used for drying organic extracts. THF was distilled from sodium diphenyl ketyl prior to use. Upon typical work-up, the product was extracted with solvent (2 x 20 cm3 for 1-10 mmol scale reaction). The organic layer was washed with water once and brine once. After being dried over sodium sulfate, the solvent was evaporated under reduced pressure. (4aR,5R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-6-hydroxy-5-(2'-hydroxyethyl)-5,8a-dimethylnaphthalen-l(ZH)-one ethylene ketal7 Ozone (10in oxygen) was bubbled through a stirred solution of the olefin 5 (5.966 g, 21.4 mmol) in dichloromethane (1 50 cm3) 25 27 26 iv 'p 28 3 I' 1 Scheme 5 Reagents and conditions: i, TBAF, THF, room temp., 7 h; ii, (COCl),, DMSO, Et,N, CH,Cl,, -60 to -20 "C; iii, 3-lithiofuran, THF, -78 "C, 15 min; iv, acetic anhydride, pyridine; v, Li, liq.NH,, THF, -78 to reflux, 2 h; vi, 0,, tungsten lamp, Rose Bengal, diisopropylethylamine, CH,Cl,, -70 to -55 "C at -70 "C for 15 min. The resulting solution was flushed with nitrogen and evaporated to dryness at room temperature. The residue hadamp; 1.07 (3 H, s), 1.25 (3 H, s), 1.2-2.8 (13 H, m), 3.9 (4 H, m), 5.03-5.24 (3 H, m) and was dissolved in anhydrous diethyl ether (100 cm3).After addition of LAH (2.41 g, 63.5 mmol) to the solution at -78 "C, the resulting slurry was stirred for 5 h and allowed to warm to room temperature. Aq. ammon- ium chloride was carefully added to the mixture which was then filtered to remove aluminium hydroxide and evaporated to leave the diol7 as an oil (5.28 g), a part of which was purified by MPLC for spectral data. The less polar minor (6s) isomer had mp 143-145 "c; aD +30 (c 0.25) (Found: C, 67.7; H, 9.9. Cl6H2,O4 requires C, 67.7; H, 9.9); vmax/cm-' 3421, 1457, J. CHEM. SOC. PERKIN TRANS. 1 1995 1384, 1335, 1283, 1234, 1177, 1128, 1104, 1047, 1012 and 950; dH(90 MHz) 0.85 (3 H, s, Me), 1.09 (3 H, s, Me), 1.2-2.04 (13 H, m),2.81-2.95(2H, br,OH)and3.614.01 (7H,m,0CH2CH20, 6-H and 2'-H); m/z 284 (M+, 8), 266 (7), 194 (S), 125 (S), 113 (9), 112 (12), 109 (9), 100 (15), 99 (loo), 87 (22) and 86 (36).The more polar major (6R) isomer had mp 108-1 11 "C; alD +14 (c 0.25) (Found: C, 67.3; H, 9.8. Cl6H2,O, requires C, 67.6; H, 9.9); vmaX/cm-' 3270, 1452, 1383, 1335, 1280, 1177, 1128, 1104, 1066 and 949; 6,(90 MHz) 0.85 (3 H, s, Me), 1.09 (3 H, s, Me), 1.39-1.99 (13 H, m), 2.67 (2 H, br s, OH), 3.50 (1 H, m, w1,2 16, 6-H), 3.73 (2 H, dd, J 8 and 7, 2'-H) and 3.85-3.96 (4 H, m, OCH2CH20); m/z 284 (M', lo), 266 (6), 222 (1 l), 194 (S), 178 (4), 125 (7), 113 (9), 100 (20), 99 (loo), 87 (19), 86 (31) and 55 (15). (4aR,5R,6S or 6R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro+ hydroxy-5,8adimethyl-5-(2'-triisopropylsiloxyethyl)-naphthalen-l(2H)-one ethylene ketal8 To a solution of the diol7 (5.28 g, 18 mmol) and 2,6-dimethyl- pyridine (3.15 cm3, 27 mmol) in dichloromethane (25 cm3) was added a solution of TIPSOTf (4.85 cm3, 18 mmol) in di- chloromethane (5 cm3) over 1 h at -8 "C.After the reaction mixture had been stirred for 4 h, the reaction was quenched by addition of aq. sodium hydrogen carbonate to the mixture. After separation of the organic layer, the aqueous layer was extracted with ethyl acetate (x 2). The combined extracts were washed with brine and evaporated to dryness. The residue was purified by column chromatography on silica gel eluent :hexane-ethyl acetate (5 :l) to give the siZyZether 8(7.47 g, 79 overall), a part of which was separated by MPLC for spectral data.The less polar minor (6s) isomer had alD +14 (c 0.37) (Found: C, 68.1; H, 11. C2amp;,O,Si requires C, 68.1; H, 11); v,,,/crn-' 3483,1463,1384,1339,1283,1210,1187,1137,1104,1068,1034, 997,952and911;dH(90MHz)0.83(3H,s,Me),1.05(3H,s,Me), 1.07 (18 H, s, MeCH x 6), 1.0-2.07 (16 H, m), 3.563.67 (1 H, m, OH), 3.75-4.0 (6 H, m, OCH2CH20 and 2'-H) and 4.19 (1 H, br d, J4,6-H); m/z440 (M', lo), 397 (39), 336 (29), 335 (48), 266 (19), 249 (33,223 (13), 205 (15), 188 (28), 187 (79), 175 (15), 162 (12), 161 (12), 161 (38) and 99 (100). The more polar major (6R) isomer had .ID +5 (c 1.16) (Found: C, 68.3; H, 11. C2,H,,O,Si requires C, 68.1; H, 11); v,,,/cm-' 3416, 1463, 1383, 1335, 1281, 1199, 1177, 1128, 1097, 1068, 1014 and 962; 6,(90 MHz) 0.85 (3 H, s, Me), 1.06 (3 H, s, Me), 1.08 (18 H, s, MeCH x 6), 1.37-1.78 (16H, m), 3.33-3.55 (1 H, m, 6-H), 3.74-3.97 (6 H, m, OCH2CH20 and 2'-H) and 4.38 (1 H, d, J 3); m/z (M+, 13), 397 (46), 336 (27), 335 (43), 266 (15), 249 (29), 223 (22), 205 (18), 162 (32), 161 (IOO), 145 (17), 131 (23), 119 (20) and 99 (97).(4aR,5R,8aR)-3,4,4a,5,8,8a-Hexahydro-5,8a+iimethyl-5 (2'-triisopropylsiloxyethy1)naph thalene- 1,6(2H,7H)-dione ethylene ketal9 To a stirred solution of alcohol 8(2.30 g, 5.22 mmol) in acetone (15 cm3) was added Jones reagent dropwise at -35 "C until an orange colour persisted. After 10 min, the reaction was quenched by addition of isopropyl alcohol to the mixture and the product was extracted with ethyl acetate ( x 2).Evaporation of the combined extracts followed by column chromatography of the residue on silica gel eluent hexane-ethyl acetate (5 :I) provided the ketone 8(2.14 g, 94), aD + 16 (c 1.01) (Found: C, 68.7; H, 10.6. C2,H4,04Si requires C, 68.4; H, 10.3); v,,,/cm-' 1742, 1705, 1463, 1382, 1239, 1184, 1128, 1103, 1047, 1013,949 and 884; 6,(90 MHz) 1.04 (3 H, s, Me), 1.06 (18 H, s, MeCH x 6),1.01-1.12(3H,m),1.18(3H,s,Me),1.41-2.37(13 H, m), 3.64 (2 H, dd, J 9 and 2, 2'-H) and 3.844.0 (4 H, m, OCH,CH,O); m/z438 (M+,l), 396 (34), 395 (loo), 333 (13), 323 (lo), 247 (18), 213 (21), 201 (39), 187(17), 185 (21), 145 (1 l), 131 (11), 113 (10) and99 (76).J. CHEM. SOC. PERKIN TRANS. I 1995 (4aR,5R,8aR)-3,4,4a,5,8,8a-Hexahydro-5,8adimethyl-5-(2'-triisopropylsi)oxyethyl)-6-trimethylsiloxynaphthden-1(2N)-one ethylene ketal10 To a stirred solution of lithium diisopropylamide prepared from diisopropylamine (219 mm3, 1.56 mmol) in THF (2 cm3) and butyllithium (1.6 mol dm3 in hexane; 0.8 cm3,1.25 mmol) was added a solution of the ketone 9 (341.6 mg, 0.78 mmol) in THF (5 cm3) at -78 "C. After the mixture had been stirred for 20 min, HMPA (0.54 cm3, 3.1 mmol) followed by a solution of trimethylsilyl chloride (0.4 cm3, 3.12 mmol) in THF (1 cm3) were added to it. Stirring was continued for 10 min after which the reaction was quenched by the addition of aq. sodium hydrogen carbonate to the mixture.The mixture was extracted with ether (x2) and the combined extracts were evaporated to afford an oil which was purified by MPLC eluent hexane-thy1 acetate 5:l); this gave the enol ether 10 (365 mg, 92); v,,/cm-' 1743, 1670, 1464, 1375, 1344, 1253, 1186 and 846; 6,(90 MHz) 0.18 (9 H, s), 0.9 (3 H, s, Me), 1.05 (18 H, s, MeCH x 6), 1.05 (3 H, s, Me), 1.01-1.12 (3 H, m), 1.47-2.33 (11 H, m), 3.64 (2 H, t like, J 8, 2'-H), 3.82-3.97 (4 H, m, OCH,CH,O) and 4.67 (1 H, dd, J 7 and 2, 7-H). (4aR,5R,8aR)-3,4,4a,5,8,8a-Hexahydro-5,8a~ethyl-7-phenylselanyl-5-(2'-triisopropylsiloxyethyl)naphthalene-1,6(2H,7H)dione ethylene ketal 11 To a stirred solution of the enol ether 10 (260 mg, 0.5 mmol) in dichloromethane (1 -5 cm3) was added a solution of phenyl- selanyl chloride (1 12 mg, 0.58 mmol) in dichloromethane (2 cm3) in one portion.After the reaction mixture had been stirred for 5 min aq. sodium hydrogen carbonate was added to it to quench the reaction. The mixture was extracted with ethyl acetate ( x 2) and evaporation of the combined extracts left residue which was purified by MPLC eluent hexane- ethyl acetate (5: l) to afford the selenide 11 (272 mg, 80) and the enone 12 (23 mg, 9 from 9); for 11, aD +120 (c 1.17) (Found: C, 62.7; H, 8.3. C3,H,,04SiSe requires C, 62.7; H, 8.5); v,,,/crn-' 1705, 1464, 1438, 1384, 1184, 1098, 1071, 1001 and 690; 6,(90 MHz) 1.07 (18 H, s, MeCH x 6), 1.11 (3 H, s, Me), 1.16 (3 H, s, Me), 1.02-1.18 (3 H, m), 1.4-2.26 (11 H, m), 3.54-3.92 (6 H, m, OCH,CH,O and 2'-H), 4.42 (I H, dd, J 12 and 8,7-H), 7.21-7.36 (3 H, m, ArH) and 7.48-7.63 (2 H, m, ArH); mJz 594 (M+, 7), 592 (4), 553 (20), 552 (26), 551 (69), 549 (38), 547 (14), 394(15), 393 (25), 333 (22), 332 (1 I), 331 (13), 201 (25), 197 (17), 185 (27), 183 (16), 176 (12), 157 (ll), 147 (ll), 131 (12), 115 (13), 103 (12) and 99 (100).(4R,4aR,8aR)-4a,5,6,7-Tetrahydro-4,8adimethyl4 (2'-triisopropylsiloxyethyl)naphthalene-3,8(4H,8aH)-dione 8ethylene ketal 12 To a stirred solution of the selenide 11 (1.91 1 g, 1 mmol) and pyridine (0.16 cm3, 1.98 mmol) in dichloromethane (8 cm3) was added hydrogen peroxide (30 wt; 0.3 cm3, 9.8 mmol) at 0 "C. After the reaction mixture had been stirred for 1.5 h at 0 "C aq.sodium hydrogen carbonate was added to it to quench the reaction. The product was extracted with ether (x 2) and the combined extracts were evaporated to dryness. The residue was purified by MPLC to give the enone 12 (541.3 mg, 74); aID +31 (c 1.58) (Found: C, 69.0; H, 10.0. C2,H4,04Si requires C, 68.8; H, 10.2); v,,,/cm-' 1672, 1464, 1387, 1276, 1249, 1186, 1106, 1068, 996, 950 and 884; 6,(90 MHz) 1.03 (18 H, s, MeCH x 6), 1.06 (3 H, s, Me), 1.0-1.1 (3 H, m), 1.25 (3 H, s, Me), 1.47-2.63(9H,m),3.61(2H,brt,J7,2'-H),3.94-4.03(4H, m, OCH,CH,O), 5.94 (1 H, d, J 10,7-H) and 7.02 (1 H, d, J 10, 8-H); m/z 436 (M', 5), 394 (16), 393 (47), 333 (1 l), 332 (33), 331 (100),289(10),247(12),235(24),175(21), 161 (14), 115(45) and 99 (36).761 (4R,4aR,8aR)-3,4,4a,5,6,7-Hexahydro-3-hydroxy-3,4,8a-trimethyl-4-(2'-triisopropylsiloxyethyl)naphthalen~8aH)-0ne ethylene ketall3 To a stirred solution of the enone 12 (27 mg, 0.062 mmol) in ether (1 cm3) was added MeLi (1 mol dm3 in hexane; 0.11 cm3, 0.13 mmol) at 0 "C under nitrogen. After the reaction mixture had been stirred for 20 min, aq. ammonium chloride was added to it to quench the reaction. The product was extracted with diethyl ether ( x 2) and the combined extracts were evaporated to dryness. MPLC purification of residue eluent hexane-thy1 acetate (5:l) afforded two diastereoisomers of 13 (27.3 mg, 98). The less polar, major diastereoisomer had rollD -12 (c 2.0) (Found: C, 68.8; H, 10.85. C26H4804Si requires C, 69; H, 10.7); v,,/c111-~ 3432,1464,1375,1335,1238,1186,1128,1079, 949 and 884; amp;(90 MHz) 0.96 (3 H, s, Me), 1.07 (18 H, s, MeCH x 6),1.15(3H,s,Me),1.0-1.17(3H,m),1.36(3H,s, Me), 1.49-2.19 (9 H, m), 3.49 (1 H, s, OH), 3.83-4.03 (6 H, m, OCH2CH20 and 2'-H) and 5.52 (2 H, d, J 1, olefinic H); m/z 452 (M+,0.6), 434 (2), 419 (4), 409 (8),347 (8), 261 (28), 234 (25), 233(100), 199(27), 173(14), 147(11), 131 (15), 115(18), 114(14), 113 (13), 112 (21), 99 (75) and 86 (24).The more polar, minor diastereoisomer had aD +20 (c 0.58) (Found: c, 69.05; H, 10.9. C2,H4,04Si requiresc, 69; H, 10.7); v,,,/cm-' 3417,1463,1375,1240,1186,1092,1072,994,949,915 and 884; amp;(90 MHz) 0.8(3 H, s, Me), 1.07 (1 8 H, s, MeCH x 6), 1.13 (3 H, s, Me), 1.0-1.17 (3 H, m), 1.23 (3 H, s, Me), 1.35-1.84 (7 H, m), 2.37-2.58 (2 H, m), 3.49 (1 H, s, OH), 3.684.01 (6 H, m, OCH,CH,O and 2'-H), 5.55 (1 H, B part of AB type quartet, J 10, olefinic H) and 5.75 (1 H, A part of AB type quartet, J 10, olefinic H); m/z 452 (M+, l), 408 (19), 393 (lo), 347 (15), 278 (16),262(119),261(52),235(13),234(12),233 (26),201(1 I), 199 (51), 175(12), 173(28), 169(25), 159(13), 147(15), 133(13), 131 (18), 119(13), 115(29), 114(16), 113(17), 112(23), 105(ll), 103 (13), 99 (100) and 86 (29).(4aR,5R,8aR)-3,4,4a,5-Tetrahydro-3,4,8a-trimethy14 (2'-triisopropylsiloxyethyl)naph thalene- 1,8(2H,8aH)- dione ethylene ketal 14 To a stirred solution of chromic anhydride (99.9 mg, 1 mmol) in dichloromethane (1 cm3) was added 3,5-dimethylpyrazole (88.7 mg, 1 mmol) at -20 "C under nitrogen.After the mixture had been stirred for 20 min, a solution of the diastereoisomeric mixture of alcohols 13(22.9 mg, 0.05mmol) in dichloromethane (3 cm3) was added and stirring was continued for 20 min. The resulting solution was neutralized with aq. sodium hydroxide (1 mol dm3) and extracted with ethyl acetate ( x 2). Evaporation of the combined extracts followed by MPLC purification of the residue gave the enone 14 (14.2 mg, 62) together with a small amount of the diene 15. The enone 14 had alD -23 (c 1.27) (Found: C, 69.4; H, 10.2. C,,H,,O,Si requires C, 69.3; H, 10.3); v,,,/cm-' 1742, 1675, 1636, 1464, 1377,. 1287, 1241, 1183, 11 11 and 883; dH(90 MHz) 1.04 (18 H, s, MeCH x 6), 1.09 (3 H, s, Me), 0.98-1.13 (3 H, m), 1.28 (3 H, s, Me), 1.42- 1.84 (7 H, m), 1.91 (3 H, d, J 1,6-Me), 2.35-2.52 (2 H, m), 3.52 (1 H, dd, J 7 and 7, 2'-HH), 3.58 (1 H, dd, J 7 and 5, 2'-HH), 3.84.35 (4 H, m, OCH,CH,O) and 5.74 (1 H, d, J 1,7-H); m/z 450 (M +,15), 407 (1 3), 363 (1 6), 25 1 (2 I), 250 (1 OO),249 (25), 189 (12), 161 (12), 131 (lo), 114 (19), 113 (18), 99 (42) and 86 (52).The diene 15 had v,,,/cm-' 1464, 1382, 1187, 1093, 1008, 949, 914, 884 and 681; 6,(90 MHz) 0.82-2.02 (12 H, m), 1.05 (21H,s),1.17(3H,s,Me),3.61(2H,brt,J8),3.91-3.99(4H, m), 4.97 (2 H, d, J 7) and 6.98 (2 H, quartet like, J 9). (4aR, 5R,6R,8aR)-3,4,4a,5,6,7-Hexahydrw5,6,8a-trimethyl-5-(2'-triisopropylsiloxyethyl)naphthalene-l,8-(2H,8aH)dione ethylene ketal4 To a stirred solution of the enone 14 (68.4 mg, 0.152 mmol) in THF (5 cm3) and liquid ammonia (30 cm3)was added lithium (8.9 mg, 1.27 mmol) at -78 "C under nitrogen.After the mixture had been refluxed for 20 min at room temperature, ethanol (0.1 cm3,1.37mmol) was added to it at -78 "C. The re- sulting solution was then allowed to warm to room temperature during 2.5 h after which aq. ammonium chloride was added to it to quench the reaction. The product was extracted with ether (x 2) and the combined extracts were washed with brine and evaporated. MPLC separation afforded the (6s)-methyl deriv- ative 4(40.2 mg, 58.5) and (4aR,5R,6S,8aRj-( +)-3,4,4a,5,6,7- hexahydro-5,6,8a-trimethyl-5-(2'-triisopropylsiloxyethyl)naph-thalene-l,8(2H,8aH)-dioneethylene ketal 16 (4.6 mg, 6.7) along with recovered enone 14(20.1 mg, 29.4).The desired (6s)-methyl ketone 4 had aD -21 (c 2.09) (Found: C, 69.0; H, 10.6. C26H4804Si requires C, 69.0; H, 10.7); vmax/cm-l1717, 1675, 1464, 1378, 1339, 1279, 1182, 1088,1038,884 and 682; 6,(400 MHz) 0.98 (3 H, d, J 6.8,6-Me), 1.0 (3 H, s, Me), 1.03-1.1 (3 H, m), 1.07 (18 H, s, MeCH x 6), 1.33 (3 H, s, Me), 1.39-1.79 (9 H, m), 2.2 (1 H, dd, J 14.4and 2.8, 7P-H),2.28(1H,dd,J12,2.8,8P-H),2.46(1H,dd,J14.4and12, 7a-H),3.75-3.94 (4 H, m, OCH2CH20 and 2'-H) and 4.06 (2 H, m, OCH,CH,O); m/z 453 (M+ + 1, 18), 452 (M+, 49), 409 (23), 365 (27), 321 (27), 267 (12), 252 (19), 196 (35), 191 (1 l), 183 (14), 175(10), 131 (16), 114(12), 113(62), 112(81), 103(16), 100 (ll), 99 (loo), 87 (21) and 86 (44).The (6R)-methyl ketone 16had aD + 16 (c 0.5) (Found: C, 68.9; H, 10.7. C,,H,,O,Si requires C, 69; H, 10.7); v,,,/cm-' 1717, 1464, 1384, 1240, 1188, 1100, 1046, 951, 884 and 682; 6,(400 MHz) 0.9 (3 H, s, Me), 0.9 (3 H, d, J6.4,6-Me), 1.05-1.1 1 (3H,m),l.O6(18H,s,MeCH x 6),1.32(3H,s,Me),1.45-1.7(9 H, m), 2.03-2.12 (2 H, m), 2.52 (1 H, dd, J 14and 14), 3.65 (2 H, m, 2'-H), 3.86-3.95 (2 H, m, OCH,CH,O), 4.05-4.1 (1 H, m, OCH,CHHO) and 4.184.25 (1 H, m, OCH,CHHO); m/z 453 (19), 452 (M', 52), 409 (22), 365 (24), 321 (32), 252 (22), 233 (13), 196 (31), 175 (12), 173 (15), 131 (22), 114 (15), 113 (55), 112 (70), 103 (18), 99 (loo), 87 (19), 86 (48) and 75 (26). (4aR,5R,6R,8aR)-3,4,4a,5,6,7,8,8a-Octahydr~hydroxy-5,6,8a-trimethyl-5-(2'-triisopropylsiloxyethyl)naphthalen-l(2H)sne ethylene ketall7 To a stirred solution of the ketone 4(208.9 mg, 0.461 mmol) in ether (3 cm3)was added LAH (18.2 mg, 0.48 mmol) at -78 "C under nitrogen.After the mixture had been stirred for 1.5 h, water was added to it to quench the reaction. The aluminium hydroxide was filtered off and the filtrate evaporated to leave an oil which was purified by MPLC eluent hexane-ethyl acetate (5: I) to give the alcohol 17(194.2 mg, 93); aD +6 (c 0.84) (Found: C, 69.0; H, 11.0. C,,H5,04Si requires C, 68.7; H, 11.1); v,,,/cm-' 3539, 1464, 1386, 1355, 1302, 1175, 1103, 1068,1014,951,884 and 681; 6,(90 MHz) 0.72 (3 H, s, Me), 0.87 (3H,d, J6,6-Me), 1.07(18H,s,MeCH x 6), 1.11 (3H,s,Me), 1.43-2.55(16H,m),3.63(2H, brt, J8,2'-H),3.72(1 H,s,8-H) and 3.94-4.09 (4 H, m, OCH,CH,O); m/z 454 (M', 49), 412 (31), 41 1 (95), 349 (36), 268 (14), 267 (17), 254 (14), 237 (24), 219 (13), 201 (26), 191 (15), 175 (38), 163 (14), 159 (22), 131 (26), 121 (19), 99 (loo), 95 (23) and 86 (29).0-(4aR,5R,6R,8aR)-l-Ethylenedioxydecahydro-5,6,8a-trimethyl-l-oxo-5-(2'-triisopropylsiloxyethyl)-8-naphthyl S-methyldithiocarbonate 18 To a stirred solution of the alcohol 17(12.6 mg, 0.028 mmol) in THF (1 cm3)was added butyllithium (1.6 mol dm3 in hexane; 0.085 cm3, 0.14 mmol) at 0 "C under nitrogen. Stirring was continued for 30 min at 0 "C and for 1 h at room temperature. After this, carbon disulfide (12 mm3, 0.2 mmol) was added at 0 "C to the mixture which was then stirred for 30 min.Iodo- methane (23 mm3, 0.37 mmol) was then added to the mixture and stirring was continued for 20 min. The reaction was J. CHEM. SOC. PERKIN TRANS. 1 1995 quenched by addition of aq. ammonium chloride to the mixture which was then extracted with ethyl acetate (x 2). The com-bined extracts were evaporated to dryness and the residue was purified by MPLC to provide the xanthate 18(15.4 mg, quant); ~JD +I2 (C 0.99) (Found: C, 61.5; H, 9.5. C~~HS,O,S,S~ requires C, 61.7; H, 9.6); v,,,/cm-' 1464, 1386, 1242, 1177, 1110, 1048, 961, 884 and 681; 6,(90 MHz) 0.75 (3 H, s, Me), 0.87 (3 H, d, J 6, 6-Me), 1.06 (18 H, s, MeCH x 6), 1.29 (3 H, s, Me), 1.42.01 (14 H, m), 2.29-2.35 (1 H, m), 2.51 (3 H, s, MeS), 3.72-4.11 (6 H, m, OCH,CH20 and 2'-H) and 4.88-5.05 (1 H, m, 8-H); m/z 501 (M+ -Pr', l), 438 (33), 437 (93), 263 (34), 237 (13), 221 (13), 201 (52), 176 (16), 175 (loo), 159 (14), 145 (15), 131 (19), 119 (13), 99 (84), 95 (13), 87 (35) and 73 (34).(4aR,5R,6R,amp;R)-3,4,4a,5,6,7,8,8a-Octahydro-5,6,8a-trimethyl-5-(2'-triisopropylsiloxyethyl)naphthalen-1(2H)-one ethylene ketal 19 A solution of the xanthate 18(254.9 mg, 0.47 mmol), butyltin hydride (0.25 cm3,0.93 mmol) and AIBN (1 5.5 mg, 0.094 mmol) in xylene (5 cm3) was heated at 150 "C for 15 min. After the mixture had been cooled to room temperature, xylene was removed by flash column chromatography (eluent hexane).Elution with ethyl acetate followed by evaporation to dryness and purification of the residue by MPLC gave the ketal 19 (182.7 mg, 89); aD +5 (c 1.78) (Found: c, 71.O; H, 11.4. C,,H,,O,Si requires C, 71.2; H, 11.5); v,,,/crn-' 1463, 1383, 1335, 1279, 1240, 1180, 1091, 980, 938, 884 and 681; 6,(90 MHz) 0.69 (3 H, s, Me), 0.82 (3 H, d, J 5, 6-Me), 1.02 (3 H, s, Me), 1.05 (18 H, s, MeCH x 6), 1.2k1.68 (17 H, m), 3.66 (2 H, dd, J 7 and 7, 2'-H) and 3.83-3.98 (4 H, m, OCH,CH,O); m/z 440 (9), 439 (31), 438 (M', 84), 396 (32), 395 (loo), 238 (20), 221 (32), 203 (75), 193 (49), 177 (95), 176 (49), 175 (75), 133 (20), 131 (28), 121 (29), 109 (29), 99 (78), 95 (40) and 86 (22). (4aR,SR,6R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-5-(2'-hydroxyethyl)-5,6,8a-trimethylnaphthalen-l(2H)+ne 20 A solution of the ketal 19 (78 mg, 0.178 mmol) and a catalytic amount of PTSA in 80aq.acetone (5 cm3) was heated under reflux for 3 h. After addition of aq. sodium hydrogen carbonate to the mixture, the product was extracted with ethyl acetate ( x 2). The combined extracts were evaporated after which MPLC purification of the residue afforded the hydroxy ketone 20 (42.3 mg, quant); mp 87-89 "C; aD +34 (c 0.90) (Found: C, 75.8; H, 11. C, 5H2602 requires C, 75.6; H, 11); vmaX/cm-' 3503, 1709, 1453, 1385, 1313, 1254, 1115, 1025, 950 and 669; 6,(90 MHz) 0.81 (3 H, s, Me), 0.84 (3 H, d, J 6, 6-Me), 1.12 (3 H, s, Me), 1.09-2.77 (14 H, m) and 3.4c13.72 (3 H, m, OH and 2'-H); m/z 238 (M', 15), 223 (28), 220 (62), 205 (44), 193 (96), 192 (47), 176 (53), 175 (95), 149 (24), 137 (56), 124 (33), 123 (30), 121 (40),111 (67), 110 (37), 109 (69), 107 (30), 97 (29), 96 (88), 95 (78), 83 (59), 81 (89), 67 (75), 55 (100) and 41 (90).(4aR,5R,6R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-5,6,8a-trimethyl-5-(2'-triisopropylsiloxyethyl)naphthalen-1(2H)-one 21 To a stirred solution of the hydroxy ketone 20 (24.0 mg, 0.101 mmol) and 2,6-dimethylpyridine (35 mm3, 0.30 mmol) in di- chloromethane (1 cm3) was added TIPSOTf (54 mm3, 0.20 mmol) at 0 "C. After the reaction mixture had been stirred for 1 h, aq. sodium hydrogen carbonate was added to it to quench the reaction. The product was extracted with ether (x 2) and the combined extracts were evaporated to dryness.The residue was purified by MPLC eluent hexane-ethyl acetate (5:l) to give the silyl ether 21 (36.3 mg, 91); alD +21 (c 0.64) (Found: C, 73.2; H, 11.9.C,,H,,O,Si requiresC, 73; H, 11.75); v,,,/cm-' J. CHEM. SOC. PERKIN TRANS. 1 1995 1709,1463,1384,1254,1094,1014,950,920,884 and 682;6,(90 MHz) 0.8 (3 H, s, Me), 0.84 (3 H, d, J 7, 6-Me), 1.04 (18 H, s, MeCH x 6), 1.12(3H,s,Me),1.25-2.62(17H,m)and3,6(2H, td, J 7 and 2, 2'-H); m/z 394 (M+, l), 351 (42), 203 (52), 177 (loo), 175 (39), 133 (21), 131 (19), 121 (27), 109 (23), 107 (21), 95 (36) and 75 (26). (4aR,SR,6R,8aR)-Decahydro-l-hydroxy-l,5,6,8a-tetramethyl-5-(2'-triisopropylsiloxyethyl)naphthalene 22 To a solution of the ketone 21 (53.3 mg, 0.135 mmol) in ether (1.5 cm3) was added MeLi (1 mol dm3 in hexane; 0.25 cm', 0.25 mmol) at 0 "C under nitrogen.The reaction was quenched by addition of aq. ammonium chloride to the mixture. The mixture was then extracted with ether ( x 2) and the combined extracts were evaporated to leave an oil which was purified by MPLC eluent hexane-ethyl acetate (5 :l) to give the alcohol 22 (56.6 mg, quant). The less polar, minor isomer had aD + 11 (c 0.41) (Found: C, 73.3; H, 12.3. C25H,,02Si requires C, 73.1; H, 12.3); v,,,/cm-' 3627, 1463, 1385, 1249, 1184, 1086,994,915, 884 and 681; amp;(90 MHz) 0.8 (3 H, s, Me), 0.84 (3 H, d, J7, 6- Me), 0.95 (3 H, s, Me), 1.04 (18 H, s, MeCH x 6), 1.12 (3 H, s, Me), 1.25-2.62 (18 H, m) and 3.60 (2 H, td, J 7 and 2,2'-H); m/z 410 (M+, 279, 367 (4), 349 (8), 220 (15), 219 (82), 193 (25), 191 (48), 177 (15), 175 (19), 163 (52), 149 (57), 137 (29), 135 (25), 131 (24), 123 (69), 121 (24), 119 (21), 109 (loo), 107 (24), 103 (21), 97 (18), 83 (25), 81 (42), 75 (36) and 69 (46).The more polar, major isomer had alD +6 (c0.58) (Found: C, 73.2; H, 12.5. C2,H,,02Si requires C, 73.1; H, 12.3); v,,,/cm 3621,1463,1384,1313,1247,1179,1093,997,884and 682; 6,(90 MHz) 0.73 (3 H, s, Me), 0.85 (3 H, d, J 5,6-Me), 1.03 (3 H, s, Me), 1.07 (18 H, s, MeCH x 6), 1.27 (3 H, s, Me), 1.34- 1.79 (18 H, m) and 3.67 (2 H, t like, J 7, 2'-H); m/z 410 (M', 473, 368 (33), 367 (loo), 235 (26), 217 (62), 191 (39), 177 (19), 131 (20), 123 (20), 109 (35), 103 (18), 95 (36), 81 (19), 75 (26) and 43 (18).(4aR,5R,6R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-l,5,6,8a-tetramethyl-5-(2'-tiisopropylsiloxyethyl)naphthalene 23 To a stirred solution of the diastereoisomeric mixture of the alcohols 22 (3 1.4 mg, 0.07 mmol) in pyridine was added thionyl chloride (0.08 cm3, 1.09 mmol) at 0 "C under nitrogen. After the mixture had been stirred for 1.5 h, ice was added to it to quench the reaction. The product was extracted with ethyl acetate ( x 2) and the combined extracts were evaporated. MPLC purifi- cation of residue provided the endo-olefin 23 and the exo-olefin 24 (20.1 mg, 74) in a 1 :2 ratio. A solution of the mixture of endo- and exo-olefins 23 and 24 (20.1 mg, 0.5 mmol) and iodine (2 mg) in xylene (3 cm3) was heated under reflux for 2 h and then cooled to room temper- ature.Aq. sodium hypochlorite was added to the mixture which was then stirred until it was colourless. The organic layer was separated, diluted with hexane and passed through short column of silica gel. Elution with ethyl acetate followed by evaporation of solvent left an oil which was chromatographed by MPLC eluent hexane to give the endo-olefin 23 (18.2 mg, 91); alD -23 (c 0.44); vmax/cm-l 1463, 1383, 1092, 1014, 884 and 688; 6,(90 MHz) 0.72 (3 H, s, Me), 0.86 (3 H, d, J7, 6-Me), 0.98 (3 H, s, Me), 1.05 (18 H, s, MeCH x 6), 1.57 (3 H, d, J 1, 1-Me), 1.24-2.25(15H,m),3.64(2H,tlike,J7,2'-H)and5.2(1 H, br s, 2-H); m/z392 (M+,7), 350(25), 349 (73), 218 (25), 217 (loo), 191 (63), 189(18), 161 (19), 147(18), 121 (27), 119(36), 109 (36), 107 (34) and 95 (52) (Found: M', 392.3474.C2,H,,0Si requires M, 392.3474). (4aR,5R,6R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-5-(2'-hydroxyethy1)-1,5,6,8a-tetramethyInaphthalene25 A solution ofthe olefin 23(56.2 mg, 0.143 mmol) in THF (1 cm3) and tetrabutylammonium fluoride (TBAF) (1.0 mol dm3 in THF; 0.7 an3,0.7 mmol) was stirred at room temperature for 7 h and then diluted with water and extracted with ethyl acetate ( x 2). Evaporation of the combined extracts followed by MPLC purification of the residue gave the alcohol 25 (34.1 mg, quant); a,, -47 (c 0.57); v,,Jcm-' 3630, 1458, 1383, 1024, 999 and 795; amp;(90 MHz) 0.74 (3 H, s, Me), 0.86 (3 H, d, J 6,6-Me), 0.99 (3 H, s, Me), 1.58 (3 H, s, 1-Me), 1.04-1.79 (11 H, m), 1.92-2.1 (2 H, m), 3.5-3.76 (2 H, m, 2'-H) and 5.2 (1 H, br d, J 1,2-H); m/z 236 (M', 23), 221 (ll), 203 (ll), 194 (17), 193 (loo), 192 (14), 191 (59), 177 (13), 175 (17), 163 (20), 149 (33), 147 (12), 136 (37), 135 (28), 133 (14), 123 (61), 122(39), 121 (47), 119 (18), 109 (36), 108 (20), 107 (73, 105 (29), 95 (71), 93 (44),91 (28), 81 (43), 79 (27), 69 (32) and 55 (37) (Found: M', 236.2140.Cl,H2,0 requires M, 236.2140). 2-(4aR,5R,6R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-l,5,6,8a-tetramethyl-5-naphthylethanal26 To a stirred solution of oxalyl dichloride (14 mm3, 0.16 mmol) in dichloromethane (1 cm3) was added DMSO (23 mm3, 0.32 mmol) at -60 "C under nitrogen. After the mixture had been stirred for 30 min, a solution of the alcohol 25 (7.7 mg, 0.033 mmol) in dichloromethane (3 cm3) was added to it and stirring was continued for 45 min.Triethylamine (45 mm3, 0.32 mmol) was then added to the mixture and the resulting slurry was stirred for 1 h at -20 "C. The mixture was then diluted with water and the product was extracted with dichloromethane (x 2). The combined extracts were evaporated to dryness to afford an oil which was purified by MPLC eluent hexane-ethyl acetate (5 :l) to give the aldehyde 26(9.0 mg, quant); aD -30 (c 0.39); v,,,/cm-' 2863, 2725, 1719, 1459, 1383, 1245, 1175, 1128,1101, 1075,1045, 1001 and 980; amp;(90 MHz) 0.82 (3 H, s, Me), 0.95 (3 H, d, J6,6-Me), 0.99 (3 H, s, Me), 1.57 (3 H, d, J2, 1-Me), 1.11-1.83(8H,m), 1.92-2.11(2H,m),2.39(2H,t,J3.5, 2'-H), 5.2 (1 H, br s, 2-H) and 9.67 (1 H, t, J 3.5, CHO); m/z234 (M+, lo), 191 (11), 190 (35), 176 (ll), 175 (65), 147 (15), 121 (20), 1 19 (15), 107 (17), 105 (17), 95 (15),93 (16), 9 1 (16), 8 1 (16), 79 (14), 69 (14), 58 (30), 55 (16), 43 (100) and 41 (29) (Found: M+,234.1982.C,,H,,O requires M,234.1984). 3-{1-H ydrox y-2-(4aR,5R,6R,8aR)-3,4,4a,5,6,7,8,8a-octahydro-1,5,6,8a-tetramethyl-5-naphthylethy1)furan 27 To a stirred solution of 3-bromofuran (21 mm3, 0.23 mmol) in THF (1 cm') was added tert-butyllithium (1.5 mol dm3 in hexane; 0.15 cm', 0.23 mmol) at -78 "C under nitrogen. After the mixture had been stirred for 30 min, a solution of the aldehyde 26 (10.9 mg, 0.047 mmol) in THF (4 cm') was added to it and the resulting solution was stirred for 25 min at -70deg;C.The reaction was quenched by addition of aq. ammonium chloride to the mixture which was then extracted with ethyl acetate (x2). The combined extracts were evaporated to dryness and the residue was purified by MPLC eluent hexane-ethyl acetate (3 :l) to afford a diastereo-isomeric mixture of the alcohols (1 :1 ratio) 27 (13.7 mg, 97); v,,,/cm-' 3613, 1501, 1458, 1450, 1383, 1161, 1128, 1101, 1044, 1023, 999, 875 and 601; amp;(90 MHz) 0.73 (3 H, s, Me), 0.91 (3 H,d, J6,6-Me), 1.0(3H,s,Me), 1.57(3H,d, J2, 1-Me), 1.25- 2.12 (13 H, m), 4.75-4.93 (1 H, m, 1'-H), 5.19 (1 H, br s, 2-H), 6.41 (1 H, br s, furan) and 7.37-7.41 (2 H, m, furan); m/z 302 (M', 273, 285 (24), 284 (loo), 190 (44),175 (62), 161 (97), 148 (46), 147 (37), 133 (34), 121 (83), 119 (54), 108 (68), 107 (58), 105 (41), 95 (43), 91 (34), 85 (32), 83 (46), 81 (47) and 55 (31) (Found: Mf -H20, 284.2140. C20H280 requires m/z 284.2 140).3-{1-Acetox y-2-(4aR,5R,6R,8aR)-3,4,4a,5,6,7,8,8a-octahydro-1,5,6,8a-tetramethy1-5-naphthylethy1)furan 28 A solution of the alcohol 27 (24.3 mg, 0.08 mmol) in acetic anhydride (1 cm3) and pyridine (1 cm3) was stirred at room 764 temperature overnight under nitrogen. The solution was evaporated to dryness under reduced pressure and the residue was purified by MPLC eluent hexane-ethyl acetate (5 :l) to provide the acetate 28 (25.5 mg, 92); v,,Jcm-l 1742, 1505, 1438, 1371, 1236, 1162, 1024, 951, 875 and 602; 6,(90 MHz) 0.72 (3 H, s, Me), 0.89 (3 H, d, J 6, 6-Me), 0.98 (3 H, s, Me), 1.53 (3 H, s, 1-Me), 1.99 (3 H, s, Ac), 1.25-2.32 (12 H, m), 5.18 (1 H, br s, 1-H), 5.85-6.03 (1 H, m, 1'-H), 6.40(1 H, br s, furan) and 7.35-7.44 (2 H, m, furan); m/z 285 (2273, 284 (M' -AcOH, loo), 269 (21), 190 (42), 175 (55), 161 (77), 148 (37), 147 (33), 133 (32), 121 (77), 119 (47), 108 (60), 107 (55), 105 (44), 95 (47), 93 (39), 91 (35), 81 (47), 55 (34) and 43 (42) (Found: M+ -AcOH, 284.2139.C20H,,0 requires m/z 284.2140). 3-{2-(4aR,5R,6R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-l,5,6,8a-tetramethyl-5-naphthyll ethy1)furan 3 To a stirred solution of lithium (1.7 mg, 0.24 mmol) in liquid ammonia (15 cm3) was added a solution of the acetate 28 (6.6 mg, 0.019 mmol) in THF (5 cm3) at -78 "C under nitrogen. The resulting solution was refluxed for 1.5 h after which liquid ammonia was removed by evaporation overnight at room temperature.Aq. ammonium chloride was added to the mixture and the product was extracted with ether (x2). Evaporation of the combined extracts followed by MPLC purification (eluent hexane) of the residue gave the furan 3 (4.9 mg, 89); aID -58 (c 0.36, CHCl,); v,,,/cm-' 1457, 1383, 1162, 1066, 1026, 874, 668 and 600; 6,(90 MHz) 0.75 (3 H, s, Me), 0.83 (3 H, d, J5, 6-Me), 1.00 (3 H, s, Me), 1.59 (3 H, d, J 2, 1-Me), 1.27-2.47 (14 H, m), 5.20 (1 H, br s, 1-H), 6.27 (1 H, br s, furan), 7.22 (1 H, br s, furan) and 7.37 (1 H, t, J 2, furan); m/z 287 (673, 286 (M+, 27), 271 (17), 191 (18), 121 (14), 107 (19), 96 (15), 95 (48), 81 (25), 58 (58), 43 (100) and 32 (69) (Found: M', 286.2297.C20H300 requires M, 286.2297). (5R,8R,9R,lOR)-16-Hydroxycleroda-3,13(14)Z-dim-15,16-olide 19 Anhydrous oxygen was passed through a solution of the furan 3 (9.2 mg, 0.032 mmol), diisopropylethylamine (56 mm3, 0.32 mmol) and a catalytic amount of Rose Bengal in dichloro- methane (6 cm3) irradiated with a tungsten lamp and held at -78 to -55 "C for 1.5 h. The resulting solution was diluted with a mixture of hexane and ethyl acetate and passed through short column of silica gel to remove Rose Bengal. Evaporation of solvent followed by MPLC purification eluent hexane-ethyl acetate (3 :l) gave the butenolide 1 (6.4 mg, 63); alD-43 (c 0.21, CHCl,) and -46(c0.21, MeOH); v,,,/cm-' 3336br, 1752, sect;Non-systematic numbering is used in this part.See text. J. CHEM. SOC. PERKIN TRANS. 1 1995 1647, 1456, 1132, 957 and 761; 6,(400 MHz) 0.77 (3 H, s, 20-Me), 0.81 and 0.82 (3 H total, d, J6.4, 17-Me), 1.00 (3 H, s, 19-Me), 1.15-1.57(6H,m), 1.59(3H,d, J1.2, 18-Me), 1.63-1.75(4 H, m), 1.99-2.43 (4 H, m), 3.99 (1 H, br s), 5.19 (1 H, br s, 3-H), 5.85 (1 H, s, 14-H) and 6.00 (1 H, s, 16-H); m/z 318 (M+, 3479, 303 (14), 285 (33), 191 (62), 190 (62), 189 (loo), 175 (18), 135 (40), 123 (79) and 107 (83) (Found: M', 318.2194. C20H3003 requires M, 318.2195). Acknowledgements We thank Professor Y. Fujimoto, Tokyo Institute of Technology, for providing spectral data of natural 1.Thanks are also due to Professor T. Tokoroyama, Osaka City University, for helpful discussions. References 1 T. Tokoroyama, J. Synth. Org. Chem., Jpn, 1993,51, 1164. 2 H. Iio, M. Monden, K. Okada and T. Tokoroyama, J. Chem. Soc., Chem. Commun., 1987,358; E. Piers and J. Y. Roberge, Tetrahedron Lett., 1992,33,6923. 3 (a) F. Bohlman, M. Ahmed, J. Jakupovic, R. M. King and H. Robinson, Rev. Latinoamer. Quim., 1984, 15, 16; (b) A. P. Phandnis, S. A. Patwardhan, N. N. Dhaneshwar, S. S. Tavale and N. Tayur, Phyrochemistry, 1988,27, 2899; (c) A. Kijjoa, M. M. M. Pinto and W. Hertz, Planta Med., 1989, 55, 205; (d) Y. K. Gupta, N. Hara, Y. Fujimoto and M. Sahai, Abstracts of Papers of Annual Meeting of Chemical Society of Japan, 1993, II,498. 4 S. Habtemariam, A. I. Gray and P. G. Waterman, Planta Med., 1992,58, 109. 5 Preliminary communication: H. Hagiwara, K. Inome and H. Uda, Tetrahedron. Lett., 1994,35, 8189. 6 (a)H. Hagiwara and H. Uda, J. Org. Chem., 1988,53,2308; (b)Bull. Chem. Soc. Jpn., 1989, 62, 624; (c) J. Chem. Soc., Perkin Trans. I, 1991, 1803. 7 Y. Ito, T. Hirao and T. Saegusa, J. Org. Chem., 1978,43, 101 1. 8 E. J. Corey and G. W. Fleet, Tetrahedron Lett., 1973,4499. 9 J. M. Lutein and A. de Groot, J. Org. Chem., 1981,46, 3448. 10 D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. I, 1975, 1574 D. H. R. Barton and W. B. Motherwell, Pure Appl. Chem., 1981,53, 15. 11 A. Yoshikoshi, M. Kitadani and Y. Kitahara, Tetrahedron, 1967, 23, 1175. 12 Molecular modelling was performed using PCMODEL (Serena Software, Bloomington, IN, USA). 13 S. Takahashi, T. Kusumi and H. Kakisawa, Chem. Lett., 1979,515; T. Tokoroyama, R. Kanazawa, S. Yamamoto, T. Kamikawa, H. Suenaga and M. Miyabe, Bull. Chem. Soc. Jpn., 1980,53,1698. 14 M. R.Kernan and D. J. Faulkner, J. Org. Chem., 1988,53,2773. 15 Personal communication from Professor Y. Fujimoto. Paper 4/07069K Received 18th November 1994 Accepted 6th December 1994