J . Org. Chem. 1989,54, 3820-3823
3820
A Formal Total Synthesis of (&)-9-Isocyanopupukeanane Shu-Ling Hsieh, Chih-Tsao Chiu, and Nein-Chen Chang* Department of Chemistry, National Sun Yat-Sen University, Kaohsiung, Taiwan 80424, Republic
of China
Received December 8, 1988 The tricyclo[4.3.1.03~7]decano1 21, a key intermediate in the Yamamoto's synthesis of 94socyanopupukeanane (l),is prepared in racemic form in 11 steps from the readily available ketone 5. The crucial steps include anionic oxy-Cope rearrangement of an endo-vinylnorbornenol 11 and cyclization of keto mesylate 16 to ketone 17. In 1975, Scheuer and co-workers reported the isolation of 9-isocyanopupukeanane (1) and 2-isocyanopupukeanane (2) from the nudibranch phyllidia varicasa and from its prey, a sponge, Hymeniacidon sp.' As a consequence of the unusual tricycl0[4.3.1.0~~~]decane carbon skeleton and the presence of an isopropyl group in the thermodynamically unfavorable endo face 1 and 2 have emerged as challenging targets for synthetic chemists.
Scheme I
We
". .-
H A
5
16
11
BC P
@
-0
A
YC
Scheme 11
3
Recently, independent syntheses of 1,22,3 and of their degradation product 9-pupukeanone (3)4 and 2-pupukeanone (4)5 have been achieved. We have also pursued a synthesis of 9-isocyanopupukeanane (1) and have developed an efficient alternative preparation of 21, a key intermediate in Yamamoto's approach2bto 1. As shown in Scheme I, the key steps of the present synthesis include (1) the anionic oxy-Cope rearrangement of diol 11 to furnish the cis-hydrindanone 16; (2) intramolecular alkylation of keto mesylate 16 to ketone 17. The preparation of diol 11 was achieved as outlined in Scheme 11. Oxidation of the readily available ketone 5,6 with Jones reagent and subsequent esterification of the intermediate keto acid with diazomethane produced keto ester 6 in 83% yield. With 6 in hand, stereoselective methylation at the C-7 position was required next. Reaction of 6 with ethylene glycol in the presence of a catalytic amount of acid furnished ester 7. Methylation of 7 was effected by deprotonation with lithium diisopropylamide and treatment with methyl iodide (4 equiv). Workup gave rise to a single alkylation product 8 in 99% yield. The stereochemistry of ester 8 is assigned on the expectation that steric shielding by the ketal at C-2 will (1)Burreson, B.J.;Scheuer, P. J.; Finer, J.; Clardy, J. J. Am. Chem. Soc. 1975,97,4763.
(2) (a) Corey, E. J.; Behforouz, M.; Ishiguro, M. J. Am. Chem. SOC. 1979,101,1608.(b) Yamamoto, H.; Sham, H. L. J. Am. Chem. Soc. 1979, 101, 1609. (3) Corey, E. J.; Ishiguro, M. Tetrahedron Lett. 1979,2745. (4)Schiehser, G. A,; White, J. D. J. Org. Chem. 1980,45, 1864. (5)Frater, G.; Wenger, J. Helu. Chin. Acta 1984,67,1702. (6)Chang, N.-C.; Lu,W.-F.; Tseng, C.-Y. J. Chem. Soc., Chem. Commun. 1988,182.
0022-3263/89/1954-3820$01.50/0
8
9
& H
"D 10
A 11
favor the formation of this geometric isomer over the diastereomeric structure. Catalytic hydrogenation of 8 yielded 12. The 'H NMR spectrum of 12 in carbon tetrachloride exhibits methyl resonances a t 1.17 and 3.53 ppm. The spectrum of the known isomeric compound 13 shows methyl resonances at 1.38 and 3.60 ppm.' Additional evidence for our initial assignment was obtained by lithium aluminum hydride reduction of 8 to give alcohol 9 whose C-7 methyl resonance appears at 1.07 ppm. The known epimer 14 exhibits its C-7 methyl resonance at 1.20 ~ p m A. further ~ advantage of converting 8 into 9 is that (2-8, which ultimately becomes (7)Grieco, P. A,; Pogonowski, C. S.; Burke, S. D.; Nishizawa, M.; Miyashita, M.; Masaki, Y.; Wang, C. L. J.; Majetich, G. J.Am. Chem. SOC. 1977,99, 4111.
0 1989 American Chemical Society
J. Org. Chem., Vol. 54, No. 16,1989 3821
Formal Total Synthesis of (&)-9-Isocyanopupukeanane
Scheme IV
Scheme 111
c
23
: j R = H
24
16 R = Ms
c
25
C-2 of 1, is present in protected form which prevents C-8 from Grignard addition in the later stage. 1.17 M e V ; ?
3.60
21
22
1.38
Meo2CYe a
0
0 9
0 3 12
23
13
1.07
M
1.20
e
Y
H
H
O
Y
"4 9
14
Having established the stereochemical requirements about carbon atom C-7 in intermediate 9 we focused our attention on the transformation of the bicyclo[2.2.llheptane derivative 9 to the key intermediate diol 11. Acidcatalyzed hydrolysis of alcohol 9 gave ketol 10 in 93% yield. Addition of isopropenylmagnesium bromide (2.2 equiv) to ketol 10 in T H F solution and heating a t 60 "C for 2 h furnished exclusively the endo addition adduct 11 in 92% yields8 None of the stereoisomer could be detected. The presence of the hydroxymethyl group at C-7 blocks the exo face of ketol 10 from attack by the Grignard reagent. With diol 11 available in reasonably large quantities, oxy-Cope rearrangement to the corresponding cishydrindanone 15 became the next objective. Exposure of 11 to potassium hydride in T H F solution a t 25 "C for 2 h produced ketol 15 in 94% yield (eq l).g
The remaining challenge in the synthesis of 9-isocyanopupukeanane (1) involved ring closure of 15 and regio- and stereoselective introduction of the isopropyl group. Since 24 is cis-fused, hydrogenation of 24 should proceed with selectivity to produce 25 with the isopropyl (8) (a) Jung, M. E.; Hudspeth, J. P. J. Am. Chem. SOC. 1980,102,2463. (b) Jung, M.E.: Hudepeth, J. P.; J. Am. Chem. SOC.1978, 100, 4039. (9) T w o group of vinyl proton appeared at 5.98 and 5.71 ppm in 7?23 ratio. The protons centered at 5.71 ppm was assigned as the vinyl protons in structure 18, which was verified by hydrolyzing pure ketal 20 to 18 under acidic condition.
group at the desired endo face. We initially chose first to install the isopropyl group and then the form the ring (Scheme 111). In order to effect ring closure, the alcohol at C-10 in 15 must be transformed into a leaving group. Since attempted tosylation of the alcohol function returned only unreaded starting material. The mesylate 16 was prepared in 96% yield. Regioselective hydroxylation of C-9 in 16 with 9-BBN would require the protection of the carbonyl function at C-4 first. However, all attempts to effect ketalization of C-4 led to complex mixtures. It appears that keto mesylate 16 is susceptible to acidic conditions and undergoes decomposition and rearrangement faster than ketalization. In view of the above results, an alternative route was devised (Scheme IV) in which the order of reactions was inverted so that the isopropyl group a t C-9 was introduced after the ring formation. Closure of the six-membered ring by addition of 2.5 equiv of potassium tert-butoxide to a solution of mesylate 16 in dry tert-butyl alcohol and stirring at 25 "C for 2 h afforded ketone 17 (52%) together with its structural isomer 18 (15%) as judged by the NMR spectrum.1° The undesired byproduct 18 becomes the major cyclization product when lithium diisopropylamide or less than 2.5 equiv of potassium tert-butoxide was used as the reagent. Finally, the synthesis of the alcohol 21 was achieved as follows. Ketalization of the mixture of 17 and 18 with ethylene glycol provided a mixture of ketal 19 and 20. This mixture was further regioselectively hydroborated at 60 "C with 9-BBN for 2 h followed by hydrogen peroxide oxidation of the corresponding borane to afford alcohol 21 and recovered 20.l' Their separation was readily achieved by flash column chromatography, and the desired alcohol 21 was obtained in 38% overall yield from 16. Oxidation of alcohol 21 with PDC afforded ketone 23. The NMR spectrum of ketone 23 is identical with that of the au(10) Soderquist, J. A,; Brown, H. C. J. Org. Chem. 1980,45,3571-3578. (11) Prolonged reaction time enriched the formation of alcohol 22. (12) Eisenbraun, E. J. Org. Synth. 1965,45, 28.
3822 J. Org. Chem., Vol. 54, No. 16, 1989
Hsieh et al.
thentic ~ a m p 1 e . l ~Since 23 has been previously converted to 9-isocyanopupukeanane ( 1),2b this constitutes a formal total synthesis of t h e racemic toxin.
1 H), 2.79 (br s, 1 H), 2.33 (dd, J = 13.0, 3.4 Hz, 1 H), 1.49 (d, J = 13.0 Hz, 1 H), 1.23 (s, 3 H). I3C NMR (300 MHz, CDCl,): 6 176.18, 137.86,131.18,117.34, 66.62,64.07,64.02, 55.59, 51.22, 47.37,38.67, 18.22. IR (neat, cm-'): 1726. Mass (HR) m/z (M+):
Experimental Section
calcd 224.1049, obsd 224.1038. Hydrogenation of Ketal Ester 8. A solution of 8 (150 mg, 0.67 mmol) in methanol (5 mL) was stirred under 1 atm of hydrogen at room temperature with 5% palladium in chaarcoal(15 mg) for 2 h. The mixture was filtered, and the filtrate was evaporated to give 132 mg (87%) of 12 as a colorless oil. 'H NMR (90 MHz, CCl,): 6 1.17 (s, 3 H), 1.97-1.20 (m, 5 H), 2.30-2.03 (m, 3 H), 3.53 (8, 3 H), 3.80 (m, 4 H).
Materials. Ether and tetrahydrofuran (THF) were distilled prior to use from a deep-blue solution resulting from benzophenone and sodium. All other reagents and solvents were obtained from commercial sources and used without further purification. Procedures. Reactions were routinely run under a dry nitrogen atmosphere with magnetic stirring. Organic solutions of products were dried with anhydrous magnesium sulfate prior to concentration in vacuo. Crude products were purified by preparative TLC or column chromatography on silica gel. All reported temperatures are uncorrected. The purity of all titled compounds was shown to be at least 95% by proton NMR and TLC analyses. Methyl 2-0xobicyclo[2.2.l]hept-5-ene-7-carboxylate(6). To a solution of 5 (15.0 g, 83.0 mmol) in acetone (30 mL) at room temperature was added excess Jones reagent.12 The mixture was stirred for 15 min and treated with 2-propanol to destroy the unreacted oxidation reagent. After the solvent was removed, the residue was diluted with water and extracted with ethyl acetate (4 X 50 mL). The organic phase was dried, filtered, and concentrated. The residue was dissolved in ether and treated with CH2N2. After 15 min, nitrogen was bubbled into the solution to remove excess CH2N2. The ether solution was concentrated, and the residue was chromatographed on silica gel (elution with 2:l n-hexanelethyl acetate) to furnish 11.5 g (83%) of keto ester 6 as a yellow oil. 'H NMR (300 MHz, CDC13): 6 6.58 (m, 1H), 6.14 (m, 1 H), 3.71 (s, 3 H), 3.39 (br s, 1 H), 3.30 (m, 1 H), 3.22 (m, 1 H), 2.09 (dd, J = 17.1, 3.0 Hz, 1H), 1.89 (dd, J = 17.1, 3.0 Hz, 1 H). 13C NMR (300 MHz, CDCl,): 6 211.84, 171.02, 142.86, 130.34, 63.79, 56.75, 52.00, 42.21, 33.36. IR (neat, cm-'): 1730 (br). Mass (HR) m / z (M'): calcd 166.0630, obsd 166.0627. Anal. Calcd for C9H1003: C, 65.06; H, 6.02. Found: C, 64.73; H, 6.11. Methyl 2,2-(Ethylenedioxy)bicyclo[2.2.l]hept-5-ene-7carboxylate. To 11.0 g (66.4 mmol) of keto ester 6 in 80 mL of benzene were added 5.0 mL (79.6 mmol) of ethylene glycol and 0.5 g (2.5 mmol) of p-toluenesulfonic acid. The mixture was heated at reflux for 3 h under a Dean-Stark trap. The product was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate solution and brine, and dried (MgSO,). The solvents were evaporated to afford 13.5 g of crude 7. Flash chromatography on silica gel (elution with 2:l n-hexanelethyl acetate) gave 12.7 g (91%) of ketal ester 7 as a colorless oil. 'H NMR (300 MHz, CDC13): 6 6.30 (m, 1H), 6.15 (m, 1 H), 3.96-3.74 (m, 4 H), 3.61 (s, 3 H), 3.00 (br s, 1 H), 2.90 (br s, 1 H), 2.70 (br s, 1 H), 2.20 (dd, J = 11.5,2.89 Hz, 1 H), 1.44 (m, 1H). 13CNMR (300 MHz, CDCl3): 6 171.27, 139.34,133.59,117.03, 64.25, 64.05, 62.07, 51.06, 50.93,41.47, 36.91. IR (neat, cm-I): 1730. Mass (HR) m / z (M'): calcd 210.0892, obsd 210.0883. Anal. Calcd for CllH1404: C, 62.86; H, 6.67. Found: C, 62.87; H, 6.68. Methyl syn -7-Methyl-2,2-(ethylenedioxy)bicyclo[2.2.1]hept-5-ene-7-carboxylate(8). To a solution of lithium diisopropylamide, prepared from 7.28 mL (52.5 mmol) of diisopropylamine in 80 mL of freshly distilled THF and 35.4 mL (56.6 mmol) of n-butyllithium (1.60 M in hexane) at -78 "C, was added a solution of 6.80 g (32.4 mmol) of the ketal ester 7 in 15 mL of THF. After storage of this mixture an additional 20 min at -78 "C, 12 mL (191.8 mmol) of methyl iodide was added. The reaction mixture was stirred at -78 "C for 1h, warmed to room temperature over 1 h, and stirred a t room temperature for an additional 1 h. The reaction was quenched with 1 mL of water, and the solvent was removed under reduced pressure. The residue was taken up with 40 mL of water and was extracted with 4 X 40 mL of ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent afforded crude 8. Purification on silica gel (elution with 3 1 n-hexanelethyl acetate) afforded 7.15 g (99%) of 8 as a colorless oil. 'H NMR (300 MHz, CDC13): 6 6.23 (m, 1 H), 6.03 (m, 1 H), 4.00-3.80 (m, 4 H), 3.67 (s, 3 H), 2.86 (br s, (13) We thank professor Hisashi Yamamoto, University of Nagoya, for providing spectra of authentic ketone 23.
syn -7-Methyl-2,2-(ethylenedioxy)-7-(hydroxymethyl)bicyclo[2.2.l]hept-5-ene (9). To a stirred cold (0 "C) slurry of LiA1H4 (1.80 g, 49.1 mmol) in THF (60 mL) was added a solution in THF (15 mL) via syringe. The mixture of 8 (5.50 g, 24.6 "01) was refluxed for 4 h, quenched with saturated ammonium chloride under cooling, and concentrated. The residue was diluted with water (45 mL) and extracted with ethyl acetate (4 X 50 mL). The organic layer was washed with brine and water, dried (MgS04), and evaporated in vacuo. The residue was chromatographed on silica gel (elution with 2:l n-hexanelethyl acetate) to give pure 9 (4.33 g, 90%) as an oil. 'H NMR (300 MHz, CDC13): 6 6.24 (m, 1 H), 6.10 (m, 1 H), 4.0-3.8 (m, 5 H), 3.56 (d, J = 11.54 Hz, 1 H), 2.48 (m, 2 H), 2.30-2.10 (m, 2 H), 1.47 (d, J = 11.54 Hz, 1 H), 1.12 (s, 3 H). I3C NMR (300 MHz, CDC13): 6 151.22, 146.10, 131.06, 90.59, 90.17, 89.74, 80.24, 68.24, 60.59, 52.72, 31.45. IR (neat, cm-'): 3600-3400 (OH). Mass (HR) m / z (M+): calcd 196.1100, obsd 196.1091. an ti-7-Methyl-7-(hydroxymethyl)bicyclo[2.2.1] hept-%-en2-one (10). To 1.55 g (7.9 mmol) of ketal 9 was added 30 mL of THF and 0.3 mL of diluted hydrogen chloride. The reaction mixture was heated at reflux for 3 h after which time it was cooled to room temperature and neutralized with a cold solution of sodium bicarbonate. The product was isolated by ethyl acetate extraction (4 X 40 mL). The combined organic extracts were washed with brine, dried (MgSO,), filtered, and evaporated in vacuo to afford crude 10. Chromatography on silica gel (elution with 3:2 n-hexanelethyl acetate) afforded 1.12 g (93%) of the desired keto alcohol 10 as a colorless oil. 'H NMR (300 MHz, CDC1,): 6 6.56 (m, 1 H), 5.98 (m, 1 H), 3.66 (d, J = 13.2 Hz, 1 H), 3.54 (d, J = 13.2 Hz, 1 H), 2.93 (br s, 1 H), 2.73 (br s, 1 H), 2.48 (br s, 1 H), 2.27 (dd, J = 15.7, 3.0 Hz, 1H), 1.89 (d, J = 15.7 Hz, 1 H), 1.22 (s, 3 H). 13C NMR (300 MHz, CDC13): 6 215.42, 114.08, 127.91, 65.66, 64.13, 62.48, 46.14, 35.78, 15.93. IR (neat, cm-'): 3500-3200,1740. Mass (HR) m / z (M'): calcd 152.0837, obsd 152.0846. endo-2-Isopropenyl-7-anti-methyl-7-(hydroxymethy1)bicycl0[2.2.l]hept-5-en-2-01(11). To a stirred solution of isopropenylmagnesium bromide, prepared from 0.8 mL (7.5 mmol) of isopropenyl bromide and 390 mg (16.3 mmol) of Mg, in THF (15 mL) was added 10 (425 mg, 2.8 mmol) via syringe under N2. After the reaction mixture was refluxed for 2 h, saturated ammonium chloride was added under cooling. After the solvent was removed, the residue was diluted with water (20 mL) and extracted with ethyl acetate (4 X 30 mL). The organic layer was washed with brine and water, and the extract was dried (MgS04). Removal of the solvent by evaporation followed by chromatography of the residue on silica gel (elution with 3 2 n-hexanelethyl acetate) to give pure diol lla (501 mg, 92%) as a white crystal (mp 68-69 "C). 'H NMR (300 MHz, CDCl,): 6 5.98 (m, 1 H), 5.80 (m, 1 H), 4.70 (m, 2 H), 4.09 (d, J = 11.54 Hz, 1H), 3.41 (d, J = 11.54 Hz, 1 H), 3.04 (br s, 2 H), 2.64 (br s, 1 H), 2.40 (br s, 1 H), 2.04 (dd, J = 13.5, 4.0 Hz, 1 H), 1.82 (d, J = 13.5 Hz, 1 H), 1.76 (s, 3 H), 1.08 (s, 3 H). 13C NMR (300 MHz, CDC13): 6 149.08, 137.03, 133.89, 111.75,83.78,67.95,62.83,56.61,48.49, 37.84, 19.80, 19.74. IR (neat, cm-'): 3600-3250, 1645. Mass (HR) m / z (M'): calcd 194.1307, obsd 194.1296. Anal. Calcd for C12H1802:C, 74.22; H, 9.28. Found: C, 73.88; H, 9.30. endo -7-(Hydroxymethyl)-3,7-dimethyl-cis -bicyclo[4.3.0]non-8-en-4-one (15). A solution of 11 (3.8 g, 19.6 mmol) in THF (10 mL) was added to a rapidly stirred suspension of potassium hydride (1.9 g, 47.5 mmol) and T H F (30 mL). The resulting mixture was stirred at room temperature for 2 h after which time methanol (1 mL) was added dropwise and concentrated. The residue was diluted with water and extracted with ethyl acetate
J. Org. Chem., Vol. 54, No. 16, 1989 3823
Formal Total Synthesis of (f)-9-Isocyanopupukeanane
(3x 20 mL). The combined organic phase was washed in brine, dried, filtered, and concentrated under reduced pressure. Purification of the crude product on silica gel (elution with 3:2 n-hexanelethyl acetate) gave 3.58g (94%) of pure keto alcohol 15 as a colorless oil. 'H NMR (300MHz, CDCl,): 6 5.75 (m, 1 H), 5.48 (m, 1 H), 3.45 (s, 2 H), 3.04(m, 1 H), 2.67 (m, 1 H), 2.38-2.03(m, 5 H), 1.5 (m, 1 H), 1.08(s, 4.5H), 1.05(s, 1.5H). 13CNMR (300MHz, CDC1,): 6 217.18135.86,134.18,66.71, 52.99, 44.94,44.53,42.44,37.54,35.53,24.14,15.81. IR (neat, cm-'): 3600-3300,1710. Mass (HR) m/z (M'): calcd 194.1307,obsd 194.1280. endo -7(Methylsulfonyl)-3,7-dimet hyl-cis-bicycle[4.3.01non-8-en-4-one (16). Methanesulfonyl chloride (1.2mL, 156 mmol) was added dropwise to a cold (0 "C), magnetically stirred solution of 15 (616mg, 3.18mmol) and triethylamine (12mL) in dichloromethane (10mL). Mter being allowed to warm to room temperature, the mixture was stirred for 2 h and concentrated. The residue was stirred with water (10 mL) and ethyl acetate (15 mL) and extracted with ethyl acetate (3 X 15 mL). The organic phase was washed successively with water (3x 10 mL) and brine. After drying and solvent removal, the crude product was chromatographed on silica gel (elution with 3:l n-hexanelethyl acetate) to afford pure 16 (828mg, 96%) as an oil. 'H NMR (300MHz, CDC1,): 6 5.73 (m, 1 H), 5.53 (m, 1 H), 4.10(s, 0.67H), 4.06(s, 1.33H), 3.04(s, 1 H), 3.02(s, 2 H), 2.40(m, 4 H), 2.12(m, 1 H), 1.82(m, 1 H), 1.44(m, 1 H), 1.18(e) and 1.17(s) (3H), 1.08(d, J = 5.77Hz,3 H). IR (neat, cm-'): 1710,1180.Mass (HR) m/z (M+): calcd 272.1083,obsd 272.1086.Anal. Calcd for C13Hm04S: C, 57.35;H, 7.35. Found: C, 57.41;H, 7.36. Cyclization of Keto Mesylate 16. Potassium tert-butoxide (155mg, 1.39mmol) was added to 1.52mg (0.56mmol) of 16 in 20 mL of tert-butyl alcohol at room temperature. The mixture was stirred for 2 h a t room temperature, water was added, and the resultant mixture was concentrated. The residue was stirred with ethyl acetate (10mL) and water (8mL), and the mixture was separated. The aqueous layer was extracted with ethyl acetate (3 X 15 mL). The combined organic solutions were washed with brine and water; flash chromatography on silica gel (elution with 14:l n-hexanelethyl acetate) gave 65 mg (67%) of 17 and 18 (77:23)as a colorless oil. 'H NMR (300MHz, CDC1,): 6 6.08(m, 0.76H), 5.87(d, J = 5.4Hz, 0.76H), 5.87-5.54(m, 0.46 H), 3.3-1.13 (m, 8.70H), 1.21 (s, 0.70H), 1.07(s, 2.31H), 1.05(d, J = 6.0Hz, 0.7H), 0.88(s, 2.31 H). IR (neat, cm-'): 1720. Mass (HR) m/z (M+): calcd 176.1202,obsd 176.1188. Acid-catalyzed hydrolysis of ketal 20 (11 mg) as before gave ketone 18 (8mg). 'H NMR (90 MHz, CDC1,): 6 5.87-5.54(m, 2 H), 3.40-1.30(m, 8 H), 1.22(9, 3 H), 1.05(d, J = 6.0 Hz, 3 H). Ketalization of the Mixture of 17 and 18. A mixture of 17 and 18 (50 mg, 0.28mmol, ratio 77:23),ethylene glycol (2mL), p-toluenesulfonic acid monohydrate (10mg), and benzene (25mL) was heated at reflux under a Dean-Stark trap for 2 h. The cooled reaction mixture was diluted with ether (10 mL) and washed successively with saturated sodium carbonate solution and brine. The aqueous washes were extracted with ether (3 X 10 mL). The combined organic phase was dried, filtered, and evaporated under reduced pressure to give crude 19 and 20. Flash chromatography
on silica gel (elution with 251 n-hexanelethyl acetate) afforded 57.5mg (0.26mmol, 92%) of a mixture of 19 and 20 as a colorless oil. 'H NMR (300MHz, CDClJ: 6 5.93 (m, 0.80H),5.71(m, 0.80 H), 5.60-5.20(m, 0.4H), 4.00-3.60(m, 4 H), 2.7-0.70 (m, 11.60 H), 0.64(s, 2.40H). Mass (HR) m/z (M'): calcd 220.1464,obsd
220.1458. 1,3-Dimethyl-9,9-(ethylenedioxy)tricycl0[4.3.1.0~~~]decan-
5-01(21). To a stirred solution of the 19 and 20 mixture (50 mg, 0.23mmol) in THF (15mL) was added 9-BBN/THF (0.5 M, 1.5 mL) via syringe under N2 The mixture was heated a t 60 OC for 2 h. Oxidation was carried out by addition of 2 mL of 30% H202/0.5N NaOH/H20 (vol: 44:l)dropwise, the mixture was held an additional 1 h a t reflux temperature, and the cooled aqueous phase was extraded with ethyl acetate. After separation, the organic layer was dried, filtered, and concentrated. Flash chromatography on silica gel (elution with 2:l n-hexanelethyl acetate) gave 34.8mg (0.15mmol) of pure ketal alcohol 21 as a colorless oil (38% overall yield from 16) followed by 11 mg of recovered 20. Spectral data for 20. 'H NMR (300MHz, CDC13): 6 5.51(dd, J = 4.6,1.8 Hz,1 H),5.34 (dd, J = 4.6,1.8Hz, 1 H), 3.8(m, 4 H),3.10(m, 1 H), 2.63 (m, 1 H),2.47 (m, 1 H), 2.00-1.45(m, 4 H), 1.25(s, 3 H), 0.88(d, J = 6.0Hz, 3 H).Spectral data for 21. 'H NMR (300MHz, CDCl,): 6 3.87-3.56(m, 6 H), 2.18-0.63(m, 10 H), 0.98(s, 3 H), 0.65(s, 3 H). 13C NMR (300MHz, CDCl,): 6 111.36,79.06,64.73,64.61,53.59,47.33,45.61,40.92,38.42,36.41, 34.76,34.16,26.14,19.57.IR (neat, cm-'): 3600-3100. Mass (HR) m/z (M+): calcd 238.1569,obsd 238.1566. Anal. Calcd for C14H2203: C, 70.58;H, 9.24. Found: C, 70.49;H, 9.19.
1,3-Dimethyl-9,9-(ethylenedioxy)tricycl0[4.3.l.O~~~]decan5-one(23). The alcohol 21 (74.5mg, 0.31mmol) was added to a mixture of pyridium dichromate (129mg, 0.34mmol) and 4-A molecular sieve powder (200mg) in 20 mL of methylene chloride. A drop of acetic acid was added. After being stirred at room temperature (25"C) for 2 h, the mixture was diluted with ethyl acetate (30mL) and filtered through a short calcium chloride and silica gel column. The filtrate was washed with water (2X 10mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by flash chromatography (silica gel, 2:l n-hexanelethyl acetate) to give 66 mg (90%)of 23 as a colorless oil. IR (CHCI,): 1743 cm-'. 'H NMR (CDCl,): 6 0.72(s, 3 H), 1.15(e, 3 H), 0.82-2.70(m, 16 H), 3.70-4.00(m, 4 H). 13C NMR (CDC13): 6 19.14,25.00,32.83,33.67,36.52,37.02,41.89,45.08, 47.47,55.71,64.81,109.86,221.51. HRMS (mle): calcd for C14H2003236.1414,found 236.1413.
Acknowledgment. We t h a n k the National Science Council of the Republic of China for generous support of t h i s research. Registry No. (f)-l, 70329-80-5;(f)-5, 73650-17-6;6, 101848-28-6; 6 (acid), 101915-49-5; 7,73178-96-8; (f)-8, 12107405-3; (f)-9,121153-54-6; (*)-lo, 121097-03-8 (f)-11, 121074-06-4; (*)-12,121153-55-7; (f)-15,121074-07-5; (*)-16,121074-08-6; (f)-17,121074-09-7; (f)-18,121074-10-0; (&)-19,121074-11-1; 20, 121074-12-2; 21,121074-13-3; 22,121074-14-4; (*)-23,70329-79-2.
