Methyl (+/-)-3-(6-(1-tert-butyldimethylsilyloxyethyl)-6-methyl-2-cyclo-hexanone)2-phenylsulphinylpropionate as a mixture of diastereoisomers.

To a solution of the silyl enol ether (0.50 g, 1.47 mmol) in THF (6 ml) was added methyllithium (1.16 ml, 1.4 M, 1.62 mmol) at 0degC. After 5 mins. the solution was cooled to -78degC and a solution of the acrylate 7 (0.46 g, 2.21 mmol) in THF (3 ml) was added to give a yellow solution. After 80 mins acetic acid (115 mg, 1.91 mmol) was added and the mixture allowed to warm to 20-25degC. This was partitioned between ethyl acetate (15 ml) and disodium hydrogen phosphate solution (20 mM, pH 8, 15 ml) and separated. The aqueous layer was extracted with ethyl acetate (4 x 15 ml), washed with brine (75 ml), dried (Na2SO4) and concentrated in vacuo to yield the sulphoxide (0.97 g) as a crude yellow gum. This was routinely used without further purification for the next synthetic step. Alternatively, chromatography (gradient elution 25-35-50% ethyl acetate, petrol) of a portion (104 mg, "0.16 mmol") of the product yielded sulphoxide (44 mg, 57%, presumed to be a mixture of the 8 possible diastereoisomers) as a yellow gum.

delta(H) - 0.09 to 0.22 (6H, m, Si(CH3)2); 0.66-0.98 (12H, m, C(CH3)3 and 6'C(CH3)); 1.00-1.20 (3H, m, 2"CH3); 1.20-2.52 (9H, m, 1'CH, 3'CH2, 4'CH2 , 5'CH2, 3CH2); 2.66, 2.97 (total 1H, each dd, J = 3 Hz, 11 Hz, 2CH); 3.30-3.82 (4H, m, CO2CH3 and 1"CH); 7.38-7.72 (5H, m, Ph).

vmax (liquid film); 2953; 2856; 1733 (ester); 1709 (ketone); 1253; 1087; 1054; 835 cm(-1).

m/z (C.I., NH3); 498 (M + NH4⁺); 481 (MH⁺).

T.L.C.; Rf ~ 0.32 (1:1 ethyl acetate, petrol).

Methyl (+/-)-(E)-3-((1R*,6S*)-6-((S*)-1-tert-butyldimethylslyloxyethyl)-6-methyl-2-cyclohexanone)acrylate

A suspension of calcium carbonate (0.37 g, 3.74 mmol) and the crude sulphoxide from the preceding reaction (~ 3.12 mmol) in tetrachloromethane (25 ml) was heated at reflux for 4 h. The mixture was concentrated in vacuo and filtered through silica (1:3 ethyl acetate, petrol) to yield the ester (1.41 g, 94% recovery) as a crude yellow oil, that was used as such in the next synthetic step.

delta(H) (~ 3:1 mixture of diastereoisomers, major isomer quoted) 0.03 (6H, d, J = 11.2 Hz, Si(CH3)2); 0.83 (3H, s, 6'C(CH3)); 0.90 (9H, s, C(CH3)3); 1.06 (3H, d, J = 6.3 Hz, 2"CH3); 1.10-2.50 (6H, m, 3'CH2, 4'CH2, 5'CH2); 3.51 (1H, d, J = 10.0 Hz, 1'CH); 3.51 (1H, q, J = 6.3 Hz, 1"CH); 3.71 (3H, s, COOCH3); 5.83 (1H, d, J = 15.8 Hz, 2CH); 6.92 (1H, dd, J = 15.8 Hz, 10.0 Hz, 3 CH).

delta(C) (major isomer quoted, except resonance for quaternary 6'C, not distinguished from minor isomer resonances); ~ 0.0 (Si(CH3)2); 17.5; 18.2; 18.3; 21.9; 26.1 (C(CH3)3); 28.9; 41.4; 51.5 (COOCH3); 58.9 (1'CH); 72.5 (1"CH); 125.1 (2C); 143.5 (3C); 166.1 (1C); 211.3 (2'C).

vmax (liquid film): 2953; 2856; 1720; 1259; 1148; 1106; 836 cm(-1).

m/z (C.I., NH3); 372 (M + NH4⁺); 355 (MH⁺) high resolution measured at 372.2578 C19H34O4Si + NH4 requires 372.2570 (~ 3 ppm error).

T.L.C.; Rf 0.41 (1:3 ethyl acetate, petrol).

Methyl (+/-)-(E)-((1S*,5R*,7S*,8R*)-5-hydroxy-1,7-dimethyl-6-oxa-bicyclo[.2.1] oct-8-yl)acrylate 18

Aqueous hydrogen fluoride (50%, ~ 0.2 ml) was added to a solution of the crude silyl ether (~ 3 mmol) in acetonitrile (14 ml) and stirred at ~ 20degC for 16 h. Saturated sodium bicarbonate solution (14 ml) was added and the acetonitrile removed in vacuo. The aqueous residue was extracted with ethyl acetate (4 x 14 ml), the combined organic phases were washed with brine (1 x 60 ml), dried (MgSO4) and concentrated in vacuo. Chromatography (35% ethyl acetate, petrol) afforded a mixture of diastereoisomers (total 0.56 g, 67% from 10). The major fraction (0.35 g, 41%) appeared to be a mixture of diastereoisomers (~3:1, contaminated with traces of ketone 16 and possibly the keto tautomer of 18). Proton nmr signals were very broad but these data were not inconsistent with the proposed stucture.

delta(H) (major isomer quoted, D2O shake); 0.80 (3H, s, 1C(CH3)); 1.18 (3H, d, J = 6 Hz, 7CH(CH3)); 1.32-2.15 and 2.15-2.48 (total 6H, each m, 2CH2, 3CH2, 4CH2); 2.54 (1H, d, J = 9 Hz, 8CH); 3.72 (3H, s, COOCH3); 3.96 (1H, q, J = 6 Hz, 7CH); 6.00 (1H, d, J = 15 Hz, 2'CH); 6.98 (1H, dd, J = 9 Hz, 15 Hz, 1'CH).

delta(C) (major isomer quoted); 13.1, 18.8, 20.7, 26.2, 31.0, 46.6; 50.6 (8CH); 51.5 (COOCH3); 82.2 (7CH); 106.1 (5C); 125.3 (2'CH); 143.2 (1'CH); 166.4 (3'C).

vmax (liquid film) 3445 (br, OH); 2954; 2873; ~ 1700 (br, carbonyls); 1652 cm(-1).

m/z (C.I., NH3); 258 (M + NH4⁺); 241 (MH⁺); high resolution measured at 258.1705 C13H20O4 + NH4 requires 258.1705 (0 ppm error).

T.L.C.; Rf ~ 0.23 (1:1 ethyl acetate, petrol).

Methyl (+/-)-(E)-((1S*,5R*,7S*,8R*)-5-methoxy-1,7-dimethyl-6-oxabicyclo[32.1] oct-8-yl)acrylate 19

A suspension of the hemiacetal 18 from the preceding reaction (50 mg, 0.21 mmol, containing traces of ketones, see preceding reaction) and silver(I) oxide (50 mg) in iodomethane (3 ml) was heated at reflux for 2.5 h. The mixture was filtered and concentrated in vacuo. Chromatography (1:3 ethyl acetate, petrol) yielded the acetal 19 (31 mg, 58%) as a colourless oil.

delta(H) (10:1 ratio of isomers after chromatography, major isomer quoted); 0.79 (3H, s, 1C(CH3)); 1.19 (3H, d, J = 6.5 Hz, 7CH(CH3)); 1.36-1.54 (2H, m) and 1.54-1.94 (4H, m) (2CH2, 3CH2, 4CH2); 2.78 (1H, br d, J = 9.3 Hz, 8CH); 3.33 (3H, s, OCH3); 3.72 (3H, s, COOCH3); 3.87 (1H, q, J = 6.5 Hz, 7CH); 5.95 (1H, dd, J = 0.6 Hz, 15.6 Hz, 2'CH); 6.94 (1H, dd, J = 9.3 Hz, 15.6 Hz, 1'CH).

delta(C) (major isomer quoted) 13.2, 18.9, 20.9, 26.8, 29.3; 46.5; 49.0 (8CH); 51.6 (COOCH3); 54.0 (OCH3); 83.1 (7CH); 108.9 (5C); 125.2 (2'CH); 143.2 (1'CH); 166.3 (3'C).

vmax (liquid film) 2953; 2871; 1726 (ester); 1652; 1268; 1050 cm(-1).

m/z (C.I., NH3); 272 (M + NH4⁺); 255 (MH⁺) high resolution measured at 272.1864; C14H22O4 + NH4 requires 272.1862 (< 1 ppm error).

T.L.C.; Rf ~ 0.29 (1:3 ethyl acetate, petrol).

Methyl (+/-)-(E)-3-((1S*,2S*,6S*)-2-((S*)-1-tert-butyldimetylsilyloxyethyl)-6-hydroxy-2-methylcyclohexyl)acrylate 20

A solution of the crude ketone (~ 0.22 mmol) in ether (~ 0.5 ml) was added to a suspension of LiAlH4 (68 mg, 1.79 mmol) in ether (2.5 ml) at -78degC. After 30 min water (0.1 ml) was added carefully followed by sodium hydroxide solution (2N, 0.1 ml) and the mixture allowed to warm to ~ 0degC. Further water (0.3 ml) was added and the mixture allowed to warm to 20-25degC. The mixture was filtered through Celite, dried (MgSO4) and concentrated. Chromatography (1:3 ethyl acetate, petrol) gave a partial separation of diastereoisomers (total yield 45 mg, 51% from 10), one fraction (27 mg, 31% from 10), a colourless oil consisting of mainly one isomer, 20.

delta(H) 0.01 (6H, d, J = 8.5 Hz, Si(CH3)2); 0.86 (12H, s, C(CH3)3 and 2'C(CH3)); 1.02 (3H, d, J = 6.2 Hz, 2"CH3); 1.12-1.80 (6H, m, 3'CH2, 4'CH2, 5'CH2); 2.51 (1H, dd, J = 4.0 Hz, 10.1 Hz, 1'CH); 3.72 (3H, s, CO2CH3); 3.78 (1H, q, J = 6.2 Hz, 1"CH); 3.90 (1H, dt, J = 7.4 Hz, 4.0 Hz, 6'CH); 5.92 (1H, d, J = 15.6 Hz, 2CH); 7.13 (1H, dd, J = 10.1 Hz, 15.6 Hz, 3CH).

vmax (liquid film); 3450 (br, OH); 2930; 2857; 1727 (ester); 1652; 1255; 1111; 835; 775 cm(-1).

m/z (C.I., NH3); 374 (M + NH4⁺); 357 (MH⁺); high resolution measured at 374.2716; C19H36O4Si + NH4 requires 374.2726 (~ 2 ppm error).

T.L.C. Rf ~ 0.15 (1:3 ethyl acetate, petrol).

Methyl (+/-)-(E)-3-((1R*,2S*,6S*)-2-((S*)-1-tert-butyldimetylsilyloxy-ethyl)-6-hydroxy-2,6-dimethylcyclohexyl)acrylate 21

Methyllithium (0.97 ml, 1.4M, 1.36 mmol) was added to a solution of the crude ketone (~ 0.68 mmol) in ether (10 ml) at -78degC and allowed to warm to 0degC. Saturated ammonium chloride solution (10 ml) was added, the mixture was separated and the aqueous phase was extracted with ethyl acetate (4 x 10 ml). The combined organic extracts were washed with brine (1 x 50 ml), dried (Na2SO4) and concentrated in vacuo. Chromatography (10% ethyl acetate, petrol) yielded unreacted ketone (74 mg, 27% from 10) and the alcohol 21 (31 mg, 11% from 10) as a yellow solid.

delta(H) 0.02 (6H, d, J = 1.1 Hz, Si(CH3)2); 0.88 (9H, s, C(CH3)3); 0.97 (3H, d, J = 6.4 Hz, 2"CH3); 1.03 (3H, s, 2'C(CH3)); 1.08 (3H, s, 6'C(OH)(CH3)); 1.20-1.38 (2H, m, 4'CH2beta and 5'CH2alpha); 1.42-1.62 (2H, m, 3'CH2alpha and 5'CH2beta); 1.62-1.72 (1H, m, 4'CH2alpha); 1.76 (1H, dt, J = ~13 Hz, J = ~3 Hz, 3'CH2beta); 2.48 (1H, d, J = 10.9 Hz, 1'CH); 3.44 (1H, q, J = 6.4 Hz, 1"CH); 3.72 (3H, s, COOCH3); 5.84 (1H, d, J = 15.9 Hz, 2CH); 7.02 (1H, dd, J = 10.9 Hz, 15.9 Hz, 3CH).

m/z (C.I., NH3); 388 (M + NH4⁺); high resonance measured at 388.2888; C20H38O4Si + NH4 requires 388.2883 (~ 1 ppm error).

Recrystallisation from pentane yielded white crystals, m.p. 103-4degC (uncorrected).

C20H38O4Si requires C, 64.82%; H, 10.33%;

found C, 64.59%; H, 10.19%.

T.L.C.; Rf 0.36 (1:3 ethyl acetate, petrol).