Process for the preparation of β hydroxy-δ lactone using novel intermediates

Preparation of cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate (3)

Finely powdered cis, cis-3,5-di(methylcarbonyloxy)cyclohexylacetate 2 (6.5 parts, 25.19 mmol parts) was suspended in 0.1 M sodium phosphate buffer (pH 7) (135 parts) and stirred vigorously. To the stirred suspension Porcine Liver Esterase (0.110 parts) was added and reaction mixture was stirred vigorously at 30° C. for 20 hr. pH of the reaction mixture was monitored at every 2 hrs and was maintained at pH 7 using 1N NaOH solution. After completion of reaction (20 hr), it was extracted with ethyl acetate (2×150 parts). Organic layers were combined and washed with brine, dried on anhydrous sodium sulfate and concentrated under vacuum to yield cis,cis-3-hydroxy-5-methylcarbonyloxycyclohexylacetate 3 yield (4.8 g parts, 88%).

1H NMR(CDCl 3 ): δ1.20-1.58 (qn, 3H), 2.08 (s, 6H), 2.28 (m, 3H), 3.78 (m, 1H), 4.78 (m, 2H)

13C NMR (CDCl 3 ): δ21.15, 36.33, 39.93, 64.83, 67.65, 170.42

IR (KBr): 754.60, 884.15, 1029.29, 1140.34, 1250.00, 1367.64, 1738.92, 2871.17, 2953.14, 3445.47

Mass: Base m/e=96 other m/e: 156, 138, 114, 73, 67, 67, 60, 55

Elemental analysis: calculated for C 10 H 16 O 5 : C, 55.56%; H, 7.40%;. Found: C,55.30%; H,8.00%;.

Preparation of cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate (4)

Cis, cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate (3, 2 parts, 9.26 mmol) and DMAP (0.113 parts, 0.926 mmol) were placed in 100 ml two-necked round bottom flask equipped with dropping funnel and two-way stopcock. It was evacuated and flushed with argon. To it, dry dichloromethane (10 parts) and dry HMPA (2 part) was added and stirred to dissolve. The solution was cooled to −10° C. with stirring. To it, solution of tert-butyldimethylsilyl chloride in 10 part dry dichloromethane was added dropwise while maintaining temperature below 0° C. Reaction mixture was stirred for 15 min and to it dry triethylamine (2.02 parts, 20 mmol) was added dropwise. Reaction mixture was stirred at room temperature for 12 hr. It was then transferred to a separating funnel and washed successively with cold, dil. HCl water, aq. NaHCO 3 and then brine. Organic layer was dried on anhydrous sodium sulfate and solvent was removed under vacuum. Residue was purified by flash column chromatography. (eluent 2-4% ethyl acetate in petroleum ether) to yield Cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate (4, yield 2.85 parts, 90%).

1 H NMR (CDCl 3 ): δ0.06(s, 9H), 0.87 (s, 6H), 1.20-1.45 (m, 3H), 2.03 (s, 6H), 2.2 (m, 3H), 3.38 (m, 1H), 4.73 (m, 2H).

13 C NMR (CDCl 3 ): δ−5.07, 17.61, 25.40, 36.17, 40.40, 65.43, 67.01, 169.64

IR (CHCl 3 ): 758.90, 838.05, 1034.91, 1106.32, 1246.82, 1368.91, 1734.01, 2858.81, 2955.07

Mass: Base m/e=117 other m/e: 273, 213, 171, 159, 129, 117, 97, 79, 75, 57

Elemental analysis: calculated for C 26 H 30 O 5 Si: C, 58.185%; H, 9.10%;. Found: C,58.19%; H,9.50%;.

Preparation of 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexyl acetate (5)

Cis, cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate (4, 5 parts, 147 mmol) was dissolved in tert-butanol (20 parts). To the solution, 0.1 M sodium phosphate buffer (230 parts, pH 8) was added and mixture was stirred vigorously. To the stirred emulsion, Porcine liver esterase (0.150 parts) was added and the mixture was stirred vigorously at 30° C. for 54 hrs. During reaction pH was maintained at 8 using 1N sodium hydroxide solution. Reaction mixture was extracted with ethyl acetate (3×200 parts). Organic layers were combined and washed with brine. It was then dried on anhydrous sodium sulfate and solvent was removed under vacuum. Oily residue contained 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate 5 along with unreacted 4. Both were separated by flash column chromatography.

Cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate: (4, 1.07 parts;

3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate: (5, 2.8 parts, 70% based on recovered starting material).

1 H NMR (CDCl 3 ): δ0.06 (s, 9H), 0.87 (s, 6H), 1.35-1.60, (m, 3H), 2.06 (s, 3H), 2.15 (m, 3H), 3.7 (m, 2H), 4.75 (m, 1H)

13 C NMR (CDCl 3 ): δ−4.60, 18.15, 21.38, 25.90, 39.98, 40.31, 43.93, 65.45, 66.40, 68.17, 170.68

IR (CHCl 3 ): 758.43, 838.93, 1049.42, 1109.15, 1218.09, 1254.01, 1370.09, 1725.03, 2859.8, 2887.95, 2952.33, 3017.48

Mass: Base m/e=75 other m/e: 231, 171, 129, 117, 105, 97, 79, 75, 67, 59

Elemental analysis: calculated for C 14 H 28 O 4 Si : C, 58.33%; H, 9.72%;. Found: C, 58.15%; H, 10.20%;.

Specific rotation [α] D =−4.8 (c 1, CHCl 3 ) e.e. >95%

Preparation of 3-oxo-5-(tert.butyldimethylsilyloxy)-(1S, 5S)-cyclohexylacetate (6)

Cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate (5, 1.40 parts, 2.78 mmol) was dissolved in dichloromethane 5 parts to the solution sodium acetate (0.1 part) and pyridinium chlorochromate (1.57 parts, 7.3 mmol) were added. The mixture was stirred for 5 hr at RT. Residue was extracted with ether (3×10 parts). Organic extracts were combined, filtered through ceilite. Filtrate was washed with brine:water (1:1), finally with brine. Organic layer was dried on anhydrous sodium sulphate and concentrated under vacuum. Residue was filtered through silica gel column to afford 3-oxo-5-(tert.butyldimethylsilyloxy)-(1S, 5S)-cyclohexylacetate 6 (1.30 parts, 93.5%).

1H NMR (CDCl 3 ): δ0.10 (d, 9H), 0.88 (d, 6H), 2.06 (s, 3H), 2.45 (m, 4H), 2.70 (m,2H), 4.00 (m, 1H), 5.00 (m, 1H)

13C NMR (CDCl 3 ): δ−4.95, 17.82, 20.97, 25.57, 39.34, 45.93, 50.30, 65.98, 67.23, 169.87, 205.27

IR (CHCl 3 ): 442.57, 756.83, 1218.50, 1244.99, 1723.00, 2857.44, 2932.80, 2953.64, 3019.98

Mass: Base m/e=163 other m/e: 185, 169, 145, 127, 117, 111, 101, 95, 75, 59

Elemental analysis: calculated for C 14 H 26 O 4 Si: C, 58.74%; 9.09%. Found: C, 58.60%; H, 9.8%;.

Specific rotation [α] D =−11.54 (c 1, CHCl 3 )

Preparation of 3-hydroxy-5-(tert-butyldimethylsilyloxy)-(3R,5S)-cyclohexan-1-one 7

3-Oxo-5-(tert.butyldimethylsilyloxy)-(1S, 5S)-cyclohexylacetate (6, 1.2 parts, 4.2 mmol ) was dissolved in DMSO (10 parts) and 0.1 M phosphate buffer (pH 6.5, 90 parts). To the mixture, PLE (0.1 parts) was added and the reaction mixture was stirred for 48 hr at room temperature. It was filtered through ceilite and filtrate was extracted with ethyl acetate (3×100 parts). Organic extracts were combined and washed with brine. Organic layer was dried on anhydrous sodium sulphate and concentrated under vacuum. Residue was chromatographed on silica gel to afford 3-hydroxy-5-(tertbutyldimethylsilyloxy)-(3R,5S)-cyclohexan-1-one 7 (0.77 parts, 75%).

1H NMR (CDCl 3 ): δ0.08 (s, 6H), 0.85 (s, 9H), 1.95-2.4 (m, 2H), 2.45-2.78 (m, 4H), 3.96 (bs, 1H), 4.37 (m, 1H), 4.56 (m, 1H)

13C NMR (CDCl 3 ): δ−5.28, −5.50, 17.55, 25.34, 38.24, 49.56, 49.89, 68.86, 70.48, 206.78

IR (CHCl 3 ): 668.15, 759.18, 837.70, 1216.14, 1255.02, 1676.48, 1712.47, 2930.89, 2955.00, 3018.43, 3387.52, 3406.91

Mass: Base m/e=75 other m/e: 187, 169, 145, 129, 101, 95, 75, 69, 59

Elemental analysis: calculated for C 12 H 24 O 3 Si : C, 59.01%; H, 9.83%;. Found : C, 59.1%; H, 9.98%;.

Specific rotation [α] D =−22.06 (c 1, CHCl 3 )

Preparation of 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4S,6R)-tetrahydro -2H-2-pyranone (1)

3-Hydroxy-5-(tert-butyldimethylsilyloxy)-(3R,5S)-cyclohexan-1-one (7, 0.1 part, 0.394 mmol) and 50% 3-chloroperbenzoic acid (0.275 parts, 0.79 mmol) were mixed and kept in dark for 24 hr. Reaction mixture was dissolved in ethyl acetate and washed successively with sodium metabisulfite solution, sodium bicarbonate solution followed by brine wash. It was then dried on anhydrous sodium sulfate and solvent was removed under vacuum. Residue was purified by flash column chromatography to yield white, crystalline 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4S,6R)-tetrahydro-2H-2-pyranone (1, yield 0.035 part, 50%).

1H NMR (CDCl 3 ): δ0.09, 0.07 (2s, 6H), 0.89 (s, 9H), 1.55-2.00(m+bs, 2H), 2.60 (d, 2H, J=3), 3.66 (dd, 1H, J=3, 12), 3.90 (dd, 1H, J=3, 12), 4.38 (m, 1H), 4.80 (m, 1H)

13C NMR (CDCl 3 ): δ−5.17, 17.66, 25.41, 32.59, 39.90, 63.24, 64.19, 76.73, 170.1

IR (CHCl 3 ): 666.31, 898.12, 1021.88, 1061.06, 1086.17, 1118.98, 1390.84, 1463.17, 1729.43, 2857.28, 3418.25

Mass: Base m/e=101 other m/e: 261, 229, 203, 185, 161, 143, 129, 111, 75, 68, 59

Elemental analysis: calculated for C 12 H 24 O 4 Si: C, 55.38%; H, 9.20%;. Found C, 55.40%; H, 9.30%;.

Specific rotation [α] D =−1.96 (c 1, CHCl 3 ) e.e. 99% (determined by chiral HPLC of corresponding benzoate derivative, column-Whelk-O1 [4.0 mm Id×25 cm] AT-256; λ=254 nm, flow rate: 1 ml/min; mobile phase: hexane:isopropanol 92:08; retention time for benzoate of 1=20.10, for benzoate of ent-1=17.48).