Methyl phenyl sulfone (1.6g, 10.2mmol) was dissolved in dry tetrahydrofuran (30ml) under argon. The solution was cooled to 0degC (ice-salt bath) and n-butyl-lithium (20.0ml of a 1.2M solution in hexane, 24.3mmol) added dropwise, after stirring for 30min., the reaction mixture was cooled to -78degC and a solution of N-tert-butoxycarbonyl-L-proline methyl ester (4) (2.3g, 10.1mmol) in dry tetrahydrofuran (5ml) added. The mixture was stirred at -78degC for 30min., then allowed to warm slowly to -30degC, and stirred at this temperature for a further 2.5h. Next, 2M hydrochloric acid (70ml) was added, and the mixture extracted with ethyl acetate (3x60ml). The organic extracts were washed with saturated sodium chloride (3x50ml), then dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to give (2'S)-2-(N-tert-butoxycarbonylpyrrolidin-2-yl)-2-oxo-ethyl phenyl sulfone (6) (2.7g, 75%) as a pale yellow oil, contaminated with small amounts (>5%) of methyl phenyl sulfone, [alpha]D -60deg (c 1.0, dichloromethane).

Proton Nmr (ca. 3:2 mixture of rotamers) deltaH (300MHz, CDCl3) 1.33(3H, s, OC(CH3)3 rotamer), 1.40(6H, s, OC(CH3)3 rotamer), 2.15-1.82(4H, m, 2xH-3', 2xH-4'), 3.52-3.39(2H, m, 2xH-5'); 4.40-4.13(3H, m, H-2', CH2SO2Ph), 7.94-7.52(5H, m, Ar-H); Vmax: 1735, 1700cm^-1; m/z (NH3, CI) 371(M+NH4⁺, 80%), 354(M+H⁺, 17%), 315(100%). Found [M+H]⁺ 354.1382, C17H24NO5S requires 354.1375.

Preparation of (2'S)-2-(N-tert-Butoxycarbonyl-L-alanylpyrrolidin-2-yl)-2-oxo-ethyl Phenyl Sulfone (7)

Methyl phenyl sulfone (0.36g, 2.03mmol) was dissolved in dry tetrahydrofuran (50ml) under argon. The solution was cooled to 0degC (ice-salt bath) and n-butyl-lithium (4.60ml of a 1.0M solution in hexane, 4.6mmol) was added dropwise. The resulting mixture was stirred at 0degC for 30min., then cooled to -78degC and a solution of N-tert-butoxycarbonyl-L-alanyl-L-proline methyl ester (5) (0.69g, 2.30mmol) in dry tetrahydrofuran (5ml) added. The mixture was stirred at -78degC for 30min., then allowed to warm slowly to -30degC, and stirred at this temperature for a further 2.5h. 2M Hydrochloric acid (50ml) was then added, the mixture warmed to room temperature, and then extracted with ethyl acetate (3x25ml). The combined organic extracts were washed sequentially with water (50ml) and saturated sodium chloride (50ml), then dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 1:1) to give (2'S)-2-(N-tert-butoxycarbonyl-L-alanylpyrrolidin-2-yl)-2-oxo-ethyl phenyl sulfone (7) (0.43g, 47%) as a colourless oil.

Proton Nmr deltaH (300MHz, CDCl3) 1.22(3H, d, J=7.0Hz, CH3), 1.37(9H, s, OC(CH3)3), 1.94-2.26(4H, m, 2xCH2), 3.49-3.74(2H, m, CH2NBoc), 4.18(1H, d, J=14.0Hz, CHaHbSO2Ph), 4.38-4.43(1H, m, CHNMe), 4.50(1H, d, J=14.0Hz, CHaHbSO2Ph), 4.64(1H, dd, J=5.5, 7.5Hz, CHNBoc), 5.19(1H, br. d, J=8.0Hz, NH), 7.51-7.87(5H, m, Ar-H); Vmax: 3240, 1704, 1642cm^-1; m/z (NH3, CI) 425(M+H⁺, 20%), 285(92%), 229(25%), 160(50%), 70(100%).