General procedure for the synthesis of BOC-trans-4-tosyl-L-proline methyl ester from N-Boc-trans-4-hydroxy-L-proline methyl ester and p-toluenesulfonyl chloride: 1-tert-butyl-2-methyl-(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (30.00 g, 122.3 mmol) and triethylamine (51.1 mL. 367 mmol) were dissolved in CH2Cl2 (500 mL), followed by the addition of p-toluenesulfonyl chloride (28.0 g, 147 mmol) and 4-dimethylaminopyridine (1.00 g, 8.18 mmol). The reaction mixture was stirred at room temperature overnight.TLC (hexane solution of 50% ethyl acetate) showed that the reaction was incomplete, so 0.5 equivalents (14 g) of p-toluenesulfonyl chloride was added additionally and stirring was continued overnight.After TLC confirmed that the feedstock was completely consumed, the reaction mixture was diluted with 300 mL of CH2Cl2, and the reaction mixture was sequentially diluted with 1.0 N HCl (2 × 100 mL), 1.0 N NaOH ( 2 × 100 mL) and brine (1 × 100 mL) was washed and the organic layer was dried with Na2SO4. The solvent was concentrated under reduced pressure to give a dark colored oil containing crystalline solids. Purification by silica gel column chromatography (450 g silica gel, 25% ethyl acetate in hexane solution) gave 47.4 g (97%) of light brown oily product.1H NMR (400 MHz, CDCl3) δ ppm 1.32-1.48 (m, 9H), 2.07-2.23 (m, 1H), 2.34-2.62 (m, 4H), 3.52- 3.66 (m, 2H), 3.72 (s, 3H), 4.28-4.46 (m, 1H), 4.96-5.12 (m, 1H), 7.33-7.41 (m, 2H), 7.79 (d, J=8.29Hz, 2H); MS ES+ m/z 300.3 (M-99) and 344.3 (M-55).
