Chemical Properties
White crystalline powder or powder
Uses
N-(Benzyloxycarbonyl)-D-proline is an an N-Cbz-protected form of D-proline (P755990). It is used to prepare trichostatin A and trapoxin B analogs as histone deacetylase inhibitors. It is also used to prepare potent and selective nonpeptide inhibitors of caspases 3 and 7.
Synthesis
Step-1: Preparation of (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a). To a stirred solution of D-proline (1.2 g, 10.42 mmol) in 2 N NaOH aqueous solution (20.85 mL, 41.7 mmol), benzyl chloroformate (1.488 mL, 10.42 mmol) was slowly added dropwise at 0°C. The reaction mixture was gradually warmed to room temperature and stirred overnight. Upon completion of the reaction, the reaction mixture was washed with methyl tert-butyl ether (MTBE, 2 × 25 mL) and then acidified with concentrated hydrochloric acid to pH ≈ 2. The aqueous phase was extracted with ethyl acetate (2 × 200 mL), and the organic phases were combined and washed sequentially with water (50 mL) and saturated saline (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) (2.41 g, 9.67 mmol) as a white solid in 93% yield. The product was characterized by 1H NMR (300 MHz, DMSO-d6) and mass spectrometry (MS): 1H NMR δ 12.66 (s, 1H), 7.42-7.25 (m, 5H), 5.14-4.97 (m, 2H), 4.20 (ddd, J = 22.7, 8.8, 3.5 Hz, 1H), 3.50-3.25 (m, 2H), 2.32-2.08 (m, 1H), 1.97-1.75 (m, 3H); MS (ES+) m/z 250.2 ([M+H]+), 272.2 ([M+Na]+), (ES-) m/z 248.2 ([M-H]-), 284.2 ([M+Cl]-), 497.4 ([2M-H]-).
References
[1] Patent: WO2015/62486, 2015, A1. Location in patent: Paragraph 00191
[2] Patent: WO2017/59178, 2017, A1. Location in patent: Page/Page column 73
[3] Journal of Pharmaceutical Sciences, 1991, vol. 80, # 9, p. 837 - 842
[4] Angewandte Chemie - International Edition, 2006, vol. 45, # 28, p. 4593 - 4597
[5] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 2807 - 2814
