Syntheses of (R)-(+)-cibenzoline and analogues via catalytic enantioselective cyclopropanation using (S)-phenylalanine-derived disulfonamide |
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| Institution: | 1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China;2. College of Pharmacy of Liaoning University, Key Laboratory of New Drug Research and Development of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 10036, PR China;1. Research Institute for Production Development, Shimogamo-morimotocho, Sakyo-ku, Kyoto 606-0805, Japan;2. Kuroshio Biochemical Research Foundation, Nishidomari-560, Ootsuki-cho, Kochi 788-033, Japan;3. Faculty of Agriculture, Kinki University, Nakamachi 3327-204, Nara-shi 631-8505, Nara, Japan;1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China;2. College of Pharmacy of Liaoning University, Key Laboratory of New Drug Research and Development of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 10036, PR China;3. Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, 11 Street, Jingjijishukaifa District, Shenyang 110142, PR China |
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| Abstract: | Cyclopropanation of 3,3-diaryl-2-propen-1-ols 1 with Et2Zn and CH2I2 proceeded in the presence of a catalytic amount of (S)-2-(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phenylpropane 2 to afford the corresponding cyclopropylmethanols with 20–76% ee. (+)-2,2-Diphenylcyclopropylmethanol 3a (76% ee) was oxidized with IBX in DMSO, followed by NaClO2, H2O2, and NaH2PO4 in MeCN–H2O to give the corresponding acid 5a, which was converted with ethylenediamine, in the presence of PyBOP and Et3N in CH2Cl2, to the amide 6a in quantitative overall yield from 3a. Amide 6a was cyclized at 160 °C under reduced pressure (2 mmHg) to afford (R)-(+)-cibenzoline in 55% yield. |
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