Syntheses of (R)-(+)-cibenzoline and analogues via catalytic enantioselective cyclopropanation using (S)-phenylalanine-derived disulfonamide

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. (c) 2006 Elsevier Ltd. All rights reserved.