First resolution of (R,R)- and (S,S)- bis(1-hydroxyphenylmethyl)phosphinic acids via diastereomeric salt formation with enantiopure 1-phenylethylamines Babak Kaboudin, a, * Hamideh Haghighat a and Tsutomu Yokomatsu b a Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran b School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan Received 13 February 2008; accepted 6 March 2008 Available online 28 March 2008 Abstract—The resolution of racemic bis(1-hydroxyphenylmethyl)phosphinic acid with enantiopure 1-phenylethylamines via diastereo- meric salt formation was investigated. X-ray crystallographic analysis of the salt clearly revealed that (S)-1-phenylethylamine was an efficient resolving agent for obtaining the single enantiomer (R,R)-bis(1-hydroxyphenylmethyl)phosphinic acid. Resolving racemic bis(1-hydroxyphenylmethyl)phosphinic acid with (R)-2-phenylethylamine gave access to (S,S)-bis(1-hydroxyphenylmethyl)phosphinic acid in good yield. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction a-Functionalized phosphinic acid derivatives have attracted significant attention due to their usefulness both in medicinal chemistry and materials chemistry. 1–7 Among the a-functional phosphinic acids, a-hydroxyphosphinic acids are chiral organic molecules involved in a wide variety of biological processes. 8–10 Some chiral a-hydroxy- phosphinic acids are useful intermediates for a-hydroxy- phosphinyl peptides showing good inhibitory activity against renin. 11 Symmetric or pseudo-symmetric chiral bis(a-hydroxyalkyl)phosphinic acid derivatives have also attracted attention in the design of HIV protease inhibi- tors. 12 In addition, the structure of the phosphinic func- tional group mimics the transition state of peptide hydrolysis, while the symmetric nature of the phosphinic acid derivatives is expected to help in their binding to the homodimer of HIV-protease with a C 2 -axis of symmetry. 13 Moreover, a-hydroxyphosphinic acid derivatives are useful intermediates in the synthesis of other phosphorus chiral organic compounds of material interest. 14 In contrast to the widely studied separation of 1-hydroxyalkylphosphonic acid derivatives, 15 there is no report for the resolution bis(a-hydroxyalkyl)phosphinic acid derivatives, although there is evidence that bis(a-hydroxyalkyl)phosphinic acids are pharmaceutically active. 13 As part of our efforts for the synthesis of organophosphorus compounds, 16 we have recently described a new method for the synthesis 17 and separation of diastereoisomeric bis(a-hydroxyalkyl)phos- phinic acids 18 from the reactions of hypophosphorous acid with aldehydes. Herein, we report the first resolution of (±)-bis(1-hydroxyphenylmethyl)phosphinic acid 1 via diastereomeric salt formation with enantiopure 1-phenyl- ethylamines. Ph P Ph O OH OH OH (R,R) 1 Ph P Ph O OH OH OH (S,S)1 1 2. Results and discussion A diastereomeric mixture of bis(a-hydroxyphenylmeth- yl)phosphinic acid derivatives rac-1 and 2 was obtained in multi-gram quantities (82% yield in a 56:45 ratio of diastereoisomers, Scheme 1) by microwave-assisted reac- tion or by heating with benzaldehyde and hypophosphorus acid as previously described (Scheme 1). 19 It has previously 0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2008.03.004 * Corresponding author. Tel.: +98 241 415 3220; fax: +98 241 421 4949; e-mail: kaboudin@iasbs.ac.ir Available online at www.sciencedirect.com Tetrahedron: Asymmetry 19 (2008) 862–866