Asymmetric Michael reaction: novel efficient access to chiral b-ketophosphonates Sandrine Delarue-Cochin, a,b, * Jian-Jung Pan, c Aure ´lie Dauteloup, a,b Fre ´de ´ric Hendra, a,b Roger Gagali Angoh, a,b Delphine Joseph, a,b Philip J. Stephens c and Christian Cave ´ a,b a Univ. Paris-Sud, Equipe de Sythe `se Organique et Pharmacochimie, UMR CNRS 8076 BioCIS, Cha ˆtenay-Malabry F-92296, France b CNRS, Cha ˆtenay-Malabry F-92296, France c Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0482, USA Received 15 February 2007; accepted 26 February 2007 Abstract—The asymmetric Michael reaction between chiral b-enaminophosphonates derived from (S)-1-phenylethylamine and various electrophilic alkenes furnished b,b-disubstituted ketophosphonates in good yields and with excellent enantioselectivity. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction The Michael reaction is known to be one of the simplest and most efficient methods for the construction of quater- nary carbon centres. The use of asymmetric variants of this reaction is well documented in the literature, the stereocon- trolled synthesis of a quaternary carbon in particular being a challenge for organic chemists. Asymmetric Michael addition onto cyclic or acyclic b-ketoesters has been con- sidered in various ways in the literature and particularly via enaminoester derivatives. 1–7 Until now, there has been no report of such a study on b-ketophosphonates which present great interest not only as precursors of b-amino- and b-hydroxy-phosphonates 8–11 but also as molecules of biological importance. 12–15 Thus, by developing simple and efficient asymmetric synthetic pathways to chiral b- ketophosphonates we would be able to find interesting applications in both organic and medicinal chemistry. In our laboratory, it has already been proven that Michael- type additions of chiral acyclic enaminoesters derived from (S)-1-phenylethylamine to various Michael acceptors fur- nished, after hydrolysis, Michael adducts in good yields and excellent enantiomeric excesses (ee). 2,3,7 This remark- able remote transfer of chirality can be explained by a six-membered ‘aza-ene-synthesis-like’ transition state which is secured by intramolecular hydrogen bonding in the enaminoester reactant. 2,3,16 By considering the phosphonate as an ester analogue, we can anticipate the existence of intramolecular hydrogen bonding in the enaminophosphonate similar to that of the enaminoester derivative. Herein, we report an investigation we have made into the reaction between chiral enaminophos- phonates and various electrophilic alkenes. 2. Results and discussion First of all, we synthesized the non-commercial b-keto- phosphonate precursors 3a–3d (Scheme 1). For dialkyl- phosphonates 3a (R = Et) and 3b (R = Me), the synthesis was performed in a three step procedure developed by Cor- bel et al: (a) protection of the ketone group via hydrazone 1, (b) Arbuzov reaction (intermediates 2a and 2b) then (c) deprotection. 17 This led to compounds 3a and 3b in good yields, around 60–70% over three steps. For dibenzyl- phosphonate 3c, the Arbuzov reaction was realized under vacuum in an attempt to eliminate benzyl chloride formed in the reaction and causing side reactions. 18 This proved to be unsuccessful, causing degradation. An alter- native strategy was used with a direct nucleophilic substitu- tion of the chlorine atom of compound 1 by the action of the anion of dibenzylphosphite. When the reaction was car- ried out at room temperature using Cs 2 CO 3 as base, 19 only the b-elimination product was obtained. However, the use 0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2007.02.023 * Corresponding author. Tel.: +33 1 46 83 54 95; fax: +33 1 46 83 56 89; e-mail: sandrine.delarue-cochin@u-psud.fr Tetrahedron: Asymmetry 18 (2007) 685–691