MeyersÕ bicyclic lactam formation under mild and highly stereoselective conditions Mae ¨l Penhoat, Stephane Leleu, Georges Dupas, Cyril Papamicae ¨l, Francis Marsais and Vincent Levacher * Laboratoire de Chimie Organique Fine et He ´te ´rocyclique UMR 6014 IRCOF, CNRS, Universite ´ et INSA de Rouen, BP 08, F-76131 Mont-Saint-Aignan Ce ´dex, France Received 6 August 2005; revised 24 September 2005; accepted 26 September 2005 Available online 11 October 2005 Abstract—New and mild conditions to prepare chiral bicyclic lactams in high yields and high diastereoselectivities are reported herein. This approach based on the activation of the carboxylic acid by means of MukaiyamaÕs reagent is an excellent alternative to MeyersÕ dehydrating conditions and provide the main advantage to work at lower temperature (40 °C). Higher diastereoselectiv- ity was obtained with 5,7-bicyclic lactams (de = 82% instead of 44% under standard dehydrating conditions). Ó 2005 Elsevier Ltd. All rights reserved. MeyersÕ bicyclic lactams have proven to be helpful chiral building blocks for the stereoselective construction of optically pure nitrogen heterocycles. 1 The classical pro- cedure used for accessing these versatile chiral bicyclic lactam templates consists of cyclodehydration of a c-, d- or x-keto acid and a chiral amino alcohol by simply heating the two in toluene overnight with azeotropic re- moval of water (Fig. 1). These dehydrating conditions, rather drastic, may prove to be incompatible with highly functionalized substrates, limiting seriously the scope of this methodology. Taking this limitation into account, the search of further reaction conditions is highly desirable. A survey of the literature reveals that no alternative pro- cedures based on the activation of the carboxylic acid 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.09.154 Keywords: MeyersÕ bicyclic lactam; Thioester; MukaiyamaÕs reagent; (R)-Phenylglycinol. * Corresponding author. Tel.: +33 02 3552 2485; fax: +33 02 3552 2962; e-mail: vincent.levacher@insa-rouen.fr H 2 N OH R' N O O R' R n O O R OH n n O O R LG Toluene, reflux - Lower temperature! - Reaction rate! - Diastereoselectivity! Classical Meyers' dehydrating conditions Approach based on an activation of the carboxylic acid n O R OH O NH R' Activation n O R LG O NH R' LG: Leaving group H 2 N OH R' Figure 1. MeyersÕ bicyclic lactam formation. Tetrahedron Letters 46 (2005) 8385–8389 Tetrahedron Letters