Doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure N-enoyl oxazolidin-2-ones: a mechanistic probe Stephen G. Davies * , Ai M. Fletcher, Gesine J. Hermann, Giovanna Poce, Paul M. Roberts, Andrew D. Smith, Miles J. Sweet, James E. Thomson Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK article info Article history: Received 15 March 2010 Accepted 26 March 2010 Available online 3 May 2010 Dedicated to Professor Henri Kagan on the occasion of his 80th birthday abstract The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(a-methylben- zyl)amide to a range of enantiopure N-enoyl oxazolidin-2-ones has been used as a mechanistic probe to determine that the reactive conformation is the anti-s-cis form. The b-amino carbonyl products resulting from these conjugate addition reactions are useful templates for further elaboration into an a,b,a- pseudotripeptide. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction The conjugate addition of nucleophiles to a,b-unsaturated carbonyl compounds plays a fundamental role in the stereoselec- tive formation of b-functionalised carbonyl compounds. Stereo- control in these reactions has been achieved by the use of chiral nucleophiles (‘donors’), chiral a,b-unsaturated carbonyl compounds (‘acceptors’) and chiral catalysts. 1,2 Within this arena, the diastereoselective conjugate addition of organocuprates to N- enoyl derivatives of oxazolidin-2-one chiral auxiliaries (e.g., 1) has been used extensively, with Lewis acids traditionally em- ployed to facilitate reactivity. 3 It is possible for an N-enoyl oxa- zolidine-2-one derivative to undergo diastereoselective 1,4- addition via any of the four possible syn- or anti- and s-cis or s-trans conformations 3A–3D. An intriguing mechanistic dichot- omy exists in this system, since the expected favoured nucleo- philic attack on the face of the double bond opposite to the C(4)-stereodirecting group of the oxazolidin-2-one scaffold in either the syn-s-cis 3A or the anti-s-trans 3C conformation leads to the same stereochemical result; the same argument may be applied to the anti-s-cis 3B or the syn-s-trans 3D pair of conform- ers. In single asymmetric transformations an assessment of the product distribution does not therefore allow conclusive deter- mination of the reactive conformation of these systems. It has been proposed however that the diastereoselective conjugate addition of organocuprates occurs preferentially via the (Lewis acid chelated) syn-s-cis conformation 3A, 4 with the reaction dia- stereoselectivity postulated to reflect the populations of the reac- tive conformers of these substrates; 5 however, the anti-s-cis conformation 3B has been proposed to account for the reversal of selectivity noted in TMSI-promoted additions of monoorgano- cuprates, 6 and a similar reversal of selectivity has been reported in conjugate addition reactions promoted by Et 2 AlCl and TiCl 4 . 7 The conjugate addition of nucleophiles other than copper-based species to N-enoyl oxazolidin-2-ones 3 has been less widely ex- plored 8,9 (Scheme 1). We have demonstrated extensively that the conjugate addition of secondary lithium amides such as lithium N-benzyl-N- (a-methylbenzyl)amide 4 to a,b-unsaturated esters and amides represents a versatile and efficient method for the preparation of b-amino esters and b-amino amides and their derivatives. 10 This methodology has found numerous synthetic applications, including the total synthesis of natural products, 11 molecular recognition phenomena 12 and resolution protocols. 13 We envis- aged that this reaction protocol could be extended to encompass N-enoyl oxazolidin-2-ones 3 as chiral a,b-unsaturated carbonyl components. In addition to these synthetic studies, it was antici- pated that an evaluation of the levels of double asymmetric induction 14 displayed upon conjugate addition of enantiopure lithium N-benzyl-N-(a-methylbenzyl)amide 4 to a chiral N-enoyl oxazolidin-2-one 3 might serve as a tool with which to examine the reactive conformation of the oxazolidinone systems, given the established requirement for lithium amides to add to (E)- a,b-unsaturated esters and amides exclusively in the s-cis confor- mation, 15 conjugate addition to an N-enoyl oxazolidin-2-one 3 may be expected to occur only via either the syn- or anti-s-cis conformation 3A or 3B, respectively. Furthermore, elaboration of the conjugate addition products 5 would facilitate the preparation of a series of a,b-pseudopeptides 6 by unmasking the oxazolidin- 2-one auxiliary as a latent a-amino acid. The results of these studies are delineated herein; part of this work has been commu- nicated previously 16 (Fig. 1). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.03.033 * Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies). Tetrahedron: Asymmetry 21 (2010) 1635–1648 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy