An Easy Stereoselective Access to ,γ-Aziridino r-Amino Ester Derivatives via Mannich Reaction of Benzophenone Imines of Glycine Esters with N-Sulfonyl r-Chloroaldimines Lora´nd Kiss, ²,‡ Sven Mangelinckx, ²,§ Reijo Sillanpa¨a¨, ¶ Ferenc Fu¨lo¨p, | and Norbert De Kimpe* ,² Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent UniVersity, Coupure Links 653, B-9000, Ghent, Belgium, Institute of Pharmaceutical Chemistry, UniVersity of Szeged, H-6701 Szeged, P.O. Box 427, Hungary, and Department of Chemistry, UniVersity of JyVa¨skyla¨, Fin-40351, JyVa¨skyla¨, Finland norbert.dekimpe@ugent.be ReceiVed May 21, 2007 Mannich-type addition of benzophenone imine glycinates across newly synthesized N-(p-toluenesulfonyl) R-chloroaldimines afforded γ-chloro-R,-diamino ester derivatives with moderate diastereoselectivity as separable mixtures of anti and syn diastereomers. The γ-chloro-R,-diamino esters were efficiently cyclized under basic conditions to the corresponding ,γ-aziridino R-amino ester derivatives, representing a new class of conformationally constrained heterocyclic R,-diamino acid derivatives. The relative configuration of the aziridines was determined via X-ray diffraction analysis. Mechanisms and intermediate transition states to explain the stereochemical outcome of the Mannich reaction with different substrates or under different conditions are proposed. The synthetic importance of the ,γ-aziridino R-amino ester derivatives is demonstrated by their conversion into the corresponding Boc-protected derivatives and ring opening reactions to R,-diamino esters and a γ-amino R,-unsaturated amino ester. Introduction The incorporation of conformationally constrained R-amino acids 1 and, more recently, -amino acids 2 into biologically active peptides has gained great interest in the preparation of peptide- based drug molecules. R,-Diamino acids 1, as biological relevant compounds and precursors of 3-amino--lactams, 3 have received far less attention. 2-Aziridinylglycines 2 and derivatives thereof, such as esters and amides, can be considered as a virtually new class of conformationally constrained heterocyclic R,-diamino acid derivatives of which only few representatives have been described. Recently, the synthesis of a N-Cbz-protected 2-aziri- dinylglycinamide 3 was reported in low yield via rearrangement of 3-{[(benzyloxy)carbonyl]amino}-4-(mesyloxymethyl)-1-(4- methoxyphenyl)-2-azetidinone upon treatment with ammonia, 4 analogous to the transformation of 4-(1-haloalkyl)-2-azetidinones with sodium methoxide in methanol to methyl 4-(alkylamino)- pentenoates via intermediate methyl 2-aziridinylacetates. 5 The ² Ghent University. | University of Szeged. ¶ University of Jyva¨skyla¨. ‡ On leave from University of Szeged. § Postdoctoral Fellow of the Research Foundation-Flanders (FWO). (1) (a) Cowell, S. M.; Lee, Y. S.; Cain, J. P.; Hruby, V. J. Curr. Med. Chem. 2004, 11, 2785. (b) Komarov, I. V.; Grigorenko, A. O.; Turov, A. V.; Khilya, V. P. Russ. Chem. ReV. 2004, 73, 785. (c) Park, K. H.; Kurth, M. J. Tetrahedron 2002, 58, 8629. 10.1021/jo0710634 CCC: $37.00 © 2007 American Chemical Society J. Org. Chem. 2007, 72, 7199-7206 7199 Published on Web 08/17/2007