The use of two optically active N-sulfinyl a-imino esters in the stereoselective aza-Diels–Alder reaction Trygve Andreassen a , Marianne Lorentzen a , Lars-Kristian Hansen b , Odd R. Gautun a, * a Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway b Department of Chemistry, Faculty of Science, University of Tromsø, NO-9037 Tromsø, Norway article info Article history: Received 25 November 2008 Received in revised form 7 January 2009 Accepted 22 January 2009 Available online 30 January 2009 Keywords: Asymmetric induction Aza-Diels–Alder reactions Sulfinimines Non-activated dienes abstract Diastereoselective aza-Diels–Alder (aza-DA) reactions of ethyl (S)-N-(tert-butanesulfinyl)iminoacetate (2a) and ethyl (S)-N-(p-toluenesulfinyl)iminoacetate (2b) with different dienes including activated, non- activated, cyclic, and acyclic dienes in the presence of Lewis acids are described. Reactions with 2a were found to be more selective. Reactions of unactivated dienes (acyclic and cyclic) with stoichiometric amounts of TMSOTf as Lewis acid afforded the aza-DA adducts in modest yields and in diaster- eoselectivities up to 99%. A strong preference for Re-approach was observed for 2a. Cyclic dienes gave the exo adducts as major products. For the aza-DA reaction with activated Danishefsky type dienes poor diastereoselectivities were observed. In these cases, the best results were obtained using stoichiometric amounts of BF 3 $Et 2 O as Lewis acid (up to 69% de, 76% yield). The absolute configurations of six of the addition products were established by chemical correlation with known compounds. Acidic cleavage of the sulfinyl group occurred without racemization to optically active non-proteinogenic a-amino acid ethyl esters. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction The aza-Diels–Alder (aza-DA) reaction between dienes and imines is a powerful synthetic method for preparation of highly functionalized six-membered aza-cycles such as piperidines and tetrahydroquinolines. 1 In general, this reaction requires a highly activated (electron-rich) diene like the Danishefsky’s diene and an electron-poor imine. The aza-DA reaction is usually slow due to the low reactivity of the imine functionality. The reactivity can often be increased by incorporation of an electron-withdrawing substituent on the imine and by addition of a Lewis acid to the reaction system. Several asymmetric protocols have appeared, involving either a diastereoselective aza-DA reaction applying chiral imines 2 or more recently, a catalytic enantioselective reaction. 3 In 2000, Jørgensen et al. reported excellent results for the cat- alytic enantioselective aza-DA reaction by reacting the double ac- tivated N-tosyl a-imino ester 1 (see Fig. 1) with different dienes including activated, non-activated, cyclic, and acyclic dienes in the presence of chiral BINAP–copper(I) complexes. 3e The described reaction provided an effective route to optically active non-pro- teinogenic a-amino acids of the piperidine type. A major drawback with this method is the removal of the p-toluenesulfonyl group (p- Ts), which requires harsh conditions. 4 The chiral non-racemic N-sulfinylimino esters 2, which are the sulfinyl analogs of 1 (see Fig. 1), have been described in the litera- ture as ‘chiral glycine cation equivalents’ for the asymmetric syn- thesis of a-amino acids with excellent diastereoselectivities. 5 The chiral and electron-withdrawing sulfinyl group has been shown to activate the C]N bond for nucleophilic addition with high and predictable asymmetric induction, and is easily removed from the product. 6 Since the known aza-DA chemistry of chiral N-sulfinyl imines (sulfinimines) as dienophiles was limited to only one report de- scribing the reaction of 2-aryl substituted N-sulfinyl imines to the highly activated (electron-rich) Rawal diene, 7 an investigation of the aza-DA reaction of 2a was initiated. We recently communicated that 2a reacts with both activated and non-activated dienes in the presence of BF 3 $OEt 2 . 8 The aza-DA adducts were obtained in N S H EtO 2 C R O N pTs H EtO 2 C 2a: R = t Bu 2b: R = pTol 1 Figure 1. Activated dienophiles for the aza-Diels–Alder reaction. * Corresponding author. Tel.: þ47 73 59 41 01; fax: þ47 73 59 42 56. E-mail address: odd.gautun@chem.ntnu.no (O.R. Gautun). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2009.01.090 Tetrahedron 65 (2009) 2806–2817 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet