Cyclosulfamide as a chiral auxiliary: application to efficient asymmetric synthesis (alkylation/aldolization) Fabien Fécourt a , Gérald Lopez a , Arie Van Der Lee b , Jean Martinez a , Georges Dewynter a,⇑ a Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Universités Montpellier 1 et 2, Bâtiment Chimie (17), Université Montpellier 2, Place E. Bataillon, 34095 Montpellier Cedex 5, France b Institut Européen des Membranes (IEM), UMR 5635 CNRS-Université Montpellier 2, Case Courrier 047, Place E. Bataillon, 34095 Montpellier Cedex 5, France article info Article history: Received 14 September 2010 Accepted 16 September 2010 Available online 18 October 2010 abstract The chiral cyclosulfamide (S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine 1,1-dioxide was designed as a chimera of Evans and Oppolzer chiral auxiliaries. The N-propionyl derivative appeared to be very power- ful for the stereocontrolled synthesis of chiral building blocks through asymmetric aldolization and alkyl- ation reactions. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction The introduction of chirality via the use of chiral auxiliaries has been demonstrated as an effectual means for preparing chiral compounds. 1 In particular, the importance of Evans 0 1,3-oxazoli- din-2-ones 1 2 and Oppolzer 0 s chiral sultams 2 3 for asymmetric car- bon–carbon bond formation has been well documented. Ahn et al. previously investigated titanium-mediated aldol reac- tions using the C 2 symmetric cyclosulfamide chiral auxiliary 3 in order to prepare syn dialdols with high stereoselection (>95:5). 4 However, the difficult dialdol cleavage of this bis-reactive chiral auxiliary appeared to be the weak point of this well-thought strategy. Herein we report a simple access to cyclosulfamides as chiral auxiliaries through the synthesis of (S)-2-benzyl-4-isopropyl- 1,2,5-thiadiazolidine-1,1-dioxide 7. 5 The applications to asymmet- ric aldol and alkylation reactions as well as the auxiliary recovery process are also discussed. 2. Results and discussion 2.1. Preparation of (S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine 1,1-dioxide 7 and N-acyl compound 8 Our synthetic strategy involves five steps as shown in Scheme 1. Inexpensive L-valine was first reduced with LiAlH 4 into L-valinol 4, which was subsequently derivatized with N,N-dimethylsulfonyl chloride to give the valinol-sulfonamide 5. Then, an APTS-mediated conversion of the free hydroxyl function into the corresponding leaving group afforded the sulfamoyl-aziridine 6 under basic conditions. Subsequent heating of 6 with 5 equiv of benzylamine in DMSO as previously described 6 gave the desired chiral sulfon- amide auxiliary 7 in 44% overall yield from L-valine. Starting from 7, the corresponding N-propionyl compound 8 was then easily ob- tained in high yield using propionyl chloride under basic condi- tions (see Fig. 1). 4 2.2. Diastereocontrolled aldolization The titanium enolate of 8 was generated by reaction with 1.2 equiv of TiCl 4 in CH 2 Cl 2 at 78 °C for 30 min followed by addition of 1.2 equiv of N-diisopropylethylamine at the same 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.09.001 ⇑ Corresponding author. Tel.: +33 467 144 819. E-mail address: Georges.Dewynter@univ-montp2.fr (G. Dewynter). H 2 N COOH LAH THF H 2 N OH Me 2 NSO 2 Cl, Et 3 N CH 2 Cl 2 HN OH S N O O p-TsCl KOH THF N N S O O BnNH 2 DMSO HN S N O O N S N O O O EtCOCl, Et 3 N THF 4 5 6 7 8 Scheme 1. Tetrahedron: Asymmetry 21 (2010) 2361–2366 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy