Application of novel sulfonamides in enantioselective organocatalyzed cyclopropanation Antti Hartikka, a Adam T. S ´ lo ´ sarczyk a and Per I. Arvidsson a,b, * a Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-75123 Uppsala, Sweden b Medicinal Chemistry, Discovery CNS and Pain Control, AstraZeneca R&D So ¨ derta ¨ lje, S-15185 So ¨ derta ¨ lje, Sweden Received 25 April 2007; accepted 29 May 2007 Available online 9 July 2007 Abstract—Three novel aryl sulfonamides derived from (2S)-indoline-2-carboxylic acid have been obtained and used as organocatalysts. The catalysts incorporate diverse functionality on the phenyl ring, enabling steric, and electronic fine tuning of the catalysts. The catalysts facilitate the reaction between a range of a,b-unsaturated aldehydes and sulfur ylides, thus providing cyclopropane products in enantio- meric excesses of up to 99%. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction The cyclopropane unit is a common structural constituent in many naturally occurring compounds. Currently over 4000 natural isolates are known and more than a hundred are known to be therapeutically active. 1 Development in the synthetic methodology that allows the construction of these structures in a stereo-controllable manner has attracted the attention of many research groups over the last twenty years. 2 Early synthetic methodology develop- ment focused on the stereoselective formation of function- alized cyclopropane adducts; however, the most recent synthetic development has focused on enantioselective con- struction of diversely substituted cyclopropane adducts. 3 Early development in stereoselective cyclopropanation reactions utilized Simmons–Smith type of reagents. 4 An increasingly important reaction type features a nucleophile containing an internal leaving group moiety. Here, the nucleophile undergoes an intermolecular Michael addition to a a,b-unsaturated carbonyl compound, and thus forms an enolate; this step is followed by an intramolecular ring closure with loss of a leaving group, present either on the Michael acceptor or on the initial nucleophile, thus furnish- ing a cyclopropanated product. 5 The most commonly employed nucleophiles in this kind of reaction are a-halocarbanions, 6 sulfur ylides, 7 phosphorous ylides, 8 arsenium ylides, 9 and telleronium ylides. 10 This methodo- logy allows for a wide range of structurally divergent sub- strates to be reacted and may thus be used to create a plethora of cyclopropane architectures. Herein we wish to report our results concerning the enan- tioselective organocatalyzed cyclopropanation reaction. The reaction was initially disclosed by Ley et al., utilizing modified cinchona alkaloids, 11 while MacMillan et al. made use of a dihydroindol carboxylic acid as a catalyst. 12 We reasoned that substitution of the carboxylic acid of (S)- ()-indoline-2-carboxylic acid to the corresponding (S)- ()-indoline-2-aryl sulfonamide should allow fine tuning of the catalyst structure by varying the substitution on the phenyl ring of the aryl sulfonamide. 2. Results and discussion To investigate the potential of aryl sulfonamides in enan- tioselective cyclopropanation we synthesized three different catalysts, that is, 1–3, containing differently substituted phenyl rings. Catalyst 1 was synthesized by converting (S)-()-indoline- 2-carboxylic acid 4 to the Boc protected derivative 5, fol- lowed by direct coupling with p-nitrophenyl sulfonamide to give 6, which was further Boc deprotected to give cata- lyst 1 (Scheme 1). Direct coupling was necessary due to the poor nucleophilicity of p-nitrophenyl sulfonamide. 0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2007.05.030 * Corresponding author. Tel.: +46 (0)855325923; fax: +46 (0)855328892; e-mail: Per.Arvidsson@astrazeneca.com Tetrahedron: Asymmetry 18 (2007) 1403–1409