Highly enantioselective organocatalytic addition of unmodified aldehydes to N-Boc protected imines: one-pot asymmetric synthesis of b-amino acids Jan Vesely, Ramon Rios, Ismail Ibrahem and Armando Co ´ rdova * Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden Received 7 October 2006; revised 29 October 2006; accepted 10 November 2006 Abstract—Highly enantioselective catalytic routes to Boc protected b-amino aldehydes, b-amino acids and c-amino alcohols are pre- sented. The organocatalytic asymmetric reactions between unmodified aldehydes and N-Boc protected aryl imines proceed with excellent chemo- and enantioselectivities to give the corresponding compounds in high yields with up to >19:1 dr and 93% to >99% ee. Ó 2006 Published by Elsevier Ltd. The Mannich reaction has found a multitude of applica- tions in organic chemistry. The resulting Mannich bases are of particular interest due to their utilization as syn- thetic building blocks and precursors of pharmaceuti- cally valuable compounds. 1,2 Chemists have developed several stoichiometric indirect stereoselective Mannich transformations that utilize preformed enol equivalents or imines. 3,4 The first successful examples of catalytic asymmetric additions of enolates to imines led to an intense study of catalytic indirect Mannich reactions. 5 Recently, heterodimetallic complexes and di-nuclear zinc organo-metallic complexes were reported as cata- lysts for highly enantioselective direct Mannich-type reactions. 6,7 Moreover, chiral copper(II) bisoxazoline (BOX) complexes are also catalysts for direct asymmet- ric Mannich-type reactions. 8 Recently, organocatalysis has been added to the synthetic repertoire for this important transformation. 9 These direct asymmetric Mannich reactions are catalyzed by chiral Brønsted acids, 10 cinchona alkaloids, 11 proline and its deriva- tives, 12 peptide derivatives 13 and amino acids. 14 In this context, we and Hayashi have reported the amino acid catalyzed addition of unmodified aldehydes to aryl N-p-methoxyphenyl (PMP) imines Eq. 1. 15,16 The corresponding PMP-protected b-amino aldehydes are not very stable and are therefore reduced in situ to the corresponding c-alcohols. In addition, removal of the PMP group requires oxidative conditions and can be low yielding. Enders recently reported two elegant examples of addition of ketones to Boc imines. 17 Based on this and our previous experience in organocatalysis, 18 we envisioned an organocatalytic reaction between Boc protected imines and unmodified aldehydes. 19 This pos- sible reaction would be of high synthetic importance since it would be a direct route to Boc protected b- amino acids, 2f,20 which can be used directly in peptide and c-amino alcohols synthesis (Eq. 2). Moreover, the side chain of Docetaxel (Taxotere), one of the most important cancer chemotherapeutic substances, is a Boc protected a-hydroxy-b-amino acid. 21 0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2006.11.076 * Corresponding author. Tel.: +46 8 162479; fax: +46 8 154908; e-mail addresses: acordova@organ.su.se; acordova1a@netscape.net Ar O O (20-30 mol%) N H COOH H H Ar H N + R NH NaBH 4 Ar OH R NH OMe MeO MeO ð1Þ Tetrahedron Letters 48 (2007) 421–425