Cooperative assistance in bifunctional organocatalysis: enantioselective mannich reactions with aliphatic and aromatic imines

Hold them tight: Guided by X-ray structures, bifunctional thiourea catalysts containing an activating intramolecular hydrogen bond were redesigned. The new catalysts were used to effect a highly enantioselective Mannich reaction between malonates and both aliphatic and aromatic imines (see scheme; Boc=tert-butoxycarbonyl).     

Organocatalytic asymmetric Mannich reactions with N-Boc and N-Cbz protected alpha-amido sulfones (Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl)

Different malonates and beta-ketoesters can react with N-tert-butoxycarbonyl- (N-Boc) and N-benzyloxycarbonyl- (N-Cbz) protected alpha-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained phase-transfer catalyst and proceeds under very mild and user-friendly conditions. The optimised protocol avoids the preparation and the isolation of the relatively unstable N-Boc and N-Cbz imines that are generated in situ from the bench-stable alpha-amido sulfones. The corresponding Mannich bases are generally obtained in good yields and enantioselectivities, and can be readily transformed into key compounds, such as optically active beta3-amino acids in one easy step. Enantioenriched N-Boc and N-Cbz protected beta-amino acids that are suitable for peptide synthesis are also available from the Mannich adducts through simple manipulations. Control experiments showed the dual role of the enolate-catalyst ion pair in this reaction, as well as the crucial role of the presence of water to achieve high enantioselectivities.     

The Direct catalytic asymmetric cross-Mannich reaction: a highly enantioselective route to 3-amino alcohols and alpha-amino acid derivatives

The first proline-catalyzed direct catalytic asymmetric one-pot, three-component cross-Mannich reaction has been developed. The highly chemoselective reactions between two different unmodified aldehydes and one aromatic amine are new routes to 3-amino aldehydes with dr>19:1 and up to >99 % ee. The asymmetric cross-Mannich reactions are highly syn-selective and in several cases the two new carbon centers are formed with absolute stereocontrol. The reaction does not display nonlinear effects and therefore only one proline molecule is involved in the transition state. The reaction was also catalyzed with good selectivity by other proline derivatives. The Mannich products were converted into 3-amino alcohols and 2-aminobutane-1,4-diols with up to >99 % ee. The first one-pot, three-component, direct catalytic asymmetric cross-Mannich reactions between unmodified aldehydes, p-anisidine, and ethyl glyoxylate have been developed. The novel cross-Mannich reaction furnishes either enantiomer of unnatural alpha-amino acid derivatives in high yield and up to >99 % ee. The one-pot, three-component, direct catalytic asymmetric reactions were readily scaled up, operationally simple, and conductible in environmentally benign and wet solvents. The mechanism and stereochemistry of the proline-catalyzed, one-pot, three-component, asymmetric cross-Mannich reaction are also discussed.     

催化不对称反应新发展: 不对称活化

介绍了催化不对称催化反应中的一个新概念－不对称活化(asymmetricactivation)及其研究的最新发展。运用不对称活化策略,一个光学活性的整或者甚至外消旋的催化剂可以被另一种手性活化剂(chiralactivator)选择性的活化,从而催化反应生成非外消旋产物。该方法较不对称活化(asymmetricactivation)方法的优点是被活化的催化剂能够产生较使用光学纯催化剂更高对映体过量的产物。     

N-Salicyl-β-aminoalcohols as a new class of ligand for catalytic asymmetric Strecker reactions

An enantioselective Strecker synthesis employing novel chiral titanium complex catalysts derived from structurally simple chiral N-salicyl-β-amino alcohols is described. Reactions of N-benzylidenebenzylamine with trimethylsilyl cyanide in the presence of the catalyst (10 mol%) gave the corresponding α-aminonitrile in good to excellent yields, along with relatively high enantioselectivity (up to 86% ee). Similar reactions with various imines derived from aromatic aldehydes resulted in moderate to good enantioselectivity (44-81% ee).