1. Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany

Correspondence to: Benjamin List¹ Correspondence and requests for materials should be addressed to B.L. (Email: list@mpi-muelheim.mpg.de).

Abstract

Small organic molecules recently emerged as a third class of broadly useful asymmetric catalysts that direct reactions to yield predominantly one chiral product, complementing enzymes and metal complexes¹. For instance, the amino acid proline and its derivatives are useful for the catalytic activation of carbonyl compounds via nucleophilic enamine intermediates. Several important carbon–carbon bond-forming reactions, including the Mannich reaction, have been developed using this approach², all of which are useful for making chiral, biologically relevant compounds. Remarkably, despite attempts^{3, 4}, the simplest of all nucleophiles, acetaldehyde, could not be used in this way. Here we show that acetaldehyde is a powerful nucleophile in asymmetric, proline-catalysed Mannich reactions with N-tert-butoxycarbonyl (N-Boc)-imines, yielding -amino aldehydes with extremely high enantioselectivities—desirable products as drug intermediates and in the synthesis of other biologically active molecules. Although acetaldehyde has been used as a nucleophile in reactions with biological catalysts such as aldolases⁵ and thiamine-dependent enzymes⁶, and has also been employed indirectly^{7, 8, 9}, its use as an inexpensive and versatile two-carbon nucleophile in asymmetric, small-molecule catalysis will find many practical applications.