Cooperative transition-metal and chiral Brønsted acid catalysis: enantioselective hydrogenation of imines to form amines.

Chiral amines are an integral part of numerous important bioactive compounds. This privileged structural motif is found in naturally occurring alkaloids and amino acid derivatives as well as in pharmaceuticals, herbicides, and insecticides. Typically, enantiomerically pure amines are key building blocks in the drug-discovery process, but they are also sold on a multi-hundred-ton-scale as kinetic-resolution reagents. With the growing importance of chiral compounds in the life-science industries, the development of efficient methodologies continues to be a topic of interest in organic chemistry and catalysis. Clearly, asymmetric hydrogenation has become a prime technology for the synthesis of chiral compounds. In this respect, the atom-efficient reaction of imines with inexpensive hydrogen to form amines has received much attention in recent years. The largest metal-catalyzed asymmetric process in industry today, the iridium-catalyzed hydrogenation in the production of metolachlor, is a prime example of this methodology. Virtually all of the known catalyst systems employed for asymmetric hydrogenation are derived from precious late transition metals in combination with specific chiral phosphine ligands for the control of enantioselectivity. An interesting alternative organocatalytic approach for the reduction of imines in the presence of chiral Brønsted acids was reported by the research groups of Rueping, List, MacMillan, and Antilla. Unfortunately, the requirement of stoichiometric amounts of expensive Hantzsch dihydropyridines as the hydrogen source has limited the application of this methodology. Over the past decade, the field of asymmetric Brønsted acid catalysis has grown at a dramatic pace. This form of catalysis provides new ways for the enantioselective preparation of various kinds of C C, C O, and C N bonds. However, the majority of these methods are restricted to the generation of a stabilized carbocation and its direct reaction with active carbonor heteroatom-based nucleophiles. Herein, we describe a different approach involving the combination of a molecularly defined iron hydrogenation catalyst with a chiral Brønsted acid for the reduction of various imines with hydrogen to form the corresponding amines with high selectivity (Scheme 1). Conceptually, the