Recent Progress in Transition-Metal-Catalyzed Asymmetric Reductive Amination

Abstract

Asymmetric reductive amination (ARA) of a prochiral carbonyl compound with an amine using a H2/hydrogen surrogate is a concise and operationally simple method for the synthesis of chiral amines. ARA proceeds via condensation of a carbonyl group with an amine/ammonia followed by the enantioselective reduction of the generated intermediate. The activation of reductant and stereoselective transfer of hydrogen to intermediate imine/enamine is often mediated by a chiral transition metal catalyst. Considering the wide applications of enantiopure amines in pharmaceuticals, agrochemicals, and materials, the development of effective catalysts for ARA has been intensively pursued in the last two decades. Since the first report by Blaser in 1999, this key research area has grown significantly in recent years, as reflected by the advances in catalyst design, diversifying substrate scope and better mechanistic understanding. Several highly efficient and general ARA methodologies applicable to challenging carbonyl and amine partners have been demonstrated, providing ready access to a variety of enantiopure amines. In this Review, we present the recent progress in ARA featuring diverse carbonyl and amine partners employing transition metal-catalysts. This Review provides an organized and critical discussion on catalyst engineering and evolution, expanding susbstrate scope and mechanistic insights. To conclude, the remaining challenges and opportunities in ARA are also highlighted.

Impact of aqueous micellar media on biocatalytic transformations involving transaminase (ATA); applications to chemoenzymatic catalysis

“…3 Representative alternatives include transition metalcatalyzed direct asymmetric reductive amination (DARA) of carbonyl compounds with transition metal hydrides. [4][5][6] Nonetheless, while there are always exceptions, oftentimes the associated conditions tend to be harsh, waste-generating organic solvents are invariably involved, and extensive use of toxic and/or precious metals (e.g., Ir, Rh, and Ru) are the norm. This latter issue can be non-trivial, as metal contamination of the desired final product(s), by FDA standards, can be a relatively common occurrence due to catalyst loadings.…”

Reductive aminations by imine reductases: from milligrams to tons

“…Asymmetric reductive amination is oen accomplished using organocatalysis [4][5][6] or chiral transition metal (TM)-based catalysis. [7][8][9][10] In an early example of the latter, Blaser showed that the precursor 1a of the herbicide (S)-metolachlor could be synthesized from methoxyacetone 1 with 2-methyl-5ethylaniline a and hydrogen using an iridium catalyst generated in situ from 2, giving the amine product (S)-1a with 78% e.e. (Scheme 2).…”

Iridium-catalyzed direct asymmetric reductive amination utilizing primary alkyl amines as the N-sources

“…1a ). The increasing demand has driven the development of novel and efficient methods for their synthesis 1 – 3 , including two practical and highly efficient routes, asymmetric hydrogenation 4 – 9 and reductive amination 10 – 15 (Fig. 1b ).…”