Transition metal-catalyzed asymmetric carbene insertion for synthesis of chiral amines

Abstract

Chiral amines are an important class of organic compounds. They are ubiquitous in organic chemistry and often serve as fundamental building blocks, versatile synthons, efficient chiral catalysts, ligands or auxiliaries in asymmetric synthesis and medicinal chemistry. During the past few decades, there has been remarkable progress in the development of efficient asymmetric methods. Accordingly, asymmetric synthesis, particularly catalytic enantioselective synthesis of chiral amines has received considerable attention from both academia and industry. Among them, transition metal-catalyzed asymmetric carbene insertion has emerged as one of the most useful and powerful methods for synthesis of various chiral amines through the efficient construction of the C−N bonds. In this review, we present the progress and advances that have been made using copper, rhodium, palladium, and iron catalysts to perform enantioselective N−H insertion reactions with diazo compounds. An overview of early examples of Cu(I) and Ag(I)-bisoxazoline-catalyzed asymmetric N−H insertion and the subsequent developments by using copper(I) complexes with chiral spiro bisoxazolines, bipyridines and binol derivatives, as well as with rhodium(II)-, palladium(II)-, iron(II)-carbene chemistry is provided. In these work, catalytic asymmetric metal-carbene insertion into the N−H bond of aromatic amines, amides (BocNH2, CbzNH2), substituted carbazoles and indoles, and benzophenone imines were achieved under mild reaction conditions, allowing access to a wide variety of structurally important chiral amines in enantiomerically enriched form. In particular, with the use of α-aryl or α-alkyl α-diazoesters as carbene precusors, both aryl and alkyl substituted α-amino esters could be prepared in good yields with high enantioselectivities. A recent major breakthrough in enantioselective transition-metal-catalyzed N−H insertion reactions with aliphatic amines is also discussed. By using a combination of an achiral copper complex and chiral amino-thiourea catalyst, highly enantioselective carbene insertion into N−H bonds of aliphatic amines was achieved to produce various chiral α-alkyl α-amino acid derivatives bearing secondary and tertiary amino substituents in good yields. Overall, this review summarizes the most prominent work on transition-metal-catalyzed asymmetric carbene N−H insertion and their applications in chiral amines and natural or unnatural chiral α-amino acid derivatives synthesis.