Asymmetric Synthesis of N‐Substituted 1,2‐Amino Alcohols from Simple Aldehydes and Amines by One‐Pot Sequential Enzymatic Hydroxymethylation and Asymmetric Reductive Amination

Abstract

The chiral N-substituted 1,2-amino alcohol motif is found in many natural and synthetic bioactive compounds. In this study, enzymatic asymmetric reductive amination of α-hydroxymethyl ketones with enantiocomplementary imine reductases (IREDs) enabled the synthesis of chiral N-substituted 1,2-amino alcohols with excellent ee values (91-99 %) in moderate to high yields (41-84 %). Furthermore, a one-pot, two-step enzymatic process involving benzaldehyde lyase-catalyzed hydroxymethylation of aldehydes and subsequent asymmetric reductive amination was developed, offering an environmentally friendly and economical way to produce N-substituted 1,2-amino alcohols from readily available simple aldehydes and amines. This methodology was then applied to rapidly access a key synthetic intermediate of anti-malaria and cytotoxic tetrahydroquinoline alkaloids.

Hot off the Press

“…A one-pot, two-step, asymmetric synthesis of N -substituted 1,2-amino alcohols has been developed using enzymatic hydroxymethylation and reductive amination. 29 Benzaldehyde lyase-catalysed hydroxymethylation of aldehydes, followed by reductive amination of the resulting α-hydroxymethyl ketones with imine reductases gave 1,2-amino alcohols with excellent enantiomeric excess (Scheme 3). Transaminases have been used for the stereoselective synthesis of ( R )- or ( S )-8-methoxy-2-aminotetraline from a prochiral β-tetralone (Scheme 4).…”

Engineered Imine Reductase for Larotrectinib Intermediate Manufacture

“…Biocatalysis is an attractive alternative to chemical methods that has been extensively applied to the commercial manufacture of fine chemicals and pharmaceuticals due to the advantages of mild reaction conditions, excellent stereoselectivity, and environmentally friendly processes. , Imine reductases (IREDs) are emerging as particularly promising catalysts for the reduction of imines and reductive amination of ketones or aldehydes to access various amines. In the past decade, a considerable number of naturally occurring IREDs have been identified and characterized for the synthesis of amines. − Recently, a few engineered IREDs with improved properties have also been developed by enzyme evolution. − However, their industrial application is still limited. Only two engineered IREDs to date have been used to catalyze reductive amination of ketones or aldehydes for industrial manufacture of pharmaceuticals such as LSD1 inhibitor GSK2879552 and JAK1 inhibitor abrocitinib …”

Engineering enzyme substrate scope complementarity for promiscuous cascade synthesis

“…14 Other C-C bond forming cascades producing 1,2-amino alcohols, such as using aminocyclases or imine reductases, have been successful, but were limited in substrate diversity. [23][24][25] Griengl and coworkers developed an enzymatic cascade to access enantioenriched 1,2-amino alcohols by coupling a promiscuous threonine aldolase with a tyrosine decarboxylase. 26,27 However, the utility of the cascade was limited by the activity of the decarboxylase, allowing preparative-scale access to only a handful of aryl 1,2-amino alcohols.…”