Asymmetric Synthesis of N‐Substituted γ‐Amino Esters and γ‐Lactams Containing α,γ‐Stereogenic Centers via a Stereoselective Enzymatic Cascade

Abstract

γ‐Amino esters and γ‐lactams containing α,γ‐stereogenic centers are widely used as chiral intermediates in various bioactive compounds, while their efficient synthesis remains a challenge. Herein, an enzymatic cascade reaction involving an ene reductase (ERED) and an imine reductase (IRED) for accessing to α,γ‐stereospecific γ‐amino esters and γ‐lactams from α,β‐unsaturated γ‐ketoesters has been developed. 21 EREDs and 13 IREDs have been identified with high activity and stereoselectivity toward various α,β‐unsaturated γ‐ketoesters and the corresponding chiral γ‐ketoesters, respectively. By employing suitable ERED and IRED, (1S,3S), (1S,3R), (1R,3S), and (1R,3R) stereoisomers of methyl 3‐(cyclopropyl amino) cyclohexane‐1‐carboxylate were obtained as a single stereoisomer in 63–72% yield, and (3R,5R)‐ and (3R,5S)‐1‐cyclopropyl‐3,5‐dimethylpyrrolidin‐2‐one and 1‐cyclopropyl‐3,5‐dipropylpyrrolidin‐2‐one were also prepared as a single stereoisomer in 60–65% yields. This study establishes an environmentally friendly enzymatic route for the synthesis of γ‐amino esters and γ‐lactams containing α,γ‐stereogenic centers.

Emerging Technologies for Biocatalysis in the Pharmaceutical Industry

“…In 2017, following on from early reports of IREDs showing activity for intermolecular reductive amination, − the Turner group at the University of Manchester reported the characterization of an enzyme able to catalyze imine formation and reduction without the need for a preformed or water-stable imine . Previously established aminating enzyme platforms such as transaminases, amine dehydrogenases, and ammonia lyases are largely limited to the production of primary amines, with a few examples of the formation of secondary amines. − In contrast, reductive amination with IREDs enabled the direct synthesis of primary, secondary, and tertiary amines …”

Ene‐Reductase: A Multifaceted Biocatalyst in Organic Synthesis

“…In another report, ene‐reductase (ER) and an imine reductase (IR) cascade were used by Li et al . for the synthesis of α , γ ‐stereospecific γ ‐amino esters and γ ‐lactams from α , β ‐unsaturated γ‐ketoesters [82] . Asymmetric hydrogenation of tetrasubstituted alkenes using transition‐metal catalyst is challenging and demands high H 2 pressure and temperature.…”

“…In another report, ene-reductase (ER) and an imine reductase (IR) cascade were used by Li et al for the synthesis of α,γ-stereospecific γamino esters and γ-lactams from α,β-unsaturated γketoesters. [82] Asymmetric hydrogenation of tetrasubstituted alkenes using transition-metal catalyst is challenging and demands high H 2 pressure and temperature. To overcome these harsh conditions, the Gatti group reported a new method using multienzyme biocatalysis to reduce tetra substituted cyclic enones.…”

Stereoselective Synthesis of Structurally Diverse (S)‐Lactams via an Engineered Amine Dehydrogenase

“…Li et al have developed an enzymatic cascade reaction using an ene reductase (ERED) and an imine reductase (IRED) to generate γ-lactams from α,β-unsaturated γ-ketoesters (Scheme 1e). [21] (3R,5R)-and (3R,5S)-1-cyclopropyl-3,5-dimethylpyrrolidin-2-one and 1-cyclopropyl-3,5dipropylpyrrolidin-2-one were prepared as a single stereoisomer in 60-65% yields. Vergne-Vaxelaire and co-workers [22] have reported an amine dehydrogenase from Petrotoga mobilis (PmAmDH) that is capable of catalyzing the reductive amination of ketones using ammonia, which is an inexpensive reagent, as the amino donor.…”