Biocatalytic Reduction of 2‐Monosubstituted 3‐Thiazolines Using Imine Reductases

Abstract

The application of a straightforward biocatalytic technology for the reduction of racemic 2‐monosubstituted 3‐thiazolines, which are easily prepared via Asinger‐multicomponent reaction, is reported. The biocatalytic reduction yields racemic 2‐monosubstituted 3‐thiazolidines, which are difficult to be prepared by means of classic chemical routes, in moderate to high yields. Moreover, our study clarifies the stereochemical reaction course of the biocatalytic reduction. Furthermore, the efficiency of this biocatalytic technology is demonstrated in an experiment at an elevated substrate concentration of 60 mM leading to 96% conversion.

Process Development of Enantioselective Imine Reductase-Catalyzed Syntheses of Pharmaceutically Relevant Pyrrolidines

“…It should be added that the evaluated IREDs are enzymes that are known in the literature ,, and that, for better readability, the IREDs are numbered in this article. In addition, for clarity reasons, the names of the original strains and literature related to each IRED enzyme are shown in Table S1.…”

“…Due to both the excellent conversion and enantioselectivity achieved by the Cs IRED, this biocatalyst was chosen for further process development. As in previous work we could successfully apply IRED-based whole-cell catalysts for heterocyclic imine reductions, ,,, we also became interested in constructing a suitable recombinant E. coli -type whole-cell catalyst for the purpose of enantioselectively reducing the pharmaceutically relevant pyrrolines 1a and 1b . Toward this end, at first, an E. coli -type whole-cell catalyst containing Cs IRED and Bs GDH was designed based on a two-plasmid concept (Figure ).…”

“…In the past decade, IREDs have received growing attention by many research groups, which led to a broad expansion of the substrate spectrum. Examples for suitable heterocyclic substrates are substituted pyrrolines, dihydroisochinolines, tetrahydropyridines, tetrahydroazepines, thiazolines, and benzooxazines. − A recently developed enzymatic approach related to IREDs is the implementation of reductive amination for the synthesis of chiral amines from ketones. − The synthetic versatility of imine reductases is demonstrated by their recent integration as key steps in enzymatic cascade reactions, e.g., for the deracemization of amines in combination with an amine oxidase . In addition, imine reductases have been also applied for the synthesis of pharmaceuticals.…”

Biocatalytic reductive aminations with NAD(P)H-dependent enzymes: enzyme discovery, engineering and synthetic applications

“…Co-expression of IRED and GDH in E. coli enabled in situ cofactor recycling and preparative synthesis of a (S)-3-thiazolidine derivative at a 18 g L À1 substrate loading, 78% isolated yields and 99% ee. [122][123][124] In addition to the sulfurcontaining cyclic imines, the same group has also investigated N and O containing heterocycles such as 2H-1,4-benzoxazines. 125 The discovery and expansion of the IREDs toolbox have provided important tools to the construction of chiral amine products.…”