Synthesis of protected 3-aminopiperidine and 3-aminoazepane derivatives using enzyme cascades

Abstract

Synthesis of Cbz-protected 3-aminopiperidine and 3-aminoazepane using a multi-enzyme cascade consisting of galactose oxidase and imine reductase variants.

Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades**

“…Galactose oxidase (GOase), a copper‐dependent alcohol oxidase, has been shown to be a useful tool in biocatalysis with a number of variants displaying a broad substrate scope. [ 33 , 34 , 35 ] Using GOase instead of choline oxidase would lead to a panel of benzylic amines as shown in Scheme 1 . However, due to the reactive copper center in GOase, amines can inhibit the biocatalyst meaning one‐pot batch reactions are not feasible with aminating enzymes.…”

Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades**

“…Galactose oxidase (GOase), ac opper-dependent alcohol oxidase,h as been shown to be auseful tool in biocatalysis with anumber of variants displaying ab road substrate scope. [33][34][35] Using GOase instead of choline oxidase would lead to ap anel of benzylic amines as shown in Scheme 1. However, due to the reactive copper center in GOase,a mines can inhibit the biocatalyst meaning one-pot batch reactions are not feasible with aminating enzymes.I ndeed, when the cascades were carried out in batch, performance as expected was poor,with no observable conversion to the corresponding amines (see Supporting Information).…”

Engineering of Thermostable β‐Hydroxyacid Dehydrogenase for the Asymmetric Reduction of Imines

“…[2 – 8] In particular, imine reductases (IREDs) have emerged as a valuable new set of biocatalysts for the asymmetric synthesis of optically active amines [1,9–17] . IREDs and related reductive aminases have been applied in biotransformations and enzyme cascades for the synthesis of chiral amines [18–29] …”

“…[1,[9][10][11][12][13][14][15][16][17] IREDs and related reductive aminases have been applied in biotransformations and enzyme cascades for the synthesis of chiral amines. [18][19][20][21][22][23][24][25][26][27][28][29] The use of sequence-based bioinformatics classification approaches enabled the identification of characteristic sequence motifs and the annotation of putative IREDs in the Imine Reductase Engineering Database (https://ired.biocatnet.de/). [30,31] A deeper analysis of the sequence space of IRED homologues revealed a significant sequence similarity and a similar quaternary structure of β-hydroxyacid dehydrogenases (βHADs).…”