Oxidoreductase-Catalyzed Synthesis of Chiral Amines

Abstract

Chiral amines are valuable constituents of many important pharmaceutical compounds and their intermediates. It is estimated that ∼40%–45% of small molecule pharmaceuticals contain chiral amine scaffolds in their structures. The major challenges encountered in the chemical synthesis of enantiopure amines are the use of toxic chemicals, the formation of a large number of byproducts, and multistep syntheses. To address these limitations, cost-effective biocatalytic methods are maturing and proving to be credible alternatives for the synthesis of chiral amines in enantiomerically pure forms. Herein, we report the recent progress achieved and current perspectives in the enzymatic synthesis of chiral amines using four important enzymes, i.e., imine reductases, amine dehydrogenases, monoamine oxidases, and cytochrome P450s. Applications to the industrial synthesis of chiral amines are highlighted. Protein engineering approaches, which play a critical role in improving or altering enzyme activity and substrate scope, are also addressed, along with the discovery of pioneering enzymatic activities from nature. This survey of recent work demonstrates that enzymatic approaches to the synthesis of chiral amines will continue to be a major focus of research in biocatalytic chemistry in the years to come.

Sequential Two‐Step Stereoselective Amination of Allylic Alcohols through the Combination of Laccases and Amine Transaminases

“…Biocatalytic methods have emerged as a sustainable solution for the synthesis of chiral amines by means of the single action of enzymes of several classes, including lipases, amine transaminases (ATAs), amine oxidases, amine dehydrogenases, imine reductases or reductive aminases, but, interestingly, great efforts have in recent years been devoted to the synthesis of chiral amines through chemo‐, photo‐ and multienzymatic approaches . As an example, the selective amination of racemic sec ‐alcohols through elegant cascades based on the combination of alcohol‐dehydrogenase‐catalysed oxidation to ketones with subsequent bioamination by using ATAs or amine dehydrogenases has been described.…”

Deracemization of Racemic Amines to Enantiopure (R)‐ and (S)‐amines by Biocatalytic Cascade Employing ω‐Transaminase and Amine Dehydrogenase

“…Although ω‐TAs have been well documented in deracemization;, the utility of AmDHs in deracemization protocols to produce enantiopure amines is still unexplored. Although, the synthesis of ( R )‐amines have been successfully carried out by easier strategies such as AmDH‐catalyzed reductive amination of ketones ,. Also, recent years have evidenced the improved array of new ( R )‐selective ω‐TAs for the scalable synthetic applications .…”

“…Also, recent years have evidenced the improved array of new ( R )‐selective ω‐TAs for the scalable synthetic applications . Since AmDHs exhibit exclusive selectivity towards ( R )‐amines,, they open a new avenue of a class of enzymes representing enantiocomplementarity to well reported ( S )‐selective ω‐TAs. We envisaged to utilize ( R )‐AmDHs in tandem with enantiomerically complementary ( S )‐ω‐TA to constitute a deracemization cascade enabling the access to both the enantiomers [( R )‐ and ( S )] of a range of chiral amines.…”

Kinetic Resolution of Racemic Primary Amines Using Geobacillus stearothermophilus Amine Dehydrogenase Variant

“…An increasing number of newly approved drugs contain an α‐chiral amine core, and the legislative regulations for their commercialisation are stringent in terms of chemical and enantiomerical purity (i. e., total impurity amount <0.15 %). In this context, several biocatalytic methods to obtain enantiopure α‐chiral amines have been developed, including asymmetric synthesis from prochiral ketones using either ω‐transaminases (ωTA), or dehydrogenases (i. e., reductive aminases (RedAm), imine reductases (IRed), amine dehydrogenases (AmDH); from alkenes using either ammonia lyases or engineered cytochrome c; and from alkanes using engineered cytochrome P411 monooxygenases . Enantiomerically pure amines can also be obtained from a racemic mixture by either kinetic resolution (KR) or applying one among several available deracemisation strategies .…”