Biocatalytic Monoacylation of Symmetrical Diamines and Its Application to the Synthesis of Pharmaceutically Relevant Amides

Monoacylated diamines are common motifs present in pharmaceuticals, agrochemicals, and natural products. However, the synthesis of these compounds often requires selective protection/deprotection steps leading to waste and poor atom economy. Here we describe the truncation of a carboxylic acid reduc...

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Bibliographic Details
Published inACS catalysis Vol. 10; no. 17; pp. 10005 - 10009
Main Authors Lubberink, Max, Schnepel, Christian, Citoler, Joan, Derrington, Sasha R, Finnigan, William, Hayes, Martin A, Turner, Nicholas J, Flitsch, Sabine L
Format Journal Article
LanguageEnglish
Published American Chemical Society 04.09.2020
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Summary:Monoacylated diamines are common motifs present in pharmaceuticals, agrochemicals, and natural products. However, the synthesis of these compounds often requires selective protection/deprotection steps leading to waste and poor atom economy. Here we describe the truncation of a carboxylic acid reductase (CAR) yielding an adenylation domain capable of selective amide bond formation under aqueous conditions. This truncated construct had a higher amidation activity compared to the full-length enzyme. The amidation reaction is mediated by ATP, which can be recycled from polyphosphate using a class III polyphosphate kinase (CHU). The wide substrate scope and selectivity of this enzymatic amidation method were confirmed through the synthesis of 24 pharmaceutically relevant amides including building blocks of six active pharmaceutical ingredients (APIs). Moreover, up-scaling of selected examples, including two API’s, was achieved demonstrating the value of this approach for synthesis.
ISSN:2155-5435
2155-5435
DOI:10.1021/acscatal.0c02228