Biocatalytic Alkylation Chemistry: Building Molecular Complexity with High Selectivity

Abstract

Biocatalysis has traditionally been viewed as a field that primarily enables access to chiral centers. This includes the synthesis of chiral alcohols, amines and carbonyl compounds, often through functional group interconversion via hydrolytic or oxidation‐reduction reactions. This limitation is partly being overcome by the design and evolution of new enzymes. Here, we provide an overview of a recently thriving research field that we summarize as biocatalytic alkylation chemistry. In the past 3–4 years, numerous new enzymes have been developed that catalyze sp3 C−C/N/O/S bond formations. These enzymes utilize different mechanisms to generate molecular complexity by coupling simple fragments with high activity and selectivity. In many cases, the engineered enzymes perform reactions that are difficult or impossible to achieve with current small‐molecule catalysts such as organocatalysts and transition‐metal complexes. This review further highlights that the design of new enzyme function is particularly successful when off‐the‐shelf synthetic reagents are utilized to access non‐natural reactive intermediates. This underscores how biocatalysis is gradually moving to a field that build molecules through selective bond forming reactions.

Stable and Functionally Diverse Versatile Peroxidases Designed Directly from Sequences

“…Thus, model-based enzyme design may dramatically increase the scope of computational design methods and address the growing need in many fields to generate functional, stable, and efficient enzyme repertoires or pathways in one shot. 41 ■ ASSOCIATED CONTENT * sı Supporting Information…”

“…Compared to previous VP engineering studies that required screening of thousands of variants, − we screened fewer than 40 designs. Thus, model-based enzyme design may dramatically increase the scope of computational design methods and address the growing need in many fields to generate functional, stable, and efficient enzyme repertoires or pathways in one shot …”

Stable and functionally diverse versatile peroxidases by computational design directly from sequence

“…Compared to previous VP engineering studies that required screening thousands of variants [13][14][15] , we screened fewer than 40 designs. Thus, model-based enzyme design may address the growing need in many fields to generate functional, stable, and efficient enzyme repertoires or pathways in one shot 37 .…”

Substrate Profiling of Anion Methyltransferases for Promiscuous Synthesis of S‐Adenosylmethionine Analogs from Haloalkanes

“…Biocatalytic alkylation chemistry is a flourishing research field. [1] Several enzymes have recently been developed that catalyze highly selective sp 3 C–C/N/O/S bond formations. Within this field, S ‐adenosyl‐ l ‐methionine (SAM)‐dependent enzymes are attracting significant attention due to their ability to perform highly selective alkylation reactions.…”

“…[ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ] In a subsequent reaction, this SAM‐related sulfonium species can be used as co‐substrates by natural and engineered MTs in highly selective sp 3 C–C/N/O/S bond forming reactions that are otherwise very difficult to achieve. [ 1 , 11 ]…”