New Trends and Future Opportunities in the Enzymatic Formation of C−C, C−N, and C−O bonds

Abstract

Organic chemistry provides society with fundamental products we use daily. Concerns about the impact that the chemical industry has over the environment is propelling major changes in the way we manufacture chemicals. Biocatalysis offers an alternative to other synthetic approaches as it employs enzymes, Nature's catalysts, to carry out chemical transformations. Enzymes are biodegradable, come from renewable sources, operate under mild reaction conditions, and display high selectivities in the processes they catalyse. As a highly multidisciplinary field, biocatalysis benefits from advances in different areas, and developments in the fields of molecular biology, bioinformatics, and chemical engineering have accelerated the extension of the range of available transformations (E. L. Bell et al., Nat. Rev. Meth. Prim. 2021, 1, 1-21). Recently, we surveyed advances in the expansion of the scope of biocatalysis via enzyme discovery and protein engineering (J. R. Marshall et al., Tetrahedron 2021, 82, 131926). Herein, we focus on novel enzymes currently available to the broad synthetic community for the construction of new CÀ C, CÀ N and CÀ O bonds, with the purpose of providing the non-specialist with new and alternative tools for chiral and sustainable chemical synthesis.

Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C–H Amidation

“…Enantiodivergent biocatalysts are highly desirable yet often hard to develop. 39 Notably, screening of the initial Mb active-site mutant library revealed a variant, Mb(L29T,H64V,V68L), that catalyzes the cyclization of 1a with inverted enantioselectivity compared to Mb*, producing the R-configured γ-lactam product ent-2a in 65% ee, albeit in modest yield (15%; Table S2). To improve the performance of this biocatalyst, Mb(L29T,H64V,V68L) was subjected to active-site mutagenesis, ultimately leading to Mb(L29T,H64T,V68L), which produces ent-2a with both an improved enantioselectivity of 91% ee and two-fold higher activity compared to the parent enzyme.…”

Oxygenating Biocatalysts for Hydroxyl Functionalisation in Drug Discovery and Development

“…[105,108] Thus, their cost-effective synthetic utility, coupled with an innate activity toward amino acid substrates, is highly attractive for CÀ O bond formation with pharmaceutical applications. [109,110] The remote hydroxylation of unactivated sp 3 CÀ H sites of amino acid substrates is a desired, but challenging, synthetic reaction. Proline hydroxylases (PHs) represent well-studied and characterised Fe/αKGs for free amino acid hydroxyl functionalisation.…”

Engineering of Hydroxymandelate Oxidase and Cascade Reactions for High-Yielding Conversion of Racemic Mandelic Acids to Phenylglyoxylic Acids and (R)- and (S)-Phenylglycines

“…Full oxidation of racemic alcohols to ketones could be achieved by using special alcohol dehydrogenase (ADH) or alcohol oxidase (AOx). Although the ambidextrous ADH , or AOX are rare, coupled enzymes could be used for the full oxidation of racemic alcohols, such as ( S )-enantioselective ADH coupled with ( R )-enantioselective ADHs, , and an enantioselective ADH mixed with a racemase. ,, The latter strategy was applied for the oxidation of racemic substituted MAs to the corresponding PGAs by using mandelate racemase (MR) with ( S )-mandelate dehydrogenase (SMDH) and d -mandelate dehydrogenase ( Lb DMDH), respectively. , While SMDH-MR afforded PGAs in 10–20 mM with 58–94% conversion, Lb DMDH-MR gave 50 mM product with 49–95% conversion.…”