Biocatalytic Alkylation Cascades: Recent Advances and Future Opportunities for Late‐Stage Functionalization

Abstract

This Concept article describes the latest developments in the emerging area of late-stage biocatalytic alkylation. Central to these developments is the ability to efficiently prepare Sadenosyl methionine (SAM) cofactor analogues and couple this with enzymatic alkyl transfer. Recent developments in the enzymatic synthesis of SAM cofactor analogues are summarized first, followed by their application as alkyl transfer agents catalyzed by methyltransferases (MTases). Second, innovative methods to regenerate SAM cofactors by enzymatic cascades is reported. Finally, future opportunities towards establishing a generalized platform for late-stage alkylation are described.

Directed Evolution of a Halide Methyltransferase Enables Biocatalytic Synthesis of Diverse SAM Analogs

“…The “magic methyl effect” refers to the ability of an appropriately placed methyl group to dramatically alter the biological properties of a compound [1] . This makes selective alkylation of molecules highly desirable [2] . Bioalkylations are important because of the exquisite chemo‐, regio‐ and stereospecificity achievable using enzymes [2, 3] .…”

Engineered Enzymes Enable Selective N‐Alkylation of Pyrazoles With Simple Haloalkanes

“…Several elegant strategies for enzymatic synthesis of NSA have been developed [19–21] . These approaches still depend on the laboratory synthesis of methionine analogs as NSA precursors that limits their application [11, 18, 22] . Liao and Seebeck have recently shown that SAM can be enzymatically synthesized and recycled (Figure 1 B).…”

A bicyclic S-adenosylmethionine regeneration system applicable with different nucleosides or nucleotides as cofactor building blocks

“…6,7 Commonly used chemical methylation agents such as methyl iodide or dimethyl sulfate are often carcinogenic, mutagenic, and harmful to the environment. The biocatalytic application of MTs, also using SAM analogues, [8][9][10][11][12] are promising starting points for sustainable methods. 13,14 While SAM analogues allowing to transfer larger alkyl chains have been widely employed for product diversification, [15][16][17][18][19][20][21][22][23][24][25] the variation of the nucleobase has become a new focus, especially regarding the long-term goal to make bioorthogonal systems available.…”