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Late-stage methylation is a key technology in the development of pharmaceutical compounds. Methyltransferase biocatalysis may provide powerful options to insert methyl groups into complex molecules with high regio- and chemoselectivity. The challenge of a large-scale application of methyltransferases is their dependence on S-adenosylmethionine (SAM) as a stoichiometric, and thus exceedingly expensive co-substrate. As a solution to this problem, we and others have explored the use of methyl halides as reagents for the in situ regeneration of SAM. However, the need to handle volatile electrophiles, such as methyl iodide (MeI), may also hamper applications at scale. As a more practical solution, we have now developed an enzyme-catalyzed process for the regeneration of SAM with methyl toluene sulfonate. Herein, we describe enzymes from the thiopurine methyltransferase family that accept sulfate- and sulfonate-based methyl donors to convert S-adenosylhomocysteine into SAM with efficiencies that rival MeI-based reactions.

A novel activation of acetonitrile for the construction of cyclobutenones by [2+2] cyclization was developed. Acetonitrile is utilized for the first time as two-carbon (C2) cyclization building block. The present protocol successfully inhibits the competitive cycloaddition with the C≡N bond of acetonitrile, but enables the in situ formation of an unsaturated carbon-carbon bond and the subsequent cycloaddition as a C2 unit. This chemistry features simple reaction conditions, high chemoselectivities, wide substrate scope, and offers a new and practical approach to cyclobutenones and cyclobuteneimines.

C-N Bond formation is of great significance due to the ubiquity of nitrogen-containing compounds. Here, a mild and efficient Rh(III) -catalyzed C(sp(3) )-H aryl amination reaction is reported. Anthranil is employed as the nitrogen source with 100 % atom efficiency. This C-H amination reaction exhibits broad substrate scope without using any external oxidants. Mechanistic studies including rhodacycle intermediates, H-D exchange, kinetic isotope effect (KIE) experiments, and in situ IR are presented.