Salinger, Matthew Tomasz; (2024) Selective Methylations and Alkylations using O-Methyltransferases. Doctoral thesis (Ph.D), UCL (University College London).

Text Matthew Tomasz Salinger - PhD Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 December 2025. Download (63MB)

Abstract

The utilisation of methyltransferase (MT) enzymes to catalyse methylations and alkylations for potential applications in chemical synthesis is rapidly gaining momentum. This is in large part due to the stereoselectivities, regioselectivities and chemoselectivities these biological catalysts offer. Additionally, the mild conditions they operate under and the avoidance of hazardous alkylating reagents and reaction solvents, that would otherwise be used in equivalent traditional synthetic methods, have interesting implications for green and sustainable chemistry. In this work, MTs that use the S-adenosyl-L-methionine (SAM) methylation cofactor were explored to assess their ability to selectively methylate various small molecule substrates of pharmaceutical relevance, such as cannabinoid precursors, catechols and tetrahydroisoquinolines (THIQs), due to the enhancements in drug bioactivity commonly imparted by methylation. Furthermore, the expansion of the range of alkyl groups that these MTs can transfer was investigated by the generation of alkyl-SAM analogues, most notably the allyl group due to the possibility for further functionalisations, such as allylic oxidations and electrophilic additions. These methylations and alkylations take place in the context of in situ SAM generation cascades that ensure a continuous and immediate supply of SAM, which is difficult to directly add to reactions at scale due to its expense and instability. The first cascade system employed halide methyltransferases (HMTs) to regenerate catalytic quantities of SAM from S-adenosyl-L-homocysteine (SAH) for MT methylation using methyl donors such as methyl iodide and methyl tosylate, with the novel addition of the methionine adenosyltransferase (MAT) enzyme to initially generate SAM from cheaper and stable ATP and L-methionine precursors. The second cascade system used MATs to generate stoichiometric alkyl-SAM/SAM quantities for MTs, along with methylthioadenosine nucleosidase (MTAN) to ensure the degradation of the inhibitory SAH by-product, and was also combined with the norcoclaurine synthase (NCS) enzyme to stereoselectively generate (S)-THIQs substrates for MT catalysed alkylations.

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