(+)-Sinefungin is a naturally occurring nucleoside and structural analogue of <i>S</i>-adenosyl methionine (SAM). Although it has limited utility as an antibiotic due to high toxicity, sinefungin has been revealed as a non-selective methyltransferase inhibitor for both protein lysine methyltransferases (PKMTs) and natural product methyltransferases (NPMTs). Thus, sinefungin serves as a useful scaffold for generating selective small molecule probes to investigate methyltransferases involved in misregulated epigenetic and metabolic processes. Considering the need for selective inhibitors of these disease relevant methyltransferases, we have designed a scalable, modular synthesis of sinefungin that accommodates late-stage synthetic diversification. In this work, we present the shortest synthesis reported to date of the natural product (+)-sinefungin in nine steps. Highlighting the modularity and utility of our approach, we have synthesized a small library of fully synthetic sinefungin analogues as potential methyltransferase inhibitors. Our synthetic strategy employs a diastereoselective, cobalt oxazoline-palladacycle (COP)-catalyzed Overman rearrangement to yield a terminal olefin. This synthetic handle serves as a critical branching point for analogue generation via a ruthenium-mediated cross metathesis to afford large quantities of chemical matter for analogue generation. Late-stage reductive amination provides robust access to a wide variety of novel <i>N</i>-alkyl sinefungin derivatives which act as transition-state mimics for PKMTs and NPMTs. The chemistry described herein provides a platform for the discovery of new methyltransferase inhibitors from a common and readily modifiable sinefungin scaffold.

Development of a synthetic platform for (+)-sinefungin and analogues

256th National Meeting (2018)

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