Asymmetric Total Synthesis of C9′-epi-Sinefungin

The natural nucleoside (+)-sinefungin, structurally similar to cofactor S-adenosyl-l-methionine, inhibits various SAM-dependent methyltransferases (MTs). Access to sinefungin analogues could serve as the basis for the rational design of small molecule methyltransferase inhibitors. We developed a route to the unnatural C9′ epimer of sinefungin that employed a diastereoselective Overman rearrangement to install the key C6′ amino stereocenter. The ability for late-stage modification is highlighted, opening an avenue for the discovery of new MT inhibitors.