MK-8591 (4’-ethynyl-2-fluoro-2’-deoxyadenosine, EfdA) is a promising nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently entering PhIII clinical trials for the treatment of HIV. Given the priority of the program, several manufacturing routes were developed and the work presented herein describes the shortest synthetic route to MK-8591 encountered during process development. Central to this route is an enantioselective 1,2-alkynylation of an α,β-unsaturated ketone, which is easily synthesized from readily available and inexpensive benzalacetone. Examples of enantioselective alkynylations of ketones are scarce in the literature, and the rapid racemic background reaction makes achieving enantioselectivity challenging. The alkynylation is accomplished using a novel Mg/salan catalyst discovered <i>via</i> high-throughput screening. Crystallographic data and mechanistic studies suggest a dimeric active catalyst, and we demonstrate control of the enantiomeric ratio through ligand design. Following alkynylation, an ozonolysis-dealkylation through-process and an enzymatic aldol-glycosylation cascade yields MK-8591.

Enantioselective synthesis of MK-8591 from benzalacetone via asymmetric ketone alkynylation and ozonolysis

2019 Fall National Meeting

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