Diverse Catalytic Reactions for the Stereoselective Synthesis ofCyclic Dinucleotide MK-1454

As practitioners of organic chemistry strive todeliver efficient syntheses of the most complex natural productsand drug candidates, further innovations in synthetic strategies arerequired to facilitate their efficient construction. These aspirationalbreakthroughs often go hand-in-hand with considerable reductionsin cost and environmental impact. Enzyme-catalyzed reactions havebecome an impressive and necessary tool that offers benefits suchas increased selectivity and waste limitation. These benefits areamplified when enzymatic processes are conducted in a cascade incombination with novel bond-forming strategies. In this article, wereport a highly diastereoselective synthesis of MK-1454, a potentagonist of the stimulator of interferon gene (STING) signalingpathway. The synthesis begins with the asymmetric construction oftwofluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the samebenign electrophilicfluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridgingthiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thoroughunderstanding of the role transition metals play in bond formation.