Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454

Abstract

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.

Manufacturing Process Development for Uprifosbuvir (MK-3682): A Green and Sustainable Process for Preparing Penultimate 2′-Deoxy-α-2′-Chloro-β-2′-Methyluridine

“…We first explored the direct conversion of 3′,5′-protected 2′-ketones 2 to olefin 3 via mild organometallic reagent-mediated olefinations, given the instability of 3 under basic conditions. Although consumption of the starting material was observed in these reactions, to our disappointment, they gave low yields and decomposition, presumably because ketone 2 is hindered and labile (Table ).…”

Industrial potential of the enzymatic synthesis of nucleoside analogs: Existing challenges and perspectives

“…Impressive demonstrations of such efforts have recently made headlines in various subfields of chemistry, 58 and we expect nucleoside synthesis to follow these developments soon. Indeed, the recent work of Benkovics et al 59 provides an inspirational example to this end. In their synthesis of the cyclic dinucleotide MK-1454, the combination of organocatalytic fluorination and thiophosphorylation with enzymatic triphosphorylation and cyclization provided the tools for a highly selective synthesis of an enormously challenging target on the process scale.…”

The STING in Non-Alcoholic Fatty Liver Diseases: Potential Therapeutic Targets in Inflammation-Carcinogenesis Pathway

“…Previous studies have shown that the CDNs of thiophosphate, rather than parent phosphoric acid CDNs, have higher bioactivity and a stronger activation of STING. MK-1454 is a CDNs of thiophosphate with efficient STING agonistic activity obtained based on P(III) chemical synthesis and structure optimization [ 103 , 104 ]. The phase-II clinical trials of MK-1454 applied to advanced solid tumors or lymphomas have been completed, showing inspiring effects when combined with pembrolizumab (a PD-1 antibody).…”