“Sampling the Catalytic Spectrum to Deliver and Ideal Manufacturing Route to STING agonist Ulevostinag”
Bio: Andrew completed his undergraduate studies at the University of North Carolina at Chapel Hill where he conducted research with Prof. Jeffrey S. Johnson. He then conducted his PhD research with Prof. F. Dean Toste at UC Berkeley, a significant portion of which involved a close collaboration with Prof. Matthew Sigman at Utah focused on the understanding the role of attractive noncovalent interactions in controlling the course of enantioselective reactions. In 2016, Andrew began his career as a process chemist at Merck in Rahway, New Jersey gaining experience in the design and development of commercial manufacturing routes for molecules in Merck’s small molecule portfolio. In 2023, Andrew began a rotation into the Discovery Process Chemistry group in Boston, MA which aims to impact the interface between discovery and development by accelerating compounds from Merck’s oncology portfolio into the clinic.
Abstract: Ulevostinag (MK-1454) is a complex cyclic dinucleotide that was selected as a clinical candidate for evaluation as an anticancer agent against multiple solid tumor types. Synthetically, Ulevostinag poses a daunting synthetic challenge featuring two non-natural fluorinated nucleoside analogues joined by two P-chiral phosphorothioate linkages. This presentation will outline how this was addressed through the invention of multiple diverse catalytic methodologies including a novel stereoselective organocatalytic fluorination and an extremely complex biocatalytic cascade to access Ulevostinag in a single pot from simple nucleoside precursors. Collectively, these innovations culminated in a robust route that is 8 linear steps (13 overall) from commodity starting materials and is capable of delivering kilograms of material to support clinical progression of this potentially important therapeutic.
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