Discovery and Development of an Unusual Organocatalyst for the Conversion of Thymidine to Furanoid Glycal

Maligres, Peter E.; Chung, Cheol K.; Dance, Zachary E. X.; Mattern, Keith; Phillips, Eric M.; Poirier, Marc; Sirk, Kevin; Wright, Timothy J.

doi:10.1021/acs.oprd.1c00186

Cited by 4 publications

(1 citation statement)

References 30 publications

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“…To this end, we have identified and developed a novel silyl transfer catalyst to produce dihydrofuran 7 in high yield and purity. The synthesis commenced with the subjection of thymidine ( 6 ) to bis(trimethylsilyl)acetamide (BSA) in the presence of N , N -bis(diphenylthiophosphoryl)amide (PTPI) in toluene. Inherent to this transformation is the in situ protection of the primary and secondary alcohols on the deoxyribose fragment.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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Development of a Kilogram-Scale Synthesis of a Key Ulevostinag Subunit Part I: Accessing a Keto-Nucleoside Intermediate from Guanosine

Turnbull

Peng

Neel

et al. 2023

Org. Process Res. Dev.

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A kilogram-scale synthesis of a key fragment of Ulevostinag (MK-1454), a cyclic dinucleotide agonist of the stimulator of interferon genes (STING), is described. Ulevostinag comprises two non-natural nucleoside derivatives linked together via two P-chiral phosphorothioate groups. The strategy utilized to prepare one of these nucleosides, namely, 3′-deoxy-3′-α-fluoroguanosine (3′-FG), hinges on a diastereoselective α-fluorination of a key keto-nucleoside derivative, followed by substrate-directed reduction of the ketone. Herein, we describe the development of a robust and scalable synthesis of this intermediate, a 3′-deoxy-2′keto-guanosine derivative, from guanosine. Salient features of the approach include activation of the 2′ and 3′-alcohol groups of guanosine as a bis-tosylate, which enables regioselective E2 elimination to simultaneously deoxygenate the 3′-position and generate the 2′-ketone.

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A Unified Strategy to Fluorinated Nucleoside Analogues Via an Electrophilic Manifold

et al. 2022

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Herein, we present a strategy for the preparation of 3′-fluorinated nucleoside analogues via the aminocatalytic, electrophilic fluorination of readily accessible and bench-stable 2′-ketonucleosides. Initially developed to facilitate the manufacture of 3′-fluoroguanosine (3′-FG)a substructure of anticancer therapeutic MK-1454this strategy has been extended to the synthesis of a variety of 3′-fluoronucleosides. Finally, we demonstrate the utility of the 2′-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues.

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Discovery and Development of an Unusual Organocatalyst for the Conversion of Thymidine to Furanoid Glycal

Cited by 4 publications

References 30 publications

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

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

Development of a Kilogram-Scale Synthesis of a Key Ulevostinag Subunit Part I: Accessing a Keto-Nucleoside Intermediate from Guanosine

A Unified Strategy to Fluorinated Nucleoside Analogues Via an Electrophilic Manifold

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