A Unified Strategy to Fluorinated Nucleoside Analogues Via an Electrophilic Manifold.

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.

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

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.

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

Highly Diastereoselective Synthesis of a HCV NS5B Nucleoside Polymerase Inhibitor.

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.

Synthesis of bis-macrocyclic HCV protease inhibitor MK-6325 via intramolecular sp²-sp³ Suzuki-Miyaura coupling and ring closing metathesis.

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (1) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular sp(2)-sp(3) Suzuki-Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (1) has been achieved.

Ullmann diaryl ether synthesis: rate acceleration by 2,2,6,6-tetramethylheptane-3,5-dione.

[reaction: see text]. In the copper salt catalyzed ether formation from aryl bromides or iodides and phenols, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD) was found to greatly accelerate the ordinarily difficult reaction, making it occur under more moderate temperatures and reaction times. A series of aryl halides and phenols were shown to form ethers in NMP as the solvent, cesium carbonate as the base, and CuCl and TMHD as the catalysts. The reaction was shown to tolerate electron-rich aryl bromides and electron-neutral phenols.