Highly Diastereoselective Synthesis of a HCV NS5B Nucleoside Polymerase Inhibitor

Abstract

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.

Photoredox-Catalyzed Stereoselective Radical Reactions to Synthesize Nucleoside Analogues with a C2′-Stereogenic All-Carbon Quaternary Center

“…We have also explored the radical vinyl transfer on cyclic lactones ( 8 , Scheme b) prepared from the same Mukaiyama adducts to achieve the synthesis of analogues of type 3 . Our strategy provides an efficient access to highly functionalized α-substituted butyrolactones that complements other approaches for nucleoside synthesis. − …”

Diastereoselective Synthesis of Arabino- and Ribo-like Nucleoside Analogues Bearing a Stereogenic C3′ All-Carbon Quaternary Center

“…5−7 This quaternary center is thought to enhance target specificity by preventing binding to enzymes or receptors susceptible to steric hindrance at this position. 8,9 Providing a versatile and straightforward methodology that extends the chemical space in this family of compounds would be useful in the field of medicinal chemistry. In this context, both arabinoand ribo-like scaffolds (Scheme 1) were targeted along with the syntheses of not only the β-anomers (1 and 3) but also the αanomers (2 and 4).…”

“…Nucleoside analogues are one of the most important families of drugs. , Our laboratory has been involved in the development of stereoselective acyclic free-radical-based transformations , toward the synthesis of therapeutic agents, such as novel nucleoside scaffolds bearing all-carbon stereogenic centers at C3′. − This quaternary center is thought to enhance target specificity by preventing binding to enzymes or receptors susceptible to steric hindrance at this position. , Providing a versatile and straightforward methodology that extends the chemical space in this family of compounds would be useful in the field of medicinal chemistry. In this context, both arabino- and ribo-like scaffolds (Scheme ) were targeted along with the syntheses of not only the β-anomers ( 1 and 3 ) but also the α-anomers ( 2 and 4 ).…”

Allenoate Prenucleophiles: A Triply Diastereoselective Approach to β-Hydroxy Esters Containing All-Carbon α-Quaternary Centers

“…In the present communication, we describe how allenyl ester prenucleophiles activated by Ti­(IV) reagents led to hydroxy esters A as single diastereomer products bearing an α-quaternary center. While a variety of multistep strategies such as the Ireland–Claisen and radical cyclization lead to similar congested products, to our knowledge, the present halo-aldol reaction is the first general approach to accomplish this transformation in a single step. Furthermore, these aldol products are synthetically useful building blocks; here, we demonstrate their utility in accessing highly functionalized indanes.…”