Practical and concise synthesis of nucleoside analogs.

ABSTRACT

Nucleoside analogs are valuable commodities in the development of antisense oligonucleotides or as stand-alone antiviral and anticancer therapies. Syntheses of nucleoside analogs are typically challenged by a reliance on chiral pool starting materials and inefficient synthetic routes that are not readily amenable to diversification. The novel methodology described in this protocol addresses several longstanding challenges in nucleoside analog synthesis by enabling flexible and selective access to nucleoside analogs possessing variable nucleobase substitution, D- or L-configuration, selective protection of C3'/C5' alcohols and C2' or C4' derivatizations. This protocol provides direct access to C3'/C5' protected nucleoside analogs in three steps from simple, achiral starting materials and is described on both research (2.8 g) and process (30 g) scales for the synthesis of C3'/C5'-acetonide protected uridine. Using this protocol, proline catalyzes the fluorination of simple heteroaryl-substituted aldehyde starting materials, which are then directly engaged in a one-pot enantioselective aldol reaction with a dioxanone. Reduction, followed by intramolecular annulative fluoride displacement, forges the nucleoside analog. The three-step parent protocol can be completed in ~5 d by using simple mix-and-stir reaction procedures and standard column chromatographic purification techniques.