Construction of quaternary stereocenters at carbon 2' of nucleosides

Abstract

The non-natural nucleosides with a quaternary stereogenic center at C2' are crucial to drug discovery. They have become a cornerstone for the treatment of cancer and various viral infections as exemplified by gemcitabine and sofosbuvir. Major research effort has been expended to gain synthetic access to these nucleoside analogues with a significant steric bulk at C2' in the furanoside ring. The 2'-ketonucleosides and 2'-deoxy-2'-methylenenucleosides emerged as key intermediates in these synthetic strategies. For example, α-face addition of methyl lithium to the 2'-ketonucleosides followed by fluorination of resulting tertiary arabino alcohol with DAST provided 2'-fluoro-2'-C-methyluridine - a core nucleoside component of sofosbuvir. The α-face addition of HCN or HN₃ to the 2'-deoxy-2'-methylene nucleosides gave access to the synthetically versatile 2'-cyano-2'-C-methyl and 2'-azido-2'-C-methyl nucleosides. Likewise, the addition of diazomethane to the 2'-exomethylene group gave access to the 2'-spirocyclopropyl analogue. This review primarily discusses synthetic strategies which employs natural nucleosides as substrates but selected approaches involving coupling of the preelaborated sugar precursors with nucleobases are also examined.

Keywords: Antiviral and anticancer drugs; Non-natural nucleosides; Quaternary stereogenic center; Sofosbuvir; Spiro nucleosides; Synthesis of nucleosides.