Synthesis of β-l-2′-Fluoro-3′-thiacytidine (F-3TC) Stereoisomers: Toward a New Class of Oxathiolanyl Nucleosides?

Abstract

The synthesis of (1′S,2′S,4′R) and (1′S,2′R,4′R) stereoisomers of 2′-fluoro-3′-thiacytidine [(2′S)-F-3TC and (2′R)-F-3TC], the earliest examples of oxathiolanyl nucleosides with a fluorine atom in the ‘sugar’ backbone, is herein reported. From of a variety of synthetic routes devised for their preparation, the Pummerer rearrangement of protected lamivudine sulfoxides was successfully exploited for fluorine atom introduction. Despite the presence of three potentially labile stereocenters in such a small molecule, the (2′R)-isomer of F-3TC exhibited good chemical stability after protective group cleavage. Conversely, the (2′S)-epimer suffered from weak stability, owing to the formation of an undesired cyclization product. Based on the remarkable antiviral efficacy of the parent drugs, the access to 2′-fluorinated oxathiolanyl nucleosides (and more generally, 2′-fluorinated heterocyclic nucleosides) may provide a new source of candidates with antiviral potential.

Key words

lamivudine - fluorinated nucleosides - Pummerer rearrangement - oxathiolanyl nucleosides - nucleoside analogues

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