Synthesis 2017; 49(05): 998-1008
DOI: 10.1055/s-0036-1588680
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© Georg Thieme Verlag Stuttgart · New York

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

Daniele D’Alonzo*
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia, 80126 Napoli, Italy   Email: dandalonzo@unina.it
,
Maria De Fenza
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia, 80126 Napoli, Italy   Email: dandalonzo@unina.it
,
Giovanni Palumbo
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia, 80126 Napoli, Italy   Email: dandalonzo@unina.it
,
Valeria Romanucci
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia, 80126 Napoli, Italy   Email: dandalonzo@unina.it
,
Armando Zarrelli
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia, 80126 Napoli, Italy   Email: dandalonzo@unina.it
,
Giovanni Di Fabio
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia, 80126 Napoli, Italy   Email: dandalonzo@unina.it
,
Annalisa Guaragna
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia, 80126 Napoli, Italy   Email: dandalonzo@unina.it
› Author Affiliations
Further Information

Publication History

Received: 01 December 2016

Accepted after revision: 01 December 2016

Publication Date:
30 December 2016 (online)

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.

Supporting Information

 
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