Diastereoselective Synthesis of (1,3-Dioxan-4-yl)pyrimidine and Purin Nucleoside Analogues

• Published in: European journal of organic chemistry Vol. 2015; no. 6; pp. 1235 - 1245
• Main Authors: Battisti, Umberto M., Sorbi, Claudia, Quotadamo, Antonio, Franchini, Silvia, Tait, Annalisa, Schols, Dominique, Jeong, Lak Shin, Lee, Sang Kook, Song, Jayoung, Brasili, Livio
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.02.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Antiretroviral drugs; Chemistry; Chemistry, Organic; Diastereoselectivity; HIV; Human immunodeficiency virus; Nitrogen heterocycles; Nucleoside analogues; Physical Sciences; Regioselectivity; Science & Technology; ASYMMETRIC-SYNTHESIS; INHIBITION; Nitrogen heterocycles; Regioselectivity; Nucleoside analogues; RESISTANCE; AGENTS; CONFORMATIONAL-ANALYSIS; Diastereoselectivity; HISTORY
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201403473

(1,3‐Dioxan‐4‐yl)‐substituted nucleoside analogues, higher homologues of antiviral and anticancer 1,3‐dioxolanes, were prepared from the key intermediate (4‐acetoxy‐1,3‐dioxan‐2‐yl)methyl benzoate and silylated bases. Glycosylation, carried out under Vorbrüggen conditions in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a catalyst, afforded the desired compounds with high stereoselectivity and regioselectivity, with only the desired β‐anomeric N‐1 pyrimidine and N‐9 purin nucleosides being obtained. 1H NMR experiments established that the β‐anomers were diequatorial, and this assignment was confirmed by single‐crystal X‐ray diffraction. Despite their structural similarities with natural nucleosides, none of the synthesized nucleosides showed antiviral activity. The first regioselective and diastereoselective synthesis of 1,3‐dioxan‐4‐yl‐substituted nucleoside analogues is reported. (4‐Acetoxy‐1,3‐dioxan‐2‐yl)methyl benzoate is regioselectively glycosylated under Vorbrüggen conditions to afford the desired products in good yields. The regioselectivity might be due to the existence of thermodynamically controlled intermediates.