Synthesis of (±)-4′-ethynyl-5′,5′-difluoro-2′,3′-dehydro-3′-deoxy- carbocyclic thymidine: a difluoromethylidene analogue of promising anti-HIV agent Ed4T

• Published in: Tetrahedron 2009-09, Vol.65 (36), p.7630-7636
• Main Authors: Kumamoto, Hiroki, Haraguchi, Kazuhiro, Ida, Mayumi, Nakamura, Kazuo T., Kitagawa, Yasuyuki, Hamasaki, Takayuki, Baba, Masanori, Matsubayashi, Satoko Shimbara, Tanaka, Hiromichi
• Format: Article
• Language: English
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Carbocyclic nucleoside; Carbohydrates. Nucleosides and nucleotides; Chemistry; d4T; Exact sciences and technology; gem-Difluoromethylidene; Human immunodeficiency virus; Medical sciences; Mitsunobu reaction; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Pharmacology. Drug treatments; Preparations and properties
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2009.06.095

Synthesis of (±)-4′-ethynyl-5′,5′-difluoro-2′,3′-dehydro-3′-deoxy-carbocyclic-thymidine ( 8) was carried out. The difluoromethylylidene group of 8 was constructed by the electrophilic fluorination to the cyclopentenone 11 by using Selectfluor ®. Introduction of thymine base was investigated based on the Mitsunobu reaction by employing cyclopentenyl allyl alcohols variously substituted at the 4-position. It was found the 4-methoxycarbonyl derivative 14 gave the highest selectivity both in terms of regio- and stereochemistry. [Display omitted]