Synthesis and biological activity of 5-(2,2-difluorovinyl)-2'-deoxyuridine

Abstract

5-(2,2-Difluorovinyl)uracil (IV) was synthesized from 2,4-dimethoxy-5-bromopyrimidine by sequential formylation, difluoromethylenation, and removal of the 2- and 4-methyl groups. Condensation of the trimethylsilyl derivative of IV with protected D-erythro-pentofuranosyl chloride followed by separation of anomers and deblocking gave 5-(2,2-difluorovinyl)-2'-deoxyuridine (V). Compound V was active against herpes simplex virus type 1 (HSV-1) infection as well as tumor cells transformed by the HSV-1 thymidine kinase gene.

A versatile difluorovinylation method: Cross-coupling reactions of the 2,2-difluorovinylzinc–TMEDA complex with alkenyl, alkynyl, allyl, and benzyl halides

“…2). Note that the double difluorovinylation of 1,1-dibromo-1-alkene 5d effectively proceeded to afford the tetrafluorinated, cross-conjugated triene ( [3]dendralene) 6d in 70% yield (eq. 3).…”

“…In addition, 2,2-difluorovinyl compounds often show substantial bioactivities. For example, they act as anti-herpes simplex virus type 1 (anti-HSV-1) agents [3] and as squalene epoxidase inbibitors in antilipemic drugs [4]. Further pharmaceutical applications of difluorovinyl compounds have been of great interest, since the difluorovinylidene moiety is considered to be a bioisostere of a carbonyl group [5].…”

Synthesis of terminal monofluoro olefins

“…94 The stereoselectivity found for the reduction of 78 by NaBH 4 and LiAlH 4 was explained by an Si ؒ ؒ ؒ F interaction. 92 Note, however, that NaBH 4 reductions of pyrimidine 71 89 and lactone 80 93 also occurred stereoselectively, and that the hydroxymethylene and fluorine groups are found in a trans-position in 3-fluoroallylic alcohols 75 90 and 83 94 as well.…”

Consecutive cross-coupling reactions of 2,2-difluoro-1-iodoethenyl tosylate with boronic acids: efficient synthesis of 1,1-diaryl-2,2-difluoroethenes

“…The 1,1-difluoroethenylidene functionality in these compounds is also known to act as a bioisostere for the carbonyl group of many biologically active compounds [9–12]. Although numerous methods for the preparation of 2,2-disubstituted-1,1-difluoroethenes have been reported in the previous literature [13–22], a consecutive cross-coupling reaction of a proper precursor such as a 1,1-difluoroethenylidene species bearing a metal functional group, a halogen substituent or a tosylate group at the vinyl carbon will provide a concise and efficient method for the synthesis of 2,2-disubstituted-1,1-difluoroethenes.…”