Synthesis of 4-O-methyl-protected 5-(2-hydroxyethyl)-2 '-deoxyuridine derivatives and their nucleophilic fluorination to 5-(2-fluoroethyl)-2 '-deoxyuridine

[[abstract]]©1999 Thieme - The novel pyrimidine base, 5-(2-hydroxyethyl)-4-methoxypyrimidin-2(1H)-one (7) was prepared from the pyrimidine derivative 2 via a three step synthesis in 72% yield. Glycosylation of 7 with an alpha-chlorosugar provided the 4-O-methyl-protected pyrimidine nucleoside 8 in 78% yield with a beta:alpha ratio ranging from 1.5:1 to 2:1. A complete cleavage of the 4-methoxy group of alcohol 8 was achieved using NaI and trimethylsilyl chloride. The synthesis of 14, an analog of 8, was also possible by using N,O-bis(trimethylsilyl)trifluoroacetimide as silylating reagent and 3,5-di-0-p-chlorobenzoyl-2-deoxy-alpha-D-erythro-pentofuranosyl chloride as the sugar moiety. A slightly improved ratio of beta/alpha (>2:1) and a yield of 54% of 14 was obtained. The two key precursors for nucleophilic fluorination, the tosylate 9 and triflate 10, were obtained in 87 and 17% yield, respectively. NOE results of 10 beta and 10 alpha indicated that H-1' of the deoxyribosyl residue interacted strongly with one of the two protons on C-8 of the 5-ethyl side chain. This interaction was even stronger than that between H-1' and H-2'. The unusual downfield chemical shift of C-1' in C-13 NMR can not be explained by the structure shown in Scheme 3. Nucleophilic fluorination of the tosylate 9 alpha under phase transfer catalyzed conditions provided the fluorinated product 11 alpha (5%), the base-induced elimination product 12 alpha (24%), and unexpectedly the chloro-substituted product 13 alpha (26%).[[department]]生醫工程與環境科學