Synthesis of 1′-fluorouracil nucleosides as potential antimetabolites

The first synthesis of 1′-fluoronucleosides, which has long been synthetic targets as the potential antimetabolites, was achieved. Electrophilic fluorination of the 1′-position occurred to form an anomeric mixture of 1′-fluorouridine derivatives, when the lithium enolate, prepared from 3′,5′-O-tetraisopropyldisiloxane-1,3-diyl (TIPDS)-protected 2′-ketouridine (10) and LiHMDS, was treated with an electrophilic fluorinating agent such as NFSI (13). Subsequent reduction of the 2′-keto-moiety of the resulting β-nucleoside gave the protected 1′-fluorouridine 16 and its arabino-type congener 17. Alternatively, nucleophilic fluorination was also successful. Thus, treatment of 2′,3′,5′-tri-O-acetyl-1′-phenylselenouridine (20) with DAST/NBS produced the 1′-fluorouridine triacetate (21) and its α-anomer 22.