Concise Synthesis of 4ʹ-Modified Thymidines via 1,5-Hydrogen Atom Transfer/Intermolecular 1,4-Addition Process

Abstract

A concise approach is presented for preparing 4ʹ-modified thymidines from oxime imidates using readily generated 4ʹ-carbon radicals. This method produces 4ʹ-modified thymidines from natural thymidine using the Mitsunobu reaction, the protection of 3ʹ-hydroxy group (when necessary), and 1,5-hydrogen atom transfer (1,5-HAT)/intermolecular 1,4-addition with electron-deficient olefins. Moreover, using a one-pot synthesis involving 1,5-HAT/intermolecular 1,4-addition, followed by the hydrolysis of the imidate intermediate under basic conditions, 4′-modified thymidine was diastereoselectively isolated. This is because the 4′-isomer transferred to the water layer in the work-up process.