A Modular Methodology for the Synthesis of 4- and 3-Substituted Benzene and Aniline C-Ribonucleosides

A modular, efficient, and practical methodology for the preparation of 4- and 3-substituted benzene and aniline C-ribonucleosides was developed. Addition of 4- or 3-bromophenyllithium (2 or 12) to TBDMS-protected ribonolactone 3 gave hemiacetal adducts 4 or 13 as pure β-anomers. Their reduction with Et3SiH and BF3·Et2O afforded the desired protected 4- or 3-bromophenyl-C-ribonucleosides 6 or 15 in 66 and 75 %, respectively, over two steps from 3. Bromophenyl intermediates 6 and 15 were subjected to a series of palladium-catalyzed cross-coupling, alkoxylation, and amination reactions to give a series of protected 1β-(3- and 4-substituted phenyl)ribonuleosides 9 and 18. Deprotection of silylated nucleosides 9 or 18 by Et3N·3HF afforded a series of free C-ribonucleosides 10 or 19 (20 examples). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)