Synthesis of (5′S)-5′-C-Alkyl-2′-deoxynucleosides

Abstract

We describe the synthesis of (5'S)-5'-C-butylthymidine (5a), of the (5'S)-5'-C-butyl-and the (5'S)-5'-Cisopentyl derivatives 16a and 16b of 2'-deoxy-5-methylcytidine, as well as of the corresponding cyanoethyl phosphoramidites 9a, b and 14a, b, respectively. Starting from thymidin-5'-al 1, the alkyl chain at C(5') is introduced via Wittig chemistry to selectively yield the (Z)-olefin derivatives 3a and 3b (Scheme 2). The secondary OH function at C(5') is then introduced by epoxidation followed by regioselective reduction of the epoxy derivatives 4a and 4b with diisobutylaluminium hydride. In the latter step, a kinetic resolution of the diastereoisomer mixture 4a and 4b occurs, yielding the alkylated nucleoside 2a and 2b, respectively, with (5'S)-configuration in high diastereoisomer purity (de 94%). The corresponding 2'-deoxy-5-methylcytidine derivatives are obtained from the protected 5'-alkylated thymidine derivatives 7a and 7b via known base interconversion processes in excellent yields (Scheme 3). Application of the same strategy to the purine nucleoside 2'-deoxyadenine to obtain 5'-C-butyl-2'-deoxyadenosine 25 proved to be difficult due to the sensitivity of the purine base to hydride-based reducing agents (Scheme 4).

Expanding the borononucleotide family: synthesis of borono-analogues of dCMP, dGMP and dAMP

“…This two step sequence compares favourably with the already reported synthesis of the N-benzoyl analogue of 15, obtained in 70% yield by reaction of 13 with methyltriphenylphosphonium ylide. 24 To our surprise, the hydroboration conditions that were successfully applied to the methylidene derived from T, C and G were found to be inefficient on compound 15. Indeed, reactions were very sluggish, difficult to interpret and all the attempts to optimize the reaction conditions failed.…”

Double-headed nucleotides in DNA-zipper structures; base–base interactions and UV-induced cross-coupling in the minor groove

“…1), 5,6,8 as it is more conveniently attached to sterically hindered secondary alcohols and works with similar efficiency in the automated solid phase DNA-synthesis. 18 However, pixylation of the 59-hydroxy group of 3 proved very problematic and several conditions were tested. It was found imperative to activate the pixyl chloride prior to use following a literature protocol.…”

Six‐Membered Heterocycles: 1,2‐, 1,3‐, and 1,4‐Diazines and Related Systems

“…When the corresponding chloride fails to provide the desired substitution compound, triazoles are also often used as leaving groups in CÀN bond formation. This procedure has been utilized by Leumann in the synthesis of deoxynucleosides 144 (Scheme 19.154) [173]. Other leaving groups, such as sulfonate, have also been reported for the introduction of N-substituents onto pyrimidines [174].…”