Synthesis of Acyclic Nucleosides with a Chiral Amino Side Chain by the Mitsunobu Coupling Reaction

Abstract

A novel and efficient synthetic method has been developed for the preparation of chiral acyclic nucleosides with a chiral amino side chain by Mitsunobu reaction between nucleoside bases and protected L-serine. This method suggests a potentially more efficient and complementary process to acquire chiral acyclic nucleosides.

Nucleobase coupling by Mitsunobu reaction towards nucleoside analogs

“…Scheme 5. Alcohol dehydration, as reported by Viña et al 46 (A), Weising et al 29 (B) and Guo et al 27…”

“…Both Viña et al 46 and Weising et al 29 experienced this problem when attempting to synthesize cis carbocyclic nucleosides (Scheme 5); in the latter case, a relationship between solvent used and the extent of elimination was found, since reactions in MeCN resulted in more elimination than those in THF. Dehydration may also occur in linear alcohols, as shown by © AUTHOR(S) Guo et al;27 in this case, the elimination reaction occurred when the L-serine amine group was protected by Boc, while the same was not verified with a trityl protecting group. Scheme 5.…”

“…The effectiveness of the nucleobase coupling by MR depends on the alcohol precursor, the nucleobase and the reaction conditions, namely the solvent, the temperature and the order in which the reagents are added. [25][26][27][28] The usual yield of a nucleobase coupling reaction through MR is in the 50% to 80% range, for carbasugar, other carbohydrates and acyclic substrates, with higher yields being generally obtained with primary alcohols. The low reactivity of the alcohol, a lack of regioselectivity, side reactions and the difficulty in purification of the complex reaction mixture may also compromise reaction yields.…”

Synthesis of Chiral Acyclic Pyrimidine Nucleosides with a Sulfur‐Containing Side Chain via Enantioselective Tandem Conjugate Addition/Protonation

“…Conventional routes to synthesize chiral pyrimidine acyclic nucleosides are based on a chiral pool strategy in which a prepared chiral side chain is coupled with a pyrimidine nucleobase . Representative routes for this approach are as follows: i) alkylation reaction of pyrimidines with halogenated chiral side chains; ii) epoxide ring‐opening reaction of pyrimidines to chiral epoxides; iii) Mitsunobu reaction of pyrimidines with chiral hydroxyl materials; iv) allylic amination reaction of pyrimidines with chiral allylic carbonates . Nevertheless, the generation of these chiral side chains often requires multi‐step reactions from chiral starting materials.…”

Synthesis of Acyclic Nucleoside Analogues through the Insertion of Carbenoids into N−H Bond of Nucleobases

“…The traditional strategy to construct acyclic nucleoside analogues is by using the nucleophilic N9 in purines or N1 in pyrimidines, and this involved four basic approaches (Scheme a): (i) the alkylation reactions of alkyl halides, methylsulfonates, and tosylates or the Mistunobu reactions of alcohols; (ii) the aza‐Michael addition of α,β‐unsaturated aldehydes/ketones; (iii) the allylation reactions with allylic carbonates; (iv) the ring‐opening reactions of epoxides or cyclopropanes . Another strategy is constructing the nucleobase skeleton (Scheme b) .…”