Premium
Synthesis of (5′ S )‐5′‐ C ‐Alkyl‐2′‐deoxynucleosides
Author(s) -
Trafelet Huldreich,
Stulz Eugen,
Leumann Christian
Publication year - 2001
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(20010131)84:1<87::aid-hlca87>3.0.co;2-1
Subject(s) - chemistry , diastereomer , alkylation , regioselectivity , alkyl , nucleoside , stereochemistry , hydride , thymidine , wittig reaction , nucleobase , organic chemistry , dna , catalysis , hydrogen , biochemistry
We describe the synthesis of (5′ S )‐5′‐ C ‐butylthymidine ( 5a ), of the (5′ S )‐5′‐ C ‐butyl‐ and the (5′ S )‐5′‐ C ‐isopentyl 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 ).