Premium
Synthesis and conformational properties of 2′‐deoxy‐2′‐methylthio‐pyrimidine and ‐purine nucleosides: Potential antisense applications
Author(s) -
Fraser Allister,
Wheeler Patrick,
Dan Cook P.,
Sanghvi Yogesh S.
Publication year - 1993
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570300518
Subject(s) - chemistry , moiety , guanosine , stereochemistry , steric effects , pyrimidine , methanethiol , nucleophile , thymine , uracil , yield (engineering) , acetic anhydride , nucleoside , methyl group , organic chemistry , group (periodic table) , dna , sulfur , biochemistry , materials science , metallurgy , catalysis
A convenient and shorter synthesis of 2′‐deoxy‐2′‐methylthiouridine analogs 5 , −5‐methyluridine 6 , ‐cyti‐dine 15 , −5‐methylcytidine 16 , ‐adenosine 27 and ‐guanosine 34 was accomplished. Successful conversion of ribonucleosides (5‐methyl U, U, A, G) into the corresponding 2′‐substituted nucleosides involves nucleophilic displacement (S N 2) of an appropriate leaving group at the 2′‐position by methanethiol, a soft nucleophile. Reaction between 2,2′‐anhydrouridine and methanethiol in the presence of N 1 , N 1 , N 3 , N 3 ‐tetramethylguani‐dine in N , N ‐dimethylformamide gave 5 , in 75% yield. Preparation of 6 by a similar route was described. Acylated 5 and 6 were transformed into their triazole derivatives, which on ammonolysis furnished 15 and 16 , respectively in good yield. Similarly, tetraisopropyldisiloxanyl (TIPS) protected 2′‐ O ‐aratriflates‐ of‐adenosine and ‐guanosine reacted with methanethiol in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene at ‐ 25°, followed by deblocking of the TIPS protecting group furnished 27 and 34 , respectively. The confor‐mational flexibility (N/S equilibrium) of the sugar moiety in nucleosides 5 , 15 , 27 and 34 was studied utilizing nmr spectroscopy, suggesting that the 2′‐methylthio group influenced the sugar conformation to adopt a rigid S‐pucker in all cases. The extra stiffness of the sugar moiety in these analogs is believed to be due to the electronegativity of the substituent and the steric bulk. The usefulness of these nucleosides to prepare uniformly modified 2′‐deoxy‐2′‐methylthio oligonucleotides for antisense therapeutics is proposed.