{Reference Type}: Journal Article
{Title}: Synthesis of 4'-Thionucleoside Analogues Bearing a C2' Stereogenic All-Carbon Quaternary Center.
{Author}: Eymard C;Manchoju A;Almazloum A;Dostie S;Prévost M;Nemer M;Guindon Y;
{Journal}: Molecules
{Volume}: 29
{Issue}: 7
{Year}: 2024 Apr 6
{Factor}: 4.927
{DOI}: 10.3390/molecules29071647
{Abstract}: The design of novel 4'-thionucleoside analogues bearing a C2' stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2' center, along with different approaches to control the selectivity of the N-glycosidic bond. Intramolecular SN2-like cyclization of a mixture of acyclic thioaminals provided analogues with a pyrimidine nucleobase. A kinetic bias favoring cyclization of the 1',2'-anti thioaminal furnished the desired β-D-4'-thionucleoside analogue in a 7:1 ratio. DFT calculations suggest that this kinetic resolution originates from additional steric clash in the SN2-like transition state for 1',4'-trans isomers, causing a significant decrease in their reaction rate relative to 1',4'-cis counterparts. N-glycosylation of cyclic glycosyl donors with a purine nucleobase enabled the formation of novel 2-chloroadenine 4'-thionucleoside analogues. These proprietary molecules and other derivatives are currently being evaluated both in vitro and in vivo to establish their biological profiles.