PDF(Pubmed)
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.
摘要：
描述了带有C2'立体异构全碳季中心的新型4'-硫代核苷类似物的设计。该合成涉及高度非对映选择性的Mukaiyama羟醛反应，和非对映选择性自由基基乙烯基转移，以产生全碳立体异构C2'中心，以及控制N-糖苷键选择性的不同方法。无环硫代氨基的混合物的分子内SN2样环化提供了具有嘧啶核碱基的类似物。有利于1'环化的动力学偏差，2'-抗硫代胺素以7:1的比例提供所需的β-D-4'-硫代核苷类似物。DFT计算表明，该动力学分辨率源于1\'的SN2样过渡状态中的额外空间碰撞，4\'-反式异构体，导致它们的反应速率相对于1'显著降低，4个顺式同行。具有嘌呤核碱基的环状糖基供体的N-糖基化使得能够形成新的2-氯腺嘌呤4'-硫代核苷类似物。目前正在体外和体内评估这些专有分子和其他衍生物以建立其生物学特性。
