Department of Chemistry, Stanford University, Stanford, California 94305, United States.
J Org Chem. 2024 Jun 7;89(11):8055-8063. doi: 10.1021/acs.joc.4c00686. Epub 2024 May 29.
Activated acyl species have proven versatile in the esterification of 2'-OH groups in RNA, enabling structure mapping, caging, profiling, and labeling of the biopolymer. Nearly all reagents developed for this reaction have been achiral; however, a recent study reported that simple chiral amino acid acylimidazole derivatives could yield diastereoselective reactions at RNA 2'-OH in water, enabling up to 4:1 selectivity in screening. Here, we investigated the effect of steric bulk on the stereoselectivity of RNA reaction and on the stability of adducts with a library of 36 chiral acylimidazole scaffolds with increasing steric demand. The results document the highest stereoselectivity yet achieved in RNA acylation reactions, with as high as >99:1 diastereoselectivity at >70% conversion. Also notably, the bulky adducts were found to have markedly improved stability on RNA.
已证实，活化的酰基种类在 RNA 2'-OH 基团的酯化中具有多功能性，可实现对生物聚合物的结构作图、封闭、分析和标记。几乎所有为此反应开发的试剂都是无手性的；然而，最近的一项研究报告称，简单的手性氨基酸酰亚胺衍生物在水中可以对 RNA 2'-OH 进行非对映选择性反应，从而在筛选中实现高达 4:1 的选择性。在这里，我们研究了空间位阻对 RNA 反应的立体选择性以及与 36 种具有增加空间位阻需求的手性酰亚胺支架库的加合物稳定性的影响。结果记录了 RNA 酰化反应中迄今为止最高的立体选择性，在 >70%的转化率下，最高可达 >99:1 的非对映选择性。同样值得注意的是，发现大体积加合物在 RNA 上的稳定性明显提高。
