Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
La Trobe Institute for Molecular Science, Melbourne, VIC 3086, Australia.
Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2208540119. doi: 10.1073/pnas.2208540119. Epub 2022 Sep 7.
Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function - a key objective of click chemistry - of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.
导向多样性点击（DOC）是一种快速合成功能文库的发现方法。它结合了经典和现代点击化学的最佳属性。DOC 策略集中在核心“SuFExable”枢纽的化学多样化上，以 2-取代-炔基-1-磺酰氟（SASF）为例，通过多种反应途径实现化合物的模块化组装。我们在这里报道了一系列从 SASF 枢纽的立体选择性迈克尔型加成途径，包括与仲胺、羧酸酯、1-1,2,3-三唑和卤化物的反应。这些高产共轭加成途径提供了前所未有的β-取代烯基磺酰氟作为单一异构体，无需纯化即可获得，极大地丰富了 DOC 的范围，并符合模块化点击化学的基本原则。此外，我们还证明了这一系列 SASF 衍生分子作为人中性粒细胞弹性蛋白酶共价抑制剂的生物学功能的潜力，这是点击化学的一个关键目标。
