基于Nugent试剂引发的还原偶联反应研究及其在生物活性分子合成中的应用

全碳季碳中心广泛存在于具有重要生理活性的分子中，其构建一直以来都是有机合成的热点和难点之一。自由基因其具有高的反应活性，可为全碳季碳中心的构建提供了全新、高效的途径。Nugent试剂（Cp2TiCl）自被发现可以作为单电子还原试剂引发自由基以来，被广泛被应用于有机反应中，但目前对其底物适用范围主要局限于三元环系、烷基卤化物以及共轭羰基化合物。本研究将探索使用Nugent试剂引发一些非三元环系的底物生成三级碳自由基，与卤化物偶联实现高效、高对映选择性构建含有乙基胺或乙基醇全碳季碳中心的方法。并尝试将该方法运用到11-β-脱氢同工酶1抑制剂及其类似物的高效合成中，为该类化合物的生物活性构效关系研究提供物质基础。

All-carbon quaternary centers are ubiquitously found in chemical compounds with significant bioactivities. Their construction is of pivotal importance in organic synthesis. However, due to their distinct steric congestion and conformation restriction, formidable challenges remain in forging all-carbon quaternary centers. Radical chemistry could provide alternative and efficient tactics owing to the intrinsic high reactivity of radical intermediates. Nugent reagent (Cp2TiCl) is frequently used in organic synthesis as a mild single electron transfer (SET) reagent since its initial reactivity to trigger radical species was disclosed in the reductive ring-opening\cyclization of epoxides. However, the current substrates suitable for the Nugent reagent are limited to three-membered rings (e.g., epoxides, cyclopropanes, aziridines), alkyl halides, or conjugated carbonyls. This research proposal is aiming to explore the feasibility of Nugent reagent triggered tertiary alkyl radical generation from non-three membered rings (e.g., oxetanes, azetidines) and their coupling reactions with halides to construct all-carbon quaternary centers with ethyl amine or ethyl alcohol moiety in an efficient and enantioselective fashion. Our long-term goal is to enable the efficient synthesis of the analogs of 11-β-dehydrogenase isozyme 1 inhibitor and expedite the structure and activity relationship study.