Scaffold-Oriented Asymmetric Catalysis: Conformational Modulation of Transition State Multivalency during a Catalyst-Controlled Assembly of a Pharmaceutically Relevant Atropisomer.
Scaffold-Oriented Asymmetric Catalysis: Conformational Modulation of Transition State Multivalency during a Catalyst-Controlled Assembly of a Pharmaceutically Relevant Atropisomer.
复制标题
支架导向的不对称催化：在药物相关阻转异构体的催化剂控制组装过程中过渡态多价的构象调节。
DOI：
10.1002/chem.202401109
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Miller,ScottJ
中科院分区：
文献类型：
--
作者：
Tampellini,Nicolò;Mercado,BrandonQ;Miller,ScottJ
提出了一种新型的超碱性双功能肽基胍催化剂，用于有机催化、逆反选择性合成轴向手性喹唑二酮类化合物。计算模型揭示了一种新型的苯基脲N-帽对催化剂的构象调节，它预先将结构组织成活性折叠状态。一种以前没有预料到的非共价相互作用，包括二氟乙酰胺作为杂化的单齿或双齿氢键供体，成为诱导阿托品选择性的决定性控制元件。这些发现来自一个面向支架的项目，该项目的灵感来自一种迷人的研究性BTK抑制剂，该抑制剂具有两个稳定的手性轴，并依赖于一个与现有不对称催化词典不同的机械框架。
A new class of superbasic, bifunctional peptidyl guanidine catalysts is presented, which enables the organocatalytic, atroposelective synthesis of axially chiral quinazolinediones. Computational modeling unveiled the conformational modulation of the catalyst by a novel phenyl urea N‐cap, that preorganizes the structure into the active, folded state. A previously unanticipated noncovalent interaction involving a difluoroacetamide acting as a hybrid mono‐ or bidentate hydrogen bond donor emerged as a decisive control element inducing atroposelectivity. These discoveries spurred from a scaffold‐oriented project inspired from a fascinating investigational BTK inhibitor featuring two stable chiral axes and relies on a mechanistic framework that was foreign to the extant lexicon of asymmetric catalysis.