Facile Access to Quaternary Stereocenters Through Anion Binding Catalysis

通过阴离子结合催化轻松获得四元立体中心

基本信息

批准号：
9315838
负责人：
Zachary Kimble Wickens
金额：
$ 4.9万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The fact that stereogenic all-carbon quaternary centers appear in many biologically active small molecules is indisputable. Unfortunately, they are also amongst the most challenging motifs to enantioselectively prepare. As a result, the diversity of these structures that can be deployed medicinally is extraordinarily limited and quaternary stereocenters in pharmaceuticals are almost exclusively prepared by semi-synthesis or classical resolution. Existing catalytic asymmetric methods suffer from several limitations: 1) reliance upon synthetically challenging stereodefined starting materials that restrict general accessibility; 2) reliance upon expensive transition metals that necessitate rigorous purification prior to biological testing; 3) reliance upon activating functional groups that inherently restrictthe scope of accessible products. An attractive alternative strategy would be an enantioconvergent SN1 reaction in which all-carbon quaternary stereocenters would be prepared by the enantioselective coupling of simple racemic tertiary alcohol derivatives with carbon nucleophiles. This approach would address each of the key limitations of previous methods to prepare enantioenriched quaternary stereocenters and thus would dramatically enhance the synthetic accessibility of the motif. Hydrogen bond donor organocatalysts are known to both abstract anions from neutral organic molecules to generate cationic intermediates and can effectively control the stereochemical outcome of the subsequent nucleophilic trapping. This anion abstraction reaction manifold has been tremendously effective in generating heteroatom-stabilized carbocations and exploiting them to produce highly enantioenriched products. However, extension of this catalytic manifold to enable the production of enantioenriched quaternary stereocenters is an unsolved problem. The goal of this proposal is to design an anion binding organocatalyst that will catalyze the first general and synthetically useful enantioconvergent SN1 reaction capable of preparing quaternary stereocenters. The research plan outlines an approach to develop such a catalyst system guided by hypothesis-driven experimentation, supramolecular chemistry and computational modeling. To complement the reaction development, a detailed thermodynamic and kinetic investigation anion abstraction from neutral alcohol derivatives will be undertaken. This study will enable these readily accessible and bench stable substrates to engage broadly in anion-abstraction catalysis as carbocation precursors. Overall, the research described herein will enable facile access to diverse quaternary stereocenters without reliance upon complex starting materials, metal catalysts or proximal activating groups and will have tremendous relevance to both medicinal chemistry research and further catalysis development.

描述（由申请人提供）：立体全碳四元中心出现在许多生物活性小分子中的事实是无可争议的，不幸的是，它们也是对映选择性制备的最具挑战性的基序之一。可在医学上应用的四元立体中心非常有限，并且药物中的四元立体中心几乎完全是通过半合成或经典拆分方法制备的。一些限制：1）依赖于合成上具有挑战性的立体定义的起始材料，限制了一般可及性；2）依赖于昂贵的过渡金属，需要在生物测试之前进行严格的纯化；3）依赖于激活官能团，这本质上限制了可使用的替代产品的范围。该策略是对映体收敛的 SN1 反应，其中通过简单的外消旋叔醇衍生物与碳的对映选择性偶联来制备全碳季立构中心这种方法将解决以前制备对映体富集的四元立构中心的方法的每个关键限制，因此将显着提高基序的合成可及性，已知氢键供体有机催化剂既可以从中性有机分子中提取阴离子以生成阳离子中间体，也可以。可以有效地控制随后的亲核捕获的立体化学结果，这种阴离子提取反应歧管在生成杂原子稳定的碳阳离子和然而，扩展这种催化歧管以生产对映体富集的四元立构中心是一个尚未解决的问题。该提案的目标是设计一种阴离子结合有机催化剂，以催化第一个通用的、合成上有用的对映体收敛剂。该研究计划概述了一种以假设驱动为指导的开发此类催化剂系统的方法。为了补充反应的发展，将从中性醇衍生物中提取阴离子进行详细的热力学和动力学研究，这项研究将使这些易于获得且稳定的底物广泛参与阴离子提取催化。总体而言，本文描述的研究将能够轻松获得不同的四元立构中心，而不依赖于复杂的起始材料、金属催化剂或近端活化基团，并且对两者都具有巨大的相关性。药物化学研究和进一步催化发展。