Facile Access to Quaternary Stereocenters Through Anion Binding Catalysis

 描述(申请人提供)：在许多生物活性小分子中出现立体致密的全碳四元中心是无可争辩的事实。不幸的是，它们也是最具挑战性的对映选择性准备主题之一。因此，可用于医药的这些结构的多样性非常有限，药物中的四元立体中心几乎都是通过半合成或经典拆分来制备的。现有的催化不对称方法有几个局限性：1)依赖于合成上具有挑战性的固定定义的起始材料，限制了一般的可及性；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，内在地限制了可获得产品的范围。一个有吸引力的替代策略将是一个对映体收敛的SN1反应，在该反应中，通过简单的外消旋叔醇衍生物与碳亲核试剂的对映选择性偶联来制备全碳四元立体中心。这种方法将解决以前制备对映体富集型四元立体中心方法的每一个关键限制，从而极大地提高基序的合成可及性。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生成阳离子中间体，又可以有效地控制后续亲核捕获的立体化学结果。这种阴离子提取反应流形在生成杂原子稳定的碳正离子并利用它们生产高对映体富集物方面非常有效。然而，将这种催化歧管扩展到能够生产富对映体的四元立体中心是一个尚未解决的问题。该方案的目标是设计一种阴离子结合的有机催化剂，它将催化第一个通用的和合成上有用的对映体聚合SN1反应，能够制备四元立体中心。该研究计划概述了一种在假设驱动的实验、超分子化学和计算建模的指导下开发这种催化剂系统的方法。为了补充反应的发展，将进行详细的热力学和动力学研究，从中性醇衍生物中提取阴离子。这项研究将使这些容易获得和工作台稳定的底物能够作为碳正离子前体广泛参与阴离子提取催化。总体而言，本文描述的研究将使人们能够方便地获得不同的四元立体中心，而不需要依赖复杂的起始材料、金属催化剂或近端活化基团，并且将对药物化学研究和进一步的催化开发具有巨大的相关性。

 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.