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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9315838
• 关键词: Address; Affinity; Alcohols; Anions; Architecture; Binding; Biological; Biological Response Modifier Therapy; Biological Testing; Carbon; Catalysis; Cations; Chemicals; Chemistry; Chlorides; Climacteric; Complement; Complex; Computer Simulation; Coupling; Development; Goals; Health; Human; Hydrogen Bonding; Investigation; Kinetics; Link; Medicine; Metals; Methodology; Methods; Modern Medicine; Molecular; National Institute of General Medical Sciences; Organic Synthesis; Outcome; Oxygen; Pharmaceutical Chemistry; Pharmacologic Substance; Production; Property; Reaction; Research; Resolution; Route; Structure; System; Thermodynamics; Transition Elements; Urea; base; catalyst; cost; design; frontier; functional group; innovation; invention; ionization; novel; novel strategies; public health relevance; small molecule; success

 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）：立体全碳季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。因此，这些结构的多样性，可以部署在医药是非常有限的，在药物中的四元立体中心几乎完全通过半合成或经典的决议。现有的催化不对称方法受到几个限制：1）依赖于限制一般可及性的合成上具有挑战性的立体限定的起始材料; 2）依赖于昂贵的过渡金属，其需要在生物测试之前进行严格纯化; 3）依赖于活化官能团，其固有地限制了可及产物的范围。一个有吸引力的替代策略将是对映收敛的SN 1反应，其中全碳季立体中心将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。这种方法将解决以前制备对映体富集的四元立体中心的方法的每个关键限制，从而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从中性有机分子中提取阴离子以产生阳离子中间体，又可以有效地控制随后亲核捕获的立体化学结果。这种阴离子提取反应歧管在产生杂原子稳定的碳正离子和利用它们产生高度对映体富集的产物方面非常有效。然而，这种催化歧管的延伸，使对映体富集的四元立体中心的生产是一个未解决的问题。本提案的目标是设计一种阴离子结合有机催化剂，其将催化第一个通用的和合成有用的对映体会聚的SN 1反应，能够制备季立体中心。该研究计划概述了一种方法来开发这样的催化剂系统，该系统由假设驱动的实验，超分子化学和计算建模指导。为了补充反应的发展，将进行详细的热力学和动力学研究中性醇衍生物的阴离子提取。这项研究将使这些容易获得和工作台稳定的基板广泛从事阴离子提取催化作为碳阳离子前体。总体而言，本文所述的研究将使得能够容易地获得不同的四元立体中心，而不依赖于复杂的起始材料、金属催化剂或近端活化基团，并且将与药物化学研究和进一步的催化开发具有巨大的相关性。