Anion Abstraction From Hypervalent Silanes: Enantioselective Synthesis of Compounds Bearing Carbon and Silicon Stereogenic Centers

从高价硅烷中提取阴离子：具有碳和硅立构中心的化合物的对映选择性合成

• 批准号: 10625318
• 负责人: Sophia Louise Shevick
• 金额: $ 6.91万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-13 至 2025-06-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625318
• 关键词: 3-Dimensional; Acids; Amides; Anions; Binding; Carbon; Catalysis; Charge; Chemicals; Chemistry; Chloride Ion; Chlorides; Clinical; Clinical Trials; Complex; Development; Electronics; Elements; Endowment; Environment; Evaluation; Generations; Health; Human; Hydrogen Bonding; Ions; Kinetics; Knowledge; Lead; Life; Link; Methanol; Methods; Molecular; Nature; Organic Chemistry; Pathway interactions; Periodicals; Pharmaceutical Preparations; Property; Reaction; Research; Role; Scientist; Silanes; Silicates; Silicon; Therapeutic; Variant; analog; base; carbonyl compound; catalyst; design; drug candidate; drug discovery; ionization; novel; novel strategies; small molecule; success; tool

Project Summary The incorporation of chiral, stereogenic centers in small molecule drug candidates is statistically linked to success in clinical trials. In order to design more structurally complex bioactive compounds, chemists must rely on efficient synthetic tools. The objective of this proposal is to develop novel modes of reactivity that deliver molecules containing carbon and silicon chiral, stereogenic centers inaccessible through existing methods. Specifically, this proposal outlines a novel application of asymmetric ion-pairing catalysis to hypervalent silicate / chloride ion pairs, engaging hypervalent chlorosilanes with dual hydrogen-bond donor catalysts via an anion- binding mechanism. Mechanistic studies of hypervalent chlorosilanes have established that ionization of the silicon-chloride bond is relevant to many transformations involving organosilanes in the presence of nucleophilic or Lewis basic additives. Despite this evidence, these reactive ion pairs have not been used as handles in the design of asymmetric transformations. Using dual hydrogen-bond donors to catalyze anion binding from hypervalent silicon will be explored in two orthogonal approaches based on shared mechanistic principles. The first approach establishes Lewis acid / hydrogen-bond donor co-catalysis utilizing cationic hypervalent silicates as highly electrophilic Lewis acid catalysts through the design of a tailored bifunctional hydrogen-bond donor catalyst. This cooperative catalytic approach will be applied to an asymmetric Passerini two-component reaction (P-2CR), generating alpha-hydroxy amides, prominent motifs in bioactive molecules. Asymmetric induction through cooperative non-covalent interactions between the silicate-electrophile / chloride-catalyst ion pair is expected to result in high enantioselectivities across a wide substrate scope. If successful, this approach to Lewis acid / HBD co-catalysis provides a new and potentially general approach to enantioselective additions to carbonyl compounds. The second application will apply anion-binding catalysis to the enantioselective synthesis of silicon-stereogenic alkoxyorganosilanes. Few catalytic methods exist to access enantioenriched alkoxyorganosilanes, which have significant, yet underexplored, roles in drug discovery. Kinetic studies and computational evaluation of putative reactive intermediates will help build a comprehensive mechanistic understanding of these reactions, guiding further application of this novel anion-binding approach to additional transformations. It is expected that these methods will aid chemists in the design and synthesis of small molecule drugs and tool compounds that positively impact human health.

项目摘要 在小分子候选药物中加入手性立体中心在统计学上与 临床试验取得成功。为了设计结构更复杂的生物活性化合物，化学家必须依靠 高效的合成工具。这项建议的目标是开发新的反应性模式，以提供 含有碳和硅手性立体中心的分子无法通过现有方法获得。 具体地说，这项提案概述了不对称离子对催化在高价硅酸盐中的新应用 /氯离子对，通过一个阴离子与双氢键供体催化剂与高价氯硅烷接合. 约束机制。高价氯硅烷的机理研究已证实电离 在亲核试剂存在下，硅氯键与涉及有机硅烷的许多转化有关。 或刘易斯碱性添加剂。尽管有这些证据，这些反应离子对还没有被用作手柄 不对称变换的设计。利用双氢键给电子体催化阴离子结合 基于共同的机械原理，我们将用两种正交的方法来探索超价硅。这个 第一种方法利用阳离子高价硅酸盐建立Lewis酸/氢键施主共催化 通过量身定制的双功能氢键供体的设计，作为高亲电性的Lewis酸催化剂 催化剂。这种合作催化方法将应用于不对称Passerini两组分反应。 (P-2CR)，产生α-羟基酰胺，生物活性分子中的突出基序。不对称诱导 通过硅酸盐-亲水性/氯离子-催化剂离子对之间的协同非共价相互作用 预计将在广泛的底物范围内产生高的对映选择性。如果成功，这种方法将 Lewis酸/HBD共催化为对映体选择性加成提供了一种新的和潜在的通用方法 羰基化合物。第二个应用是将阴离子结合催化应用于对映选择性合成。 硅立体生成烷氧基有机硅烷。几乎没有催化方法来获得富含对映体的化合物 烷氧基有机硅烷，它们在药物发现中具有重要但未被开发的作用。动力学研究和 对假定的活性中间体的计算评估将有助于建立一个全面的机制 了解这些反应，指导这一新的阴离子结合方法的进一步应用 变形。这些方法有望帮助化学家设计和合成小分子。 对人类健康有积极影响的药物和工具化合物。