A Dual Catalytic Strategy for Enantioselective Pyridinium Photochemistry

对映选择性吡啶光化学的双重催化策略

• 批准号: 9396295
• 负责人: Mark Daniel Levin
• 金额: $ 5.63万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2020-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396295
• 关键词: Amination; Amines; Anions; Architecture; Binding; Biological; Catalysis; Cations; Chemicals; Communities; Complex; Data; Development; Diagnostic; Disease; Event; Generations; Glean; Goals; Health; Human; Hydrogen Bonding; Ions; Knowledge; Life; Light; Link; Measures; Medical; Medicine; Methodology; Modernization; Molecular; National Institute of General Medical Sciences; Nature; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacology; Photochemistry; Photons; Process; Production; Reaction; Reagent; Research; Savings; Science; Scientific Advances and Accomplishments; Structure; Structure-Activity Relationship; System; Techniques; Technology; Titrations; absorption; bioactive natural products; catalyst; chemical synthesis; combat; cost; cycloaddition; enantiomer; grasp; improved; innovation; manufacturing process; next generation; novel; novel strategies; novel therapeutics; peer; scaffold; success; therapeutic target; wasting

Project Summary/Abstract Control over the enantioselectivity of photochemical processes has remained an open problem despite the inherent promise of light-driven methodologies to deliver a broad range of medicinally-relevant scaffolds. Indeed, absorption of a photon energetically enables substantial increases in molecular complexity (commensurate with modern pharmaceuticals) without the generation of any additional waste. The key challenge, to reign in the substantial energetic input and direct it towards selective formation of a single enantiomer, has been met with limited success by the synthetic community. Triumph in this arena would represent a major step forward for our collective ability to synthesize biologically important compounds, enabling the next generation of life-saving pharmaceuticals and diagnostic probes to be developed, while cutting costs and reducing waste for existing manufacturing processes. This proposal outlines a novel strategy to circumvent the central challenges in this sphere by employing a combination of hydrogen-bond donor and primary amine organocatalysts to selectively activate substrates for photochemical transformation. This dual catalytic reactivity manifold has been fabulously successful in the past for the generation, stabilization, and enantiofacial control of myriad cationic intermediates, and extension into photochemical reaction space will further the synthetic potential of the strategy immensely. The research plan outlines a specific line of attack for identifying an appropriate catalyst system to enable enantioselective pyridinium photochemistry, accessing densely functionalized aminocyclopentenone motifs which are in turn poised for synthetic elaboration to a wide variety of bioactive molecules. The key strategic underpinning is the ability to induce a bathochromic shift in the absorption spectrum of the substrate upon complexation with the catalyst pair via both covalent and non-covalent interactions. Advances in LED technology in recent years put this specific scientific advance within tangible grasp, and the implementation of the catalytic strategy outlined herein is poised to deliver on the promise of enantioselective photochemistry. Moreover, enantioinduction will in turn allow for mechanistic information to be gleaned. By extracting precise structure-activity relationships, a glimpse behind the rate-limiting photoexcitation step can be obtained. Overall, the proposed research will enable facile access to complex medicinally relevant compounds in a methodologically novel and efficient fashion while substantially increasing scientific knowledge.

项目总结/摘要 控制光化学过程的对映选择性一直是一个悬而未决的问题 尽管光驱动方法固有地承诺提供广泛的 与医学相关的支架实际上，光子的吸收在能量上使得能够实现实质性的 分子复杂性的增加（与现代药物相当）， 产生任何额外的废物。关键的挑战是，控制大量的能量输入， 并将其导向单一对映体的选择性形成， 合成社区的成功。在这个竞技场上的胜利将代表着我们迈出的重要一步 我们的集体能力，以合成生物重要的化合物，使 下一代救生药物和诊断探针有待开发， 为现有的制造工艺降低成本并减少浪费。该提案概述了 新的战略，以规避在这一领域的核心挑战，采用一个组合， 氢键供体和伯胺有机催化剂选择性活化底物 光化学转化这种双催化反应歧管已经惊人地 在过去成功地产生，稳定，和对映体控制无数的 阳离子中间体，并延伸到光化学反应空间将进一步 战略的综合潜力巨大。研究计划概述了一条具体的攻击路线 用于鉴定合适的催化剂体系以使对映选择性吡啶 光化学，访问密集官能化的氨基环戊烯酮基序，其依次 准备合成各种生物活性分子。重点战略 支撑是诱导的吸收光谱中的红移的能力， 通过共价和非共价两者与催化剂对络合后， 交互.近年来LED技术的进步将这一特定的科学进步 在实际掌握之中，并且准备实施本文概述的催化战略 来实现对映选择性光化学的承诺。此外，对映体诱导将在 反过来允许收集机械信息。通过提取精确的构效关系 关系，可以获得限速光激发步骤背后的一瞥。总的来说， 拟议的研究将使人们能够轻松获得复杂的医学相关化合物， 方法上新颖和有效的方式，同时大大增加科学知识。