Novel Catalysis for Macrocyclization Processes

大环化过程的新型催化

• 批准号: RGPIN-2020-05006
• 负责人: Collins, Shawn
• 金额: $ 5.76万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740341
• 关键词: Novel; Catalysis; Macrocyclization; Processes

Macrocycles are a unique chemotype in chemistry that impact the fields of pharmaceuticals, agrochemicals, aromachemicals and materials science, affecting the technological and economic welfare of society. The interest in complex macrocycles in biology, medicine and energy-related fields, has highlighted the need for new catalytic strategies. The proposed program will address these state-of-the-art challenges through innovative solutions in catalysis. The program recognizes the potential of unique chiral architectures in macrocycles, and describes the development of catalytic routes towards planar chiral macrocycles as short term goals. Importantly, atropisomerism is a recognized challenge in many fields, including drug discovery, where planar chiral macrocyclic scaffolds are essentially unexplored. Specifically, the proposal describes using asymmetric organo- and Bronsted acid catalysis to prepare planar chiral macrocycles from common, readily available building blocks. A common theme is the design of processes that include versatile "handles" that can be used to tailor the macrocycles for applications in various fields. The proposal describes long-term goals to address the critical need for chemoselectivity in macrocyclization via photocatalysis. The preparation of novel chemotypes of essential macrocyclic disulfides is described via a photochemical deprotection/macrocyclization sequence. Also, photocatalysis will enable new chemistry using ubiquitous functionality found in macrocycles employed by the pharmaceutical and aromachemical industries. Transformations involving nitroindoline amides will facilitate macrocyclizations to form acyl functionality, permit the synthesis of challenging macrocyclic ketones, or enable SNAr reactions that are problematic under thermally-mediated processes. In addition, the preparation of enantioenriched macrocyclic amides and esters via dynamic kinetic resolution (DKR) would exploit photocatalysis to chemoselectively racemize key secondary amines and alcohols during the DKR process. The research goals create new tools for photomacrocyclization that will be more energy efficient and generate less waste. Lastly, the development of copper-based complexes as photocatalysts for macrocyclization is proposed. Elucidating key structural features of the catalysts for application in energy transfer or for reductive quenching processes, which remain a challenge in the area of copper-based photocatalysis, is described. The development of base metal photocatalysis has considerable potential impact for sustainable molecular synthesis, particularly when developed in parallel with continuous flow methods that are compatible with industrial scale applications. In sum, the proposed research should have a significant impact and form HQP that are trained in state-of-the-art synthetic techniques.

大环化合物是化学中一种独特的化学类型，影响着制药、农用化学品、芳香化学品和材料科学领域，影响社会的技术和经济福利。生物学、医学和能源相关领域对复杂大环化合物的兴趣凸显了对新催化策略的需求。拟议的计划将通过催化方面的创新解决方案来应对这些最先进的挑战。该计划认识到大环中独特的手性结构的潜力，并将平面手性大环催化路线的开发描述为短期目标。重要的是，阻转异构现象是许多领域公认的挑战，包括药物发现，其中平面手性大环支架基本上尚未被探索。具体来说，该提案描述了使用不对称有机酸和布朗斯台德酸催化从常见的、容易获得的结构单元制备平面手性大环化合物。一个共同的主题是包括多功能“手柄”的工艺设计，可用于为各个领域的应用定制大环化合物。该提案描述了通过光催化解决大环化中化学选择性的关键需求的长期目标。通过光化学去保护/大环化序列描述了重要大环二硫化物的新型化学型的制备。此外，光催化将利用制药和芳香化学行业使用的大环化合物中普遍存在的功能来实现新化学。涉及硝基吲哚啉酰胺的转化将促进大环化形成酰基官能团，允许合成具有挑战性的大环酮，或实现在热介导过程中存在问题的SNAr反应。此外，通过动态动力学拆分（DKR）制备对映体富集的大环酰胺和酯将利用光催化在 DKR 过程中化学选择性地外消旋关键的仲胺和醇。研究目标是创造新的光大环化工具，该工具将更加节能并产生更少的废物。最后，提出了开发铜基配合物作为大环化光催化剂。阐明了用于能量转移或还原猝灭过程的催化剂的关键结构特征，这在铜基光催化领域仍然是一个挑战。贱金属光催化的发展对可持续分子合成具有相当大的潜在影响，特别是当与与工业规模应用兼容的连续流动方法并行开发时。总之，拟议的研究应该产生重大影响，并形成接受过最先进合成技术培训的 HQP。