Novel Catalysis for Macrocyclization Processes

大环是化学中一种独特的化学类型，它影响着医药、农用化学品、芳香族化合物和材料科学等领域，影响着社会的技术和经济福利。生物、医学和能源相关领域对复杂大环的兴趣，突显了新催化策略的必要性。拟议的计划将通过催化领域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，并将开发平面手性大环的催化路线作为短期目标。重要的是，在包括药物发现在内的许多领域，阿托品异构化是一个公认的挑战，在这些领域，平面手性大环支架基本上是未知的。具体地说，该提案描述了使用不对称有机酸和Bronsted酸催化从常见的、容易获得的构筑块制备平面手性大环。一个共同的主题是流程的设计，其中包括可用于为不同领域的应用程序量身定做宏周期的通用“句柄”。该提案描述了通过光催化来解决大环反应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，描述了新型必需大环二硫化物的制备。此外，光催化将利用制药和芳香化工行业使用的大环中无处不在的功能来实现新的化学。涉及硝基吲哚酰胺的转化将促进大环化反应形成酰基官能团，允许合成具有挑战性的大环酮，或者使在热中介过程中存在问题的SNAR反应成为可能。此外，通过动态动力学拆分(DKR)制备富含对映体的大环酰胺和酯将利用光催化在DKR过程中对关键的仲胺和醇进行化学选择性外消旋。这些研究目标为光环化创造了新的工具，这种工具将更加节能，产生的废物更少。最后，展望了铜基配合物光催化剂在大环化反应中的应用前景。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，这些过程仍然是铜基光催化领域的一个挑战。贱金属光催化的发展对可持续的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发展时。总之，拟议的研究应该会产生重大影响，并形成HQP，这些HQP都接受了最先进的合成技术培训。

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.