New Catalysis and Continuous Flow Strategies Toward the Synthesis of Compounds of Interest in Medicinal Chemistry and Materials Science

化学合成在医药和材料科学等领域的发展中起着至关重要的作用。目前的建议描述了新的合成策略，以获取可以显著影响药物化学（大环）和材料科学（螺旋手性芳烃）的分子，但缺乏有效的合成方法来制备它们。该提案解决了与每一类化合物相关的长期合成挑战。特别是，新形式的催化和连续流技术将得到发展。对于大环的合成，开发新的催化方法来生成不同功能化骨架是探索大环新性质的限制因素。我们的建议描述了在有机化学中尚未开发的官能团二炔在大环化化学中的新环反应的发展。环状结构允许将杂环快速引入大环框架。利用连续流动的大环化技术，可以在高浓度合成路线的早期形成大量的大环框架。嵌入杂环的新大环可以通过已建立的协议进一步功能化，以提供多种独特的大环结构。该提案的第二个方面涉及螺旋手性碳基材料或螺旋烯的合成，螺旋烯在化学科学中有许多应用。不幸的是，对高衍生物的探索受到40多年前发展起来的传统紫外光介导方法的限制。该提案描述了可见光介导的光氧化还原策略和连续流动技术的组合，以改善较小螺旋烯的合成，同时允许获得较高的碳和杂螺旋烯。基于丰富金属的新型敏化剂结构的合成，或用于对映选择性催化的有机手性敏化剂的合成是由发展“绿色”合成工艺的需要所驱动的。流动技术的应用显著加快了光化学过程，并将首次实现目标化合物的克级合成。总之，本提案中描述的分子合成基础研究旨在提供更节能、环保、安全且产生更少废物的方法。虽然所提出的方法将允许访问有趣和重要的分子结构，催化和连续流技术也将应用于各种各样的化合物类别。因此，拟议的研究应具有重大影响，并形成在最先进的合成技术训练的HQP。

Chemical synthesis plays a critical role in the development of fields such as the medicinal and the materials sciences. The present proposal describes new synthetic strategies to access molecules that can significantly impact medicinal chemistry (macrocycles) and materials science (helically chiral aromatics), but suffer from a lack of efficient synthetic methods for their preparation. The proposal addresses the longstanding synthetic challenges associated with each of the classes of compounds. In particular, new forms of catalysis and continuous flow technology will be developed. For the synthesis of macrocycles, the development of new catalytic methods to generate diversely functionalized skeletons is a limiting factor in the exploration of new properties of macrocycles. Our proposal describes the development of novel annulations reactions of diynes, an underexplored functional group in organic chemistry, in macrocyclization chemistry. The annulations allow for the rapid introduction of heterocycles into macrocyclic frameworks. Through exploiting macrocyclization technology in continuous flow, large quantities of macrocyclic frameworks can be formed early in a synthetic route at high concentrations. The new macrocycles with embedded heterocycles can be further functionalized using established protocols to afford diverse unique macrocyclic structures. The second aspect of the proposal concerns the synthesis of helically chiral carbon based materials, or helicenes, which have found numerous applications in chemical sciences. Unfortunately, the exploration of higher derivatives is limited by the traditional UV light mediated methods developed over 40 years ago. The proposal describes a combination of visible light-mediated photoredox strategies and continuous flow techniques to improve the synthesis of smaller helicenes while allowing access to higher carbo- and heterohelicenes. The synthesis of new sensitizer structures based on earth-abundant metals, or organic chiral sensitizers for enantioselective catalysis is motivated by the need to develop "greener" synthetic processes. The application of flow technologies significantly accelerates photochemical processes and will allow gram-scale syntheses of the target compounds for the first time. Altogether, the fundamental research in molecular synthesis described in the present proposal aims to provide methods which are ever more energy efficient, environmentally friendly, safe and produce less waste. While the methods proposed would allow access to interesting and important molecular structures, the catalysis and continuous flow techniques would also have application for a wide variety of compound classes. Consequently, the proposed research should have a significant impact and form HQP that are trained in state-of-the-art synthetic techniques.