Selective Functionalization of Aliphatic Amines - Supplement to Support Mariah Ramos

首席调查员：托米斯拉夫的ROVIS 摘要 近年来，人们对结构-活性关系(SARS)的理解有了很大的提高 与生物相关的化合物。因此，更需要精简、互补的 合成以获得实用的药物支架。目前的方法集中在编辑药物的外围 用于安装多功能手柄的化合物。或者，改变目标分子的核心将 提供多种药物支架，同时保持外围手柄不变。直接核心编辑 将显著减少设计-合成-测试时间，因为大多数药物核心改变需要完全 新的合成方法。该方案描述了一种从容易获得1，2-二氮卓类药物的有效合成路线 可通过脱芳环扩张获得吡啶。目标1概述了使用先前建立的 方法获得多克量级的叶立德中间体，可得到二氮卓类化合物 在370 nm光照射下，通过6π的电环打开。1，2-二氮卓类药物是 FDA批准的药物中存在的最不常见的氮杂环，可能是由于缺乏合成的 能够接触到这些支架的途径，而不是它们的生物特性。而吡啶 扩展通常是多步骤的过程，我们的工作表明有希望通过一锅粥的方式实现这一点 扩展产品。此外，目标2和目标3提出了获得这些有价值的新的、可选的方法 产品。一锅催化转移同时辐射可制得1，2-二氮杂卓 还有变种。综上所述，这一提议提供了获得合成难度很大的药物核心的途径，同时也 引入合成手柄以进一步衍生化。 5.

Principal Investigator: Rovis, Tomislav Abstract Recent years have brought about a greatly enhanced understanding of structure-activity relationships (SARs) of biologically relevant compounds. Accordingly, there is a greater need for streamlined, complementary syntheses to access practical drug scaffolds. Current methods focus on editing the periphery of drug compounds to install versatile functional handles. Alternatively, altering the core of target molecules would provide access to diverse drug scaffolds while leaving peripheral handles untouched. Direct core editing would significantly decrease the design-synthesis-test time, as most drug core alterations require an entirely new synthesis. This proposal describes an efficient synthetic route to access 1,2-diazepines from readily available pyridines through dearomative ring expansion. Aim 1 outlines using previously established methods to obtain the pyridinium ylide intermediate on multi-gram scale, the diazepine can be obtained through a 6π electrocyclic ring opening upon irradiation with 370nm light. 1,2-Diazepines are among the least common nitrogen heterocycles present in FDA approved drugs, likely due to the lack of synthetic pathways that enable access to these scaffolds rather than their biological properties. While pyridine expansions are generally multistep procedures, our work has shown promise for a one-pot route to this expansion product. Additionally, Aims 2 and 3 propose novel, alternate methods of obtaining these valuable products. A one-pot catalytic nitrene transfer with simultaneous irradiation could afford the 1,2 diazepine and variants. Taken together, this proposal provides access to synthetically difficult drug cores, while also introducing synthetic handles for further derivatization. 5