Extended aromatic polyheterocycles via scaffold-guided photoinduced cascades

CAS数据库花了半个世纪才清除了1亿种化合物的象征性里程碑 2015年仅仅四年后，这一数字就达到了1.56亿，证明了2010年的惊人增长。 生产力在很大程度上由药物设计和发现驱动。然而，FDA批准的比率 新的分子实体，不包括生物制剂，已经贫血了很长一段时间，振荡 每年10到30次。如此低的产量部分是由于缺乏真正的新产品。 管道中的复杂结构，这反过来可能是因为数量非常有限的 合成反应在现代药物化学中占据主导地位。 这使得新方法的开发对合成化学至关重要。 鉴于最近兴起的合成光化学，这是成为一个广泛接受的工具， 在有机化学和药物化学的工具箱中，我们的总体目标是发现新的 光诱导反应，并将其发展成为强大的和强大的合成方法。在 根据这项建议，我们将集中精力采取三种前所未有的反应措施， 芳族多杂环分子结构通过（i）一个新的光诱导级联引发 通过激发态质子转移（ESIPT）与后光化学脱羧 初级光产物的芳构化，（ii）一个新的光诱导级联，涉及一个6e- 芳族亚胺中的电环化，随后光诱导形成氮宾， 随后的电环化或重排，和最后（iii）新的氢原子转移 （HAT）引发的光诱导级联，导致复杂的稠合吡咯并喹唑啉酮。在 在复杂芳香多杂环化合物的多样性导向合成的背景下， 概述了一个明确的路径，以新的分子结构占据未开发或未充分开发的 化学空间。广泛的目标是通过以下方式产生潜在的药效团： 系统地采样化学空间与多样化的核心结构， 一系列外围功能。 在合成化学的武器库中增加了三个新的强大的光诱导级联反应， 创新和有影响力。初步研究显示有几种生物活性， 该项目将涉及在合成过程中合成的化合物的靶向生物筛选， 本研究此外，作为R15区域，该多方面项目将提供充足的培训 在PI的实验室为本科研究生提供机会。学生们将参与其中 与合成，学习光化学和光物理，分子建模，光谱分析 并对药物化学和生物筛选有初步了解。

It took half a century for the CAS database to clear a symbolic milestone of 100M compounds in 2015. Only four years later, this number stands at 156M, attesting to an impressive growth of productivity in a large part driven by drug design and discovery. Yet, the rate of FDA approvals of new molecular entities, excluding the biologics, has been anemic for a long time, oscillating between 10 and 30 annually. Such a small yield was explained, in part, by the lack of truly new and complex structures in the pipeline, which in turn, could be because a very limited number of synthetic reactions happen to dominate the chemical landscape of modern medicinal chemistry. This makes new methods development critically important for synthetic chemistry. Given the recent rise of synthetic photochemistry, which is becoming a broadly accepted tool in the toolbox of organic and medicinal chemistry, our overall goal is to discover new photoinduced reactions and develop them into robust and powerful synthetic methodologies. In this proposal, we will focus our effort on three unprecedented reactions offering rapid access to aromatic polyheterocyclic molecular architectures via (i) a new photoinduced cascade initiated by the excited state proton transfer (ESIPT) with post-photochemical decarboxylative aromatization of the primary photoproducts, (ii) a new photoinduced cascade involving a 6e- electrocyclization in aromatic imines followed by a photoinduced formation of a nitrene and subsequent electrocyclization or rearrangement, and finally (iii) a new hydrogen atom transfer (HAT)-initiated photoinduced cascade leading to complex fused pyrroloquinazolinones. In the context of diversity-oriented synthesis of complex aromatic polyheterocycles, this proposal outlines a clear path to new molecular architectures occupying an unexplored or underexplored areas of chemical space. The broad objective is to generate potential pharmacophores by systematically sampling the chemical space with diversified core structures augmented with a range of peripheral functionalities. Adding three new powerful photoinduced cascades to the arsenal of synthetic chemistry is innovative and impactful. With several indications of biological activity in the preliminary studies, this project will involve targeted biological screening of compounds synthesized in the course of this study. Also, as an AREA R15, this multifaceted project will provide ample training opportunities for undergraduate research students in the PI’s lab. The students will be involved with synthesis, learn photochemistry and photophysics, molecular modeling, spectra analysis and prediction, and gain initial understanding of medicinal chemistry and biological screening.