Complexity-building Approaches in Photoassisted Synthesis of Heterocycles

通过这个奖项，美国国家科学基金会化学部的化学合成项目正在支持丹佛大学化学和生物化学系Andrei Kutateladze教授的研究。研究的重点是开发合成含有多环亚结构的复杂有机分子的新方法。这将使用光子作为一种环境丰富且安全的试剂，该方法以最少的实验步骤实现结构复杂性。除了在合成化学的背景下学习光与物质相互作用的基本重要性之外，目标复杂的多杂环（即含有氮、硫或氧原子作为环的一部分的分子）被故意设计成类似于生物碱（一类天然存在的有机碱）和其他可能具有有用治疗特性的生物活性天然产物。重要的是，该奖项支持本科生和研究生的研究经验，特别是那些来自历史上代表性不足的科学群体的学生，为他们提供现代有机化学和光化学方面的有用技能；为学术界或工业界的职业道路做好了充分的准备。本研究通过几种新的光辅助合成反应级联扩展了基于激发态分子内质子转移（ESIPT）的合成光化学工具箱。光诱导反应级联使实验人员能够实现大阶跃归一化的复杂性增加，并快速组装新的融合多杂环分子结构。额外的复杂性增长是通过光化学转化实现的，如多步碳阳离子级联和重排。研究这些esipt触发级联的反应机制和立体化学有助于控制立体化学和区域化学结果。该实验工作通过计算得到了扩充，特别是便于用核磁共振对复杂的多杂环产物的溶液结构进行解析。新的集成的DU8+方法快速准确地计算核磁共振参数包括PCM模型和溶剂特定的参数化方案。该计算工具不仅对该项目的成功至关重要，而且对复杂合成和天然产物靶分子的结构解析也具有更广泛的意义。此外，本研究为研究生和本科生以及研究助理，特别是那些历史上在科学领域代表性不足的群体提供了动手实验训练。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Andrei Kutateladze, Department of Chemistry and Biochemistry at the University of Denver. The research is focused on developing new methods for synthesis of complex organic molecules containing multiple ring substructures. This will be done using photons of light as an environmentally abundant and safe reagent and the approach achieves structural complexity with a minimal number of experimental steps. Besides the fundamental importance of learning about interactions of light and matter in the context of synthetic chemistry, the targeted complex polyheterocycles (i.e. molecules which contain nitrogen, sulfur, or oxygen atoms as a part of a ring) are intentionally designed to resemble alkaloids (a class of naturally occurring organic bases) and other biologically active natural products that may potentially possess useful therapeutic properties. Importantly, this award supports research experiences for undergraduate and graduate students, especially those from historically underrepresented groups in science, provided them with useful skill sets in modern organic chemistry and photochemistry; excellent preparation for career paths in either academia or industry.This research expands the toolbox for excited state intramolecular proton transfer (ESIPT)-based synthetic photochemistry with several new photo-assisted synthetic reaction cascades. The photo-induced reaction cascades allow the experimentalist to achieve large step-normalized complexity increases and rapidly assemble novel fused polyheterocyclic molecular architectures. Additional growth of complexity is realized through post-photochemical transformations, such as multi-step carbocationic cascades and rearrangements. Investigations of reaction mechanisms and stereochemistry of these ESIPT-triggered cascades help achieve control of stereochemical and regiochemical outcomes. This experimental work is augmented by computation, especially to facilitate solution structure elucidation of the complex polyheterocyclic products by NMR. The new integrated DU8+ method for fast and accurate calculation of NMR parameters includes PCM models and solvent-specific parameterization schemes. This computational tool is are critical for success of this project, but also has broader implications for structure elucidation of complex synthetic and natural product target molecules. Additionally, this research provides hands-on laboratory training for graduate and undergraduate students, and research associates, especially those from historically underrepresented groups in science.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.