Complexity-building Approaches in Photoassisted Synthesis of Heterocycles

通过这一奖项，美国国家科学基金会化学部化学合成计划支持丹佛大学化学和生物化学系Andrei Kutateladze教授的研究。这项研究的重点是开发合成含有多环子结构的复杂有机分子的新方法。这将使用光子作为环境丰富和安全的试剂来完成，该方法以最少的实验步骤实现了结构复杂性。除了在合成化学的背景下学习光和物质的相互作用的基本重要性外，目标复杂的多杂环(即作为环的一部分包含氮、硫或氧原子的分子)被故意设计成类似生物碱(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，特别是那些来自科学领域历史上代表性不足的群体的研究经验，为他们提供了现代有机化学和光化学方面的有用技能；为学术或工业的职业道路做好了出色的准备。这项研究通过几个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)的合成光化学的工具箱。光诱导反应级联使实验者能够实现大的步长归一化复杂性增加，并快速组装新型的融合多杂环分子结构。复杂性的额外增长是通过后光化学转化实现的，例如多步碳阳离子级联和重排。对ESIPT引发的级联反应机理和立体化学的研究有助于实现立体化学和区域化学结果的控制。这项实验工作通过计算得到了补充，特别是便于通过核磁共振来阐明复杂的多杂环产物的溶液结构。用于快速准确计算核磁共振参数的新的集成DU8+方法包括PCM模型和特定于溶剂的参数化方案。这种计算工具对这个项目的成功至关重要，但对于复杂的合成和天然产物目标分子的结构解释也有更广泛的影响。此外，这项研究为研究生和本科生以及研究助理提供动手实验室培训，特别是那些来自科学领域历史上代表性不足的群体的学生。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.