CAREER: Developing a modular synthesis of 6-7-5 terpenoid natural products and analogs

美国国家科学基金会化学部的化学合成项目用这个职业奖来支持佛罗里达大学Alexander J. Grenning教授的研究。他的团队正在简化如何在实验室中制备生物活性萜类天然产物，这些有机分子通常来自具有重要生物活性的植物。这一现代挑战需要解决的原因有几个：首先，大自然通常只产生极少量的天然产物，而大量的化学物质需要用于研究和社会使用。从一种给定的天然产物中，可以通过化学家所谓的“半合成”制备出一组有限的类似化合物。半合成是指对天然产物进行特定的有限改变。在进行旨在了解这些分子与生物系统相互作用方式的研究时，获得各种类似化合物对于理解和提高母体分子的反应性至关重要。其次，以高效方式大量合成高度复杂分子的实验室合成（“全合成”）本身就具有挑战性。虽然已经有几十年的研究目标，但很少有制造复杂萜烯分子的通用策略。格伦宁实验室正在研究实验室萜烯合成，以更好地了解这种分子在体内的功能，并使大量生产最佳分子成为可能。这个项目的教育方面旨在让公众了解天然产品。格伦宁实验室正在设计免费提供的萜烯“信息图表”，以便向公众分发。格伦宁实验室还在组织各种活动和会议，从为高中生举办的为期一天的化学庆祝活动“Chemathon”，到“佛罗里达杂环和合成会议（FloHet）”，这是一个专门的国际会议，聚集了合成有机化学领域的领导者，以传播他们的研究成果。其他好处包括招募代表性不足的群体，包括本科生和研究生，参与本职业奖概述的项目。格林宁实验室专注于合成具有三环基序的多环烷烃天然产物。这是一种常见的萜类结构，由于其固有的结构复杂性而难以获得。酮类、丙二酸和烯丙基亲电试剂可作为起始原料，通过操作简单和广泛的反应序列，包括解共轭烯化、异位重排和闭合环复合，可以获得各种“萜烯支架”。然后，这些萜烯支架作为反应发展的平台，旨在制备萜烯靶点和靶点类似物。选定的分子将接受生物学评估，以验证我们的化学进展。目标分子包括天然产物的tigliane， daphnane和rhamnofolane家族及其类似物。更广泛的影响包括增加与圣达菲社区学院的互动。通过对当地社区进行有机化学和天然产品的教育，格雷宁教授和他的团队创造了一种对话，激励学生考虑从事化学职业。该团队还设计萜类信息图表，并组织活动和会议，以教育学生和传播结果。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 CAREER Award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Alexander J. Grenning at the University of Florida. His group is streamlining how bioactive terpenoid natural products, organic molecules commonly derived from plants with important biological activity, are prepared in the laboratory. There are several reasons why this modern challenge needs to be addressed: first, nature often only produces minute quantities of natural products and significant amounts of the chemical are needed for study and use in society. From a given natural product, a limited set of similar compounds can be prepared via what chemists call "semi-synthesis". Semi-synthesis refers to specific limited changes to a natural product. When performing studies designed to understand the way these molecules interact with biological systems, access to a variety of similar compounds is crucial for understanding and improving the reactivity of the parent molecule. Second, the laboratory synthesis of highly complex molecules ("total synthesis") forming large quantities in efficient ways is inherently challenging. Although targeted for decades, there are few general strategies to make the complex terpene molecules. The Grenning lab is studying the laboratory terpene synthesis to better understand the function of this molecule in the body and to enable the advanced manufacturing of the best molecules in large quantities. Educational aspects of this project are aimed at informing the public about the natural products. The Grenning lab is designing freely available "infographics" on terpenes for distribution to the general public. The Grenning lab is also organizing events and conferences ranging from the "Chemathon," a day-long celebration of chemistry for high-school students, to the "Florida Heterocyclic and Synthetic Conference (FloHet)," a specialized international meeting that gathers synthetic organic chemistry leaders to disseminate their research findings. Additional benefits include the recruitment of underrepresented groups, both at the undergraduate and graduate student level, for participation in the projects outlined in this CAREER Award.The Grenning lab is focusing on the synthesis of polycycloalkane natural products bearing tricyclic motifs. This is a common terpenoid architecture that is difficult to access due to its inherent structural complexity. Ketones, malonic acids, and allylic electrophiles serve as starting materials and through an operationally simple and generalized reaction sequences consisting of deconjugative allylations, sigmatropic rearrangements, and ring-closing metathesis, a variety of "terpene scaffolds" are accessible. These terpene scaffolds then serve as platforms for reaction development aimed at preparing terpenoid targets and target-analogs. Select molecules are subject to biological evaluation to validate our chemical advancements. The molecules targeted include the tigliane, daphnane and rhamnofolane families of natural products and their analogs. Broader Impacts include the increased interaction with Santa Fe Community College. By educating the local community on organic chemistry and natural products, Professor Grenning and his group create a dialogue and inspire students to consider careers in chemistry. The team also designs terpenoid infographics and organizes events and conferences for educating students and disseminating results.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.