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

有了这个职业奖，美国国家科学基金会化学部的化学合成计划正在支持佛罗里达大学的亚历山大·J·格勒宁教授的研究。他的团队正在简化生物活性萜类天然产物的实验室制备方法，萜类天然产物是通常来自具有重要生物活性的植物的有机分子。需要应对这一现代挑战的原因有几个：首先，大自然往往只生产极少量的天然产品，社会需要大量的化学物质来研究和使用。从一种给定的天然产物中，可以通过化学家们所说的“半合成”来制备一组有限的类似化合物。半合成是指对一种天然产物进行特定的有限的改变。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，获得各种类似的化合物对于了解和提高母体分子的反应性至关重要。其次，实验室合成以有效方式形成大量高度复杂的分子(“全合成”)本身就具有挑战性。尽管几十年来一直以此为目标，但几乎没有通用的策略来制造复杂的萜类分子。格勒宁实验室正在研究实验室中的萜烯合成，以更好地了解这种分子在体内的功能，并使大量生产最好的分子成为可能。该项目的教育方面的目的是让公众了解自然产品。格勒宁实验室正在设计免费提供的关于萜类化合物的“信息图”，以分发给普通公众。格勒宁实验室还在组织各种活动和会议，从为期一天的高中生化学庆祝活动“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导人来传播他们的研究成果。其他好处包括在本科生和研究生水平招募代表性不足的团体，以参加这一职业奖概述的项目。格勒宁实验室专注于合成含有三环基元的多环烷烃天然产物。这是一种常见的萜类建筑，由于其固有的结构复杂性，很难进入。以酮、丙二酸和烯丙基亲电化合物为起始原料，通过操作简单和通用的反应序列，包括去共轭烯丙化、S型重排和闭环歧化反应，可以获得各种“萜类支架”。然后，这些萜类支架用作反应发展的平台，目的是制备萜类靶标和靶标类似物。选定的分子要接受生物学评估，以验证我们的化学进步。目标分子包括天然产物的三丁烷、瑞香烷和鼠李叶烷家族及其类似物。更广泛的影响包括加强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方面的教育，格伦宁教授和他的团队建立了对话，并激励学生考虑从事化学工作。该团队还设计了萜类信息图，并组织了教育学生和传播结果的活动和会议。该奖项反映了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 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.