Natural product synthesis via attached ring formation

通过附着环形成的天然产物合成

• 批准号: 1856747
• 负责人: Ryan Shenvi
• 金额: $ 45万
• 依托单位: The Scripps Research Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1856747&HistoricalAwards=false
• 关键词: Natural; product; synthesis; via; attached

With this award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Ryan Shenvi of the Scripps Research Institute. Professor Shenvi and his team are developing new chemical reactions to force two molecules to bond between crowded atoms. Over the last four decades, organic chemists have learned how to connect relatively simple, flat (two-dimensional) rings of atoms. Connecting three-dimensional rings, however, remains challenging, especially when the atoms that constitute the connection points are crowded or possess different geometries. Some of the most complex molecules found in nature exhibit these congested, attached-ring structures, yet there are few good ways to make them in the laboratory. In this project, the Shenvi group is developing ways to synthesize molecules with attached-rings and apply the new methods to making molecules with potential biological applications. For example, the target molecules, Illicium terpenes, are approved by the FDA to treat peripheral arterial disease. Professor Shenvi teaches advanced topics in chemical synthesis, mentors summer undergraduate researchers, and conducts public outreach in science education. Professor Shenvi and his students are exploring two reactions capable of forging challenging attached-ring motifs from simple building blocks. In the first area of study, the group is developing an understanding of the very low energy barrier to butenolide heterocoupling, which establishes polyfunctional attached rings bearing vicinal, fully-substituted carbons. The origin of specificity and selectivity is being investigated and applied to the synthesis of Illicium terpenes. In the second area of study, the group is developing a catalytic cross-coupling method that alters the normal steric demand for arylation reactions. Application to the synthesis of attached rings embedded within polycyclic alkaloids is being explored. This work is helping to expand the repertoire of chemical reactions that can forge attached rings beyond biaryls, which heavily populate synthetic libraries, and where sp3-sp3 attached ring motifs are underrepresented. Students in the laboratory are gaining experience in mechanistic inquiry, chemical methods development, and complex molecule synthesis.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.

有了这个奖项，NSF化学部的化学合成计划正在支持斯克里普斯研究所的Ryan Shenvi教授的研究。Shenvi教授和他的团队正在开发新的化学反应，以迫使两个分子在拥挤的原子之间结合。在过去的四十年里，有机化学家已经学会了如何连接相对简单的平面（二维）原子环。然而，连接三维环仍然具有挑战性，特别是当构成连接点的原子拥挤或具有不同的几何形状时。在自然界中发现的一些最复杂的分子表现出这些拥挤的附着环结构，但在实验室中几乎没有好的方法来制造它们。在这个项目中，Shenvi小组正在开发合成带有附加环的分子的方法，并将新方法应用于制造具有潜在生物应用的分子。例如，靶分子八角萜类被FDA批准用于治疗外周动脉疾病。 Shenvi教授讲授化学合成的高级主题，指导暑期本科研究人员，并在科学教育中进行公共宣传。Shenvi教授和他的学生正在探索两种反应，能够从简单的积木中锻造具有挑战性的附着环图案。在第一个研究领域，该小组正在发展对丁烯二醇异源偶联的非常低的能量障碍的理解，该异源偶联建立了带有邻位、完全取代的碳的多官能连接环。这种特异性和选择性的来源正在研究中，并应用于八角萜类化合物的合成。在第二个研究领域，该小组正在开发一种催化交叉偶联方法，该方法可以改变芳基化反应的正常空间需求。应用于嵌入多环生物碱的连接环的合成正在探索中。这项工作有助于扩大化学反应的范围，这些反应可以在联芳基化合物之外形成连接的环，联芳基化合物大量填充合成库，而sp3-sp3连接的环基序代表性不足。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Synthesis and target annotation of the alkaloid GB18.

• DOI: 10.1038/s41586-022-04840-9
• 发表时间: 2022-06
• 期刊: Nature
• 影响因子: 64.8

Natural Product Synthesis through the Lens of Informatics.

通过信息学的视角进行天然产物合成。

• DOI: 10.1021/acs.accounts.0c00791
• 发表时间: 2021
• 期刊: Accounts of chemical research
• 影响因子: 18.3
• 作者: Woo,Stone;Shenvi,RyanA
• 通讯作者: Shenvi,RyanA

Chemical syntheses of the salvinorin chemotype of KOR agonist.

• DOI: 10.1039/d0np00028k
• 发表时间: 2020-11-18
• 期刊: Natural product reports
• 影响因子: 11.9
• 作者: Hill SJ;Brion AUCM;Shenvi RA
• 通讯作者: Shenvi RA

Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction.

• DOI: 10.1126/science.abn8343
• 发表时间: 2022-03-18
• 期刊: Science (New York, N.Y.)

Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists

• DOI: 10.1038/s41557-019-0413-8
• 发表时间: 2020-02-10
• 期刊: NATURE CHEMISTRY
• 影响因子: 21.8
• 作者: Huffman, Benjamin J.;Chen, Shuming;Shenvi, Ryan A.
• 通讯作者: Shenvi, Ryan A.