
NSF Org: |
CHE Division Of Chemistry |
Recipient: |
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Initial Amendment Date: | July 22, 2019 |
Latest Amendment Date: | May 20, 2020 |
Award Number: | 1856747 |
Award Instrument: | Continuing Grant |
Program Manager: |
Jon Rainier
CHE Division Of Chemistry MPS Directorate for Mathematical and Physical Sciences |
Start Date: | August 1, 2019 |
End Date: | July 31, 2023 (Estimated) |
Total Intended Award Amount: | $449,997.00 |
Total Awarded Amount to Date: | $449,997.00 |
Funds Obligated to Date: |
FY 2020 = $299,998.00 |
History of Investigator: |
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Recipient Sponsored Research Office: |
10550 N TORREY PINES RD LA JOLLA CA US 92037-1000 (858)784-8653 |
Sponsor Congressional District: |
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Primary Place of Performance: |
10550 N TORREY PINES RD La Jolla CA US 92037-1000 |
Primary Place of
Performance Congressional District: |
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Unique Entity Identifier (UEI): |
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Parent UEI: |
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NSF Program(s): | Chemical Synthesis |
Primary Program Source: |
01002021DB NSF RESEARCH & RELATED ACTIVIT |
Program Reference Code(s): |
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Program Element Code(s): |
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Award Agency Code: | 4900 |
Fund Agency Code: | 4900 |
Assistance Listing Number(s): | 47.049 |
ABSTRACT
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.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
Chemistry is the science of transforming matter. Our laboratory invents new chemical reactions to build complex molecules from simple chemicals. This allows us to access cellular metabolites, for example, that may be difficult to source due to the restraints of technology, ecology or safety. These metabolites tend to be highly complex organic molecules that have evolved to selectively bind to biological molecules, some of which are targets of interest for the development of new medicines. Similarly, molecular complexity in drugs can impart specificity and limit side-effects. However, the synthesis of complex molecules requires many iterative chemical reactions, which can be costly, time-consuming and wasteful. Therefore, we develop new reactions to lower costs, accelerate synthesis and generate less chemical waste. Our NSF-supported project led to new understanding of chemical reactions and methods to modify and understand complex plant metabolites from traditional medicine. For example, we began this work with the investigation of a chemical reaction originally developed for a neuroactive plant metabolite, but discovered the potential to target antagonism of the cGAS-STING pathway involved in inflammation and cancer. Investigation of a similar neuroactive compound identified unusual mechanistic properties of a chemical reaction that simplified its access. Finally, we developed a concise approach to produce alkaloids from the Galbulimima genus that have eluded large scale production and biological study. These discoveries completed journeys from basic chemistry research to identification of potential new medicines and began new journeys to translate these discovery into new medicines.
Last Modified: 08/31/2023
Modified by: Ryan Shenvi
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