Award Abstract # 1856747
Natural product synthesis via attached ring formation

NSF Org: CHE
Division Of Chemistry
Recipient: SCRIPPS RESEARCH INSTITUTE
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 2019 = $149,999.00
FY 2020 = $299,998.00
History of Investigator:
  • Ryan Shenvi (Principal Investigator)
    rshenvi@scripps.edu
Recipient Sponsored Research Office: The Scripps Research Institute
10550 N TORREY PINES RD
LA JOLLA
CA  US  92037-1000
(858)784-8653
Sponsor Congressional District: 50
Primary Place of Performance: The Scripps Research Institute
10550 N TORREY PINES RD
La Jolla
CA  US  92037-1000
Primary Place of Performance
Congressional District:
50
Unique Entity Identifier (UEI): PHZJFZ32NKH4
Parent UEI:
NSF Program(s): Chemical Synthesis
Primary Program Source: 01001920DB NSF RESEARCH & RELATED ACTIVIT
01002021DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 8091
Program Element Code(s): 687800
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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Hill, Sarah J. and Brion, Aurélien U. and Shenvi, Ryan A. "Chemical syntheses of the salvinorin chemotype of KOR agonist" Natural Product Reports , v.37 , 2020 https://doi.org/10.1039/d0np00028k Citation Details
Huffman, Benjamin J. and Chen, Shuming Luca and Schwarz, J. Erik and Plata, R. N. and Chin, Emily L. and Lairson, Luke N. and Houk, K. A. and Shenvi, Ryan "Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists" Nature Chemistry , v.12 , 2020 10.1038/s41557-019-0413-8 Citation Details
Huffman, Benjamin J. and Chu, Tiffany and Hanaki, Yusuke and Wong, Jonathan J. and Chen, Shuming and Houk, Kendall N. and Shenvi, Ryan A. "Stereodivergent AttachedRing Synthesis via NonCovalent Interactions: A Short Formal Synthesis of Merrilactone A" Angewandte Chemie International Edition , v.61 , 2021 https://doi.org/10.1002/anie.202114514 Citation Details
Landwehr, Eleanor M. and Baker, Meghan A. and Oguma, Takuya and Burdge, Hannah E. and Kawajiri, Takahiro and Shenvi, Ryan A. "Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction" Science , v.375 , 2022 https://doi.org/10.1126/science.abn8343 Citation Details
Woo, Stone and Shenvi, Ryan A. "Natural Product Synthesis through the Lens of Informatics" Accounts of Chemical Research , v.54 , 2021 https://doi.org/10.1021/acs.accounts.0c00791 Citation Details
Woo, Stone and Shenvi, Ryan A. "Synthesis and target annotation of the alkaloid GB18" Nature , v.606 , 2022 https://doi.org/10.1038/s41586-022-04840-9 Citation Details

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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