The central objectives of this application are: (a) to develop new, reliable, and efficient, methodologies that enable the construction of stereochemically rich scaffolds and (b) to achieve the concise chemical syntheses of naturally occurring small molecules that possess intricate chemical structures. The synthesis of complex small molecules continues to be a vital area of research. In fact, most medicinal agents on the market are prepared by organic synthesis, including the large majority of all new drugs that have become available over the past three decades. Additionally, it should be emphasized that natural products serve as valuable leads for the ultimate discovery of new medicines, in addition to inspiration for the development of new synthetic strategies and methods. However, one of the key challenges we now face is uncovering reliable means to construct ever more complex architectures, but with increased efficiency and predictability. This proposal is focused on the development of methodology that will allow chemists to harness transiently generated strained intermediates in order to efficiently build complex molecular scaffolds. More specifically, we propose the use of uncommon and highly reactive heterocyclic allenes to assemble complex architectures through the introduction of up to two new bonds and three sp3 centers. Preliminary results demonstrate the feasibility of the proposed methodologies, including enantiospecific and catalytic enantioselective variants. In the final section, we propose a concise and ambitious total synthesis of lissodendoric acid, a bioactive member of the manzamine family of alkaloids that has yet to be synthesized. The results of our studies should lead to powerful new strategies and tools for accessing various molecules of importance, including natural products and medicines.

Public Health Relevance

The central objectives of this application are: (a) to develop new, reliable, and efficient, methodologies that enable the construction of stereochemically rich scaffolds and (b) to achieve the concise chemical syntheses of naturally occurring small molecules that possess intricate chemical structures. The results of these efforts should lead to the development of new strategies and tools for the preparation of various molecules of importance, including medicines.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM132432-01
Application #
9713765
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Yang, Jiong
Project Start
2019-09-01
Project End
2023-05-31
Budget Start
2019-09-01
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Graduate Schools
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095