An urgent need exists for new methods to rapidly prepare complex organic molecules with the potential to become new drugs. There is a widening gap in both the accessibility of complex core structures that are difficult to exploit and in the availability of core structures that are not already the subject of numerous patents. This gap will be addressed by identifying new synthetic methods that achieve the dual goals of enabling efficient access to useful cores while also exploring previously inaccessible chemical space. The long-term goal is to understand the reactivity of unstabilized carbenes and their immediate precursors. The objective of this application is to explore rhodium-catalyzed C?H insertion reactions of carbenes that are generated without the isolation of diazo compounds while also exploring new tandem cycloaddition/rearrangement processes. The central hypothesis is that appending two donor groups to a carbene precursor will open up new avenues of reactivity for organic chemistry. This hypothesis is supported by preliminary results regarding a) the unique ability of donor/donor carbenes to engage in highly enantioselective C?H insertion reactions and b) a remarkable cycloaddition/ rearrangement sequence that produces drug-like heterocyclic core structures absent from the patent literature! Small molecules comprise the vast majority of treatments for both acute and chronic diseases in both the developed and developing world. Research in this application will lay the groundwork to save lives and enable the next generation of pharmaceutical discovery by advancing three Specific Aims. 1) Synthesis of oxygen and sulfur heterocycles by catalytic C?H insertion.
This aim will explore asymmetric carbene reactions under conditions that avoid isolation of dangerous intermediates, exhibit unprecedented functional group tolerance, and lead to core structures common to both drug discovery leads and natural products that modulate biological phenomena. 2) Assembly of densely-substituted indolines, indanes and tetrahydro-isoquinolines (THIQs) by catalytic C?H insertion. The insertion technology will become a platform for discovery in the assembly of nitrogen- and carbon-based polycyclic systems representing useful starting points for drug discovery. 3) Rapid construction of complex heterocycles from new one-pot dipolar cycloaddition-[1,5] shift sequence. Our one-pot system for the generation and immediate reaction of diazo intermediates will be used to construct complex spiro-heterocycles in a single step, yielding unexplored molecules for pharmaceutical and biomedical applications. The proposed approach is innovative because it is based on a new methodological platform that accesses previously inaccessible chemical reactivity. This research is significant because it will change the way synthetic chemists approach targets while at the same time opening up new vistas for discovery of useful molecules for medicine and other fields. Ultimately, the discoveries emerging from our research will represent a vertical step in the assembly of molecular architectures that will translate into new medicines to address our society's most pressing health challenges.

Public Health Relevance

. The proposed research is relevant to public health because the development of novel chemistry to synthesize small molecules with new core structures is critical to the discovery of new leads for drug discovery. As such, the experiments described in this proposal are relevant to the NIH?s mission because they will enable the discovery of previously inaccessible molecules with the potential to become new medicines that will 'enhance health, lengthen life, and reduce illness and disability.'

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM124234-02
Application #
9674507
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2018-04-01
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Davis
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Souza, Lucas W; Squitieri, Richard A; Dimirjian, Christine A et al. (2018) Enantioselective Synthesis of Indolines, Benzodihydrothiophenes, and Indanes by C-H Insertion of Donor/Donor Carbenes. Angew Chem Int Ed Engl 57:15213-15216