The overarching goal of this research program is to develop new chemical reactions and synthetic strategies for the preparation and study of chiral bioactive small molecules. Over the past decade, researchers in the pharmaceutical industry have begun to recognize the benefit of structural complexity in drug candidates, wherein molecules with greater complexity exhibit higher success rates as the proceed through the process of clinical testing and FDA approval. In order to enable the preparation of bioactive molecules with increased complexity, it is imperative to develop both the synthetic tools - new chemical reactions - and the synthetic logic for assembling molecules with chiral centers and polycyclic frameworks. The proposed research program will seek to address this need through chemical research in two general areas. The first research area will focus on the development of new Nickel-catalyzed enantioselective reductive cross-coupling reactions. These reactions tolerate an array of functional groups, occur under mild conditions, and employ inexpensive, earth abundant metals as catalysts and stoichiometric reductants. Most importantly, they do not require the use of pre-generated organometallic reagents. Preliminary results obtained for a series of new asymmetric reductive cross-coupling reactions provide compelling evidence for the feasibility of this research. The second research area will focus on the synthesis of complex, polycyclic natural products of the epidithiodiketopiperazine and alkaloid diterpenoid families. The expected outcomes of this research are two-fold: it will provide new reactions and strategies for preparing complex polycyclic molecules, and it will provide access to medicinally relevant natural products and their derivatives, which could serve as lead compounds in drug discovery efforts. This research will be carried out by a team composed of the PI, five chemistry graduate students and three postdoctoral researchers. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.

Public Health Relevance

The enantioselective synthesis of chiral small molecules is a scientific area of fundamental importance to the discovery of new medicines. This proposal seeks to develop both new synthetic tools - chemical reactions - and design strategies to enable the efficient preparation of structurally complex, bioactive molecules. In doing so, this research will accelerate the discovery of new medicines and enable study and treatment of human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118191-04
Application #
9690127
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Lees, Robert G
Project Start
2016-05-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Hofstra, Julie L; Cherney, Alan H; Ordner, Ciara M et al. (2018) Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling. J Am Chem Soc 140:139-142
Xu, Chen; Han, Arthur; Reisman, Sarah E (2018) An Oxidative Dearomatization Approach To Prepare the Pentacyclic Core of Ryanodol. Org Lett 20:3793-3796
Poremba, Kelsey E; Kadunce, Nathaniel T; Suzuki, Naoyuki et al. (2017) Nickel-Catalyzed Asymmetric Reductive Cross-Coupling To Access 1,1-Diarylalkanes. J Am Chem Soc 139:5684-5687
Suzuki, Naoyuki; Hofstra, Julie L; Poremba, Kelsey E et al. (2017) Nickel-Catalyzed Enantioselective Cross-Coupling of N-Hydroxyphthalimide Esters with Vinyl Bromides. Org Lett 19:2150-2153
Xu, Chen; Han, Arthur; Virgil, Scott C et al. (2017) Chemical Synthesis of (+)-Ryanodine and (+)-20-Deoxyspiganthine. ACS Cent Sci 3:278-282