Stereodivergent Approaches to Pd-Catalyzed Cross-Coupling Reactions

Cuny City College, New York NY

Investigators

Abstract

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Mark R. Biscoe of the City College of New York (CCNY) is studying so called 'cross-coupling reactions' that are important carbon-carbon bond forming reactions in synthetic chemistry, with relevance to a broad range of applications, including pharmaceutical, agricultural and materials chemistry. Two molecules that ostensibly have the same composition and structure but which are mirror images of each other, can elicit very different biological responses. Consequently, synthetic methods that enable precise control of three-dimensional molecular structure are essential to the fields of chemical biology and medicinal chemistry. The chemical processes under development in this research embody a versatile strategy wherein a single precursor building block can be used to access either mirror image form of a desired target molecule. Arriving at this level of control will require advances in the fundamental understanding of the molecular-level mechanisms that underpin the cross-coupling reactions of interest. The new methods emerging from the supported studies are anticipated to be broadly enabling for stereoselective synthesis. The broader impacts of the project are extended by a range of educational and outreach activities that Professor Biscoe and his team of coworkers are engaged in that are designed to increase the diversity of students participating in the science and engineering enterprise. As part of these outreach efforts, Professor Biscoe has initiated a joint research program between CCNY and the High School for Math, Science, and Engineering (HSMSE) of City College. The goal of this endeavor is to create a means through which high school students can gain exposure to cutting-edge academic research, thereby potentially fostering their interest in pursuing future careers in science-related fields. Under this award, the Biscoe team will be focused on the study and development of stereodivergent palladium-catalyzed cross-coupling reactions from stereochemically defined gem-dimetallated alkyl nucleophiles. Boron, germanium, and tin constitute the main group metals contained within the enantioenriched gem-dimetallated nucleophiles of interest and new methods to access these versatile synthons will be investigated alongside their deployment in a variety of cross-couplings (e.g., Suzuki-Miyaura and Stille reactions). It is envisioned that the strategic application of stereodefined gem-dimetallated alkyl nucleophiles in iterative stereospecific cross-coupling processes will enable precise control of three-dimensional molecular structure in a reliable and general manner. Because alkyl transfer can occur with retention or inversion of stereochemical configuration, the mechanism of the transmetallation step from the gem-dimetal species will be probed in detail to facilitate the development of synthetic tactics through which both enantiomers of a desired cross-coupling product can be accessed from a single enantioenriched precursor. Due to the fact that nucleophile transfer to palladium is a fundamental step in the catalytic cycle of cross-coupling reactions, it is anticipated that the new knowledge gained from this exercise will lead to significant advances in technology for the stereoselective formation of carbon-carbon bonds. 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.