Development of Difluorobenzyl Synthons for Cross-Coupling Chemistry
The benzylic methylene unit (Ar-CH2-R) is a common motif in drug candidates and pharmaceuticals. However, the propensity of its C-H bonds toward oxidation creates the challenge of metabolic stability. One solution is the substitution of this motif with the benzylic difluoromethylene or difluorobenzyl units (Ar-CF2-R), wherein the reactive C-H bonds are substituted with metabolically more stable C-F bonds. However, despite the potential advantage of such an approach, few pharmaceuticals containing this motif have been commercialized. This project focuses on the development of novel Ar-CF2-M synthons for C-C cross-coupling chemistry. First, the substrate scope of the difluorocarbene insertion into Au(I)-aryl bonds will be investigated. We envision that a variety of aryl and heteroaryl-Au(I) species can undergo the difluorocarbene insertion. Secondly, conditions to couple these synthons with sp2-electrophiles will be screened and optimized. Lastly, the mechanism of the formal difluorocarbene insertion and the stability of the new aryldifluoromethyl-Au(I) species will be investigated through experimental and computational studies. This will assist the development of similar synthons involving cheaper metals such as copper, avoiding use of the precious metal gold.
Message to Sponsor
- Major: Chemistry
- Sponsor: Rose Hills Foundation
- Mentor: Zeng-Rong Wong