New Catalytic Methods to Prepare Axially Chiral Compounds

University Of Delaware, Newark DE

Investigators

Abstract

With the support of the Chemical Catalysis Program in the Division of Chemistry, Professor Donald Watson of the University of Delaware is studying a nickel-catalyzed process for the preparation of a class of compounds know as axially chiral biarenes. Such compounds are useful materials with a range of societally relevant applications, for example, as pharmaceutical agents or as modulators for chemical manufacturing processes, but traditional methods for their preparation are limited in scope and/or dependent on the use of precious metal-based catalysts. By contrast, the process of interest is quite versatile and its dependence on nickel, an earth abundant metal, means that the chemistry is more environmentally sustainable. A prominent feature of the process is that it enables the generation of biarenes in which one twisted form of the molecule (analogous to the concept of handedness) predominates over the other. The broader impacts of the award will extend to the benefits accrued to society as Professor Watson and his coworkers engage in a variety of education and outreach activities. Most notably, the Research Experiences for Academic Chemists in Training (REACT) program which is designed to maintain engagement in the physical sciences from students who are initially disadvantaged upon entering college due to poor academic preparation and consequently, of high risk of dropping out. The REACT program is anticipated to be particularly beneficial to students belonging to groups underrepresented in the STEM (science, technology, engineering and mathematics) workforce. The funded project involves further study of the enantioselective Ni-catalyzed reductive aryl halide coupling recently reported by the Watson laboratory and which offers potential gains in efficacy and scope over established procedures for the synthesis of non-racemic axially chiral biarenes. The investigation is divided across three objectives designed to allow for development of the method while more fully realizing its synthetic potential. The first objective is focused on extending the homocoupling process to substrates not previously explored to target binaphthyl and biphenyl systems from a range of ortho-halo- (typically bromo-) substituted arenes including aryl phosphines/phosphine oxides, esters, amines, and thioethers. The second objective involves pursuit of an intramolecular variant of the method to achieve enantioselective reductive cyclizations of suitably tethered bis(haloarenes) and leading to both C2-symmetric and non-symmetric polycyclic biaryls. The latter include examples of MOP and PHOX type systems which may be useful in their own right as tunable chiral ligand frameworks. The final and most ambitious objective is directed at the realization of a highly enantioselective cross-coupling between two distinct aryl halide substrates. Here, the necessary conditions to avoid competing homocoupling events will be identified to allow for the potential emergence of a general platform for the preparation of biaryls with broad applicability. The High Throughput Experimentation (HTE) laboratory at the University of Delaware will be used extensively during the course of the outlined studies to facilitate the rational screening campaigns needed to evaluate and optimize factors such as ligand structure, additive and solvent effects, temperature, and other reaction variables. The findings of this work are anticipated to lead to fundamental advances impactful to the practice of biaryl synthesis and to the wider field of enantioselective catalysis. 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.