The development of milder and more efficient methods towards complex molecule construction is a vibrant area of research within organic synthesis. In particular, certain structural motifs have achieved a privileged status within organi chemistry, due to their seemingly ubiquitous presence in bioactive molecules. For example, the benzylic carbon stereocenter is a common motif found in medicinal agents, agrochemicals, and natural product isolates. The substitution and functionality provided on the carbon framework can profoundly alter cell membrane permeability, half-life time of the molecule in a biological environment, and potency of a drug within the human body. Thus, the generation of a broad catalytic platform for this motif would be highly desirable. Recent advances in copper(I) hydride chemistry have demonstrated the potential of this catalytic platform for producing diastereoenriched and enantioenriched molecules under mild conditions with inexpensive sources of copper and silane. Still, significant advances could be achieved with this chemistry towards other asymmetric methodologies.
Two specific aims outlined in this proposal detail two transformations that are catalyzed through reductive copper catalysis: enantioselective hydroarylation and enantioselective benzylic alkylation. The starting material proposed is styrene, a class of molecules produced on a millions of tons scale each year, and a variety of commercially available or easy-to-produce electrophilic sources. Lastly, mechanistic investigations will be pursued to isolate any competent intermediates in the catalytic cycle, identify the presence of any Cu(II)/Cu(III) or radical intermediates, and to develop a stereochemical model. Computational, kinetic, and spectroscopic investigations will, in turn, be applied to second-generation ligand framework synthesis and the expansion of this asymmetric methodology to other classes of olefins.

Public Health Relevance

The development of chemical technologies that enable the synthesis of drug candidates is of extreme importance in modern society. Molecules containing benzylic carbon stereocenters, such as 1,1-diarylalkanes, have been found to hold a range of biological properties, yet are still challenging to manufacture in a simple and economical manner. The proposed research details an asymmetric platform that would provide access to these molecular architectures through a mild and relatively facile process.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04A-W (20)L)
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Lees, Robert G
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Friis, Stig D; Pirnot, Michael T; Dupuis, Lauren N et al. (2017) A Dual Palladium and Copper Hydride Catalyzed Approach for Alkyl-Aryl Cross-Coupling of Aryl Halides and Olefins. Angew Chem Int Ed Engl 56:7242-7246
Gribble Jr, Michael W; Pirnot, Michael T; Bandar, Jeffrey S et al. (2017) Asymmetric Copper Hydride-Catalyzed Markovnikov Hydrosilylation of Vinylarenes and Vinyl Heterocycles. J Am Chem Soc 139:2192-2195
Pirnot, Michael T; Wang, Yi-Ming; Buchwald, Stephen L (2016) Copper Hydride Catalyzed Hydroamination of Alkenes and Alkynes. Angew Chem Int Ed Engl 55:48-57
Corcoran, Emily B; Pirnot, Michael T; Lin, Shishi et al. (2016) Aryl amination using ligand-free Ni(II) salts and photoredox catalysis. Science 353:279-83
Friis, Stig D; Pirnot, Michael T; Buchwald, Stephen L (2016) Asymmetric Hydroarylation of Vinylarenes Using a Synergistic Combination of CuH and Pd Catalysis. J Am Chem Soc 138:8372-5
Bandar, Jeffrey S; Pirnot, Michael T; Buchwald, Stephen L (2015) Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins. J Am Chem Soc 137:14812-8