The work described in this proposal aims to address two longstanding challenges associated with catalytic radical cations chemistry. First, we demonstrate that the absolute stereochemistry of radical cations reactions can be controlled using chiral counterions that remain electrostatically associated with the positively charged intermediates during the selectivity determining steps of a catalytic cycle. Specifically, various amine radical cations can be reversibly generated through selective electron transfer events with the excited state of a visible light photoredox catalyst. The resulting amine radical cations form highly stabilizing ionic hydrogen bond complexes with chiral phosphate anions, which are too weakly basic to result in N-H deprotonation. Additional non-covalent interactions within these ion pairs can energetically differentiate the competing diastereomeric transition states providing a basis for asymmetric induction. These findings present a novel manifold for carrying out radical cation chemistries ? both new and classical ? in a catalytic asymmetric fashion. Second, we propose to develop a new catalytic strategy for accessing reactive carbocation electrophiles under neutral conditions based on the mesolytic cleavage reactions of radical cations derived from TEMPO ethers. In these reactions the nitrogen lone pair of a TEMPO ether substrate is oxidized by the excited state of a visible light photoredox catalyst removes to furnish a transient radical cation. This oxidation event considerably weakens the strength of the adjacent C-O bond, resulting in facile mesolytic bond cleavage to furnish TEMPO radical and a new carbocation intermediate. We demonstrate that these cations can be engaged by a wide range of nucleophilic partners, and present evidence that chiral counterions can be used to control stereoselectivity in the these bond-forming events. These methods provide unprecedented access to reactive carbenium ion intermediates in a catalytic manifold, and present a pathway to extend the use of cation intermediates in more complex settings than can be accommodated using classical approaches. Taken together, these technologies and their applications in proposed Specific Aims have the potential to simplify and improve the synthesis of drugs and other small-molecule probes of biological function, creating a significant benefit for human health and the associated biomedical sciences.
In this proposal, we demonstrate that reactions of radical cation intermediates can be rendered enantioselective through ion-pairing interactions with chiral counterions and describe a new catalytic protocol for generating unstabilized carbocations under neutral conditions. This work provides a solution to a significant and long-standing gap in the synthetic literature and provides a basis for the development of novel methods to enable the construction of both complex targets and common pharmacophores. The reactions and processes enabled by these technologies will provide new tools to simplify the discovery, design and manufacture of drugs and other small molecule probes of biological function, creating a significant benefit for human health and the associated biomedical sciences.
| Gentry, Emily C; Rono, Lydia J; Hale, Martina E et al. (2018) Enantioselective Synthesis of Pyrroloindolines via Noncovalent Stabilization of Indole Radical Cations and Applications to the Synthesis of Alkaloid Natural Products. J Am Chem Soc 140:3394-3402 |
| Musacchio, Andrew J; Lainhart, Brendan C; Zhang, Xin et al. (2017) Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines. Science 355:727-730 |
| Zhu, Qilei; Gentry, Emily C; Knowles, Robert R (2016) Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage of Alkoxyamine Radical Cations. Angew Chem Int Ed Engl 55:9969-73 |
| Musacchio, Andrew J; Nguyen, Lucas Q; Beard, G Hudson et al. (2014) Catalytic olefin hydroamination with aminium radical cations: a photoredox method for direct C-N bond formation. J Am Chem Soc 136:12217-20 |
