Novel Strategies in the Field of Synthetic Chemistry to Forge Carbon-Carbon Bonds and Identify Novel Bioconjugation Reagents
Patricia Zhang, Ph.D.
Department of Chemistry
University of California, Berkeley
CBC Faculty Candidate
The ability of photoredox catalysts to move electrons from one reaction intermediate to another via single-electron transfer (SET) events allows for access to non-traditional, and otherwise elusive, reactivity platforms of organic substrates and transition metal catalysts. On this basis, we recently strived to develop a cross-electrophile coupling between alkyl and aryl halides for a mild Csp3–Csp2 bond formation. Realization of this idea would streamline Csp3-Csp2 coupling, and allow for expedient generation of complexity from simple building blocks as well as address the pharmaceutical need for more Csp3 centers to come out of “the flatlands” (Csp2-Csp2). In specific, we hypothesized a photocatalytic generation of a silyl radical intermediate could activate a wide number of commercially available alkyl halides under mild conditions. Previous strategies for accomplishing this reductive coupling have utilized stoichiometric metal reductants, which can be harshly reducing and difficult to purify away from the products. The implementation of metallaphotoredox towards this goal has resulted in a mild, user-friendly cross-electrophile coupling that negates the need for moisture-sensitive reagents and prior preparation of traditional nucleophile partners (i.e. Grignards, boronic acids, organozinc and organotin). A vast substrate scope for this photoredox reaction has led to the widespread implementation of this technology in several medicinal chemistry programs including Merck & Co., Inc., Genetech, Bristol-Meyers-Squibb, Johnson & Johnson, Pfizer, Bayer, and Mercachem. Discovery of the photocatalytic conditions to generating a silyl radical for carbon-halide bond activation has led to a new area of research in the MacMillan group, with several other working projects deriving from the initial discovery. Specifically, we recognized the silyl radical cross-electrophile coupling had beneficial ramifications for radiolabeling with the discovery that methyl tosylate successfully couples in our standard protocol with aryl bromides, leading to the first cross-coupling protocol demonstrating generality for installing [3H]methylation (CT3) into pharmaceutical compounds. We have successfully tritiated top-selling pharmaceuticals including Celebrex, Lidoderm, and Skelaxin. Additionally, findings of a silanol byproduct laid the groundwork for the development of a method that abstracts halogens from aryl halides to generate aryl radicals. This work has been combined with copper catalysis to enable trifluoromethylation of heteroarenes with a broad scope.
Lastly, studies in the development of new small molecule reagents for labeling rare amino acids are discussed. A novel oxaziridine reagent is optimized for methionine modification in cells and for use in proteomics, revealing new anti-cancer targets in the proteome. The discovery of aminal reagents for tryptophan and histidine modification has been demonstrated to be selective on a protein and has the possibility for proteomic work as well.