Catalytic and Stereoselective C-C-Heteroatom Bond Forming Reactions

Strategies to access desirable analogues of natural products and pharmaceuticals in efficient, practical, cost-effective, and stereoselective manners are central to organic synthesis and drug discovery. Total synthesis of such analogues is often lengthy and inefficient, thus increasing the time required to secure the desired molecules, as well as the cost of preparing compounds that are important to human healthcare. Particularly attractive but challenging are schemes that enable direct transformation of ubiquitous but otherwise chemically inert C–H bonds that are contained in the polyfunctional bioactive molecules. We will develop catalytic processes that entail oxidation of amine, ether, or thioether-based small molecule drugs into the corresponding enamine, enol ether or thioenol ether derivatives; such intermediates will then be coupled with various chemical tagging agents to generate – in a single operation – a library of drug derivatives. The resulting compounds will contain ‘clickable’ handles that can be used as a handle for bioconjugation. Some will carry tags for structure-activity relationship studies (e.g., biotin, fluorophore), and/or photoaffinity labels for chemoproteomics (e.g., arylazide, diazirine). Various desirable analogues of N, O, and/or S-based medicinal agents will thus become readily accessible; preparation of these entities by total synthesis would either be impossible or substantially more cumbersome. A combination of Lewis acid and Brønsted base catalysts will be used to promote the proposed transformations. We will utilize the above strategies to design pathways that are significantly more efficient and broadly applicable than those previously disclosed. Among the medicinally relevant molecules that will be subjected to the late-stage functionalization are important anticancer agents such as alectinib, carfilzomib, and venetoclax.