Dynamic covalent strategies for the remote c-h functionalization of alkaloids - title: dynamic covalent strategies for the remote c-h functionalization of alkaloids PI: michael young…

The National Institute of General Medical Sciences awarded $380,870 to the University of Toledo on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop dynamic covalent strategies for remote C-H functionalization of alkaloids.

The project, led by Principal Investigator Michael Young, aims to create a new family of trityl-based transient directing groups designed to enable remote and transannular C-H functionalization of amine substrates, including cyclic and polycyclic frameworks, through radical and organometallic pathways. The work addresses two core objectives: developing new C-H functionalization reactions leveraging photoredox or palladium mechanisms in conjunction with transient directing groups for C(sp³)-H activation at remote positions, and applying these reactions to create novel opioid analogs tested for biased agonism and receptor subtype selectivity. The research targets scaffolds such as morphinanes and lysergamides to provide new access points for semi-synthesis of complex alkaloids and medicinally relevant compounds. The effort responds to a substantial challenge in late-stage C-H functionalization of amine-containing compounds, which comprise over 40 percent of active pharmaceutical ingredients.

Performance occurs at the University of Toledo campus in Ottawa Hills, Ohio, with a period of performance running from September 1, 2026, through April 30, 2031. The assistance type is a Project Grant.

Dynamic covalent strategies for the remote c-h functionalization of alkaloids - title: dynamic covalent strategies for the remote c-h functionalization of alkaloids PI: michael young amine-containing compounds comprise over 40% of active pharmaceutical ingredients (apis), with many alkaloids derived from natural products either directly or through semi-synthesis. Despite humanity's reliance on natural product-derived therapeutics, late-stage c-h functionalization of these motifs remains a substantial challenge. Existing approaches are typically limited to proximal c-h bonds to directing groups, resulting in limited opportunities for diversification. This proposal aims to develop a new family of trityl-based transient directing groups (tdgs) designed to enable remote and transannular c-h functionalization of amine substrates, including cyclic and polycyclic frameworks, through radical and organometallic pathways. Our central hypothesis is that tunable electron density and conformational bias introduced by trityl-derived tdgs can facilitate regioselective activation of otherwise inaccessible positions. These transformations will be used to derivatize scaffolds such as morphinanes and lysergamides, providing new access points for the semi-synthesis of complex alkaloids and medicinally relevant compounds. This effort will address two core objectives: (1) develop new c-h functionalization reactions that leverage photoredox or PD(0)/PD(i) mechanisms in conjunction with tdgs for c(SP3)-h activation at remote positions; and (2) apply these reactions to create novel opioid analogs that will be tested for biased agonism and receptor subtype selectivity. Success will advance both synthetic methodology and medicinal chemistry, positioning this work to provide foundational tools for the broader community and seed follow-up drug development pipelines. The results will inform future campaigns focused on late-stage derivatization of alkaloids, natural products, and feedstock amines, and ultimately aim to enable the rapid exploration of structure-activity relationships (sars) for therapeutics targeting the opioid crisis and beyond.