Attached-Ring Cross-Coupling to Explore Chemical Space and Receptor Selectivity

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With the support of the Chemical Synthesis program in the Division of Chemistry, Professor Ryan Shenvi of The Scripps Research Institute is studying a series of unusual processes that will facilitate the chemical synthesis of bioactive substances of possible utility in chemical biology and medicinal chemistry. Specifically, the work will focus on the preparation of derivatives of psychoactive agents that were originally discovered in the bark of rainforest trees belonging to the genus Galbulimima. The methods being developed for this purpose are based on the use of non-precious metal-containing reagents and they are anticipated to enable not only concise syntheses of Galbulimima alkaloid derivatives, but also other complex target molecules that likewise contain so-called 'attached-ring' motifs. The prepared compounds will be evaluated for biological activity, specifically opioid receptor antagonism. The broader impacts of the funded project will extend to the benefits accrued to society as the PI and other members of the Shenvi research group engage in a broad range of educational and outreach activities involving students from elementary school through college level, both within the US and beyond its borders. A significant portion of these efforts focus on individuals belonging to groups traditionally underrepresented in STEM (science, technology, engineering and mathematics) fields.Modular syntheses of sp2–sp2 attached-rings, such as those found in biaryl systems, can be readily accomplished via transition metal-mediated cross-coupling. By contrast, the attachment of cyclic substructures by sp2–sp3 and sp3–sp3 bond linkages remains a challenge. The synthesis of tetrahedral equivalents of biaryls is complicated by increased steric encumbrance about the bond linking the two rings, the need to navigate point-chiral stereoselectivity issues and, occasionally, chemical instability. As a consequence, attached rings embedded within natural product scaffolds are typically synthesized indirectly: by initial generation of the adjoining bond and then a cyclization event to form the desired new ring. The Shenvi group recently identified an attached-ring Galbulimima alkaloid that potently, yet non-selectively, antagonizes two receptors involved in psychotropic activity in humans. A ligand-controlled cross-electrophile coupling process co-mediated by Ni and Mn was discovered that offers a means to install the attached ring with the necessary contrasteric (endo face) diastereoselectivity. This curious process may offer a general approach for the installation of attached rings, but it is currently poorly understood, and especially with regard to the origin of stereoselectivity. The objectives of the funded project are two-fold. First, the unusual ligand-controlled stereo-invertive attached-ring cross-coupling that positions one fragment onto the hindered, endo-face of its partner, will be optimized and its scope explored. It is anticipated that the Galbulimima alkaloid analogues generated during the course of these studies will show different selectivity profiles between two target opioid receptors and across their larger protein superfamily. Second, the findings made will be extended to a generalized model of ligand-controlled cross-coupling that will fill a significant gap in methods to synthesize natural product-like attached-ring systems. Molecules containing such motifs have been hitherto little investigated and useful new fundamental knowledge is anticipated to emerge from this endeavor.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.