Molecular Specificity of Transition Metal and Lanthanide-Cyclic Depsipeptide Complexes

University Of Tennessee Knoxville, Knoxville TN

Investigators

Abstract

With support from the Chemical Structure and Dynamics (CSD) program in the Division of Chemistry, Professor Thanh D. Do at the University of Tennessee, Knoxville is combining sophisticated gas-phase and condensed-phase experimental approaches with density functional theory calculations to investigate the complexation of cyclic depsipeptides with transition metals and lanthanides, resulting in sandwich-like structures that govern metal selectivity and transport. Cyclic depsipeptides are naturally derived macrocycles featuring N-methylated amides, ester-amide linkages, and ion-binding motifs that enable selective interactions with biological targets. Yet, the structures and reactivities of their metal complexes remain poorly understood, despite their relevance to biological activity. Professor Do and his students will investigate how metal size and coordination geometry influence the formation of these complexes, enabling unusual reactivities such as C–H activation. To achieve this, they will employ ion mobility spectrometry–mass spectrometry (IMS-MS), synchrotron-based X-ray spectroscopy (APS, Chicago), and the Free-Electron Lasers for Infrared experiments (FELIX, Netherlands). Their discoveries could advance the fundamental understanding of metal–ligand recognition and reactivity, enabling the design of new macrocyclic scaffolds for metal separation and catalysis. The project supports broader impacts through interdisciplinary training, outreach to high school students, and internships that foster participation in chemical research. This research investigates how metal complexation alters the conformational preferences and reactivity of cyclic depsipeptides. The research team will use IMS-MS to separate and structurally characterize distinct conformers of metal–ligand complexes, followed by ion activation experiments to explore transitions between low-energy conformers and those with reshaped coordination geometries. Particular emphasis is placed on lanthanide ions, which offer high and tunable coordination numbers, enabling the study of structural selectivity driven by excess donor groups or flexible ligand architectures. These experiments will be complemented by infrared multiple-photon dissociation (IRMPD) spectroscopy, nuclear magnetic resonance (NMR), X-ray crystallography (XRC), and X-ray absorption spectroscopy (XAS), along with density functional theory (DFT) calculations to support structural assignments and mechanistic insight. In addition, the research examines how lanthanide-bound cyclic depsipeptides can induce C–H bond deprotonation and promote reactivity such as enolate formation and aldol condensation. Together, these studies will provide a fundamental understanding of metal-mediated structure and function in macrocyclic ligands. The project will also train students in cutting-edge experimental techniques and computational modeling, preparing them for careers across academia, industry, and national laboratories. 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.