A Model for the Rapid Assessment of Solution Structures for 24-Atom Macrocycles: The Impact of β-Branched Amino Acids on Conformation

Authors

• Alexander J. Menke, Texas Christian University
• Camryn J. Gloor, Texas Christian University
• Liam E. Claton, Texas Christian University
• Magy A. Mekhail, Chapman UniversityFollow
• Hongjun Pan, University of North Texas
• Mikaela D. Stewart, Texas Christian University
• Kayla N. Green, Texas Christian University
• Joseph H. Reibenspies, Texas A&M University
• Giovanni M. Pavan, University of Applied Sciences and Arts of Southern Switzerland
• Riccardo Capelli, Université degli Studi di Milano
• Eric E. Simanek, Texas Christian University

Document Type

Article

Publication Date

2-13-2023

Abstract

Experiment and computation are used to develop a model to rapidly predict solution structures of macrocycles sharing the same Murcko framework. These 24-atom triazine macrocycles result from the quantitative dimerization of identical monomers presenting a hydrazine group and an acetal tethered to an amino acid linker. Monomers comprising glycine and the β-branched amino acids threonine, valine, and isoleucine yield macrocycles G-G, T-T, V-V, and I-I, respectively. Elements common to all members of the framework include the efficiency of macrocyclization (quantitative), the solution- and solid-state structures (folded), the site of protonation (opposite the auxiliary dimethylamine group), the geometry of the hydrazone (E), the C2 symmetry of the subunits (conserved), and the rotamer state adopted. In aggregate, the data reveal metrics predictive of the three-dimensional solution structure that derive from the fingerprint region of the 1D ¹H spectrum and a network of rOes from a single resonance. The metrics also afford delineation of more nuanced structural features that allow subpopulations to be identified among the members of the framework. Well-tempered metadynamics provides free energy surfaces and population distributions of these macrocycles. The areas of the free energy surface decrease with increasing steric bulk (G-G > V-V ∼ T-T > I-I). In addition, the surfaces are increasingly isoenergetic with decreasing steric bulk (G-G > V-V ∼ T-T > I-I).

Comments

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in The Journal of Organic Chemistry, volume 88, issue 5, in 2023 following peer review. This article may not exactly replicate the final published version. The definitive publisher-authenticated version is available online at https://doi.org/10.1021/acs.joc.2c01984.

Recommended Citation

Menke, A. J.; Gloor, C. J.; Claton, L. E.; Mekhail, M. A.; Pan, H.; Stewart, M. D.; Green, K. N.; Reibenspies, J. H.; Pavan, G. M.; Capelli, R.; et al. A Model for the Rapid Assessment of Solution Structures for 24-Atom Macrocycles: The Impact of β-Branched Amino Acids on Conformation. The Journal of Organic Chemistry 2023, 88 (5), 2692-2702. https://doi.org/10.1021/acs.joc.2c01984

Copyright

American Chemical Society