Issue 2, 2018

Unequivocal determination of caulamidines A and B: application and validation of new tools in the structure elucidation tool box

Abstract

Ambiguities and errors in the structural assignment of organic molecules hinder both drug discovery and total synthesis efforts. Newly described NMR experimental approaches can provide valuable structural details and a complementary means of structure verification. The caulamidines are trihalogenated alkaloids from a marine bryozoan with an unprecedented structural scaffold. Their unique carbon and nitrogen framework was deduced by conventional NMR methods supplemented by new experiments that define 2-bond heteronuclear connectivities, reveal very long-range connectivity data, or visualize the 35,37Cl isotopic effect on chlorinated carbons. Computer-assisted structural elucidation (CASE) analysis of the spectroscopic data for caulamidine A provided only one viable structural alternative. Anisotropic NMR parameters, specifically residual dipolar coupling and residual chemical shift anisotropy data, were measured for caulamidine A and compared to DFT-calculated values for the proposed structure, the CASE-derived alternative structure, and two energetically feasible stereoisomers. Anisotropy-based NMR experiments provide a global, orthogonal means to verify complex structures free from investigator bias. The anisotropic NMR data were fully consistent with the assigned structure and configuration of caulamidine A. Caulamidine B has the same heterocyclic scaffold as A but a different composition and pattern of halogen substitution. Caulamidines A and B inhibited both wild-type and drug-resistant strains of the malaria parasite Plasmodium falciparum at low micromolar concentrations, yet were nontoxic to human cells.

Graphical abstract: Unequivocal determination of caulamidines A and B: application and validation of new tools in the structure elucidation tool box

Supplementary files

Article information

Article type
Edge Article
Submitted
03 May 2017
Accepted
03 Nov 2017
First published
06 Nov 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2018,9, 307-314

Unequivocal determination of caulamidines A and B: application and validation of new tools in the structure elucidation tool box

D. J. Milanowski, N. Oku, L. K. Cartner, H. R. Bokesch, R. T. Williamson, J. Saurí, Y. Liu, K. A. Blinov, Y. Ding, X. Li, D. Ferreira, L. A. Walker, S. Khan, M. T. Davies-Coleman, J. A. Kelley, J. B. McMahon, G. E. Martin and K. R. Gustafson, Chem. Sci., 2018, 9, 307 DOI: 10.1039/C7SC01996C

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