In Silico Modeling of Spirolides and Gymnodimines: Determination of S Configuration at Butenolide Ring Carbon C-4

• Published in: Toxins Vol. 12; no. 11; p. 685
• Main Authors: Zurhelle, Christian, Harder, Tilmann, Tillmann, Urban, Tebben, Jan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 29.10.2020; MDPI AG
• Subjects: gymnodimines; marine biotoxins; shielding tensors; simulated NMR; spirolides; stereochemistry; stereochemistry; gymnodimines; spirolides; simulated NMR; shielding tensors; marine biotoxins
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins12110685

Only few naturally occurring cyclic imines have been fully structurally elucidated or synthesized to date. The configuration at the C-4 carbon plays a pivotal role in the neurotoxicity of many of these metabolites, for example, gymnodomines (GYMs) and spirolides (SPXs). However, the stereochemistry at this position is not accessible by nuclear Overhauser effect-nuclear magnetic resonance spectroscopy (NOE-NMR) due to unconstrained rotation of the single carbon bond between C-4 and C-5. Consequently, the relative configuration of GYMs and SPXs at C-4 and its role in protein binding remains elusive. Here, we determined the stereochemical configuration at carbon C-4 in the butenolide ring of spirolide- and gymnodimine-phycotoxins by comparison of measured C NMR shifts with values obtained in silico using force field, semiempirical and density functional theory methods. This comparison demonstrated that modeled data support configuration at C-4 for all studied SPXs and GYMs, suggesting a biosynthetically conserved relative configuration at carbon C-4 among these toxins.