Macrocycles All Aflutter: Substitution at an Allylic Center Reveals the Conformational Dynamics of [13]-Macrodilactones

Kelli M. Rutledge, Trevor A. Hamlin, Donna M. Baldisseri, F. Matthias Bickelhaupt*, Mark W. Peczuh

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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The shapes adopted by large-ring macrocyclic compounds play a role in their reactivity and their ability to be bound by biomolecules. We investigated the synthesis, conformational analysis, and properties of a specific family of [13]-macrodilactones as models of natural-product macrocycles. The features of our macrodilactones enabled us to study the relationship between stereogenic centers and planar chirality through the modular synthesis of new members of this family of macrocycles. Here we report on insights gained from a new [13]-macrodilactone that is substituted at a position adjacent to the alkene in the molecule. Analysis of the compound, in comparison to an α-substituted regioisomer, by using X-ray crystallography, NMR coupling constants, and reaction-product characterization in concert with computational chemistry, revealed that the alkene unit is dynamic. That is, the data support a model in which the alkene in our [13]-macrodilactones oscillates between two conformations. A difference in reactivity of one conformation compared to the other leads to manifestation of this dynamic behavior. The results underscore the local conformational dynamics observed in some natural-product macrocycles, which could have implications for biomolecule binding.

Original languageEnglish
Pages (from-to)2623-2633
Number of pages11
JournalChemistry - An Asian Journal
Issue number19
Early online date7 Aug 2017
Publication statusPublished - 5 Oct 2017


M.W.P. and K.M.R. thank Katie McGeough, Chengsheng Chen, and Anniefer Magpusao for the initial synthesis of compound 6. Anniefer Magpusao and Brandon Q. Mercado at the Yale CBIC are acknowledged for the X-ray crystallography study of compound 7. The NSF partially supported this work through a grant to M.W.P. (CHE-0957626). F.M.B. and T.A.H. thank the Netherlands Organization for Scientific Research (NWO) for financial support through the Planetary and Exo-Planetary Science program (PEPSci) and the Dutch Astrochemistry Network (DAN).

FundersFunder number
Dutch Astrochemistry Network
Planetary and Exo-Planetary Science program
National Science FoundationCHE-0957626
Nederlandse Organisatie voor Wetenschappelijk Onderzoek


    • activation strain model
    • conformation analysis
    • density functional calculations
    • macrocycles


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