Induced folding by chiral nonplanar aromatics

Sri Kamesh Narasimhan, Deborah J. Kerwood, Lei Wu, Jun Li, Rosina Lombardi, Teresa B. Freedman, Yan Yeung Luk

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

(Chemical Equation Presented) We report a structural motif based on a C3-symmetric bowl-shaped core, on which three substituted amino acids on the periphery adopt either a folded or a spread-out conformation. This class of chiral folded structures is achieved by controlling the reactivity of the stereogenic protons on the nonplanar aromatic rings of trioxatricornan to afford predominantly C3-symmetric isomers. Bromination of trioxatricornan afforded a C1-symmetric and a C3-symmetric trisubstituted isomer, with the former being the major product as a statistical consequence during the reaction cascade. To obtain the C3 symmetric isomer as the major product, C-H activation by means of ortho-lithiation with the bulky tert-butyl lithium and tetramethylethylenediamine was followed by a nucleophilic substitution that successfully reversed the statistically controlled regioselectivity. Further derivatization of the trioxatricornan with amino acids or menthol afforded diastereomers that were resolved by preparative chromatography. The absolute configurations of the diastereomers were determined by vibrational circular dichroism (VCD) in combination with density functional theory (DFT) and electronic circular dichroism (ECD). The folding structure of cysteine-derivatized trioxatricornan diastereomers was determined by two-dimensional NMR spectroscopy and molecular dynamics calculation, which revealed that one diastereomer has the amino acids folded toward the cavity of trioxatricornan and the other has a "spread-out" structure.

Original languageEnglish (US)
Pages (from-to)7023-7033
Number of pages11
JournalJournal of Organic Chemistry
Volume74
Issue number18
DOIs
StatePublished - Sep 18 2009

ASJC Scopus subject areas

  • Organic Chemistry

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    Narasimhan, S. K., Kerwood, D. J., Wu, L., Li, J., Lombardi, R., Freedman, T. B., & Luk, Y. Y. (2009). Induced folding by chiral nonplanar aromatics. Journal of Organic Chemistry, 74(18), 7023-7033. https://doi.org/10.1021/jo9013047