Induced folding by chiral nonplanar aromatics.
We report a structural motif based on a C(3)-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 C(3)-symmetric isomers. Bromination of trioxatricornan afforded a C(1)-symmetric and a C(3)-symmetric trisubstituted isomer, with the former being the major product as a statistical consequence during the reaction cascade. To obtain the C(3) 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.
Narasimhan
Sri Kamesh
SK
Department of Chemistry, Syracuse University, Syracuse, New York 13244, USA.
Kerwood
Deborah J
DJ
Wu
Lei
L
Li
Jun
J
Han
Yongbin
Y
Zhu
Shifa
S
Shah
Akshay
A
Lombardi
Rosina
R
Freedman
Teresa B
TB
Luk
Yan-Yeung
YY
D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry*; D002244:Carbon / Q000737:chemistry; D002845:Chromatography; D002942:Circular Dichroism; D003545:Cysteine / Q000737:chemistry; D005029:Ethylenediamines / Q000737:chemistry; D054879:Halogenation; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry; D008094:Lithium / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008610:Menthol / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry; D017510:Protein Folding; D011789:Quantum Theory; D013237:Stereoisomerism
D000596:Amino Acids; D005029:Ethylenediamines; D006841:Hydrocarbons, Aromatic; D009942:Organometallic Compounds; C005798:N,N,N',N'-tetramethylethylenediamine; D008610:Menthol; D002244:Carbon; D006859:Hydrogen; D008094:Lithium; D003545:Cysteine