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Non‐racemic atropisomeric (thio)ureas as neutral enantioselective anion receptors for amino‐acid derivatives: Origin of smaller K ass with thiourea than urea derivatives
Author(s) -
Roussel Christian,
Roman Mihaela,
Andreoli Federico,
Rio Alberto Del,
Faure Robert,
Vanthuyne Nicolas
Publication year - 2006
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20320
Subject(s) - thiourea , chemistry , thio , hydrogen bond , intramolecular force , urea , bifunctional , chirality (physics) , medicinal chemistry , enantiomer , enantioselective synthesis , proton nmr , stereochemistry , organic chemistry , molecule , catalysis , nambu–jona lasinio model , chiral symmetry breaking , physics , quantum mechanics , quark
The synthesis of a limited series of non‐racemic atropisomeric 1‐(2‐(4‐methyl‐2‐thioxothiazol‐3( 2H )‐yl)phenyl)‐3‐(hetero)aryl‐(thio)ureas is described. Using NMR titration experiments monitoring the shift of the two NH of the (thio)urea and the C‐5 hydrogen of the heterocycle, the binding constants for some optically pure (thio)‐ureas with the enantiomers of N‐protected amino acid tetrabutylammonium salts were determined in CD 3 CN. The obtained enantioselectivities were modest. Contrary to what was expected on the basis of the NH acidity in thiourea versus urea group, the association constants were smaller with the thiourea than with the corresponding urea. X‐ray data, DFT calculations, and NMR provided the explanation of that unexpected behavior: the urea presents a pre‐organized ( Z , Z ) conformation suitable for a double hydrogen bond with the carboxylate anion, the thiourea presents a ( Z , E ) conformation, which must be reorganized in a constrained ( Z , Z ) conformation in the complex. An intramolecular hydrogen bond between one NH and the thiocarbonyl group of the heterocycle, which is present in the thiourea and absent in the urea, might also contribute to the smaller K ass for the thiourea. The possible implication of these observations in the field of bifunctional organocatalysis is briefly discussed. Chirality, 2006. © 2006 Wiley‐Liss, Inc.