Oxazoline amino acid bioconjugates: one-pot synthesis and analysis of supramolecular interactions

This publication describes oxazoline-amino acid bioconjugates 1 capable of supramolecular interactions. The bioconjugates contain three main building blocks: an oxazoline ring, a central aromatic unit and an amino acid substituent. Benzene, naphthalene or anthracene with several substitution motifs was used as the central aromatic unit. Two synthetic pathways to β-amino alcohol precursors 3 - 5 are presented; one-pot synthesis with various coupling reagents is compared to linearly sequenced synthesis using protecting groups. In the final step, a cyclization of precursors 3 - 5 to oxazolines 1 is described. Single crystal X-ray diffraction of seven oxazoline bioconjugates is reported ( 1 p , 1 m6 , 1 n2 , 1 n4 , 1 n5 , 1 a and 1 t4 ), with an emphasis on supramolecular interactions in the solid state. The capability of bioconjugates 1 to participate in supramolecular interactions in solution was screened by NMR and CD spectroscopy, varying concentrations, temperatures and solvents. The results obtained by crystallography and spectroscopy were further corroborated by computational results for most interesting bioconjugate 1 t1 . Computational analysis was performed using a CREST/CENSO protocol. In particular, the free energy of formation, Δ G , as well as mean absolute error (MAE) values and correlations of experimental and GIAO calculated NMR parameters have been compared for 1 t1 DFT models of monomers and dimers. These results revealed that for 1 t1 , the supramolecular dimer ensembles are more stable than monomer ensembles. Oxazoline amino acid bioconjugates were synthesized; the relative stability of a supramolecular dimer of a tris-derivative was investigated using mean absolute error values (MAE), derived from 1 H NMR experiments and DFT calculations.