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

Abstract

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, ΔG, 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.