Synthesis and binding properties of a macrobicyclic receptor for N-protected peptides with a carboxylic acid terminus

Henley, P. D., Waymark, C. P., Gillies, I. and Kilburn, J. D. (2000) Synthesis and binding properties of a macrobicyclic receptor for N-protected peptides with a carboxylic acid terminus. Journal of the Chemical Society, Perkin Transactions 1, (6), 1021-1031. (doi:10.1039/a908090b).

Abstract

A novel macrobicyclic receptor, 3, has been synthesised by linking together a diaminopyridine with suitable amino acids, followed by a double intramolecular cyclisation of a suitably activated precursor. Macrobicycle 3 features a diamidopyridine unit, designed to serve as a specific binding site for carboxylic acid functionality, at the base of an open, bowl-shaped cavity. Incorporation of additional amide functionality around the rim of the bowl-shaped structure provides further hydrogen bonding sites to interact with peptidic guests. The binding properties of 3 with N-protected amino acid and peptide derivatives have been investigated by NMR titration experiments, which reveal that 3 is a strong and selective receptor for peptides with a carboxylic acid terminus in CDCl3 solution, the strongest binding being observed with Cbz-beta-alanyl-D-alanine (-Delta G(ass)=22.8 kJ mol(-1)). The macrobicycle is reasonably enantioselective (Cbz-beta-alanyl-L-alanine, -Delta G(ass)=19.1 kJ mol(-1)) and notably the binding of Cbz-beta-alanyl lactic acids is considerably weaker than the binding of the corresponding Cbz-beta-alanyl alanines (Delta Delta G(ass)similar to 8-9 kJ mol(-1)). Molecular modelling and 2D NMR studies have been carried out on the free macrobicycle and the 1:1 complex formed with the most strongly bound substrate (Cbz-beta-alanyl-D-alanine). These studies provide a consistent picture of the macrobicycle as a flexible receptor, which is able to bind the Cbz-beta-alanyl-D-alanine substrate in the macrobicyclic cavity with a series of well defined hydrogen bonds to the alanylalanine amide, and less well defined hydrogen bonds to the benzylcarbamate functionality.

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