Synthesis and binding properties of a macrocyclic peptide receptor

Macrocyclic receptor 1 has been synthesised, as a racemate and as a single enantiomer, utilising a Stifle coupling for the formation of the biphenyl p ortion and a macrolactamisation as the final step. The binding properties f or the racemic and the homochiral macrocycle with amino acid and dipeptide derivatives, in CDCl3 solution, have been investigated. In the case of race mic 1, addition of homochiral peptide substrates led to two distinct diaste reomeric complexes, and the well separated signals for several protons in t he H-1 NMR spectrum could be conveniently followed in titration experiments , allowing determination of both binding constants for the two diastereoiso meric complexes, and indicating that 1 is capable of enantioselective recog nition. Titration of homochiral 1 with the same peptide substrates allowed the sense of the enantioselectivity to be determined, and experiments with a greater range of substrates indicated that 1 is particularly effective fo r the recognition of N-Cbz-beta-alanyl-L-amino acids, the strongest binding being observed with N-Cbz-beta-alanyI-L-alanine (- Delta G(ass) = 19.9 kd mol(-1)). Notably the binding of N-Cbz-beta-alanyl-L-lactic acid was consid erably weaker (- Delta G(ass) = 13.1 kJ mol(-1)), presumably due to replace ment of an NH hydrogen-bond donor in the case of N-Cbz-beta-alanyl-L-alanin e with an oxygen lone-pair in the case of N-Cbz-beta-alanyl-L-lactic acid. Molecular modelling and 2D NMR studies on the free macrocycle 1 and associa ted complexes did not provide conclusive evidence for the structure of the host-guest complexes, but did serve to emphasise the flexibility of 1, whic h despite this flexibility, shows strong, selective binding of certain pept ide guests.