Mets7 motif peptides in coordinative Cu(I) complexes: application in asymmetric Henry reaction

The development of a hybrid catalyst involves the synergic combination of a biomacromolecular scaffold such as a protein and an active catalytic moiety such as a transition metal complex. 1,2 With respect to the use of modified protein frames, the use of small peptides able to bind transition metals is much more convenient because of the easiness of their synthesis if compared to protein expression. Human Ctr-1 (hCtr-1) is a glycosylated membrane protein of 190 amino acids belonging to the highly conserved family of copper transporters. Mimicking the Met-rich motif in the N-terminal domain of yeast yCtr1, a 8-mer sequence (MTGMKGMS), called Mets7, particularly prone to binding Cu(I) and Pt(II) drug complexes was synthesized. 3 By modifying the Mets7 sequence in methionines’ number and position different peptides were prepared by solid phase synthesis using the Fmoc strategy. 4 Furthermore, the synthesis of peptide mimetic S1 containing the unnatural scaffold X was also planned with the idea of stabilizing the turn conformation of the peptide in solution. To support this hypothesis, REMD calculations were performed to compare the conformational behavior of metal-free Mets7 and S1. 5 The catalytic performance of such peptide–Cu(I)-complexes was thus investigated in the asymmetric nitro-aldol Henry condensation under green conditions. In all cases the reaction was found effective, especially using Mets7 and S1 complexes affording the S isomer of the product with moderate enantioselectivity in the condensation reaction of 4-NO2-benzaldehyde whereas starting from benzaldehyde the reaction led to the opposite enantiomer in good 75% e.e., an unprecedented result with such a catalytic system. 6