New crown-carrier Cα,α-disubstituted glycines derived from α-methyl-(l)-DOPA

The side-chain catechol function of α-methyl-(l)-DOPA was utilized for the synthesis of a new series of crown-carrier Cα,α-disubstituted glycines. During N-protection of α-methyl-(l)-DOPA methyl ester (H-Mdp-OMe) with Boc anhydride, the formation of N,O-di-Boc derivatives was observed. Selective aminolysis of the catechol tert-butyl carbonate group was achieved using pyrrolidine as nucleophile. Treatment of the resulting Boc-Mdp-OMe by Cs2CO3 in MeOH, followed by bis-O-alkylation with cyclization using various polyethyleneglycol ditosylates or catechol-derived bis-polyethyleneglycol ditosylates in DMF at 60°C, led to the derivatives Boc-[15-C-5]-Mdp-OMe, Boc-[18-C-6]-Mdp-OMe, Boc-[benzo-18-C-6]-Mdp-OMe, Boc-[benzo-24-C-8]-Mdp-OMe and then after saponification, to the corresponding Nα-protected amino acids. The tripeptides Fmoc-Ala-[18-C-6]-Mdp-Ala-OMe and Boc-Aib-[18-C-6]-Mdp-Ala-OMe were prepared in solution by using Ala and Aib UNCAs for coupling at the N terminus of the [18-C-6]-Mdp residue and the EDC/HOAt method for coupling Ala at its C terminus.