Synthesis of 'head-to-tail' cyclized peptides on solid support using a chelating amide as new orthogonal protecting...

The synthesis of 'head-to-tail' cyclized peptides requires orthogonal protecting groups. Herein, we report on the introduction of bis(2-pyridylmethyl)amine (Bpa) as a new protecting group for carboxylic functions in SPPS. The synthesis of the Bpa-protected aspartic acid was straightforward, and its utility was investigated under standard peptide synthesis conditions. The new protecting group was cleaved in a very mild way using Cu(OAc)2 and 2-(trimethylsilyl)ethanol as nucleophile in a microwave oven without affecting other groups. Hence, the new group is ideally suited for the synthesis of 'head-to-tail' cyclic peptides, as demonstrated for a cyclic pentapeptide and cyclic hexapeptides.