Synthesis of differentially protected N-acylated reduced pseudodipeptides as building units for backbone cyclic peptides

Backbone cyclization has become an important method for generating or stabi lizing the bioactive conformation of peptides without affecting the amino a cid side-chains. Up to now, backbone cyclic peptides were mostly synthesize d with bridges between N-amino- and N-carboxy-functionalized peptide bonds, To study the influence of a more flexible backbone on the biological activ ity, we have developed a new type of backbone cyclization which is achieved via the N-functionalized moieties of acylated reduced peptide bonds. As de scribed in our previous publications, the formation of N-functionalized dip eptide units facilitates the peptide assembly compared with the incorporati on of N-alkyl amino acids. Besides the racemization-free synthesis of Fmoc- protected pseudodipeptide esters with reduced peptide bonds, the new type o f backbone modification allows the use of a great variety of omega-amino- a nd alpha,omega-dicarboxylic acids differing in chain length and chemical pr operties. Best results for the coupling of the omega-amino- and alpha,omega -dicarboxylic acids to the reduced peptide bond were obtained by the format ion of mixed anhydrides with alkyl chloroformates. Whereas the protecting g roup combination of Z/OBzl in the dipeptide unit and Boc/OtBu for the N-fun ctionalized moiety leads to the formation of 2-ketopiperazine during hydrog enation, the combination of Fmoc/ OtBu and Alloc/OAll is very suitable for the synthesis of backbone cyclic peptides on solid support. Copyright (C) 2 000 European Peptide Society and John Wiley & Sons, Ltd.