Submonomer Solution Synthesis of Hydrazinoazapeptoids, a New Class of Pseudopeptides.

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The development of oligomeric peptidomimetics is actually the focus of increasing attention.1 This arises from the very low bioavailability of peptides, which seriously limited their therapeutical applications. Azapeptides,2 peptoids,3 and ureapeptoids4 belong to a new conceptual class of peptidomimetic in which the side chains are carried by nitrogen atoms. Moreover, the potentiality to automate the synthesis of such oligomers by iterative procedures in the solid phase enables the creation of libraries useful for lead-finding in drug discovery. Our present results come within that general framework. More precisely, we are interested in the synthesis of new kinds of pseudopeptides that we termed hydrazinoazapeptoids by analogy with peptoids. These “hybrid” peptidomimetics combine a C-terminal azaamino acid unit (aza) or an N-substituted azaglycine (Naza) with NRsubstituted hydrazinoglycines (NRh) (Figure 1). Although the chemistry of azaamino derivatives has been widely explored and is well documented,2 that of hydrazino acids has been the object of much less attention.5 Recently, some progress has been made in their preparation, although through laborious methods, in particular concerning the synthesis of optically enriched compounds.6 Nevertheless, only a limited number of side chains seem to be compatible with the chemical methods involved at that time. Moreover, due to the presence of the additional NR, difficulties sometimes occurred during the preparation of hydrazino acids,6b and their utilization in pseudopeptides design for which the coupling with amino acids is not always regioselective.5 This should be the reason why commercially available hydrazinoacids are NR protected.