Isocyanides peptide-based

The peptide-based isocyanides 50a-e were successfully polymerized by Ni(II) catalysts under an inert atmosphere [63-66]. An alanine-derived isocyanide, whose isocyano group was labeled using 13C and 15N, was prepared and successfully polymerized for structure elucidation [67]. Several solvent systems were used in the polymerization of the peptide-based isocyanides, depending upon the solubility of the isocyanides. As mentioned earlier, the use of alcohols as a solvent or co-solvent can accelerate the polymerization. The protective groups on the ester, hydroxy, and imidazole groups were removed after polymerization by treatment with aqueous NaOH to yield poly(isocyanide)s bearing unprotected peptide side chains. 

Isocyanide polymerization has also been used to polymerize peptide-based monomers. Cornelissen et al. [31,32] prepared oligopeptides based on alanine and functionalized the N-terminus with an isocyanide moiety. These monomers were subsequently polymerized using a Ni catalyst into /3-helical poly isocyanopeptides with the dipeptides in the side chain. It was found that these polymers formed rigid rods, which were revealed by AFM to have extremely long persistence lengths. This rigidity was caused by the formation of /5-sheets between the alanines in the side chain. The same group... 

Piperazines and derivatives are archaetypical scaffolds and can be considered as efficient, however, structurally simple peptidomimics. The scaffolds combine conformational rigidity with peptide-like spacial placement of amino acid side chains or isosteres thereof. Moreover, piperazines can be used to confine compounds with beneficial properties such as water solubihty. Piperazines are therefore in the center of synthetic interest and many different synthetic pathways have been designed [16-19]. A preferred way to synthesize different piperazine scaffolds with plenty of variabihty provides MCR chemistry. Several piperazine scaffolds are currently only accessible by isocyanide-based MCR. Likely they could be assembled by sequential synthesis as well however, the synthetic efficiency, the diversity, and the size of the alternative chemical space will be inferior. The application of... 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

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