Corralling Peptides

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Science  19 Mar 2010:
Vol. 327, Issue 5972, pp. 1430
DOI: 10.1126/science.327.5972.1430-b

There's an inherent entropic challenge in preparing cyclic molecules from linear precursors, because the two ends must be coaxed together before they can form a bond. In zwitterionic peptides, the negative carboxylate and positive ammonium groups at either end attract one another electrostatically, and so, in principle, favor a conformation poised to close the loop. Unfortunately, traditional coupling agents used to facilitate formation of the amide bond eliminate the charged motifs, and with them the convenient conformational biasing. Hili et al. present an alternative coupling scheme that conserves the zwitterionic attraction. Instead of forming amide linkages directly, they interpose an aziridine-bound aldehyde and an isocyanide. In the ensuing reaction, the isocyanide bridges the negative carboxylate at one end of the peptide strand and a positive iminium (formed by amine attack on the aldehyde) at the other end. The reaction tolerates the full range of natural amino acids, with no observed disruption of chirality. Cycles comprising one to five amino acids, in addition to the aziridine coupling unit, were isolated in good yield after simple precipitation, and the aziridine's reactivity allows for further functionalization of the ring perimeter.

J. Am. Chem. Soc. 132, 2889 (2010).

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