Organic & Biomolecular Chemistry 2014-08-07

Solid phase oxime ligations for the iterative synthesis of polypeptide conjugates.

Isidore E Decostaire, Dominique Lelièvre, Vincent Aucagne, Agnès F Delmas

Index: Org. Biomol. Chem. 12(29) , 5536-43, (2014)

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Abstract

Peptide-based complex biomacromolecules are now optimally assembled by sequential ligation of unprotected peptide segments. However, this approach is still limited by the laborious chromatographic purification and handling steps needed for multiple successive chemoselective couplings, which leads to loss of material. An efficient alternative is solid phase chemical ligation (SPCL) initially developed for native chemical ligation. We report here an extension of this approach to iterative oxime ligation reactions, and describe a streamlined approach for the modular preparation of oxime-containing polypeptides. In particular, we determined optimal conditions to remove the Aloc group in the presence of aminooxy and oxime ether groups, and we extended the applicability of iterative C-to-N SPCL through simplification of the access to a C-terminally-grafted, unprotected peptide segment, using solid supported chemical transformations only. The high purity of the crude oxime-containing polypeptides highlights the efficiency of our approach.