New Chemoselective Ligation Reactions for Biomolecule Synthesis

The discovery of novel chemoselective reactions for selectively joining two unprotected fragments under mild, physiologically compatible reaction conditions has enabled remarkable progress in the synthesis and study of biological molecules including proteins and carbohydrates. We are contributing to this area through the development of unprecedented organic reactions leading directly to amide bond formation. Recently, we developed the first general method for chemoselective amide bond formation by direct decarboxylative condensations of alpha-ketoacids and N-alkylhydroxylamines.

• Angew. Chem. Int. End. 2006, 45, in press. Link

The wide-spread availability of the starting materials, minimal byproducts, and ability to utilize these reactions under aqueous conditions and in the presence of biologically relevant functional group will enable these methodologies to significantly impact progress in the synthesis of proteins, glycoproteins, biomaterials, and biologically active natural products.

We have extended this remarkable reaction to the iterative synthesis of beta-oligopeptides in water by using a unique set of isoxazolidine substrates. Each coupling leads to the formation of an easily hydrolyzed alpha-keto ester primed for chain extension with another equivalent of isoxazolidine.

• J. Am. Chem. Soc. 2006, 127, in press.