Objective: The goal of the proposed research is to develop a comprehensive method for the direct coupling of unprotected molecules via a new chemoselective amidation reaction. The basis for this project is the reagent-less reaction of alpha-ketoacids and N-alkylhydroxylamines to give amides via decarboxylation and dehydration. These studies will provide new methods for the synthesis of biomolecule targets including proteins, glycopeptides, and peptidomimetics.
Specific Aims : (1) To investigate the substrate scope, limitations, and mechanism of the ketoacid-hydroxylamine (KAMA) ligation and explore peptide ligations at various amino acid pairs, reaction conditions, and fragment sizes. Further efforts will apply this process to new approaches for the synthesis of large peptides. (2) To advance new chemistries for the practical synthesis of fragments containing the requisite functional groups, namely C-terminal alpha-ketoacids and N-terminal hydroxylamines. The ketoacids are prepared by a mild two step protocol based on a new solid phase linker. For the synthesis of hydroxylamines, practical approaches to the preparation of monomers that can be easily introduced into a synthetic peptide or carbohydrate will be identified. (3) To develop a new approach to the iterative synthesis of poly-beta-peptides without coupling reagents or protecting groups. This unique approach to polypeptide synthesis will be expanded by synthesizing new monomers suitable for the synthesis of new peptidomimetics. The design of a suitable solid support will enable direct application of this process to longer poly-beta-peptides of biological significance. Significance. The proposed research will provide a new chemical tool for the direct synthesis of amides under physiologically compatible reaction conditions. It will significantly impact the synthesis of complex biomolecules including proteins, glycoproteins, peptidomimetics, and biocompatible materials.
|Ju, Lei; Bode, Jeffrey W; Toma, Tatsuya et al. (2010) AMIDE FORMATION BY DECARBOXYLATIVE CONDENSATION OF HYDROXYLAMINES AND ?-KETOACIDS: N-[(1S)-1 PHENYLETHYL]-BENZENEACETAMIDE. Organic Synth 87:218-225|
|Medina, S Irene; Wu, Jian; Bode, Jeffrey W (2010) Nitrone protecting groups for enantiopure N-hydroxyamino acids: synthesis of N-terminal peptide hydroxylamines for chemoselective ligations. Org Biomol Chem 8:3405-17|
|Flores, Melissa A; Bode, Jeffrey W (2010) Chemoselective protection of alpha-ketoacids by direct annulations with oximes. Org Lett 12:1924-7|
|Juarez-Garcia, M Elisa; Yu, Shouyun; Bode, Jeffrey W (2010) Asymmetric synthesis of enantiopure isoxazolidinone monomers for the synthesis of ?-oligopeptides by chemoselective amide ligation. Tetrahedron 66:4841-4853|
|Ishida, Hiroshi; Carrillo, Nancy; Bode, Jeffrey W (2009) Synthesis of an enantiopure isoxazolidine monomer for ?-aspartic acid in chemoselective ?-oligopeptide synthesis. Tetrahedron Lett 50:3258-3260|
|Fukuzumi, Takeo; Bode, Jeffrey W (2009) A reagent for the convenient, solid-phase synthesis of N-terminal peptide hydroxylamines for chemoselective ligations. J Am Chem Soc 131:3864-5|
|Ju, Lei; Bode, Jeffrey W (2009) A general strategy for the preparation of C-terminal peptide alpha-ketoacids by solid phase peptide synthesis. Org Biomol Chem 7:2259-64|
|Ju, Lei; Lippert, Alexander R; Bode, Jeffrey W (2008) Stereoretentive synthesis and chemoselective amide-forming ligations of C-terminal peptide alpha-ketoacids. J Am Chem Soc 130:4253-5|