Synthesis and evaluation of conformationally constrained peptide replacements and studies toward the total synthesis of kidamycin



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A series of conformationally constrained pseudopeptides derivative of the tripeptide pYVN were designed and synthesized. The conformationally restricted compounds contained either trans- or cis-cyclopropanes as replacements to enforce locally extended and reverse turn peptide conformations, respectively. In addition, the proper flexible control molecules were prepared. All compounds were evaluated for the ability to bind to the Grb2-SH2 domain in order to determine the energetic consequences of introducing a conformational constraint into peptide ligands. No difference in the ∆Gbinding between the trans-cyclopropane and its control partner was observed. Surprisingly, there was an entropic disadvantage when comparing the binding energetics of the constrained and flexible pseudopeptides. Therefore, the introduction of the cyclopropane constraint was associated with an entropic disadvantage in the system, which is the opposite of conventional wisdom. An X-ray crystal structure of the trans- cyclopropane containing ligand bound to the Grb2-SH2 domain was obtained and vii discussed. On the other hand, cis-cyclopropane containing pseudopeptides do not seem to enforce the desired turn conformation of the ligand. A method to allow access to unsymmetrical C-aryl glycoside natural products was developed through employing a disposal tether to enforce the desired regioselectivity in a [4+2] cycloaddition between benzyne and glycosyl-substituted furan. Application of this novel strategy toward the synthesis of kidamycin is discussed. Additional synthetic routes, including utilizing Suzuki’s O → C glycoside rearrangement are also provided. Studies toward the synthesis of sugar ring E and F are illustrated.