Total synthesis of chlorofusin, its seven chromophore diastereomers, and key partial structures.

Journal of the American Chemical Society
Ryan C ClarkDale L Boger

Abstract

Chlorofusin is a recently isolated, naturally occurring inhibitor of p53-MDM2 complex formation whose structure is composed of a densely functionalized azaphilone-derived chromophore linked through the terminal amine of ornithine to a nine residue cyclic peptide. Herein we report the full details of the total synthesis of chlorofusin, resulting in the assignment of the absolute stereochemistry and reassignment of the relative stereochemistry of the complex chromophore. Condensation of each enantiomer of an azaphilone chromophore precursor with the N(delta)-amine of a protected ornithine-threonine dipeptide, followed by a one-step oxidation/spirocyclization of the most reactive olefin provided all eight diastereomers of the fully elaborated chromophore-dipeptide conjugate. Comparison of the spectroscopic properties for these eight compounds and those of simpler models with that reported for the natural product allowed the full assignment of the (4R,8S,9R)-stereochemistry of the chlorofusin chromophore. The natural, but stereochemically reassigned, diastereomer of the dipeptide conjugate was incorporated in a convergent total synthesis of chlorofusin confirming the stereochemical reassignment and establishing its absolute stereoc...Continue Reading

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Citations

Sep 8, 2011·Chemical Reviews·Alan R Katritzky, Stanislaw Rachwal
Apr 16, 2013·Chemical Reviews·Jin-Ming GaoJian-Chun Qin
Mar 24, 2012·Journal of Agricultural and Food Chemistry·Long LinGuang-Fu Yang
Mar 29, 2014·Chemical Reviews·Madhu AeluriPrabhat Arya
Nov 20, 2015·Organic Letters·Keisuke NishikawaYoshiki Morimoto
Jul 28, 2012·Chemical Biology & Drug Design·Long LinGuang-Fu Yang
Jul 22, 2017·Organic Letters·Mehdi MakrerougrasXavier Franck
Aug 11, 2011·Natural Product Reports·Luiz F Silva, Berit Olofsson
Jan 9, 2013·Organic & Biomolecular Chemistry·Andrew Michael BeekmanRussell Allan Barrow
Jan 29, 2011·Angewandte Chemie·Alexander Duschek, Stefan F Kirsch
Jan 5, 2010·Tetrahedron·Sang Yeul Lee, Dale L Boger

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