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J Am Chem Soc. 2008 Sep 17;130(37):12355-69. doi: 10.1021/ja8012819. Epub 2008 Aug 20.

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

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  • 1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

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 stereochemistry. Similarly and enlisting the late stage convergent point in the total synthesis, the remaining seven diastereomers of the chromophore-dipeptide conjugates were individually incorporated into the nine-residue cyclic peptide of chlorofusin (4 steps each) providing all seven remaining possible chromophore diastereomers of the natural product.

PMID:
18712872
[PubMed - indexed for MEDLINE]
PMCID:
PMC2587114
Free PMC Article

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