Studies toward the synthesis of the Chlorofusin chromophore and development of diazonium ion mimics for organic transformations

Michele Natasha Williams, Purdue University

Abstract

Chlorofusin is a natural product that was found to inhibit the p53/MDM2 protein-protein interaction with an IC50 of 4.6μM. The structure of Chlorofusin includes a cyclic peptide linked to a highly functionalized tricyclic chromophore. Solution and solid-phase syntheses, as well as biological studies, for the cyclic peptide are available in literature. The cyclic peptide alone, however, has not been found to be an inhibitor of the p53/MDM2 interaction, which suggests that the sidechain chromophore is primarily responsible for the inhibitory activity or there is a cooperative binding event that occurs between the two components of the molecule. An efficient and cost-effective synthesis of the Chlorofusin sidechain has been developed for the determination of its biological activity, as well as the activity of key synthetic intermediates via in vivo detection of disruption of the p53/MDM2 protein complex. A novel procedure has also been developed for the synthesis of diazonium ion mimics by the formal abstraction of N- from azides. Diazonium ions are a widely used functional group in organic synthesis transformations. Their synthesis routinely involves strongly acidic conditions that may be undesirable for acid sensitive compounds. This novel methodology involves the conversion of aryl azides to Staudinger intermediates that react under neutral conditions or under Lewis acid catalysis to form synthetically useful diazonium ion mimics. These synthons were isolated and characterized as their diazo adducts. This reaction was then applied to the design and synthesis of a benzotriazole-derived carbonyl activating group.

Degree

Ph.D.

Advisors

Savinov, Purdue University.

Subject Area

Organic chemistry

COinS