Synthetic studies and biological evaluation of the perylenequinones: Total synthesis of cercosporin, (+)-calphostin D, (+)-phleichrome and novel photodynamic perylenequinones

The efforts described in this dissertation encompass the total synthesis and biological assessment of the perylenequinone family of natural products. The perylenequinones are characterized by a helical chiral oxidized pentacyclic core combined with stereogenic C7,C7'-substitution. This chromophore permits their use as photosensitizers upon exposure to light (photodynamic therapy = PDT). In addition, they are potent protein kinase C (PKC) inhibitors with unique binding to the PKC regulatory domain.;Initial research concentrated on the total syntheses of these architecturally complex compounds, including cercosporin, (+)-phleichrome, and (+)-calphostin D. Specifically, the evolution of the first total synthesis of cercosporin was the central focus of the synthetic investigations. These efforts comprised two generations culminating in the development of a highly convergent and flexible strategy toward all of the perylenequinone natural products.*;The first generation synthesis of cercosporin provided invaluable information, including the discovery of the common enantiopure intermediate. An enantioselective oxidative biaryl coupling and biscuprate epoxide alkylation permitted complete control of the helical and centrochiral stereochemical elements of the perylenequinones. Additionally, the challenges encountered during methylidene acetal installation and removal of the C3,C3'-methyl esters were resolved, resulting in the completion of the atropisomerically sensitive cercosporin without any accompanying atropisomerization. However, the PIFA C5,C5'-oxygenation was identified as a major limitation of the synthesis due to high cross reactivity with other functional groups and low generality.;In the second generation cercosporin synthesis, an alternate C5,C5'-oxygenation was identified relying on a palladium-catalyzed O-arylation. This protocol enabled the formation of a key advanced intermediate on preparative scale with enhanced yields and no loss of enantioenrichment. Furthermore, the O-arylation proved to be general and the strategy was used in the total syntheses of (+)-phleichrome and (+)-calphostin D. This strategy permitted rapid access to a broad range of analogs, which was crucial for an accurate assessment of the structural features necessary for PKC inhibition.;In the evaluation of perylenequinone architecture on PKC activity, (M)-helicity and hydrophobic C7,C7'-substitution were discovered to be advantageous, leading to the development of simpler analogs with improved potency. In line with the docking studies, substitution at the C2,C2'-positions provided superior inhibitors. Additionally, the perylenequinone chromophore was extended through C3,C3'-substitution, generating analogs with improved photodynamic properties (increased absorption in the 600-800 nm range). Finally, cercosporin and a simple analog displayed enhanced activity against nine cancer cell lines and significantly higher levels of photopotentiation relative to the other natural products.;*Please refer to dissertation for diagrams.