A Synthetic Route to the Dihydroanthracenone Core of the Trioxacarcins

The trioxacarcins are a class of DNA-reactive natural products with antiproliferative activity in cultured human cancer cells. The trioxacarcin aglycone is comprised of a dihydroanthracenone chromophore fused to an oxygenated ring system containing three ketal functions and a spiro epoxide. This thesis presents the chemical synthesis of the chromophore common to all of the trioxacarcin natural products and describes the first studies on the reactivity of non-glycosylated trioxacarcins toward a DNA oligonucleotide.*;The trioxacarcin dihydroanthracenone chromophore was prepared from two building blocks: cyanophthalide 25 and enone 26. The cyanophthalide 25 was prepared in eight steps from 4-methylsalicylic acid. The enone 26 was prepared using three distinct synthetic routes. The first route to 26 was accomplished in eight steps from resorcinol, the second route was accomplished in ten steps from L-malic acid, and the third route was accomplished in ten steps from D-quinic acid. The building blocks 25 and 26 were combined using a cyanophthalide annulation reaction to provide the dihydroanthracenone 99, and, in two steps, 99 was elaborated to the aldehyde 23. The aldehyde 23 was converted into the natural product DC-45-A2 (4) in five steps, as described in a Ph.D. thesis presented by Dr. Jakub Svenda in 2010 at Harvard University in the Department of Chemistry and Chemical Biology titled A Convergent Synthetic Route to Trioxacarcins.;Trioxacarcin A, a glycosylated member of the trioxacarcin family, has previously been shown to form a covalent adduct with duplex DNA through a reaction between the N7 atom of a guanine residue and the epoxide function of the natural product. Herein, experiments that assessed the reactivity of the non-glycosylated trioxacarcins DC-45-A2 (4), iso-DC-45-A2 (109), and dideoxy-DC-45-A2 (84) towards the self-complementary duplex DNA oligonucleotide d(AATTACGTAATT) using DNA-gel electrophoresis and a liquid chromatography-mass spectrometry method are described. Both techniques showed that DC-45-A2 (4) and dideoxy-DC-45-A2 (84), which possess the stereochemical configuration of the natural trioxacarcins, form complexes with the DNA oligonucleotide, while iso-DC-45-A2 (109 ), which does not possess the stereochemical configuration of the natural trioxacarcins, does not form a complex with the DNA oligonucleotide.;*Please refer to dissertation for diagrams.