Synthetic studies towards substituted aceanthrenes: Synthesis of 3 -methyl-7-tosyloxy-8-bromoaceanthrene, 11H -benz(bc)aceanthrylene, and 3-methylcholanthrene.

Abstract

Different synthetic approaches to the synthesis of substituted aceanthrenes and aceanthrylenes have been studied. A novel approach has been developed for the construction of the aceanthrene skeleton by the initial reaction of N,N-diethylarylamides with in situ protected homophthalic anhydrides, featuring a highly regioselective double Friedel-Crafts cyclization reaction. The chemistry of the 6-hydroxy-1(2H)-aceanthrylenones that are produced from the above cyclization, has been studied, and the synthesis of 3-methyl-7-tosyloxy-8-bromoaceanthrene has been completed. This aceanthrene corresponds to the requisite aryne precursor for the employment of the "aryne-furan" methodology to the synthesis of the optically pure active diol epoxide metabolites of 3-MC. The double Friedel-Crafts cyclization method has been successfully applied to the synthesis of the benzannulated analogues of aceanthrene. The syntheses of an environmental contaminant and tumorigen, 11H-benz (bc) aceanthrylene, and a potent carcinogen, 3-methylcholanthrene (14), have been completed in five steps in 28% and 55% overall yields, respectively. In both cases, these new synthetic routes compare favorably with previously reported syntheses in terms of yields and availability of the starting compounds. Moreover, in the 11H-benz(bc) aceanthrylene system, a re-evaluation of the structure of two previously reported intermediates has been conducted, leading to the unequivocal assignment of the structure of one intermediate through single-crystal x-ray crystallography. These results, along with the serendipitous preparation of 4-methoxy-benz(d) indeno(2,1-b) pyran-5(7H)one, provided evidence that, under acidic conditions, cyclization of ortho-(1-(2-alkoxy)indenyl) - or ortho- (1-(2-keto)acenaphthyl) -benzoic acid leads to the corresponding pyranone skeleton. The scope and efficacy of a number of established experimental procedures, such as ortho-lithiation of N,N-diethylarylamides, Friedel-Crafts cyclization in PPA, and activated zinc reduction were augmented. More importantly, the application of a novel double Friedel-Crafts cyclization method towards both aceanthrene and benz (a) aceanthrene systems that contain peripherally fused five-membered rings completed our study and demonstrated the potential of this new methodology.Ph.D.ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/103592/1/9332069.pdfDescription of 9332069.pdf : Restricted to UM users only