Date of Award
Doctor of Philosophy
Part I describes the construction of the major carbon framework of olivin, the aglycone of a number of antitumor antibiotics collectively known as the olivomycins. A palladium(O) mediated cross-coupling of a metallated ethyl vinyl ether unit and an enol triflate derived from a readily available carbohydrate was accomplished. In this first key step, most of the carbon and oxygen atoms of the side chain and A ring of the aglycone were assembled in the form of a diene. The second key step was the Diels-Alder cycloaddition of the complex carbohydrate substituted diene to a highly functionalized naphthoquinone. The resulting cycloadduct, which was formed with complete regiochemical control, has all of the necessary functionality intact for eventual conversion to olivin;Part II describes a direct and operationally convenient synthesis of the DCB ring subunit of aklavinone, the aglycone of the potent cytostatic agent aclacinomycin A. The synthesis begins with a Diels-Alder reaction between 1-trimethylsilyoxybutadiene and 2-cyano-5-methoxy-3-phenylthio-1,4-naphthoquinone. Oxidation of the Diels-Alder adduct produced a novel blocked anthraquinone tautomer. The blocked anthraquinone was converted to the DCB subunit of aklavinone by conjugate addition of a mixed ketene acetal, selective mercaptan oxidation, and elimination of benzenesulfenic acid and hydrocyanic acid. The three rings of the aklavinone precursor were constructed in high yield and with complete stereochemical control;Part III describes successful syntheses of nanaomycin A and deoxyfrenolicin, important members of the naphtho 2,3-c pyran-5,10-quinone class of antibiotics. In addition, synthetic efforts toward the more complex members, griseusins A and B, are described. A key step in the syntheses of the two former members is a tandem Diels-Alder-retro-Claisen reaction between 3-acyl-5-methoxy-1,4-naphthoquinones and mixed vinyl ketene acetals. The resulting 2,3-dihydro-naphtho 1,2-b furans are oxidized in high yield to intermediate 3-acyl-2-(2-hydroxyalkyl) substituted naphthoquinones which spontaneously form hemiketals. Finally, the hemiketals were stereospecifically reduced to afford advanced intermediates in previously published syntheses of nanaomycin A and deoxyfrenolicin.
Digital Repository @ Iowa State University, http://lib.dr.iastate.edu/
John Allen Walling
Walling, John Allen, "Synthetic approaches to aromatic antitumor agents and antibiotics " (1986). Retrospective Theses and Dissertations. 8320.