Studies on the total synthesis and evaluation of antitumor antibiotics including (1) vindoline, (2) vindorosine, (3) minovine, (4) aspidospermidine, (5) (-)-vindoline, (6) (+)-vinblastine, (7) an extensive series of (+)-vinblastine aryl analogues, (8) yatakemycin and a series of analogues, (9) ningalin D, (10) an extensive library of ningalin derivatives as multidrug resistant (MDR) reversal drugs, (11) bleomycin A derivatives, (12) indolocarbazoles, (13) cordytropolone, and (14) piericidin A1 and key structural analogues are detailed. In the course of the studies, the investigation, development, and implementation of: (1) heteroaromatic azadiene Diels-Alder reactions, (2) the LUMOdiene-controlled Diels-Alder reactions of N-sulfonyl-l-azadienes, (3) the thermal reactions of cyclopropenone ketals including those of reversibly generated pi-delocalized singlet vinylcarbenes, (4) tandem Diels-Alder/1,3-dipolar cycloadditions of 1,3,4-oxadiazoles, and (5) acyl radical alkene addition reactions will be pursued and provide the opportunity to comprehensively extend past studies. The proposed studies include the examination of antitumor compounds that mediate their cellular effects through sequence selective DNA binding and provide well-defined problems on the design, preparation, and evaluation of synthetic, mechanism-based analogues in which fundamental studies of the structural features responsible for DNA binding affinity, selectivity, and functional reactivity may be addressed.
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