THE TOTAL SYNTHESIS OF DYNEMICIN-A LEADING TO DEVELOPMENT OF A FULLY CONTAINED BIOREDUCTIVELY ACTIVATED ENEDIYNE PRODRUG

The title compound has been synthesized as its racemate in 33 steps. A n intramolecular Diels-Alder reaction (see Scheme 5, 24 --> 25) was us ed to provide control over the eventual cis C-4-C-7 relationship. The installation of another cis related ethynyl group at C-2 arose from tr ansformation 40 --> 42 (see Scheme 8) whose directionality is governed by a benzophenone ketal functioning as a temporary steric control uni t. Closure of the enediyne unit was accomplished on a trimethylsilylet hoxycarbonyl (TEOC) protected dihydroquinoline derivative. It involved use of a novel bis-iodoalkyne/distannylethylene interpolative couplin g transformation (61 + 58 --> 63, Scheme 12). In the terminal phase of the synthesis, a novel iminoquinone ketal 74 (Scheme 15) was condense d with homophthalic anhydride derivative 78 (Scheme 16) as indicated i n Scheme 17. The final deprotection involved cleavage of a methoxymeth yl ester and two methoxymethyl phenol ethers. From this work, there ar ose the concept and demonstration of p-quinone monoimines 82 and 93 (S cheme 18), as bioreductively activated enediyne prodrugs.