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. An intramolecular Diels-Alder reaction (see Scheme 5, 24 --> 25) was used 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 transformation 40 --> 42 (see Scheme 8) whose directionality is governed by a benzophenone ketal functioning as a temporary steric control unit. Closure of the enediyne unit was accomplished on a trimethylsilylethoxycarbonyl (TEOC) protected dihydroquinoline derivative. It involved use of a novel bis-iodoalkyne/distannylethylene interpolative coupling transformation (61 + 58 --> 63, Scheme 12). In the terminal phase of the synthesis, a novel iminoquinone ketal 74 (Scheme 15) was condensed with homophthalic anhydride derivative 78 (Scheme 16) as indicated in Scheme 17. The final deprotection involved cleavage of a methoxymethyl ester and two methoxymethyl phenol ethers. From this work, there arose the concept and demonstration of p-quinone monoimines 82 and 93 (Scheme 18), as bioreductively activated enediyne prodrugs.