Novel Approaches to Antitumor and Antiviral Agents

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The therapeutic importance of antitumor antiviral agents requires a continued effort to develop new methodology to define better synthetic strategies. Choosing classes of compounds known for this type of biological activity as targets, this project develops new chemical principles that may evolve into unprecedented strategies for creating such molecular architectures. Asymmetric allylic akylation involving palladium and epoxides or related cyclic carbonates may provide a simple strategy to form a building block directed toward mitomycin - type structures. Inducing asymmetry at a prochiral nucleophile represents one of the most challenging tasks ever for chiral recognition in a catalytic asymmetric event. Preliminary successes stimulates its exploration. The breadth of applications is huge - ranging from alkaloids like the clinically important vinca alkaloids to macrocycles like peloruside A. A novel version combines asymmetric induction of a pronucleophile with a new class of pro-electrophiles, allenes, to create an extremely short synthesis of unusual amide types such as spirotyprostatin. A series of tandem stereospecific processes initiated by the asymmetric allylic alkylation invoking cyclic diketones creates a conceptually unprecedented approach to novel terpenes like terpestacin. New Ru catalyzed reactions being invented will be tested and explored in the synthesis of diverse polyketides like the laulimalides and pelorusides. A totally new concept for simple polyfunctional ring construction by atom economic additions is visualized via Ru catalyzed cycloisomerization or water addition to suitable diynes. Numerous targets emerge with the most exciting. In a number of projects, totally unprecedented selectivities in hdyrosilylation helps simplify the synthetic design including the mitomycin mimic and ptsloruside A. A direct asymmetric aldol protocol provides access to numerous structural types represented by leustroducsin, peloruside A, and apicularen A. By expediting access to very diverse arrays of structural types, the best opportunities to discover new therapeutic agents arise.