NOVEL APPROACHES TO ANTITUMOR AND ANTIVIRAL AGENTS

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The therapeutic importance of antitumor and antiviral agents requires a continued effort to define better synthetic strategies. Choosing classes of compounds known for their biological activity as targets, this project develops new chemical principles that may evolve into unprecedented strategies for creating such molecular architectures. Asymmetric induction utilizing a chiral Pd catalyst offers a number of ways to effect asymmetric induction. Differentiating enantiotopic leaving groups opens the prospect of a new paradigm for nucleoside synthesis from furan. Exploration of a variety of structural types wherein the heterocyclic base, the C-5 side chain, and the 2- and 3- substituents can be varied will be examined to establish the validity and flexibility of this new concept. Practical asymmetric syntheses of such diverse systems as AZT, DDI, DDDC, stavudine, fazarabine, showdomycin, cadequomycin, queuosine, sinefugin, polyoxins, and chryscandin may result. A novel way to effect the molecular recognition required for the related antitumor agents staurosporine and K252a can result in simple syntheses of these compounds. Considering the concept of complexation of prochiral allyl esters can provide a strategy for the synthesis of indole alkaloids represented by the antiviral agent eudistomin E. Building upon the type to nuclephile that can be used in such a synthesis, suggests a new thrust for forming cyclic peptides possessing unusual amino acids to capitalize on the efficiency of macrocyclizations as illustrated by the antitumor agents, the glidobactins. Creation of a family of new reactions derived from the concept of metal catalyzed inter- and intramolecular addition reactions leads to several new strategic insights. Based upon a Ru catalyzed ene type reaction, retrosynthetic analysis of a number of a growing class of highly active agents, the acetogenins, may be broached in a highly convergent, efficient and simple fashion. A cycloisomerization of an ene type using either Pd or Ru provides an approach to a commonly found structure as represented by the saponaceolides. Extension of the concept to an alkylative enyne cyclization sets the stage for a very short synthesis of epipodophyllotoxin. Mechanistic considerations led to the creation of another dimension-an enyne metathesis-which creates opportunities to the novel bridge bicyclic antitumor agents represented by roseophilin and, more significantly, taxol. A new type of metal catalyzed additions involving terminal alkynes leads to a different paradigm for creation of nucleosides as illustrated by griseolic acids. The highly sensitive functionality of ynediene antitumor agents like tricholomenym A and B become natural targets for such methodology. The true mettle of synthetic methods cannot be judged until it is tested in "the field of battle"-a complex synthesis target. The diversity of the challenges posed by the antitumor and antiviral agents represent highly meaningful tests of their use. Equally important, new avenues to vary structure around these cores in order to establish structure-activity relationships with the aim to create better therapeutic agents become available.