The therapeutic importance of antitumor and antiviral agents requires a continued effort 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 unprecendented strategies for creating such molecular architectures. Asymmetric allylic alkylation with catalysts derived from palladium and molybdenum requires a rethinking of synthetic strategy, but also brings unprecedented potential power. Developing new paradigms for making nucleosides free of a dependence on carbohydrate starting materials has the real prospect of simplifying and streamlining syntheses, providing either enantiomeric series with equal ease, and allowing access to unusual analogues. This chemistry can make carbocyclic analogues as easily available as the furanose ones. A novel way to effect glycosylations may provide the first diastereocontrolled systems represented by staurosporine, K252a, and indocarbazostatin. Using tandem palladium catalyzed processes, the first one of which is an asymmetric allylic alkylation provides an entry to such diverse structures as the furaquinocins, macrocycles like cochleamycin, and glycosidase inhibitors by a new class, the broussonetines which may help to define protein targets as well as lead to new therapies. Understanding the phenomena of tumor promoting agents like phorbol will derive from having access to agents like karamatsuic acid which inhibits such actions. 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 amphidinolides, may be broached in a highly convergent, efficient and simple fashion. Wedding the alkyne-alkene coupling to a palladium catalyzed asymmetric allylic alkylation opens the opportunity to the novel 14-membered macrolide, callipeltoside, which inhibits proliferation of human non-small lung carcinoma as well as protect cells infected with the HIV virus. Modifications of the palladium catalyst shifts the alkyne-alkene ene-type reaction into a novel metathesis process. This new chemistry provides access to bridged macrobicyclics as illustrated by neoliacinic acid, a new type of germacranolide-sesquiterpene exhibiting good antitumor activity. By accessing a very diverse range of structural types, the best opportunities to discover new therapeutic agents arise.
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