Exploring biological phenomena at a molecular level provides the basis of understanding from which new therapeutic agents derive. The ability to construct a defined molecular architecture requires highly selective reactions and reagents to permit the development of effective synthetic strategies. Cyclic compounds have biological activities across a broad spectrum. Furthermore, constraining conformations of mobile molecules by forming rings also frequently enhances biological potency. Thus, a concerted effort to apply new chemical principles being developed in the PI's laboratories to the formation of rings becomes an important objective. In the first phase, a new concept to create macrocycles (rings larger than seven members) may provide a unique opportunity to approach a variety of significant targets. Some examples include the antiinflammatory nine membered macrolides ascidiatrienolides, the antitumor eight membered carbocycles, the shikoccins, and the azocines, FR-99048 and FR-66979, the ten membered macrolactam neuropeptidase inhibitor CGS-25155,the fourteen membered antiviral and antifungal fluviricinines, and the nineteen membered serine protease inhibitors, the cyclotheonamides. In the second phase, a new reactivity mode for shuffling protons in totally unconventional methods offers novel approaches to cyclizations. Vitamin D analogues and derivatives represent a most important direction for creation of clinically important therapeutic agents. A new concept for their synthesis based upon novel strategies for asymmetric induction will be pursued. A variation on this methodology may extend the reaction to a facile asymmetric synthesis of either cis or trans fused drimanes and related classes of terpenoids from a common intermediate, a class of compounds that have remarkably broad biological activities including antibacterial, antifungal, antimalarial, antiinflammatory, cytotoxic, and insecticidal. A new class of reactions provides a novel atom economical approach for formation of heterocycles. This invention stimulates exploration of a potentially, greatly simplified strategy to the important food toxin, aflatoxin. The envisioned asymmetric route also may provide a simple protocol for the asymmetric synthesis of physostigmines, one of whose members is a candidate for treatment of myasthenia gravis, glaucoma, and Alzheimer's disease. A third phase examines a new class of cycloaddition reactions to create odd membered rings. Exploring a new class of acceptors in conjunction with a novel class of reactive intermediates creates a conceptual framework to the anthelmintic and antinematodal mold metabolites paraherquamide and marcfortine. An unusual (6+3) cycloaddition may create strategies for the structurally unusual farnesyl transferase inhibitor CP-263,114 and simpler analogues. Ring expansion methods may convert these cores into the taxoid skeleton with appropriate functionality at key points for analog development.
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