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 these laboratories to the formation of rings becomes an important objective. In the first domain, a new strategy to effect cyclizations, in general, and macrocyclizations, in particular, asymmetrically may provide a unique opportunity to approach a variety of significant targets. The concept involves a new dinuclear catalyst design for an asymmetric aldol addition that involves no preactivation of either partner (i.e., no stoichiometric formation of an enol or enolate) and that could also provide an unusual ability to perform macrocyclizations at high concentration. This development leads to the use of hydroxyacetone as a lynchpin to form macrocycles aymmetrically and a synthesis of the antitumor amphidinolides. In the second domain, the development of a new annulation to form heterocycles leads to a novel convergent and practical approach to the potent antitumor agents, the bryostatins, and potential analogues. The asymmetric aldol reaction also will play an important role. This domain embodies an atom economic cross-coupling of two different alkynes. This new concept for C-C bond formation performed intramolecularly sets the stage for macrocyclizations that can lead to the cochleamycins, new structural class of antitumor antibiotics. The third domain embodies 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 simple analogues. A new bifunctional conjunctive reagent combined with a ring expansion provides a novel approach to the antitumor agent penostatin 1. A (4+3) cycloaddition combines with two other concepts being developed in these laboratories, asymmetric allylic alkylation and metal catalyzed enyne cycloisomerizations, to create a powerful strategy to the neurotrophic agents, the erinacines. The fourth domain transitions to ruthenium catalysis for (5+2) cycloadditions. This new concept sets the stage for solutions to a long standing problem, the ion channel blockers, the grayanotoxins. as well as the more recently discovered rameswaralide, a potent antiinflamatory.
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