Synthesis of Macrolides, Steroids, Cyclopentanoids, etc.

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DESCRIPTION (provided by applicant): 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. Two new methods for accessing pyrans by simple one operation cycloaddition - like strategy relying on palladium and / or ruthenium catalysis may lead to biologically active targets containing such subunits illustrated by dactyolide and the bryostatins. Unprecedented cycloadditions of norcarane type substrates will be a major focus that may lead to a structural motif so common to a great number of bioactive molecules ranging from ion channel blockers like grayanotoxin to anti-inflammatories like ramaswaralide. Cascade reactions involving creation of three rings in one step can provide rapid entry to complex targets like guanacastepene. The reactivity and selectivity of palladium complexes of chemically reactive intermediates to form odd membered rings including five, seven and even nine members can lead to strategies to families of compounds possessing powerful antihelmintic and antinematodol mold metabolites ranging to squalene synthase and Ras farnesyl transfer inhibitors. A new concept for the synthesis of macrocyclic compounds at high concentrations will be examined in the context of the antitumor amphidinolide and the immunosuppressive ushikulide families. These new synthetic methods apply to many structural types beyond those illustrated and constitutes a significant to gain access to complex molecular targets more easily.