Transition metal-promoted higher-order cycloaddition reactions are capable of creating structurally elaborate and stereochemically homogeneous products that are frequently difficult or even impossible to access using conventional synthetic methods. This proposal seeks to develop and exploit the full potential of these novel transformations for the synthesis of pharmacologically significant natural products. Projected studies will address important issues such as the development of ambient temperature, catalytic cycloadditions, conditions for effecting cycloaddition with high levels of asymmetric induction, and mild conditions for solid-supported catalysis. ? ? An important new class of higher-order cycloaddition will be studied that involves simultaneous bonding of multiple reaction partners to afford products possessing substantial molecular complexity. Deconvolution of these complex adducts will be examined as a strategy for the efficient synthesis of natural products known to exhibit potent medicinal activities. New and more powerful """"""""multicomponent"""""""" cycloadditions will be developed during these studies as well. ? ? An important outgrowth of our studies on metal-mediated reactions is the development of traceless linkers for applications to solid-supported synthesis. This new methodology will be examined during the coming grant period and applications to the preparation of pharmacologically interesting compounds will be featured. Studies directed toward developing more versatile linkers are also projected for the next grant period. ? ? Several total syntheses of bioactive natural products are proposed as a means for demonstrating the unique attributes of metal-promoted higher-order cycloadditions for complex synthesis. ? ?
