GENERAL METHODS FOR SYNTHESIS OF BIOACTIVE MATERIALS

这项研究计划的目的是开发高效的化学品

The objective of this research program is to develop efficient chemical methods for the preparation of complex organic molecules. Our ultimate goal is to develop sufficiently versatile and efficient synthesis tools so that any desired molecule can be synthesized in a practical manner. If the aims of this application are achieved, biomedical researchers will have new tools for preparing and modifying the structure of stereochemically complex, polycyclic organic molecules. In the long term, the availability of the new organic synthesis methodology we are developing will facilitate discovered and production of improved chemical agents for treating medical disorders. The major focus of this project are two classes of pharmacologically significant molecules whose chemical synthesis is beyond the capability of existing methods: complex cardenolides and polyindoline alkaloids. Specific aims for the project are: (1) Develop methodology for enantioselective synthesis of polyindoline alkaloids; specific targets include- the octaazadodecacyclic alkaloids psycholeine and quadrigemine, which are structurally novel stimulants of growth hormone (GH) release; the trispyrroloindoline alkaloid hodgkinsine; representative chiral 3a- bispyrroloindoline; and more complex, fungal-derived 3-a bispyrroloindoline alkaloids which display a variety of pharmacological activities including anti-cancer and antagonism of substance P, neurokinin 1 and cholecystokinin type B receptors. (2) Prepare the powerful Na+/K+-ATPase-inhibitor ouabain; if analogs or stereoisomers of ouabain are confirmed to be endogenous regulators of this enzyme expand our cardenolide program to prepare these agents as well. (3) Invent/develop new ways to control relative and absolute stereochemistry in constructing vicinal quaternary carbon centers. (4) Further develop our bis-cyclization route to morphine. (5) Collaborate in pharmacological evaluation of our synthesis targets and selected analogs. The proposed studies are founded on recent discoveries in our laboratories on controlling stereochemistry in the synthesis of vicinal quaternary carbon centers and the unique utility of intra molecular Heck reactions to fashion sterically congested carbon-carbon bonds.