DESCRIPTION (provided by applicant): The primary objective of this research is to continue to discover new strategies for the construction of complex carbocyclic or heterocyclic ring systems. A theme throughout this proposal is the further development and exploitation of new, reactive dienophiles and/or heterodienes derived from retrocycloaddition reactions. The new reactants derived from these retrocycloaddition reactions can also be utilized in additional types of cyclization reactions such as intramolecular conjugate addition reactions, olefin metathesis reactions, internal Wittig reactions, etc. It is expected that this new methodology will expedite the syntheses of biologically active natural products and/or analogs. Thus, the architecturally complex cytotoxin communesin B will be assembled by an intramolecular cycloaddition reaction of an indole with an aza-orthoxylylene. The potent anti-microtubule agent welwistatin will be assembled using our newly developed bridged bicycloalkane and indole annulation methodologies. This will permit structure-activity studies of this anticancer agent that has certain pharmacological properties that are superior to the clinically used vinca alkaloids. A related fused bicycloannulation strategy will be used to assemble the perhydroazulene core ring system of the potent antifungal/anticancer natural product pseudolaric acid. The mechanism of action of this compound may be novel and upon completion of the total studies collaborative biological work will be directed toward the identification of the cellular protein target. The potent neuronal nictotinic acetylcholine receptor antagonist dihydro-beta-erythroidine will be assembled using a novel intramolecular cycloaddition of an amidoacrolein. Subsequent analog work will hopefully define the structure activity relationship for this compound and lead to an antagonist with improved subtype selectivity, of potential therapeutic value in smoking cessation and psychostimulant abuse. Finally, the cytotoxic xenicanes, isolated from soft coral, will be prepared from Z-2-acylenal hetero cycloadducts and thence direct metal mediated ring closure of the strained cyclononene. The total synthesis will provide larger quantities of these compounds for biological studies than has heretofore been available.
|Effective start/end date||6/1/03 → 2/28/04|
- National Institute of General Medical Sciences: $307,460.00