The principal objective of the proposed research is to continue to develop general and efficient methods for the synthesis of pyrrolidine-containing molecules of biological significance. A general synthetic method may be useful for the preparation of a wide variety of target molecules rather than a single class. The proposed research will attempt to use the anionic (3+2) cycloaddition of 2-azaallyl anions with alkenes and the 1,3-dipolar cycloaddition of azomethine ylides with alkenes for the construction of a cross-section of biologically relevant target molecules. The 2-azaallyl anions are prepared by tin-lithium exchange on (2-azaallyl)stannanes. The same (2-azaallyl)stannanes are also precursors of several novel types of non-stabilized azomethine ylides, which are also capable of (3+2) cycloadditions to produce pyrrolidines. These two types of reactive intermediates are proving to be complementary in their reactivity and diastereoselectivity. Applications of these methods to the synthesis of biologically interesting molecules is proposed in order to provide a context for methodology development. Each example is meant to test a different aspect of the (3+2) methodology. Targets include: (1) monomorine 1, the trail pheromone of the pharoah ant, (2) pictamine, a novel quinolizidine alkaloid isolated from tunicates with antimicrobial, antifungal, and antitumor activity, (3) lundurines B and C, isolated from Kopsia, the extracts of which find medicinal use for rheumatoid arthritis, dropsy, and tonsillitis in China, (4) 7-epiaustraline, a highly hydroxylated pyrrolizidine alkaloid with a unique hydroxymethyl group, a member of a class of such alkaloids that have activity as glucosidase I inhibitors, antiviral agents and antiretroviral agents, (5) scandine, a component of a Chinese folk medicine used for the treatment of rheumatic heart disease, and (6) erycibelline, a member of the tropane class of alkaloids. These targets will allow examination of the scope of the 2-azaallyl anion and azomethine ylide cycloaddition methods in several ways. For example, the types of anions or ylides required are diverse (e.g., simple aliphatic substituents, functionalized side chains, heterosubstituted versions, more conjugated versions, and cyclic versions), each with their unique chemistry and method of preparation. The issues of regiocontrol and stereocontrol, both absolute and relative, must be addressed. Tandem processes that involve the combination of (3+2) cycloaddition followed by additional reactions that lead to a second or third ring formation or a rearrangement are also being studied.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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