I. Synthesis of N,N-bis(3-butenyl)amines from (2-azaallyl)nitriles. II. Synthesis of highly substituted pyrrolizidines from cyclic carbinol amides. III. Synthesis of potential phototriggered DNA crosslinking agents.

The formation of nitrogen-containing molecules is of great importance in synthetic organic chemistry owing to the abundance of alkaloids that exhibit biological activity. While the first two projects deal with expanding the synthetic tools available for synthesis of such compounds, the final project focuses on using existing methodology to create and test novel potential clinical agents. The use of (2-azaallyl)nitriles in double allylation reactions with allylmagnesium bromide to generate N, N-bis(3-butenyl)amines is described. The (2-azaallyl)nitriles function as synthetic equivalents of amine alpha,alpha'-dications, also called 2-azaallyl dications. This chemistry allows for the expeditious construction of highly substituted amines, resulting in the formation of two new carbon-carbon bonds adjacent to the nitrogen atom. The doubly allylated products are converted to 2,3,6,7-tetrahydroazepines by ring-closing metathesis. Many biologically-active natural products contain the azepine ring, so facile methods for its formation provide valuable synthetic tools. Also discussed is the formation of pyrrolizidines from N-(tri- n-butylstannyl)methylphthalimides. Through nucleophilic addition of an organometallic reagent, the phthalimides could be converted to cyclic carbinol amides, which were shown to undergo ionization and destannylation under acidic conditions to generate azomethine ylides. Inclusion of a suitable dipolarophile resulted in capture of the azomethine ylide to provide the pyrrolizidine. Various substituents on the phthalimide were tolerated by this methodology, and stabilized succinimide derivatives also underwent successful cycloadditions. Given the large number of biologically-active natural products that possess the pyrrolizidine ring structure, this chemistry could find wide synthetic application. Finally, the preparation of 2-(2,5-dihydropyrrol-1-yl)-1,4-quinones by the coupling of quinones with pyrrolines is discussed. The 2-(2,5-dihydropyrrol-1-y1)-1,4-quinones were designed to be masked alkylating agents, revealed upon exposure to light. The pyrroline of the 2-(2,5-dihydropyrrol-1-yl)-1,4-quinones is relatively unreactive toward nucleophiles, but upon photolysis, an internal oxidation/reduction reaction occurs, transforming the quinone into a hydroquinone and the pyrroline into a pyrrole. The newly-formed pyrrole is highly electrophilic and readily undergoes an alkylation reaction. Eventually, the presence of oxygen may reoxidize the hydroquinone to a quinone. The design of such photoactivatable alkylating agents is a worthwhile endeavor because it provides a handle for control of the alkyation, thereby making it more attractive as a potential clinical agent.Ph.D.Organic chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125341/2/3192619.pd