This project is centered on the further exploration of 2-methyleneoxetanes, 1,5-dioxa-spiro[3.2]hexanes, 4-oxaspiro[2.3]hexanes and 3-alkylidene-2-methyleneoxetanes, strained heterocycles with useful reactivities. Improved access to a range of 3-alkylidene-2-methyleneoxetanes will allow preliminary examination of the utility of these compounds as inhibitors of fatty acid synthases. Initial studies have shown that novel, oxetane-containing nucleosides, which may serve as anti-viral or anti-bacterial agents, can be accessed with this methodology. In addition, a new, mechanistically interesting approach to usefully functionalized tetrahydrofurans will be investigated.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Amy R. Howell of the Department of Chemistry at the University of Connecticut. Professor Howell's research efforts revolve around exploiting unusual, strained heterocycles as scaffolds for efficient organic synthesis. Such chemistry will contribute to the preparation of novel, biologically interesting small molecules and will have an impact on the pharmaceutical and agricultural sectors.
Research in this funding period focused on the synthesis of unusual oxetanes and exploration of their reactivity. General approaches to 2-methyleneoxetanes, 1,5-dioxaspiro[3.2]hexanes, and 4-oxaspiro[2.3]hexanes had been previously developed. These novel systems have shown interesting and valuable reactivity. This proposal centered on further exploration of all three oxetane-containing systems. Goals were to: 1. exploit dioxaspirohexanes and methyleneoxetanes as scaffolds for novel oxetane-containing nucleosides , as well as oxetane analogs of the potent herbicidal spironucleoside, hydantocidin; 2. use a 2-methyleneoxetane as a scaffold for preparing the potent antimalarial natural product, laureatin; 3. optimize and explore the scope and utility of a newly discovered platinum-catalyzed conversion of 4-oxaspriorhexanes to 3-methylenetetrahydrofurans. Intellectual merit of the proposed activity: These unusual oxetanes have already displayed valuable reactivity. The current proposal exploited their utility in new and significant directions. Both dioxaspirohexanes and 2-methyleneoxetanes were converted to novel psico-nucleosides, which will be tested in the near future for their ability to inhibit HSV and HIV. Computational and experimental studies examined the role of neighboring group participation in enhancing the yield and selectivity of reactions that incorporated the nucleobase. In the second aim, it was shown that oxetanes can act as nucleophiles, relaying stereochemical information from established beta-lactone syntheses and providing more complex ring systems. These findings will be used to complete the synthesis of laureatin and related laurenans in the near future. Metal insertions into strained rings can also provide the basis for powerful methodologies. Our group discovered that Ziese’s dimer, a Pt(II) species, catalyzes the conversion of 4-oxaspiro[2.3]hexanes to 3-methylenetetrahydrofurans, disubstituted terminal alkenes or cyclopentanones, depending on the substitutuents. Understanding the mechanism of these divergent pathways will allow the rearrangements to be efficiently controlled and utilized. Very recently, the ability of 2-methyleneoxetanes to serve as enols in aldol reactions has lead to new approaches to synthetically useful tetrahydropyran-4-ones and to previously difficult to access 2-alkylideneoxetanes. Elucidating mechanistic features will allow the full utility of these reactions to be accessed. Broader impact of the proposed activities: The undergraduate and graduate students who participated in this research gained valuable experience in laboratory practice and critical thinking and skills in communicating scientific information. Through industrial internships and career development activities, studentsobtained a foundation for making informed choices about future careers in chemistry and established networks with peers and mentors from a range of disciplines and backgrounds. The research completed provided novel and efficient approaches to useful synthetic intermediates and laid a foundation for programs that over the long term may provide novel chemotherapies.
