With this award, the Chemical Synthesis Program is funding Professor David R. Williams of the Department of Chemistry at Indiana University to explore the behavior of electrocyclization reactions of pentadienyl carbanions. The proposed methodologies will elucidate reactivity leading to electrocyclic ring closures which provide efficient access to unique ring systems. Initial studies will generate substrates for investigations of tandem reactions of stereoselective rhodium-catalyzed hydroacylations and iron-catalyzed Pauson-Khand processes. These transformations target the efficient molecular assembly of architectures that are difficult to access or as yet unattained by the prior art. The inclusion of these molecular frameworks in naturally-occurring antitumor antibiotics and recently discovered marine natural products provides additional significance for the proposed studies. Moreover, these studies will contribute a better understanding of the reactivity, scope, and mechanisms of the key proposed reactions.

Successful development of the proposed research plan will impact the need for new methodologies and strategies for chemical synthesis in the pharmaceutical, chemical, and agricultural industries. The project will provide training in sophisticated modern synthesis toward biologically relevant targets to both undergraduate and graduate students, including underrepresented minorities in a supportive environment emphasizing scholarship and creativity.

Project Report

Project outcomes included a number of findings of intellectual merit. A summary of significant discoveries documented a new regioselective reaction leading to the formation of propargylic stannanes, and the selective Stille cross-coupling to yield allenes. We have also described a new pathway for iron-mediated Pauson–Khand reactions which involve a 3-membered iron cyclopropane metallacycle. Mechanistic studies demonstrate a stereoselective pathway for [2+2+1] cyclizations. Kinetic studies and computational studies provide a detailed understanding of the iron-mediated cross-coupling process. We have applied these findings to accomplish the first synthesis of ileabethoxazole, a marine alkaloid with potent activity towards Mycobacterium tuberculosis. Bifunctional reagents have been developed for bidirectional SE' reactions leading to the preparation of 1,5-syn and 1,5-anti stereocontrol in the formation of skipped polyols. Stereocontrolled Stille cross-couplings of bifunctional alkenyl stannanes have been applied for studies which have led to the total synthesis of trichoaurantianolides C and D. An efficient route for the enantiocontrolled synthesis of the tricyclic amine component of daphnicyclidin A has been described. We have reported the preparation of Z-hexahydro-(1H)-azocines, an unexplored class of nine-membered amines. We have also recorded the first synthesis of the 4-azabicyclo[5.3.2]dodecane ring system via a novel reductive cyclization. The daphnicyclidin compounds are components of traditional Chinese medicines and are of interest because they show anticancer activity. A second aspect of our project outcomes incorporates the broad impact of our research. During the project period, eight predoctoral students received support for their research and training. Of these individuals, one is African-American and another is Asian-American and two students are women. Students presented nine poster presentations of their findings at conferences and gave five oral presentations at scientific meetings and conferences. Six Ph.D. dissertations were completed with the awarding of the doctoral degree. The PI was an invited speaker at five national/international symposia and conferences, and the research results were communicated in nine publications in leading journals of the field. The PI gave an invited lecture at St. Jude Children’s Hospital and established collaborations with Professors Dean Tantillo (California-Davis) and Mu-Hyun Baik (Indiana University) in the course of these studies. Four undergraduate participants were introduced to laboratory research in the field of organic chemistry during the project.

Agency
National Science Foundation (NSF)
Institute
Division of Chemistry (CHE)
Application #
1055441
Program Officer
Richard Johnson
Project Start
Project End
Budget Start
2011-02-01
Budget End
2015-01-31
Support Year
Fiscal Year
2010
Total Cost
$420,000
Indirect Cost
Name
Indiana University
Department
Type
DUNS #
City
Bloomington
State
IN
Country
United States
Zip Code
47401