Professor Nancy I. Totah of Syracuse University is supported by the Chemical Synthesis Program of the Chemistry Division to develop new methods for the efficient preparation of compounds that contain functionalized tetrahydropyrans and their derivatives. This research is focused on the use of exocyclic enol ethers for the formation of carbon-carbon bonds. Specifically, this research is directed towards the use of 2-methylenetetrahydropyrans in carbonyl ene and related processes. In addition, it explores the direct addition, tandem, and two-directional manifestations of this process and the development of efficient, enantioselective protocols. Carbon-carbon bond forming reactions that capitalize on the nucleophilic nature of exocyclic enol ethers have been underutilized. These studies will provide fundamental knowledge about the chemistry of 2-methylenetetrahydropyrans, and will provide a basis for the further manipulation of these interesting substrates in complex molecule synthesis.

Tetrahydropyrans and their derivatives are common components of molecules that have useful biological activity and interesting structural features. The exploration, development, and application of the chemistry proposed in this application will provide new methods and strategies for the introduction and manipulation of tetrahydropyrans. Such efforts benefit society at large by providing improved access to molecules with important applications in medicine, agriculture, and materials chemistry. Further, this project will provide training for graduate students, postdoctoral associates and undergraduates, including those from groups historically underrepresented in the sciences.

Project Report

The long term objective of this research program was to develop and apply new methods for the synthesis of complex natural products. The main focus of this award was the development of new synthetic methods and strategies for the efficient preparation of functionalized tetrahydropyrans, tetrahydrofurans, and their derivatives. Such compounds are ubiquitous in nature and are common components of molecules that have useful biological activity and interesting structural features. Toward this end, we explored the use of exocyclic enol ethers for the formation of carbon-carbon bonds. Exocyclic enol ethers have been underutilized in organic synthesis, especially in this context. Over the period of this award we expanded both the scope and utility of the carbonyl ene reaction of exocyclic enol ethers, a process previously developed in our laboratories. As part of this process we identified several catalysts that allow us to influence both relative and absolute stereochemistry of these transformations. Control of stereochemistry has practical value as the relative orientation of groups within a molecule and the spatial orientation of individual compounds may affect biological activity and other chemical properties. Several new methodologies were also developed; the ruthenium-catalyzed Alder-ene and imine addition reactions of exocyclic enol ethers, and a direct alkylation reaction of endocyclic enol ethers. The products of these reactions are useful building blocks for organic synthesis. The preparation of more complex systems, including some not readily accessible by other means, was achieved by the implementation of both two-directional and tandem reaction sequences. As part of this work, a fragment that corresponds to a subunit of the spirastrellolides was prepared. These natural products impede cell division at the 1nM level and are leads for anticancer therapeutics. Overall, these studies have resulted in the development of synthetically useful methodologies that can be used for the efficient preparation of structurally diverse, functionalized tetrahydropyrans and related compounds. The fundamental knowledge gained through these studies provides a foundation for the further manipulation of both exocyclic and endocyclic enol ethers in complex molecule synthesis. The development of new synthetic methods for small molecule synthesis broadly impacts disciplines in science and engineering that make use of organic compounds. For example, application of these methods for the synthesis of biologically active molecules may result in the development of new therapeutic agents and thus contributes broadly to disciplines in the pharmaceutical and health sciences. Small molecule synthesis can also impact industries involved in the use and development of pesticides, flavors & fragrances, and materials, among others. The research described above has also provided professional training for three graduate students and ten undergraduates. This training included the development of experimental techniques, data collection and analysis, and the presentation of research results in both written and oral formats. Graduate students gain leadership skills and teaching experience by helping to mentor the undergraduates in the laboratory. Three of these students who contributed to this work were women and one was a minority. Of the eight students who have received Ph.D., M.S. or B.S. degrees since the start of this award, all are employed in the chemical industry, are pursuing advanced study in chemistry or biochemistry Ph.D. programs, or are attending professional school in health related fields.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Suk-Wah Tam-Chang
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Syracuse University
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