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William J. Chain, Assistant Professor, Associate Dept. Chair

Contact

Department of Chemistry
University of Hawai’i at Manoa
2545 McCarthy Mall
Honolulu, HI 96822-2275

Phone: (808) 956-5795
Fax: (808) 956-5908
Email: William Chain
Office: Bilger 205B

Educational Background

William Chain received his B.S. degree in Chemistry from the Pennsylvania State University in 2001. At Penn State, he conducted research in the laboratories of Professor Blake R. Peterson studying the synthesis of ribonucleoside analogues. He received his Ph.D. from Harvard University in 2006. Under the guidance of Professor Andrew G. Myers, he developed protocols for the stereocontrolled construction of quaternary carbon centers by the alkylation of disubstituted pseudoephedrine amide enolates. He then moved to Princeton University to begin postdoctoral studies with Professor Erik J. Sorensen. At Princeton, he worked on the total synthesis of maoecrystal V, a potent and selective HeLa cell inhibitor. In the fall of 2009, he joined the faculty at the University of Hawai’i as an Assistant Professor of Chemistry.

Research Interests

The Chain group is focused on exploring classical and fundamental reactivity as a means of approaching new and long standing synthetic challenges. We are interested in the synthesis of several natural products with potent and selective anti-cancer activity, utilizing carbonyl-enabled carbon-carbon bond formations to construct their core structures in short order. We are also actively developing new methods for the synthesis of medium-sized rings.

Targets under Investigation in the Chain Group

Englerin A

We have recently achieved an efficient synthesis of englerin A, a guaiane sesquiterpene that was isolated from the bark of Phyllanthus engleri, a plant indigenous to east Africa. The englerins consist of a 5-6-5 fused tricyclic structure with an ether bridge and two ester bearing stereogenic centers, including a highly unusual glycolate residue. Englerin A is a potent and selective inhibitor of the growth of six human renal cancer cell lines, and appears to operate by a new and unknown mechanism of action. The englerins have been the subject of intense study in the synthetic organic chemistry community and several elegant solutions have been described. Our eight-step synthesis of englerin A leverages simple carbonyl-enabled reactions.

Our route is the shortest, most efficient preparation of the englerins reported to date, and it is amenable to the production of a diverse series of analogs for structure-function studies and determining the mode of action of these natural products. These studies are currently underway as part of a collaboration with cancer biologists at the University of Hawaii Cancer Center.

Azepinone Synthesis

Azepinones are important heterocycles embedded in the structures of many biologically-relevant alkaloids, and can serve as intermediates in the synthesis of a variety of complex nitrogen-containing molecules. We recently reported a one-pot synthesis of 1H-azepin-5(2H)-ones and noted their sensitivity to base; 1H-azepin-5(2H)-ones undergo an unexpectedly facile isomerization to the corresponding 1H-azepin-5(4H)-ones under conditions that were previously described for their synthesis. The 1H-azepin-5(2H)-ones are robust toward acid, an observation we used to our advantage in developing an efficient synthetic protocol. The 1H-azepin-5(2H)-ones are obtained in high yield in a one-pot procedure via the cycloaddition of Danishefsky’s diene to 2H-azirine-3-carboxylate ethyl ester, followed by a ring expansion in the presence of silica gel. We have also developed protocols for the alkylation of azepinones at nitrogen with alkyl halides and epoxides and noted an unexpected ring contraction under oxidative conditions.

Recent Publications

  • Chain, W. J. Synthetic Strategies Toward the Guaiane Sesquiterpene Englerin A. Synlett, 2011, 2605–2608. DOI: 10.1055/s-0030-1289521
  • Li, Z.; Nakashige, M.; Chain, W. J. A Brief Synthesis of (–)-Englerin A. J. Am. Chem. Soc. 2011, 133, 6553–6556. DOI: 10.1021/ja201921j. One of the “Most Read Articles” in May 2011. Highlighted in Chemical and Engineering News 2011, 89, 36. (April 18, 2011), and in Angew. Chem. Int. Ed. 2011, 50, 7737–7739.
  • Dubinina, G. G.; Chain, W. J. Reactions of azepinones with electrophiles. Tetrahedron Lett., 2011, 52, 939-942. DOI: 10.1016/j.tetlet.2010.12.091
  • Dubinina, G. G.; Yoshida, W. Y.; Chain, W. J. On the preparation of azepinones Tetrahedron Lett. 2010, 51, 5325-5327. DOI: 10.1016/j.tetlet.2010.08.003