University of Delaware
010 Lammot du Pont Lab
Newark, DE 19716
(b. 1979) B.S., 2001 Pennsylvania State University; A.M., 2003, Harvard University; Ph.D., 2006 Harvard University; Postdoctoral Fellow, 2006 – 2009, Princeton University.
Research in the Chain group is focused primarily on the efficient total synthesis of natural products and the development of new bond-forming processes in that pursuit. We are attracted to natural products whose inherent structural features create opportunities for rapid assembly – opportunities afforded us by the reactivity bestowed upon organic molecules by the carbonyl function and by the manipulation of aromatic systems. Natural products with promising anti-cancer activity and therapeutic potential are of particular interest.
We are also deeply interested in the manipulation of aromatic systems and bond formations that occur by the temporary loss of aromaticity. By elevating or inverting the normal reactivity of electron-rich aromatics, we are developing new bond formations that are not easily achieved by classical substitutive chemistry.
We are interested in the synthesis of several complex terpenoids that are potent cell growth inhibitors of renal, hepatocellular, and breast cancer. We collaborate with cancer biologists in structure-function and target identification studies with our natural products, with the overall goal of contributing new chemotherapeutics for the fight against cancer. Our targets are selected for structural complexity, for opportunities in new methods development, and for biological interest. We 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. These natural products have been intensely studied in the synthetic organic chemistry and cancer biology. Our eight-step synthesis of englerin A leverages simple carbonyl-enabled reactions. Other targets of interest in the group include the anti-cancer natural products psiguadial A (a meroterpenoid that contains a novel fused 7-5-7 oxatricyclic ring system) and premnalatifolin A (a dimeric icetexane terpenoid consisting of two oxygenated subunits containing an interesting 6-7-6 tricyclic ring system), as well as the grandilodine alkaloids (complex polycyclic alkaloids that may reverse drug resistance in some human cancers).
Michael Additions Involving ortho-Quinone Methides
ortho-Quinone methides (o-QMs), or o-methylene cyclohexadienones, are highly reactive species that participate in a variety of organic reactions. o-QMs are ubiquitous in nature and are known to be biosynthesized by a variety of animals and plants as both defensive and therapeutic agents. Their high reactivity, while a benefit in terms of synthetic utility, is often aliability that necessitates their generation and consumption in situ. We have developed a new carbon-carbon bond forming reaction in which ketone- or ester-derived enolates and o-QMs are generated simultaneously in situ in the same reaction flask under the same reaction conditions and joined to give a variety of functionalized phenols. In this reaction, mixtures of silyl-protected phenolic benzyl halides or acetates and silyl enol ethers or silyl ketene acetals reveal o-QMs and enolates, respectively, upon treatment with anhydrous fluoride. The enolates then add to the o-QMs in a Michael addition to give a ketophenoxide, thus restoring aromaticity.
Metal-Free Functionalization of Anilines
The direct functionalization of anilines is often compromised by the high nucleophilicity of the aromatic ring, and the facility with which the nitrogen atom is engaged directly rather than the aromatic ring itself. The nucleophilicity of anilines at nitrogen can be modulated by the use of temporary protective groups, however such groups can limit the synthetic latitude one might typically enjoy with aromatic systems. We are exploring chemistry that leverages the nitrogen functionality of aniline to enable selective reactivity on the aromatic ring. Transient functionalization of the amino group affords us the ability to introduce carbon–heteroatom and carbon–carbon bonds via inversion of reactivity – thus converting the typical liability experienced with anilines into an advantage that enables controllable, metal-free, and environmentally friendly aromatic substitution reactions.
- Lewis, R. S.; Garza, C. J.; Dang, A. T.; Pedro, T.-K. A.; Chain, W. J. Michael Additions of Highly Basic Enolates to ortho-Quinone Methides. Org. Lett. 2015, 17, 2278–2281.
- Lewis, R. S.; Nakashige, M. L.; Chain, W. J. Transformation of N,N-Dimethylaniline-N-oxides into N-methylindolines by a Tandem Polonovski-Mannich Reaction. Tetrahedron Lett. 2015, In press.
- Lewis, R. S.; Wisthoff, M. W.; Grissmerson, J.; Chain, W. J. Metal-Free Functionalization of N,N-Dialkylanilines via Temporary Oxidation to N,N-Dialkylaniline-N-Oxides and Group Transfer. Org. Lett. 2014, 16, 3832–3835.
- Sulzmaier, F. J.; Li, Z.; Nakashige, M. L.; Fash, D. M.; Chain, W. J.; Ramos, J. W. Englerin A selectively induces necrosis in human renal cancer cells. PLoS ONE,2012, 7, e48032.
Li, Z.; Nakashige, M.; Chain, W. J. A Brief Synthesis of (–)-Englerin A. J. Am. Chem. Soc. 2011, 133, 6553–6556.
Dubinina, G. G.; Yoshida, W. Y.; Chain, W. J. On the Preparation of Azepinones. Tetrahedron Lett. 2010, 51, 5325–5327.
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