Christopher D. Spilling, Chairman
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Chemistry & Biochemistry: Summer 2015
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Robert W. Murray Lecture
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Dr. Spilling received his B.Sc. (Hons.) degree and Ph.D. degree from the University of Technology, Loughborough, England. He was a Postdoctoral Fellow at Northwestern University before joining the UM-St. Louis faculty in 1989. He was a Visiting Scholar at Cambridge University in 1996-97 and has served as Department Chair since 2004. He served as the chair of the Faculty Senate and University Assembly from 2012-2014.
The last decade has seen a rapid expansion in the interest in the asymmetric synthesis of 1-substituted phosphonates. The unique properties of phosphorus provide a fascinating and challenging approach to stereoselective reactions. Our goal is to examine the use of chiral phosphonamides and phosphonates in stereoselective reactions. We reported the first example of a lathanide chiral catalyst in the addition of simple phosphites to achiral aldehydes. More recently, we discovered some promising titanium alkoxide systems. We are attempting to expand the chemistry of allylic hydroxy phosphonamides and phosphonates formed in the chemistry discussed above. Allylic hydroxy phosphonates are similar to regular allylic alcohols and should undergo similar chemistry. However, the presence of the phosphonate significantly alters the electronics of the system, and enables control of both regiochemistry and stereochemistry. Our initial work focused on the palladium catalyzed addition of amines to the carbonate derivatives of allylic hydroxy phosphonates, and several examples of this reaction have been performed. The rearrangement proceeds with complete retention of chirality. A number of 3,3 sigmatropic rearrangements and alkene addition reactions have been studied. The newly developed chemistry of the hydroxy phosphonates is being applied toward the synthesis of the cathepsin B, cruzain, and renin inhibitors, lactones and lactams.
Psammapsylin, fistularin, and the bastadins are related metabolites isolated from sponges found worldwide. This family of highly brominated compounds possess wide ranging biological activity, including anti-HIV activity, and anti-tumor properties. They are related in their biosynthetic origin, as oxidation products of tyrosine. We are exploring biomimetic approaches to the synthesis of several of these metabolites. The development of new methodology is guided by the biosynthetic pathway proposed for the formation of the tyrosine metabolites. As an extension of this project, we recently initiated research into methods for the facile synthesis of unsymmetric biaryl ethers.
"Trapping hemiacetals with phosphono substituted palladium π-allyl complexes for the synthesis of substituted cyclic ethers", N: Sutivisedsak, S. Dawadi and C. D. Spilling, Tetrahedron Lett. 2015, 56, 3534
"Rat hormone sensitive lipase inhibition by cyclopostins and their analogs", E. Vasilieva, S. Dutta, R. K. Malla, B. P. Martin, C. D. Spilling and C. M. Dupureur, Bioorganic & Med. Chem. 2015, 23, 944.
"A New Class of Salicylic Acid Derivatives for Inhibiting YopH of Yersinia pestis", M. P. Paudyal, L. Wu, Z.-Y. Zhang, C. D. Spilling and C. F. Wong, Bioorg. Med. Chem. 2014, 22, 6781.
″Relay cross metathesis reactions of vinylphosphonates″, R. K. Malla, J. N. Ridenour and C. D. Spilling, Beilstein J. Org. Chem. 2014, 10, 1933.
"Support of academic synthetic chemistry using separation technologies from the pharmaceutical industry", E. L. Regalado, M. C. Kozlowski, J. M. Curto, T. Ritter, M. G. Campbell, A. R. Mazzotti, B. C. Hamper, C. D. Spilling, M. P. Mannino, L. Wan et al. Org. & Biomolecular Chem. 2014, 12, 2161
"Enantioselective Inhibition of Microbial Lipolytic Enzymes by Nonracemic Monocyclic Enolphosphonate Analogues of cylcophostin", V. Point, R. K. Malla,F. Carriere, S. Canaan, C. D. Spilling and J-F. Cavalier, J. Med. Chem. 2013, 56, 4393.
"Synthesis and Kinetic Evaluation of Cyclophostin and Cyclophostins Phosphonate Analogs as Selective and Potent Inhibitors of Microbial Lipases", V. Point, Vanessa; R. K. Malla, S. Diomande, B. P. Martin, V. Delorme, F. Carriere, S. Canaan, N. P. Rath, C. D. Spilling and J-F. Cavalier, J. Med. Chem., 2012, 55, 1024.
"Synthesis and Biological Evaluation of Purpurealidin E-Derived Marine Sponge Metabolites: Aplysamine-2, Aplyzanaine A, and Suberedamines A and B", S. K. Kottakota, D. Evangelopoulos, A. Alnimr, S. Bhakta, T. D. McHugh, M. Gray, P. W. Groundwater, E. C. L. Marrs, J. D. Perry, C. D. Spilling, and J. J. Harburn, J. Nat. Prod., 2012, 75, 1090.
"An Expeditious Total Synthesis of Both Diastereomeric Lipid Dihydroxytetrahydrofurans from Noptheia anomala", S. Roy and C. D. Spilling, Org. Lett., 2012, 14, 2230.
"Chelating compounds and immobilized tethered chelators," R. A. Yokel, W. R. Harris, C. D. Spilling, R. J. Kuhn and S. Dawadi, U.S. Pat. Appl. Publ. 2012, US 2012-0061325 A120120315.
"The First Total Synthesis of ()-Cyclophostin and ()-Cyclipostin P: Inhibitors of the Serine Hydrolases Acetyl Cholinesterase and Hormone Sensitive Lipase", R. K. Malla, S Bandyopadhyay, C. D. Spilling, S. Dutta and C. M. Dupureur, Organic Lett. 2011, 13, 3094.
"Concise synthesis of 1,3-di-O-substituted tetrahydropyran derivatives as conformationally stable pyranose mimetics", L. K. Mydock, C. D. Spilling and A. V. Demchenko, Comptes Rendus Chim. 2011, 14, 301.
"A Formal Synthesis of the C1-C9 Fragment of Amphidinolide C Employing the Tamaru Reaction", M. P. Paudyal, N. P. Rath and C. D. Spilling, Organic Lett. 2010, 12, 2954.
"Synthesis and kinetic analysis of some phosphonate analogs of cyclophostin as inhibitors of human acetylcholinesterase". S. Dutta, R. K.Malla, S. Bandyopadhyay, C. D. Spilling, and C. M. Dupureur, Bioorg. & Med. Chem. 2010, 18, 2265.
"Total synthesis of rapamycin", S. V. Ley, M. N. Tackett,M. L. Maddess, J. C. Anderson, P. E. Brennan, M. W. Cappi, J. P. Heer, C. Helgen, M. Kori, C. Kouklovsky, S. P. Marsden, J. Norman, D. P. Osborn, M. A. Palomero, J. B. Pavey, C. Pinel, L. A. Robinson, J. Schnaubelt, J. S. Scott, C. D. Spilling, H. Watanabe, K. E. Wesson and M. C. Willis, Chemistry-A Eur. J. 2009, 15, 2874.