Cynthia M. Dupureur, Interim Department Chair
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Chemistry & Biochemistry: Summer 2016
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Dr. Hamper received his B.A. from Kalamazoo College and his Ph.D from the University of Illinois-Urbana. He began with Monsanto in St. Louis, and later joined G.D. Searle to pursue discovery medicinal chemistry. This led to research assignments in Pharmacia and Pfizer following a number of industry mergers/acquisitions. In 2010, he joined the faculty at UMSL and is now Assistant Teaching Professor.
Our lab investigates continuous flow chemistry for the preparation of biologically relevant target molecules and improvement of reaction processes. Chemical reactions in continuous flow processes are inherently more efficient than batch processes, and can lead to advantages based on green chemistry principles. Monoliths and functionalized polymeric beads incorporating specifically designed organic molecules are prepared and evaluated for catalysis of reactions and selective absorption of solute molecules in flow devices. We employ a number of spectroscopic and chromatographic techniques to determine the nature of intermolecular interactions. This allows optimal selection of candidate molecules for incorporation into a larger molecular superstructure such as silica monoliths or polymeric materials.
Direct Uncatalyzed Amination of 2-Chloropyridine using a Flow Reactor
Chloropyridines are efficiently converted to 2-aminopyridines by uncatalyzed nucleophilic aromatic substitution (SNAr) in NMP, DMF or DMA using a continuous flow reactor. A variety of secondary amines undergo SNAr with both electron rich and electron deficient 2-chloropyridines to afford 2-aminopyridines in good to excellent yield. The flow reactor, which provides a short reaction time and high temperatures up to 300 oC, can overcome the activation barrier for reactions with unactivated substrates. Short reaction times result in fewer side products and can afford milligram to multi-gram quantities of product using continuous flow.
Parallel Solid Phase Synthesis and High Throughput 1H NMR Evaluation of a 96-Member 1,2,4-Trisubstituted-pyrimidin-6-one-5-carboxylic Acid Library
We have used a simple malonate resin 7 to prepare a multifunctional pyrimidinone heterocycle by multistep solid phase synthesis. This system is amenable to flow chemistry allowing synthesis of complex organic compounds without isolation of any of the intermediates.
We have use solid phase synthesis as a platform for preparation of a number of novel heterocycles and oligomers. These reaction methods can be used for parallel synthesis of libraries of compounds for a variety of targets. Compounds can be chosen for pharmaceutical targets, new materials or agrochemicals based on design. The input for preparation and purification of the targeted compounds is greatly improved over single compound synthesis and allows preparation of sets of compounds having unique information content.
Selected Recent Publications
″Enantioseparation of α-Hydroxyallylphosphonates and Phosphonoallylic Carbonate Derivatives on Chiral Stationary Phases Using Sequential UV, Polarimetric, and Refractive Index Detection,″ B. C. Hamper, M. P. Mannino, M. E. Mueller, L. T. Harrison and C. D. Spilling, Chirality, 2016, Ahead of Print
″Discovery of N-(4-Fluoro-3-methoxy-benzyl)-6-(2-(((2S,5R)-5-(hydroxy-meth-yl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methyl-pyrimidine-4-carbox-amide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis,″ P. G. Ruminski, M. Massa, J, Strohbach, C. E. Hanau, M. Schmidt, J. A. Scholten, T. R. Fletcher, B. C. Hamper, Bruce C.; J. N. Carroll, H. S. Shieh, N. Caspers, B. Collins, M. Grapperhaus, K. E. Palmquist, J. Collins, J. E. Baldus, J. Hitchcock, H. P. Kleine et al. J. Med. Chem., 2016, 59, 313.
″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, J-Q. Yu, J. Liu and C. J. Welch. Org. & Biomol Chem. 2014, 12, 2161
″A Practical and Scalable Synthesis of (S)- and (R)-1-(Dimethoxyphosphoryl)allyl Methyl Carbonates, ″ S. Roy, N. Sutivisedsak, B. C. Hamper, A. M. Lyss and C. D. Spilling, Synthesis 2014, 46, 3669
"Stucture-based parallel medincinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors," L. Xing, B. Hamper, T. R. Fletcher, J. M. Wendling, J. Carter, J. K. Gierse and S. Liao, Bioorg. Med. Chem. Lett. 2011, 21, 993
"The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 3: The three microdose candidates," J. L. Wang, K. Aston, D. Lindburg, C. Ludwig, A. E. Hallinan, F. Koszyk, B. Hamper, D. Brown, M. Graneto, J. Talley, T. Maziasz, J. Masferrer and J. Carter, Bioorg. Med. Chem. Lett. 2010, 20, 7164-7168.
J L. Wang, D. Lindburg, M. J. Graneto, J. Springer, J. Rogier, B. Hamper, S. Liao, J. L. Pawlitz, R. G. Kurumbail, T. Maziasz, J. J. Talley, J. R. Kiefer and J. Carter, "The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life", Bioorg. Med. Chem. Lett. 2010, 20, 7159.
"Discovery of pyridine-4-yl -2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis," M. E. Schnute, P. M. O’Brien, J. Nahra, M. Morris, W. H. Roark, C. E. Hanau, P. G. Ruminski, J. A. Scholten, T. R. Fletcher, B. C. Hamper, J. N. Carroll, W. C. Patt, H. S. Shieh, B. Collins, A. G. Pavlovsky, K. E. Palmquist, K. W. Aston, J. Hitchcock, M. D. Rogers, J. McDonald, A. R. Johnson, G. E. Munie, A. J. Wittwer, C.-F. Man, S. L. Settle, O. Nemirovskiy, L. E. Vickery, A. Agawal, R. D. Dyer and T. Sunyer, Bioorg. Med. Chem. Lett. 2010, 20, 576.
"Discovery of an Oral Potent Selective Inhibitor of Hematopoietic Prostaglandin D Synthase HPGDS , C. P. Carron, J. I. Trujillo, K. L. Olson, W. Huang, B. C. Hamper, T. Dice, B. E. Neal, M. J. Pelc, J. E. Day, D. C. Rohrer, J. R. Kiefer, J. B. Moon, B. A. Schweitzer, T. D. Blake, S. R. Turner, R. Woerndle, B. L. Case, C. P. Bono, V. M. Dilworth, C. L. Funckes-Shippy, B. L. Hood, G. M. Jerome, C. M. Kornmeier, M. R. Radabaugh, M. L. Williams, M. S. Davies, C. D. Wegner, D. J. Welsch, W. M. Abraham, C. J. Warren, M. E. Dowty, F. Hua, A. Zutshi, J. Z. Yang and A. Thorarensen," ACS Med. Chem. Lett. 2010, 1, 59.
"Parallel solid phase synthesis and high throughput 1H NMR evaluation of a 96-member 1,2,4-trisubstituted-pyrimidin-6-one-5-carboxylic acid library", J. B. C. Hamper, A. S. Kesselring, R C. Chott and S. Yang, Combinatorial Chem. 2009, 11, 469.
"Direct uncatalyzed amination of 2-chloropyridine using a flow reactor," B. C. Hamper ;and E. Tesfu ,Synlett, 2007, 14, 2257.