Our research program focuses on (a) The total synthesis of natural products; (b) organometallic and heterocyclic methodology, which in many cases is strongly connected to new approaches to natural products; (c) combinatorial chemistry, which is used as a tool to evaluate the biomedical potential of natural products; and (d) the computational prediction of macroscopic properties, in particular optical rotations.
· Total Synthesis of Natural Products
Total Synthesis encompasses all aspects of organic chemistry: The development of new methodology, mechanistic and physical organic experiments, conformational and configurational analysis by spectroscopic and computational methods, and bioorganic and medicinal chemistry. Total Synthesis is also one of the broadest and most effective training experiences for synthetic chemists. Some of the natural products that we have completed in recent years are shown below. We select target molecules on the basis of their unique architectures, biological activity, and as showcases for our methodology. Most recently, we have completed total syntheses of disorazole C1, tuberostemonine and bistramide C.
· Organometallic Chemistry
Our methodology studies in organometallic chemistry aim at the discovery of fundamentally new reactions. Recently, we have developed the asymmetric Zr-Zn transmetalation and discovered the water acceleration effect in catalytic asymmetric carbometalations of alpha-olefins. We have extended the latter discovery toward the first tandem Claisen-carbometalation. The Zr/Zn bimetallic system offers amazingly diverse reaction pathways and the opportunity to form 10-12 new carbon-carbon bonds in a one-pot sequence.
· Heterocyclic Chemistry
We are interested in the development of new stereo-selective methods for the preparation of highly functionalized heterocycles. In particular, we have reported numerous examples of innovative new protocols for the preparation of five-membered heterocycles that are now the methods of choice applied by many researchers in industry and academe.
Since most of our current targets for total synthesis contain heterocyclic moieties, we continue our search for new preparations of diverse heterocyclic ring systems.
· Combinatorial Synthesis and Medicinal Chemistry
We apply modern automated synthesis methods in heterocyclic and organometallic chemistry, and for the structure-activity analysis of bioactive natural products and new lead structures. Specifically, pursue interdisciplinary, collaborative drug development in cancer therapy and aging research. All of our targets in phosphatase & kinase inhibition, antitubulin agents, and mitochondrial targeting are structurally novel. These projects take advantage of the infrastructure of our Combinatorial Chemistry Center (CCC, http://ccc.chem.pitt.edu) and the Center for Chemical Methodologies & Library Development (UPCMLD, http://ccc.chem.pitt.edu/UPCMLD/index.html).
Pharmacophore Mapping at the Colchicine Binding Site of ab-Tubulin:
· Computational Prediction of Macroscopic Properties
In another exciting interdisciplinary collaboration, we are exploring the computational assignment of the relative and absolute stereochemistry of organic molecules. After our initial benchmark success with hennoxazole A, we have expanded this approach to several other natural products and new synthetic organic compounds with unassigned absolute configurations.
J. Am. Chem. Soc.2003, 125,
1569.
Boltzmann weighted atomic maps of monomer and dimer species superimposed on minimum energy conformers of pantolactone, with color legend for sign and magnitude of atomic contribution to [a]D
· Selected References (2004-2005)
Total Synthesis of Natural Products:
• "Asymmetric Total Syntheses of Tuberostemonine, Didehydrotuberostemonine and 13-Epituberostemonine." Wipf, P.; Rector, S. R. J. Am. Chem. Soc. 2005, 127, 225 .
• "Total Synthesis and Structure Elucidation of (+)-Bistramide C." Wipf, P.; Hopkins, T. D. Chem. Commun.2005, 3421-3423.
• "Total Synthesis of (-)-Disorazole C1." Wipf, P.; Graham, T. H. J. Am. Chem. Soc. 2004, 126, 15346.
• "Synthesis of the Tubuvaline-Tubuphenylalanine (Tuv-Tup) Fragment of Tubulysin." Wipf, P.; Takada, T.; Rishel, M. J. Org. Lett. 2004, 6, 4057.
Synthetic Methodology, Heterocyclic and Organometallic Chemistry:
• "Convergent Approach to (E)-Alkene and Cyclopropane Peptide Isosteres." Wipf, P.; Xiao, J. Org. Lett. 2005, 7, 103-106.
• "Microwave-Assisted Synthesis of Allylic Amines: Considerable Rate Acceleration in the Hydrozirconation-Transmetalation-Aldimine Addition Sequence." Wipf, P.; Janjic, J.; Stephenson, C. R. J. Org. Biomol. Chem. 2004, 2, 443-445.
• "Selective Carbon-Carbon Bond Formations with Alkenylzirconocenes." Wipf, P.; Nunes, R. L. Tetrahedron (Symposium-in-Print No. 102 on Recent Advances in the Chemistry of Zirconocenes) 2004, 60, 1269-1279.
• "Electrostatic vs Steric Effects in Peptidomimicry. Synthesis and Secondary Structure Analysis of Gramicidin S Analogs with (E)-Alkene Peptide Isosteres." Wipf, P.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 5742.
• Synthesis and Hetero-Michael Addition Reactions of 2-Alkynyl Oxazoles and Oxazolines." Wipf, P.; Graham, T. H. Org. Biomol. Chem. 2005, 3, 31-35.
• "Synthesis of Homoallylic Amines by Hydrozirconation–Imine Addition of Allenes." Wipf, P.; Pierce, J. G. Org. Lett. 2005, 7, 3537-3540.
• "Three-Component Synthesis of a,b-Cyclopropyl-g-Amino Acids." Wipf, P.; Stephenson, C. R. J. Org. Lett. 2005, 7, 1137-1140.
• "Microwave-Assisted Synthesis of Allylic Amines: Considerable Rate Acceleration in the Hydrozirconation-Transmetalation-Aldimine Addition Sequence." Wipf, P.; Janjic, J.; Stephenson, C. R. J. Org. Biomol. Chem. 2004, 2, 443-445.
• "Silver(I)-Catalyzed Addition of Zirconocenes to Glycal Epoxides. A New Synthesis of a-C-Glycosides." Wipf, P.; Pierce, J. G.; Zhuang, N. Org. Lett. 2005, 7, 483-485.
• "Oxidative Spiroacetalizations and Spirolactonizations of Arenes." Rodriguez, S.; Wipf, P. Synthesis 2004, (17), 2767-2783.
• "Diversity-Oriented Synthesis of Azaspirocycles." Wipf, P.; Stephenson, C. R. J.; Walczak, M. A. A. Org. Lett. 2004, 6, 3009-3012.
Combinatorial Synthesis and Medicinal Chemistry:
• "Microwave-Assisted “Libraries from Libraries” Approach toward the Synthesis of Allyl- and C-Cyclopropylalkylamides." Wipf, P.; Coleman, C. M.; Janjic, J. M.; Iyer, P. S.; Fodor, M. D.; Shafer, Y. A.; Stephenson, C. R. J.; Kendall, C.; Day, B. W. J. Comb. Chem. 2005, in press.
• "Chemistry and Biology of Wortmannin." Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053-2061.
• "A Pregnane X Receptor Agonist with Unique Species-Dependent Stereoselectivity and its Implications in Drug Development." Mu, Y.; Stephenson, C. R. J.; Kendall, C.; Saini, S. P. S.; Toma, D.; Ren, S.; Cai, H.; Strom, S. C.; Day, B. W.; Wipf, P.; Xie, W. Mol. Pharmacol. 2005, 68, 403-413.
• "Synthesis and Biological Evaluation of Synthetic Viridins Derived from C(20)-Heteroalkylation of the Steroidal PI-3-Kinase Inhibitor Wortmannin." Wipf, P.; Minion, D. J.; Halter, R. J.; Berggren, M. I.; Ho, C. B.; Chiang, G. G.; Kirkpatrick, L.; Abraham, R.; Powis, G. Org. Biomol. Chem. 2004, 2, 1911-1920.
• "Dual Specificity Protein Phosphatases: Therapeutic Targets for Cancer and Alzheimer’s Disease." Ducruet, A. P.; Vogt, A. Wipf, P.; Lazo, J. S. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 725-750.
• "Natural Product Based Inhibitors of the Thioredoxin – Thioredoxin Reductase System." Wipf, P.; Lynch, S. M.; Birmingham, A.; Tamayo, G.; Jimenez, A.; Campos, N.; Powis, G. Org. Biomol. Chem. 2004, 2, 1651-1658.
• "Molecular Pharmacology and Antitumor Activity of PX-866, a Novel Inhibitor of Phosphatidylinositol-3-kinase Signaling." Ihle, N. T.; Williams, R.; Chow, S.; Chew, W.; Paine-Murrieta, G.; Minion, D. J.; Halter, R. J.; Wipf, P.; Abraham, R.; Kirkpatrick, L.; Powis, G. Mol. Cancer Therap. 2004, 3, 763-772.
• "New Antiestrogens from a Library Screen of Homoallylic Amines, Allylic Amines, and C-Cyclopropylalkylamines." Janjic, J. M.; Mu, Y.; Kendall, C.; Stephenson, C. R. J.; Balachandran, R.; Raccor, B. S.; Lu, Y.; Zhu, G.; Xie, W.; Wipf, P.; Day, B. W. Bioorg. Med. Chem. 2005, 13, 157-164.
• "Small Molecule Modulators of Endogenous and Co-Chaperone-Stimulated Hsp70 ATPase Activity." Fewell, S. W.; Smith, C. M.; Lyon, M. A.; Dumitrescu, T. P.; Wipf, P.; Day, B. W.; Brodsky, J. L. J. Biol. Chem. 2004, 279, 51131-51140.
Computational Studies:
• "Assignment of the Absolute Configuration of [n]-Ladderanes by TD-DFT Optical Rotation Calculations." Zuber, G.; Goldsmith, M.-R.; Beratan, D. N.; Wipf, P. Chirality 2005, 17, 507-510.
• "Towards Raman Optical Activity Calculations of Large Molecules." Zuber, G.; Wipf, P.; Beratan, D. N. ChemPhysChem 2005, 6, 595-597.