Research in the Wipf Group

9/1/2005

Our research program focuses on:

• total synthesis of natural products;

• organometallic and heterocyclic methodology;

• automation mediated organic synthesis (AMOS), mainly used in the context of medicinal chemistry;

• computational prediction of macroscopic properties, specifically ORD, CD, RAO and NMR computation.

 

Total Synthesis encompasses all aspects of organic chemistry: The development of new methodology, mechanistic and physical organic experiments, conformational and stereochemical analysis by spectroscopic and computational methods, and bioorganic and medicinal chemistry. Total Synthesis is also one of the most effective student training experiences. We select target molecules on the basis of their unique architectures, biological activity, as well as for showcasing our methodologies.

Tuberostemonine is a member of the Stemona family of alkaloids that has attracted increasing interest from synthetic chemists in the last 10 years. Our recent publication ("Asymmetric Total Syntheses of Tuberostemonine, Didehydrotuberostemonine and 13-Epituberostemonine." Wipf, P.; Rector, S. R. J. Am. Chem. Soc. 2005, 127, 225-235) further elaborates on the oxidative cyclization of tyrosine as a unified strategy toward the major Stemona alkaloid ring scaffolds:

Furthermore, the tuberostemonine synthesis highlights a threefold use of ruthenium catalysts, first in azepine ring-closing metathesis and then in alkene isomerization and cross-metathesis propenyl-vinyl exchange, as well as methodology developments from our laboratory such as the stereoselective attachment of the g-butyrolactone ring to the tetracycle core structure by use of a lithiated ABO-orthoester.

While tuberostemonine illustrates the strategic and tactical motivations for our total synthesis program, disorazole C1 and bistramide C are examples for recent natural product syntheses inspired by the pursuit of interesting biological activities and fundamental computational studies, respectively.

We prepare analogs of disorazole C1 in order to determine the mode of action and potential therapeutic applications of this highly potent antimitotic agent ("Total Synthesis of (-)-Disorazole C1." Wipf, P.; Graham, T. H. J. Am. Chem. Soc. 2004, 126, 15346-15347; "Cellular Analysis of Disorazole C1 and Structure-Activity Relationship of Analogs of the Natural Product." Wipf, P.; Graham, T. H.; Vogt, A.; Sikorski, R.; Ducruet, A. P.; Lazo, J. S. Chem. Biol. Drug Design 2006, 67 (1), 66-73). Bistramide C represents the most complex organic compound to date whose relative configuration could be assigned based on ab initio chiroptical calculations ("Total Synthesis and Structure Validation of (+)-Bistramide C." Wipf, P.; Hopkins, T. D. Chem. Commun. 2005, 3421-3423; "Systematic Assignment of the Configuration of Flexible Natural Products by Spectroscopic & Computational Methods: The Bistramide C Analysis." Zuber, G.; Goldsmith, M.-R.; Hopkins, T. D.; Beratan, D. N.; Wipf, P. Org. Lett. 2005, 7 (23), 5269-5272).

We use our zirconocene methodology for the preparation of alkene and cyclopropane building blocks, and our Center has expanded this work toward chemical library synthesis ("Application of Divergent Multi-Component Reactions in the Synthesis of a Library of Peptidomimetics Based on g-Amino-a,b-Cyclopropyl Acids." Wipf, P.; Werner, S.; Woo, G. H. C.; Stephenson, C. R. J.; Walczak, M. A. A.; Coleman, C. M.; Twining, L. A. Tetrahedron (Symposium-in-Print No. 114 on Multicomponent Reactions) 2005, 61 (48), 11488-11500).

We are also actively exploring the study of fundamental conformational and electronic substituent effects on amide bond peptide isosteres. Since its discovery in 1942, the cyclodecapeptide antibiotic Gramicidin S (GS, cyclo[(Val-Orn-Leu-DPhe-Pro-)2]) has served as an inspiration for the design of antibacterial agents and antimicrobial peptides, as well as the study of conformational mimicry. GS is therefore a particularly significant target for the evaluation of peptide mimetics as surrogates for the b-turn inducing sequence ("Electrostatic vs Steric Effects in Peptidomimicry. Synthesis and Secondary Structure Analysis of Gramicidin S Analogs with (E)-Alkene Peptide Isosteres." Xiao, J.; Weisblum, B.; Wipf, P. J. Am. Chem. Soc. 2005, 127, 5742-5743). In an exciting biomedical application of these principles, we were able to design and synthesize a mitochondrial membrane targeting sequence that has shown in vivo efficacy against hemorrhagic shock (Hoye, A. T.; Davoren, J. E.; Wipf, P.; Fink, M. P.; Kagan, V. E., "Targeting mitochondria." Acc. Chem. Res. 2008, 41, 87-97, and references cited therein).

The application of modern synthetic methodology for solving challenging biological and medical problems is an extremely fertile paradigm, and an increasing amount of our resources is dedicated to exploring opportunities in this interdisciplinary and collaborative research. For example, we have recently applied zirconocene methodology for C-glycoside synthesis and the efficient preparation of analogs of a galactosylceramide ("Expedient Synthesis of the a-C-Glycoside Analogue of the Immunostimulant Galactosylceramide (KRN7000)." Wipf, P.; Pierce, J. G. Org. Lett. 2006, 8, 3375-3378). The interest among biomedical researchers to use this compound as a probe for the study of dendritic cells prompted us to scale up our synthesis and make the compound freely available to interested biological groups. Several collaborative studies will spawn from this exploratory research, which, in turn, will provide incentives to further refine the synthetic methodologies.

Another representative illustration of the synergism between chemical probe development and diversity-oriented synthesis is our recent work on intramolecular cycloaddition reactions of bicyclobutanes ("Rhodium(I)-Catalyzed Cycloisomerizations of Bicyclobutanes." Walczak, M. A. A.; Wipf, P. J. Am. Chem. Soc. 2008, 130(22), 6924-6925). This project is of particular significance for us since it combines the fundamental chemical study of organometallics, highly strained carbocycles, and novel heterocyclic scaffolds, with the potential for innovative applications in the biological sciences.

In an exploratory line of research that aims to provide alternatives to the current rigid separation of chemical synthesis and biological screening, we are investigating dynamic combinatorial libraries ("Metathesis Reactions of Pyrazolotriazinones Generate Dynamic Combinatorial Libraries." Wipf, P.; Mahler, S. G.; Okumura, K. Org. Lett. 2005, 7, 4483-4486). While these approaches are clearly still in their infancy, in the future they could resolve the impracticality of synthesizing and analytically characterizing tens of thousands of small organic molecules as well as the spiraling costs of high-throughput screening.

In conclusion, our research program aims to broaden the arsenal of synthetic organic chemistry, showcase new methodology in natural product and designed molecule synthesis, apply these tools to cutting edge biological problems, and move forward with the development of new therapeutic strategies.

Selected recent publications

303. "Titanocene(III)-Catalyzed Formation of Indolines and Azaindolines." Wipf, P.; Maciejewski, J. P. Org. Lett. 2008, 10(x), in press.

299. "Formal Alder-Ene Reaction of a Bicyclo[1.1.0]butane in the Synthesis of the Tricyclic Quaternary Ammonium Core of Daphniglaucin." Ueda, M.; Walczak, M. A. A.; Wipf, P. Tetrahedron Lett. 2008, 49, 5986-5989.

294. "Computational Design, Synthesis and Biological Evaluation of para-Quinone-Based Inhibitors for Redox Regulation of the Dual-Specificity Phosphatase Cdc25B." Keinan, S.; Paquette, W. D.; Skoko, J. J.; Beratan, D. N.; Yang, W.; Shinde, S.; Johnston, P. A.; Lazo, J. S.; Wipf, P. Org. Biomol. Chem. 2008, 6, 3256-3263.

291. "Rhodium(I)-Catalyzed Cycloisomerizations of Bicyclobutanes." Walczak, M. A. A.; Wipf, P. J. Am. Chem. Soc. 2008, 130(22), 6924-6925.

287. "A Mitochondria-Targeted Nitroxide/Hemigramicidin S Conjugate Protects Mouse Embryonic Cells Against Gamma Irradiation." Jiang, J.; Belikova, N.; Hoye, A. T.; Epperly, M. W.; Greenberger, J. S.; Wipf, P.; Kagan, V. E. Int. J. Radiat. Oncol. Biol. Phys. 2008, 70, 816.

286. "An Experimental Survey of the Transition between Two-State and Downhill Protein Folding Scenarios." Feng, L.; Du, D.; Fuller, A. A.; Davoren, J. E.; Wipf, P.; Kelly, J. W.; Gruebele, M. Proc. Natl. Acad. Sci. USA 2008, 105(7), 2369-2374.

284. "Exploring the Optical Activity Tensor by Anisotropic Rayleigh Optical Activity Scattering." Zuber, G.; Wipf, P.; Beratan, D. N. ChemPhysChem 2008, 9(2), 265-271.

283. "Pyrimidinone-Peptoid Hybrid Molecules with Distinct Effects on Molecular Chaperone Function and Breast Cancer Cell Proliferation." Wright, C. M.; Chovatiya, R. J.; Jameson, N. E.; Turner, D. M.; Zhu, G.; Werner, S.; Huryn, D. M.; Pipas, J. M.; DayB. W.; Wipf, P.; Brodsky, J. L. Bioorg. Med. Chem. 2008, 16, 3291-3301.

282. "Targeting Mitochondria." Hoye, A. T.; Davoren, J.; Wipf, P.; Fink, M. P.; Kagan, V. E. Acc. Chem. Res. 2008, 41 1), 87–97.

280. "Chiral Ligand Optimization in the Asymmetric Zirconium-Zinc Transmetalation Aldehyde Addition Reaction." Wipf, P.; Jayasuriya, N. Chirality (Special Issue Honoring N. Berova), 2008, 20(1), 425-430.

279. "Pharmacology and Antitumor Activity of a Quinolinedione Cdc25 Phosphatase Inhibitor DA3003-1 (NSC 663284)." Guo, J.; Parise R. A.; Joseph, E.; Lan, J.; Pan, S.-S.; Joo, B.; Egorin M. J.; Wipf, P.; Lazo J. S.; Eiseman J. L. Anticancer Res. 2007, 27, 3067-3073.

278. "CDelineating the contribution of a Solutelvent’s “Chiral Solvent Imprint” to the Optical Rotation." Mukhopadhyay, P.; Zuber, Wipf, P.; Beratan, D. N. Angew. Chem., Int. Ed. 2007, 46(34), 6450-6452.

277. "Structure-Activity and High-Content Imaging Analyses of Novel Tubulysins." Wang, Z.; McPherson, P. A.; Raccor, B. S.; Balachandran, R.; Zhu, G.; Day, B. W.; Vogt, A.; Wipf, P. Chem. Biol. Drug Design 2007, 70(2), 75-86.

276. "Synthesis of (+/-)-thio-Halenaquinone by Iterative Metalations of Thiophene." Wakefield, B.; Halter, R. J.; Wipf, P. Org. Lett. 2007, 9(16), 3121-3124.

270. "Origins of the High 14-Helix Propensity of Cyclohexyl-Rigidified Residues in b-Peptides." Lee, M.; Raguse, T. L.; Schinner, M.; Pomerantz, W. C.; Wang, X.; Wipf, P.; Gellman, S. H. Org. Lett. 2007, 9(9), 1801-1804.

269. "Total Synthesis of N14-Desacetoxytubulysin H." Wipf, P.; Wang, Z. Org. Lett. 2007, 9, 1605.

266. "Synthesis and Biological Activity of a Focused Library of Mitogen-activated Protein Kinase Phosphatase Inhibitors." Arnold, D. M.; Foster, C.; Huryn, D. M.; Lazo, J. S.; Johnston, P.; Wipf, P. Chem. Biol. Drug Design, 2007, 69(1), 23-30.

263. "Treatment with a Novel Hemigramicidin-TEMPO Conjugate Prolongs Survival in a Rat Model of Lethal Hemorrhagic Shock." Macias, C. A.; Chiao, J. W.; Xiao, J.; Arora, D. S.; Tyurina, Y. Y.; Delude, R. L.; Wipf, P.; Kagan, V. E.; Fink, M. P. Ann. Surg. 2007, 245(2), 314.

262. "From Natural Products to Biological Tools." Wipf, P.; Graham, T. H.; Xiao, J. Pure Appl. Chem. 2007, 79(4), 753-761.

261. "Mitochondrial Targeting of Radioprotectants Using Peptidyl Conjugates." Kanai, A.; Zabbarova, I.; Amoscato, A.; Epperly, M.; Xiao, J.; Wipf, P. Org. Biomol. Chem. 2007, 5(2), 307.

258. "Spiroketals via Oxidative Rearrangement of Enol Ethers." Waller, D. L.; Stephenson, C. R. J.; Wipf, P. Org. Biomol. Chem. 2007, 5, 58-60.

257. "HPLC Determinations of Enantiomeric Ratios." Wipf, P.; Werner, S.; Twining, L. A.; Kendall, C. Chirality 2007, 19, 5-9.

 

 

 

 

 

 

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.