Research in the Wipf Group

http://ccc.chem.pitt.edu/wipf/index.html

12/24/2008

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 as well as molecular modeling. 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 activi ty, as well as for showcasing our methodologies.

S

N

H H

OMe

N

SS

NN

S

Ph

O

N

MeNH O

N

O

N

O OMeCH3O

OH

H

O

O

NN N

O

OO

O

HN

O

O

OHNH

O O

O

O

O

OH

HN

O

O

OHN

HN

O

NH

H

N

OH

NHCHO

O

O

HN

NHH2N

O

N

O

O

N

H

H

OHO

O

O

OH

HN

O

O

O

O

OH

O

O

N

N

N

S

O

N

NHN

O

Ph

O

H

HON

O

O

O

H

O

H

Cl

NH

OO

N

HO

NHOONH

HNNH2

NH

O

HO

OH OH

O NH

HN

O

O O

OH

O

O

O

O

O

O

N

O

NHCO2Me

O O

O

OMe

Curacin A

Muscoride A

LL-C10037!

Aranorosin

Tuberostemonine

Cyclotheonamide A

Thiangazole

Hennoxazole A

Nisamycin

Diepoxin "

Trunkamide A

Pitiamide A

Aeruginosin 298-A

Leucascandrolide A

Bistramide C

OO

O

Disorazole C1

HO O

O

N

OHO

O

N

O

O

MeO

OMe

N

NH

O

NHMe

R1

Caulibugulone E

NH

COOH

Ph

N

S

N

OAc OHN

O

ON

N14-Desacetoxytubulysin H

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:

H

H

H

N

O

O

O O

H

H

OO

OO

O

NO

HH

H

H

H

O

NO O

H

OO

H

H

H

H

H

H

CO2Me

OH

N

CbzO

HO

CbzHN

CO2Me

Unified Retrosynthetic Approach toward Stemona Alkaloids

Tuberostemonine

L-Tyrosine

extend chainannulate

extend chain

reduce or fragment

Tuberostemonone

Parvistemonine 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 γ-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.

Disorazole C1

Me

HO O

Me Me

O

N

Me

OHO

MeMe

O

N

O

O

MeO

OMe

Bistramide C

O

O

HN

OHO O

HNO

O

O

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). Our program in peptide mimicry is representative of another synergistic combination of two areas of research - synthetic methodology and medicinal chemistry. Peptides demonstrate a wide range of diverse physiological properties as hormones, enzyme inhibitors, growth promoters, signaling pathways modulators, antimicrobial agents, and others. In order to overcome one of the general shortcomings of peptides, i.e. their limited bioavailability, we are studying the synthesis and pharmacological evaluation of bioisosteric replacements of the amide bond. The relatively rigid trisubstituted (E)-alkene dipeptide isosteres (ψ[(E)-C(R)=CH], R≠H) maintain ω-angle planarity and represent useful structural surrogates of hydrolytically labile amide bonds. In addition, these isosteres were found to have a range of promising biological activities, including nuclear hormone receptor binding and RNA splicing modulation.

HN

R

O

!-Amino-",#-Cyclopropyl Acids

NH

HN

O

Ri+1

Ri+2

O

NH

R

Ri+1

Ri+2

O

NH

R

Ri+1

Ri+2

O

$-Amino-#,!-Cyclopropyl Acids

$-Amino-#,!-Unsaturated Acids

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 γ-Amino-α,β-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 ("Treatment with a Novel Hemigramicidin-TEMPO Conjugate Prolongs Survival in a Rat Model of Lethal Hemorrhagic Shock." Delude, R. L.; Wipf, P.; Kagan, V. E.; Fink, M. P. et al. Ann. Surg. 2007, 245(2), 314.).

The application of modern synthetic methodology for solving challenging biological and medical problems is an extremely fertile field, and we continue to explore opportunities in this interdisciplinary and collaborative research. For example, we have recently applied zirconocene methodology for the efficient preparation of analogs of a galactosylceramide (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 in the US and in Europe.

Another representative illustration of the synergism between chemical probe development and diversity-oriented synthesis is our recent work on intramolecular cycloaddition reactions of bicyclobutanes (J. Am. Chem. Soc. 2008, 130, 6924; Tetrahedron Lett. 2008, 49, 5986). This project is of particular significance for us since it combines the fundamental chemical study of organometallics, highly strained carbocycles, and novel heterocyclic scaffolds.

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). In the future, these approaches 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.

+ R2CHO

- R1CHO

N

N

O

NHN

R1

RN

N

O

NHN

R2

R

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 308. "A Microwave Assisted Intramolecular-Furan-Diels-Alder Approach to 4-Substituted

Indoles." Petronijevic, F.; Timmons, C.; Cuzzupe, A.; Wipf, P. Chem. Commun. 2009, (1), 104. 306. "Triple Hybrids of Steroids, Spiroketals, and Oligopeptides as New Biomolecular

Chimeras." Banerjee, A.; Sergienko, E.; Vasile, S.; Gupta, V.; Vuori, K.; Wipf, P. Org. Lett. 2009, 11(1), 65-68.

304. "Mitochondria-Targeted Disruptors and Inhibitors of Cytochrome c/Cardiolipin Peroxidase Complexes: A New Strategy in Anti-apoptotic Drug Discovery." Kagan, V. E.; Bayir, A.; Bayir, H.; Stoyanovsky, D.; Borisenko, G. G.; Tyurina, Y. Y.; Wipf, P.; Atkinson, J.; Greenberger, J. S.; Chapkin, R. S.; Belikova, N. A. Mol. Nutr. Food Res. 2009, 53, 104-114.

302. "Potent and Selective Disruption of Protein Kinase D Functionality by a Benzoxoloazepinolone." Sharlow, E. R.; Giridhar, K. V.; LaValle, C. R.; Chen, J.; Leimgruber, S.; Barrett, R.; Bravo-Altamirano, K.; Wipf, P.; Lazo, John S.; Wang, Q. J. J. Biol. Chem. 2008, 283(48), 33516-33526.

301. "Titanocene(III)-Catalyzed Formation of Indolines and Azaindolines." Wipf, P.; Maciejewski, J. P. Org. Lett. 2008, 10(19), 4383-4386.

300. "Synthesis of Hydroxylated Bicyclic Amino Acids from l-Tyrosine: Octahydro-1H-indole Carboxylates." Pierce, J. G.; Kasi, D.; Fushimi, M.; Cuzzupe, A.; Wipf, P. J. Org. Chem. 2008, 73, 7807-7810.

296. "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.

295. "A Precursor Specific Role for Hsp40/Hsc70 during Tail-Anchored Protein Integration at the Endoplasmatic Reticulum." Rabu, C.; Wipf, P.; Brodsky, J. L.; High, S. J. Biol. Chem. 2008, 283(41), 27504-27513.

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.

288. "Tubulin-Perturbing Naphthoquinone Spiroketals." Balachandran, R.; Hopkins, T. D.; Thomas, C. A.; Wipf, P.; Day, B. W. Chem. Biol. Drug Design 2008, 71(2), 117-124.

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.

278. "Contribution of a Solute’s Chiral Solvent Imprint to 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.

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