Advances in Host-Guest Chemistry Megan Jacobson University of Wisconsin-Madison April 21, 2005

Outline Background Industrial Applications Chemical Applications Reactions and Catalysis Scavengers Receptors Sensors Host Design Conclusions

Host-Guest Chemistry Host-Guest Chemistry involves: According to Cram: Two or more molecules, a “host” and a “guest”, involved in non-bonding interactions to form a supramolecular complex. According to Cram: The host component is a molecule or ion whose binding sites converge in the complex The guest component is any molecule or ion whose binding sites diverge in the complex Supramolecular Chemistry, Steed, J. W.; Atwood J. L.; John Wiley and Sons, Ltd, 2000.

Early Development of Host-Guest Chemistry Szejtli, J. Chem. Rev. 1998, 98, 1743-1753 Dodziuk, H. Introduction to Supramolecular Chemistry. Kluwer Academic Publishers, 2002. Supramolecular Chemistry, Steed, J. W.; Atwood J. L.; John Wiley and Sons, Ltd, 2000.

Guest Complexation Complexes stabilized by non-covalent interactions: Hydrophobic complexation Hydrogen bonding Aromatic interactions:  and edge-face Ion-ion and dipolar interactions Szejtli, J. Chem. Rev. 1998, 98, 1743-1753 Whitlock, B.J.; Whitlock, H. W. J. Am. Chem. Soc. 1994, 116, 2301. Nassimbeni, L. R. Acc. Chem. Res. 2003, 36, 631. www.yakko.pharm.kumamoto-u.ac.jp/KH/modb/molst.html

Advantages of Complexation Altered solubility Often increased water solubility Sequestration and precipitation of products Controlled volatility Encapsulation of gases Perfume release Altered reactivity Selective catalysis Stabilized guests Introduction to Supramolecular Chemistry; Dodziuk, H, Kluwer Academic Publishers, 2002. Separations and Reactions in Organic Supramolecular Chemistry; Lehn, J.-M.; Ed: Toda, F.; Bishop, R. Wiley & Sons, Ltd, 2004. www.yakko.pharm.kumamoto-u.ac.jp/KH/modb/molst.html

Structure of Cyclodextrins Number of Glucose Units A (Å) B (Å) -CD 6 5.3 14.6 -CD 7 6.5 15.4 -CD 8 8.3 17.5 Composed of Glucose units alpha 1-4 Numbers for a, b, g Puckered if bigger Primary edge, secondary edge Chiral -Cyclodextrin (-CD) Szejtli, J. Chem. Rev. 1998, 98, 1743-1753 D’Souza, V. T.; Lipkowitz, K. B. Chem. Rev. 1998, 98, 5, 1741.

Manufacture of CDs Produced enzymatically from starch by cyclodextrin glucosyl transferase Precipitation of desired product CDs using guest molecules to select CD size -CD from 1-decanol -CD from toluene -CD from cyclohexadecanol Think about cavity size correlation. Cyclodextrin Glucosyl Transferase Szejtli, J. Chem. Rev. 1998, 98, 1743-1753 www.xray.chem.rug.nl/ Gallery1.htm

Areas of CD Research Szejtli, J. Chem. Rev. 1998, 98, 1743-1753

Cyclodextrin Complexed Pharmaceuticals Prostavasin (alprostadil alphadex, PGE1) Prostaglandin-based treatment of peripheral circulatory disorders Instability requires intra-arterial administration in uncomplexed form. -CD complex improved metabolic stability, injectable formulation. Schwartz Pharma product 23 worldwisd Davis, M. E.; Brewster, M.E.; Nature Rev. 2004, 3, 1023-1035

Cyclodextrin Complexed Pharmaceuticals Sporanox (itraconazole) Antifungal triazole Aqueous solubility estimated 1 ng/mL Hydroxypropyl -CD complex improves solubility to 10 mg/mL First orally available drug effective against Candida spp. and Aspergillus spp. Janssen product Davis, M. E.; Brewster, M.E.; Nature Rev. 2004, 3, 1023-1035

Calixarenes “Vase” shaped cavity Condensation products of phenols and formaldehyde Common host starting point Low water solubility Many points for further functionalization Often used as scaffolds for sensors. Ikeda, A.; Shinkai, S. Chem.Rev. 1997, 97, 1713 Calixarenes 2001; Asfari, Z.; Bohmer, V.; Harrowfield, J.; Vicens, J. Kluwer Academic Publishers 2001. filippoberio.com/Tradition/History.asp

Possible Applications of Calixarenes Ion Sensors Selective ion sensing electrodes Optical transduction sensors Fluorescent sensors Separations Chiral recognition Chromatographic stationary phases Solid phase extraction McMahon, G.; O’Malley, S.; Nolan, K.; Diamond, D. ARKIVOC, 2003, vii, 23.

Outline Background Industrial Applications Chemical Applications Reactions and Catalysis Scavengers Receptors Sensors Host Design Conclusions

Directed Aromatic Chlorination >95% para chlorination observed with -CD 1.48 : 1.0 p/o without CD Internal delivery of Cl from 2° OH Methylation of all but C-3 2° OH groups affords 4.4x tighter binding and improved selectivity Breslow, R.; Campbell, P. J. Am. Chem. Soc. 1969, 91, 3085 Breslow, R.; Kohn, H.; Siegel, B. Tet. Lett. 1976, 20, 1645-1646

Cavity Accelerated Diels-Alder Requires small reaction components -CD shows rate accelerations of up to 1800 x rates in isooctane and 2-10 x those in water for small substrates. -CD inhibits reaction even with small substrates. Too large for cavity Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7817-7818

Cavity Accelerated Diels-Alder Modest increase in diastereoselectivity observed in cyclodextrins over reactions in water Dienophile Endo / Exo In Water Endo / Exo in 0.015M -CD 1.10 ± 0.05 2.2 ± 0.08 47 ± 4 69 ± 4 48.5 ± 4 112 ± 5 More compact transition state Schneider, H-J.; Sangwan, N. K. Angew. Chem. Int. Ed. Engl. 1987, 26(9), 896-897

Photochemical Control Products of UV irradiation ( 312 nm) of CD complexed E-stilbene depend on cavity size. Herrmann, W.; Wehrle, S.; Wenz, G. Chem. Commun. 1997, 1709

Photochemical Control CD Reaction Time (h) % E Stilbene % Z Stilbene % Trans -Dimer % Cis-Dimer % Phenanthrene None 24 10 62 7 2 19 -CD 20 60 -CD 16 83 1 -CD 72 79 1:1 complexation in  or -CD favors isomerization. Complexation in -CD nearly prevents phenanthrene formation. 2:1 Complexation in -CD favors dimerization. Herrmann, W.; Wehrle, S.; Wenz, G. Chem. Commun. 1997, 1709

“Biomimetic” Steroid Hydroxylation Regioselective for C-6 Stereoselective for the  face. 10 equivalents of PhI=O oxidant and pyridine Reaction in water Breslow, R.; Zhang, X.; Huang, Y. J. Am. Chem. Soc. 1997, 119, 4535-4536. Breslow, R.; Huang, Y.; Zhang, X.; Yang, J. Proc. Natl. Acad. Sci. USA. 1997, 94, 11156-58.

“Biomimetic” Steroid Hydroxylation t-Butyl-Phenyl groups form CD complex Sulfonate groups improve water solubility. 3-5 catalytic turnovers Breslow, R.; Zhang, X.; Huang, Y. J. Am. Chem. Soc. 1997, 119, 4535-4536. Breslow, R.; Huang, Y.; Zhang, X.; Yang, J. Proc. Natl. Acad. Sci. USA. 1997, 94, 11156-58.

“Biomimetic” Steroid Hydroxylation Yang, J.; Breslow, R. Angew. Chem. Int. Ed. 2000, 39, 15, 2692-2694

“Biomimetic” Steroid Hydroxylation Oxidative stability of catalyst greatly improved by fluorination - 95 % yield 95 turnovers at 1% catalyst. Breslow, R.; Gabriele, B.; Yang, J. Tet. Lett. 1998, 39, 2887-2890

“Biomimetic” Steroid Hydroxylation meta-CD placement and altered tether points give C-9 OH para-CD placement gives a mixture of C-9 and C-15 OH Breslow, R.; Yan, J.; Belvedere, S. Tet. Lett. 2002, 43, 363-365

Antioxidant Enzyme Mimic Glutathione Peroxidase (GPX) mimic - antioxidant activity Catalyzes reduction of hydroperoxides by glutathione using natural coenzymes and cofactors Prevents oxidative damage to biological systems 2-TeCD Luo, G. et al. ChemBioChem 2002, 3, 356-363

Antioxidant Enzyme Mimic Superior to Ebselen, a common GPX mimic Slows damage to mitochondria by hydroperoxides May be useful in bioelectric devices GPX mimic Hydroperoxide Activity (U m-1) Ebselen H2O2 0.99 PhSeSePh 1.95 2-SeCD 7.4 2-TeCD 46.7 tBuOOH 32.8 Cumene hydroperoxide 87.3 NADPH is beta nicotinamide adenine dinucleotide phosphate GSH is Glutathione GPX Dicyclodextrinyl ditelluride GSH = Glutathione, NADPH = -nicotinamide adenine dinucleotide phosphate Luo, G. et al. ChemBioChem 2002, 3, 356-363

Outline Background Industrial Applications Chemical Applications Reactions and Catalysis Scavengers Receptors Sensors Host Design Conclusions

Anesthetic Scavenger Rocurionium bromide is a common neuromuscular blocking drug. Conventional reversal medications have many side-effects. Org 25969 is currently in Phase II Human Clinical Trials. Rocurionium Bromide Decreased heart rate, increased salivation, Lowered Blood pressure, nausea, vomiting, abdominal cramping, bronchiochonstriction Side effect combating drugs cause rapid heart rate, dry mouth, blurred vision Org 25969 Zhang, M-Q. et al. Angew. Chem. Int. Ed. 2002, 41, 2, 265-270

Anesthetic Scavenger Host EC50 [M] Max % Reversal -CD >360 9.7 -CD 29 -CD 34.6 94.1 Org 25969 1.2 95.1 Data from mouse hemidiaphram studies Extending cavity depth from 7.9 to ~ 11 Å greatly improves complexation. Patients show significant recovery in minutes. Dosage for 95% reversal is the same as the Rocuronium Bromide dosage Zhang, M-Q. et al. Angew. Chem. Int. Ed. 2002, 41, 2, 265-270

Outline Background Industrial Applications Chemical Applications Reactions and Catalysis Scavengers Receptors Sensors Host Design Conclusions

Choline Receptor Trimethylammonium moiety challenges receptor design Quaternary ammonium does not allow hydrogen bonding Roughly spherical shape limits binding site design Ballester, P.; Shivanyuk, A.; Far, A. R.; J. Rebek Jr. J. Am. Chem. Soc. 2002, 124, 14014-14016

Choline Receptor Complex stablized by deep aromatic cavity Larger NR4+ ions excluded from binding Vase shaped complex “stitched” together by DMSO Weak H-bond from alcohol to amine (0.6 kcal /mol) Ka = 1.2 x 104 Ballester, P.; Shivanyuk, A.; Far, A. R.; J. Rebek Jr. J. Am. Chem. Soc. 2002, 124, 14014-14016

Receptor Synthesis Ballester, P.; Shivanyuk, A.; Far, A. R.; J. Rebek Jr. J. Am. Chem. Soc. 2002, 124, 14014-14016

Outline Background Industrial Applications Chemical Applications Reactions and Catalysis Scavengers Receptors Sensors Host Design Conclusions

Sensor Requirements Selective binding Detection at low levels Fast response for dynamic sensing Tolerance for changing conditions Clear, intense signaling Bell, T.W.; Hext, N. M. Chem. Soc. Rev. 2004, 33, 589. Pinalli, R,; Suman, M.; Dalcanale, E. Eur. J. Org. Chem. 2004, 451.

Fluorescent Hg2+ Sensor Calix[4]-aza-crown binding site Maintains activity in aqueous solution Dansyl fluorescence quenched by binding Hg2+ Chen, Q-Y; Chen, C-F, Tet. Lett. 2005, 46, 165-168

Fluorescent Hg2+ Sensor Selective binding over Li+, Na+, Mg2+, K+, Ca2+, Mn2+, Co2+, Ni2+, Ag+, Ba2+ Little selectivity over Cu2+, Zn2+, Cd2+, Pb2+ Ka = 1.31 x 105 M-1 Detection Limit 4.1x10-6 mol /L Quenching proposed to be by electron transfer from excited dansyl to mercuric ion. Chen, Q-Y; Chen, C-F, Tet. Lett. 2005, 46, 165-168

Radical Cation Sensor for Nitric Oxide Green Radical cation stabilized by electron-rich substituents Stable at room temperature Rathore, R. Abdelwahed, S.H.; Guzei, I. A. J. Am. Chem. Soc. 2004, 126, 13582-13583

Synthesis of NO Binding Calixarene Inverse Freidel-Crafts, SN2, Electrophilic Bromination, Kumada Coupling Rathore, R.; Abdelwahed, S.H.; Guzei, I. A. J. Am. Chem. Soc. 2004, 126, 13582-13583

Radical Cation Sensor for Nitric Oxide Electron deficient cavity binds electron-rich nitric oxide Dramatic color change on binding Ka > 108 M-1 Blue Rathore, R. Abdelwahed, S.H.; Guzei, I. A. J. Am. Chem. Soc. 2004, 126, 13582-13583

Outline Background Industrial Applications Chemical Applications Reactions and Catalysis Scavengers Receptors Sensors Host Design Conclusions

New Host Design “Apple peel” helix completely encloses water molecule Garric, J.; Leger, J-M.; Huc, I. Angew. Chem. Int. Ed. 2005, 44, 1954-1958

New Host Design “Soft ball” like bimolecular assembly Chiral guest “templates” chirality of assembled host 8 hydrogen bonds “stitch” complex together Rivera, J. M.; Craig, S. L.; Martin, T.; Rebek, J. Jr. Angew. Chem. Int. Ed. 2000, 39(12) 2130-2132

New Host Design Guest exchange is faster than decomposition of host molecule. Rivera, J. M.; Craig, S. L.; Martin, T.; Rebek, J. Jr. Angew. Chem. Int. Ed. 2000, 39, 12 2130-2132

Outline Background Industrial Applications Chemical Applications Reactions and Catalysis Scavengers Receptors Sensors Host Design Conclusions

Summary Host-guest chemistry is applied in: Catalysis Scavenging Sensors Pharmaceuticals - both drugs and delivery Mimicking and understanding biological systems New host design opens more fields for research

Conclusions The field of host-guest chemistry has matured sufficiently to have utility in many important and interesting applications and remains a fruitful area for research.

Acknowledgements Professor Helen E. Blackwell Blackwell Group Members Brian Pujanauski Adam Siegel Emily Guerard Jamie Ellis Chris Paradise Katie Alfare Kara Waugh Blackwell Group Members Matt Bowman Qi Lin Ben Gorske David Miller Jenny O’Neill Sarah Jewell Rachel Wezeman Grant Geske