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 2

Host-Guest Chemistry

• Host-Guest Chemistry involves: – 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.

3

Early Development of Host Guest Chemistry

1891- Villiers isolates "cellulosine" 1953 Freudenberg, Cramer and Plieninger patent 1969 First cyclodextrin-based intra-complex catalyst. 1987 D. J. Cram, J-M Lehn, and C. J. Pedersen win the nearly all important aspects of cyclodextrins for drug delivery 1985 First Calixarene Ion Sensors Nobel Prize for work in Supramolecular Chemistry applications. 1903- Schardinger prepares cyclodextrin-iodine Complexes 1954 Cramer publishes

Einschlussverbindungen

(Inclusion Compounds) Late 1970s Calixarene Late 1980s Cyclodextrin-Drug Complexes Research Begins 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.

4

Guest Complexation

K 1:1 = [H• G] [H] [G]

• 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

5

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

6

2004

.

www.yakko.pharm.kumamoto-u.ac.jp/KH/modb/molst.html

Structure of Cyclodextrins

OH H O H yd rop hilic Su rface O OH H O O O OH O H O H O O OH O H O OH O OH H yd rop hobic Cavity H O O OH O OH O OH O H O OH H O O O OH H O O H O  -Cyclodextrin (  -CD) Szejtli, J.

Chem. Rev

.

1998

,

98

, 1743-1753 D ’Souza, V. T .; Lipkowitz, K. B. Chem. Rev. 1998 ,

98, 5,

1741.

2° H yd roxyls 1° H yd roxyls B A 7.9 Å 

-CD



-CD



-CD Number of Glucose Units 6 7 A (Å) 5.3

6.5

8 8.3

B (Å) 14.6

15.4

17.5

7

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 QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.

Cyclodextrin Glucosyl Transferase 8 Szejtli, J.

Chem. Rev

.

1998

,

98

, 1743-1753 www.xray.chem.rug.nl/ Gallery1.htm

Areas of CD Research

Distribution of the 1706 Abstracts Published in 1996 by

Cyclodextrin News

Chemistry of CD Complexes

16%

Analytical Chemistry (Mainly Chromatography) Foods and Cosmetics

11%

Pharmaceuticals Pesticides Chemical and Biochemical Processes and Products Chemistry, Enzymology, Biological Effects, Production of CDs and Derivatives

1% 24% 7% 22% 19%

Szejtli, J.

Chem. Rev

.

1998

,

98

, 1743-1753 9

Cyclodextrin Complexed Pharmaceuticals

O O H OH H CH 3 H O H OH H • Prostavasin (alprostadil alphadex, PGE 1 ) – 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 10 Davis, M. E.; Brewster, M.E.;

Nature Rev

.

2004

,

3,

1023-1035

Cyclodextrin Complexed Pharmaceuticals

Cl O N O O N N N Cl N H O N • Sporanox (itraconazole) N N – 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 11 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.

OH OH OH H O 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

12

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. 13

Outline

• Background • Industrial Applications • Chemical Applications – Reactions and Catalysis – Scavengers – Receptors – Sensors • Host Design • Conclusions 14

O

Directed Aromatic Chlorination

O Cl O H OCl  or  CD Cl O • >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 15

Cavity Accelerated Diels-Alder

R + R • R • • 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. O CH 2 OH O EtN N Et

Too large for cavity

O O H OH 2 C 16 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

EtOOC COOH

Endo / Exo In Water

1.10 ± 0.05

Endo / Exo in 0.015M



-CD

2.2 ± 0.08

COOH H COOR 47 ± 4 69 ± 4 H COOR' COOH end o + COOR COOR' exo COOR COOR' COOH COOEt 48.5 ± 4 112 ± 5 17 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.

R R

E

Stilbene R = CH 2 N HMe 2

R R R R

t rans

D imer

R R R

Z

Stilbene

R R

Phenanthrene

R Herrmann, W.; Wehrle, S.; Wenz, G.

Chem. Commun

.

1997

, 1709 R

cis

D imer

R 18

Photochemical Control

CD Reaction Time (h) % E Stilbene % Z Stilbene % Trans Dimer % Cis Dimer % Phenanthren e

19 None 24 10 62 7 2  -CD  -CD 24 24 20 16 60 83 0 0 0 0 20 1  -CD 72 0 • 1:1 complexation in  0 79 19 2 or  -CD favors isomerization. • Complexation in  -CD nearly prevents phenanthrene formation.

• 2:1 Complexation in  -CD favors dimerization . 19 Herrmann, W.; Wehrle, S.; Wenz, G.

Chem. Commun

.

1997

, 1709

“Biomimetic” Steroid Hydroxylation

R O 3 H 3 C 11 9 H 3 C H O H 15 R 17 H 6 Catalyst PhI=O Pyrid ine Water R O 3 H 3 C 11 9 H 3 C H O 17 H 15 R H 6 OH and rostane 3,17 d iol CON H CH 2 CH 2 SO 3 H O R = • Regioselective for C-6 • Stereoselective for the  face.

• 10 equivalents of PhI=O oxidant and pyridine • Reaction in water 20 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.

 -cyclod extrin

“Biomimetic” Steroid Hydroxylation

CON H CH 2 CH 2 SO 3 H O H 3 C O H 3 C H O 3 SH 2 CH 2 CH N OC S O H H O H S N N N Mn + N 3-5 catalytic turnovers S S •

t

-Butyl-Phenyl groups form CD complex • Sulfonate groups improve water solubility. 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.

21

“Biomimetic” Steroid Hydroxylation

Yang, J.; Breslow, R.

Angew. Chem. Int. Ed

. 2000, 39 , 15, 2692-2694 22

“Biomimetic” Steroid Hydroxylation

 -cyclod extrin S F F F F S F F F F N N N Mn + N F F S F F F F F F S Oxidative stability of catalyst greatly improved by fluorination – 95 % yield – 95 turnovers at 1% catalyst. 23 Breslow, R.; Gabriele, B.; Yang, J. Tet. Lett. 1998 ,

39

, 2887-2890

F N S F F

“Biomimetic” Steroid Hydroxylation

H 3 C H 3 C O 17 H 3 C 11 9 H O 17 15 Catalyst PhI=O Pyrid ine Water H 3 C 9 R O 3 H H 6 O R R O 3 OH H 6 O R H 15 O CON H CH 2 CH 2 SO 3 H R = S N F F F N Mn + N N N F F N F S F F S N F • •

meta

-CD placement and altered tether points give C-9 OH

para

-CD placement gives a mixture of C-9 and C-15 OH 24 Breslow, R.; Yan, J.; Belvedere, S.

Tet. Lett

.

2002

,

43,

363-365

Antioxidant Enzyme Mimic

R-OOH ROH + H 2 O

• Glutathione Peroxidase (GPX) mimic - antioxidant activity • Catalyzes reduction of hydroperoxides by glutathione using natural coenzymes and cofactors • Prevents oxidative damage to biological systems Te Te 2-TeCD  -cyclod extrin 25 Luo, G. et al. ChemBioChem 2002 ,

3

, 356-363

Antioxidant Enzyme Mimic

N AD PH N AD P + 2 GSH + H 2 O 2 2-TeCD 2 H 2 O + GSSG GSSG Reductase

• Superior to Ebselen, a common GPX mimic

GPX mimic 2 GSH Hydroperoxide

• Slows damage to Ebselen H 2 O 2 mitochondria by PhSeSeP h H 2 O 2 hydroperoxides 2-SeCD H 2 O 2 • May be useful in bioelectric 2-TeCD H 2 O 2 devices 2-TeCD tBuOOH GSH = Glutathione, NADPH =  -nicotinamide adenine dinucleotide phosphate 2-TeCD Cumene hydroperoxide

Activity (U



m -1 )

0.99

1.95

7.4

46.7

32.8

87.3

Luo, G. et al. ChemBioChem 2002 ,

3

, 356-363 26

Outline

• Background • Industrial Applications • Chemical Applications – Reactions and Catalysis – Scavengers – Receptors – Sensors • Host Design • Conclusions 27

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.

Zhang, M-Q.

et al. Angew. Chem. Int. Ed

.

2002

,

41

, 2, 265-270 O OAc N N N aO 2 C S N aO 2 C H O H O Rocurionium Bromide CO 2 N a N aO 2 C S S O O OH O H O O OH H O OH O H O S O O OH OH H O O H O O S O OH OH OH H O O O O OH O H O O S N aO 2 C S S Org 25969 CO 2 N a Br CO 2 N a CO 2 N a 28

Anesthetic Scavenger

Host  -CD  -CD  -CD Org 25969 EC 50 [  M] >360 >360 34.6

1.2

Max % Reversal 9.7

29 94.1

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.

Zhang, M-Q.

et al. Angew. Chem. Int. Ed

.

2002

,

41

, 2, 265-270 29

Outline

• Background • Industrial Applications • Chemical Applications – Reactions and Catalysis – Scavengers – Receptors – Sensors • Host Design • Conclusions 30

Choline Receptor

• Trimethylammonium moiety challenges receptor design – Quaternary ammonium does not allow hydrogen bonding – Roughly spherical shape limits binding site design H 2 N H 2 N O O O N

Choline

O OH O O N H 2 N H 2 O O H 2 N H 2 N N H 2 N H 2 31 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 NR 4 + from binding ions excluded • Vase shaped complex “stitched” together by DMSO • Weak H-bond from alcohol to amine (0.6 kcal /mol) K a = 1.2 x 10 4 Ballester, P.; Shivanyuk, A.; Far, A. R.; J. Rebek Jr. J. Am. Chem. Soc. 2002 ,

124

, 14014-14016 32

Receptor Synthesis

H O H O H O H O OH OH O 2 N O 2 N OH OH F O 2 N O 2 N O F O O O O 2 N O 2 N O O N O 2 N O 2 H 2 N H 2 N O O 1. SnCl 2 , EtOH / H Cl 2. N H 4 OH , EtOAc O O N O 2 N O 2 H 2 N H 2 N O O O N H 2 N H 2 O O O N H 2 N H 2 Ballester, P.; Shivanyuk, A.; Far, A. R.; J. Rebek Jr. J. Am. Chem. Soc. 2002 ,

124

, 14014-14016 33

Outline

• Background • Industrial Applications • Chemical Applications – Reactions and Catalysis – Scavengers – Receptors – Sensors • Host Design • Conclusions 34

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.

35

Fluorescent Hg

2+

Sensor

• Calix[4]-aza-crown binding site • Maintains activity in aqueous solution • Dansyl fluorescence quenched by binding Hg 2+ O H N O OH OH N H N O S O O N H O N 36 Chen, Q-Y; Chen, C-F,

Tet. Lett

.

2005

,

46

, 165-168

Fluorescent Hg

2+

Sensor

• Selective binding over Li + , Na + , Mg 2+ , K + , Ca 2+ , Mn 2+ , Co 2+ , Ni 2+ , Ag + , Ba 2+ • Little selectivity over Cu 2+ , Zn 2+ , Cd 2+ , Pb 2+ • K a = 1.31 x 10 5 • Detection Limit 4.1x10

-6 mol/L M -1 N O O O H N H N S O OH OH

Hg 2+

O N H O N 37 Chen, Q-Y; Chen, C-F,

Tet. Lett

.

2005

,

46

, 165-168

Radical Cation Sensor for Nitric Oxide

Ar Ar O Ar O O O -e Et 3 O + SbCl 6 OCH 3 H 3 CO Ar Ar Ar Ar O Ar O O H 3 CO O O O O OCH 3

Green

Ar H 3 CO O OCH 3 • Radical cation stabilized by electron-rich substituents • Stable at room temperature Ar = H 3 CO CH 3 OCH 3 38 Rathore, R. Abdelwahed, S.H.; Guzei, I. A.

J. Am. Chem. Soc

.

2004

,

126,

13582-13583

Synthesis of NO Binding Calixarene

OH OH OH H O NBS, MeOH Ar = H 3 CO CH 3 OCH 3 PhOH, AlCl 3 toluene, reflux OH OH OH H O n-propyltosylate, Cs 2 CO 3, DMF, 80° Ar Ar O Br Br O MgBr H 3 CO OCH 3 (PPh 3 ) 2 PdCl 2 , THF O O Br Br O Ar O O H 3 CO O O O OCH 3 O O Rathore, R.; Abdelwahed, S.H.; Guzei, I. A.

J. Am. Chem. Soc

.

2004

,

126

, 13582-13583 39

Radical Cation Sensor for Nitric Oxide

• Electron deficient cavity binds electron-rich nitric oxide • Dramatic color change on binding • K a > 10 8 M -1 Rathore, R. Abdelwahed, S.H.; Guzei, I. A. J. Am. Chem. Soc. 2004 ,

126,

13582-13583

Blue

40

Outline

• Background • Industrial Applications • Chemical Applications – Reactions and Catalysis – Scavengers – Receptors – Sensors • Host Design • Conclusions 41

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 O O N O N 2 H N 2 N H N O N O N O 2 N H N N H N O O 2 OBn 42

New Host Design

O O OH O O H N R H N N R N N N N N R N N OH O O O R = n-hep tylp henyl • “Soft ball” like bimolecular assembly • Chiral guest “templates” chirality of assembled host • 8 hydrogen bonds “stitch” complex together O N H R N H H O ( ) ( ) OH OH Pinane d iol Gu ests OH 43 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.

t 1/2 = 1 min

H O OH

Matched Pair

OH OH Pinane d iol Gu ests

t 1/2 = 10-20 h Enantiomers t 1/2 = 10-20 h Matched Pair t 1/2 = 1 min

44 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 45

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 46

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.

47

Acknowledgements

Professor Helen E. Blackwell Blackwell Group Members

Matt Bowman Qi Lin Ben Gorske David Miller Jenny O’Neill Sarah Jewell Rachel Wezeman Grant Geske Brian Pujanauski Adam Siegel Emily Guerard Jamie Ellis Chris Paradise Katie Alfare Kara Waugh 48