advances in host-guest chemistry megan jacobson university of wisconsin-madison april 21, 2005

Advances in Host-Guest Chemistry

Megan JacobsonUniversity of Wisconsin-Madison

April 21, 2005

2

Outline

• Background • Industrial Applications• Chemical Applications

– Reactions and Catalysis– Scavengers– Receptors– Sensors

• Host Design• Conclusions

3

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.

4

Early Development of Host-Guest Chemistry

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

1891- Villiers isolates "cellulosine"

1903- Schardinger prepares cyclodextrin-iodine Complexes

1953 Freudenberg, Cramer and Plieninger patentnearly all important aspects of cyclodextrins for drug delivery applications.

1954 Cramer publishes Einschlussverbindungen (Inclusion Compounds)

Late 1970s CalixareneResearch Begins

1985 First Calixarene Ion Sensors

1969 First cyclodextrin-basedintra-complex catalyst.

Late 1980sCyclodextrin-Drug Complexes

1987 D. J. Cram, J-M Lehn, and C. J. Pedersen win the Nobel Prize for work in Supramolecular Chemistry

5

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, 1743-1753Whitlock, 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

K1:1 =[H•G]

[H] [G]

6

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

7

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

Szejtli, J. Chem. Rev. 1998, 98, 1743-1753

D’Souza, V. T.; Lipkowitz, K. B. Chem. Rev. 1998, 98, 5, 1741.

-Cyclodextrin (-CD)

O

OHHO

OH

O

O

HO

HOOH

O

OHO

OH

OH

O

O

HOOH

HO

OO

OH

OH

HOO

OOH

OH

HO

O

O

OH

HO

HO

O

Hydrophobic Cavity

Hydrophilic Surface

A

B

7.9 Å

2° Hydroxyls

1° Hydroxyls

8

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

Szejtli, J. Chem. Rev. 1998, 98, 1743-1753

www.xray.chem.rug.nl/ Gallery1.htm

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Cyclodextrin Glucosyl Transferase

9

Areas of CD Research

Szejtli, J. Chem. Rev. 1998, 98, 1743-1753

Distribution of the 1706 Abstracts Published in 1996 by Cyclodextrin News

22%

19%

7%24%

1%

16%11%

Chemistry of CD Complexes

Analytical Chemistry (MainlyChromatography)

Foods and Cosmetics

Pharmaceuticals

Pesticides

Chemical and Biochemical Processes andProducts

Chemistry, Enzymology, Biological Effects,Production of CDs and Derivatives

10

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

Davis, M. E.; Brewster, M.E.; Nature Rev. 2004, 3, 1023-1035

O

OH

CH3

H OH

O

H

H

HHO

11

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

O

OH

N

NN

Cl

ClNNNN

N

O

O

Davis, M. E.; Brewster, M.E.; Nature Rev. 2004, 3, 1023-1035

12

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.

OHOH HOOH

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

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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.

14

Outline

• Background • Industrial Applications• Chemical Applications

– Reactions and Catalysis– Scavengers– Receptors– Sensors

• Host Design• Conclusions

15

Directed Aromatic Chlorination

O

OCl

• >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

O

HOClor CD

O

Cl

Breslow, R.; Campbell, P. J. Am. Chem. Soc. 1969, 91, 3085 Breslow, R.; Kohn, H.; Siegel, B. Tet. Lett. 1976, 20, 1645-1646

16

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.

R

R

+

R

CH2OH

NEt

O

O

EtN

O

O

HOH2C

Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7817-7818

Too large for cavity

17

Cavity Accelerated Diels-Alder

DienophileEndo / ExoIn Water

Endo / Exo in 0.015M

-CD

1.10 ± 0.05 2.2 ± 0.08

47 ± 4 69 ± 4

48.5 ± 4 112 ± 5

COOH

EtOOC

COOH

COOH

COOH

COOEt

• Modest increase in diastereoselectivity observed in cyclodextrins over reactions in water

Schneider, H-J.; Sangwan, N. K. Angew. Chem. Int. Ed. Engl. 1987, 26(9), 896-897

H

COOR'

COOR

H

COOR'COOR COOR'

COOR+

endo exo

18Herrmann, W.; Wehrle, S.; Wenz, G. Chem. Commun. 1997, 1709

RR

R R

RR

R

trans Dimer

cis Dimer

R R

R

R

R RR

R = CH2NHMe2

E Stilbene

Z Stilbene

Phenanthrene

Photochemical Control• Products of UV irradiation ( 312 nm) of

CD complexed E-stilbene depend on cavity size.

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Photochemical Control

• 1:1 complexation in or -CD favors isomerization.

• Complexation in -CD nearly prevents phenanthrene formation.

• 2:1 Complexation in -CD favors dimerization.

CDReaction Time (h)

% E Stilben

e

% Z Stilben

e

% Trans -Dimer

% Cis-Dimer

% Phenanthre

ne

None 24 10 62 7 2 19

-CD 24 20 60 0 0 20

-CD 24 16 83 0 0 1

-CD 72 0 0 79 19 2

Herrmann, W.; Wehrle, S.; Wenz, G. Chem. Commun. 1997, 1709

20

“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.

RO

H3CH3C

H

OR

H H

OH

androstane 3,17 diol

RO

H3CH3C

H

OR

H H

3 6

9

17

15

11

3 6

9

17

15

11CatalystPhI=OPyridineWater

OCONHCH2CH2SO3H

R =

21

“Biomimetic” Steroid Hydroxylation

•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.

3-5 catalytic turnovers

O

H3C

H3C

H

O

H HO

HO3SH2CH2CHNOC

O CONHCH2CH2SO3H

N N

N NMn+

S

S

S

S

-cyclodextrin

22

“Biomimetic” Steroid Hydroxylation

Yang, J.; Breslow, R. Angew. Chem. Int. Ed. 2000, 39, 15, 2692-2694

23

“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

N N

N NMn+

S

S

S

S

-cyclodextrin

F F

FF

F

FF

F

F F

FF

F

F

F

F

24

“Biomimetic” Steroid Hydroxylation

N N

N NMn+N N

N

N

F F

FS

F

FS

F

F S

FF

F

F

F

S

• 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

RO

H3CH3C

H

O

OH H

RO

H3CH3C

H

O

H H

OR OR3 6

15

17

9

11

3 6

15

17

9CatalystPhI=OPyridineWater

OCONHCH2CH2SO3H

R =

25

Antioxidant Enzyme Mimic

Te Te• Glutathione Peroxidase (GPX)

mimic - antioxidant activity • Catalyzes reduction of

hydroperoxides by glutathione using natural coenzymes and cofactors

• Prevents oxidative damage to biological systems

Luo, G. et al. ChemBioChem 2002, 3, 356-363

2-TeCD

R-OOH ROH+ H2O

-cyclodextrin

26

Antioxidant Enzyme Mimic

2 GSH + H2O2 2-TeCD 2 H2O + GSSG

GSSG Reductase

NADPH NADP+

2 GSH

• 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

H2O2 1.95

2-SeCD H2O2 7.4

2-TeCD H2O2 46.7

2-TeCD tBuOOH 32.8

2-TeCDCumene

hydroperoxide

87.3

Luo, G. et al. ChemBioChem 2002, 3, 356-363

GSH = Glutathione, NADPH = -nicotinamide adenine dinucleotide phosphate

27

Outline

• Background • Industrial Applications• Chemical Applications

– Reactions and Catalysis– Scavengers– Receptors– Sensors

• Host Design• Conclusions

28

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.

Org 25969

Rocurionium Bromide

Zhang, M-Q. et al. Angew. Chem. Int. Ed. 2002, 41, 2, 265-270

OAc

NN

O

HHO Br

O

OHHO

S

O

O

HO

HOSO

OHO

HO

S

O

O

HOOH

S

O

O

OH

OH

S

O OH

OH

S

O

O

OH

HO

S

O

O

OH

OH

S

O

O

NaO2CCO2Na

CO2Na

CO2Na

CO2Na

NaO2C

NaO2C

NaO2C

29

Anesthetic ScavengerHost EC50 [M] Max %

Reversal

-CD >360 9.7

-CD >360 29

-CD 34.6 94.1

Org 25969

1.2 95.1

Data from mouse hemidiaphram studies

Zhang, M-Q. et al. Angew. Chem. Int. Ed. 2002, 41, 2, 265-270

• Extending cavity depth from 7.9 to ~ 11 Å greatly improves complexation.

• Patients show significant recovery in minutes.

30

Outline

• Background • Industrial Applications• Chemical Applications

– Reactions and Catalysis– Scavengers– Receptors– Sensors

• Host Design• Conclusions

31

Choline Receptor

NOH

Choline

• 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

O O

O

O

O O

O

O

H2N

H2N

NH2

NH2

NH2

NH2H2N

H2N

32

Choline Receptor

Ka = 1.2 x 104

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

• 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)

33

Receptor Synthesis

HO OH

HO

HO

HO OH

OH

OH

O O

O

O

O O

O

O

O2N

O2N

NO2

NO2

NO2

NO2O2N

O2N

O O

O

O

O O

O

O

H2N

H2N

NH2

NH2

NH2

NH2H2N

H2N

O2N

O2N

F

F 1. SnCl2, EtOH/ HCl2. NH4OH, EtOAc

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

34

Outline

• Background • Industrial Applications• Chemical Applications

– Reactions and Catalysis– Scavengers– Receptors– Sensors

• Host Design• Conclusions

35

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.

36

Fluorescent Hg2+ Sensor

OHOH OO

NH

O

HN

O

N

HN

SO

O

N

• 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

37

Fluorescent Hg2+ Sensor

OHOH OO

NH

O

HN

O

NHN

S

O

O

N

Hg2+

• 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

Chen, Q-Y; Chen, C-F, Tet. Lett. 2005, 46, 165-168

38

Radical Cation Sensor for Nitric Oxide

Green

Rathore, R. Abdelwahed, S.H.; Guzei, I. A. J. Am. Chem. Soc. 2004, 126, 13582-13583

CH3

H3CO

OCH3Ar =

OO

O

Ar

Ar

O

OCH3

H3CO

Ar

-e-

Et3O+ SbCl6- OO

O

Ar

Ar

O

OCH3

H3CO

Ar

OO

O

Ar

Ar

O

OCH3

H3CO

Ar

• Radical cation stabilized by electron-rich substituents

• Stable at room temperature

39

Synthesis of NO Binding Calixarene

CH3

H3CO

OCH3Ar =

Rathore, R.; Abdelwahed, S.H.; Guzei, I. A. J. Am. Chem. Soc. 2004, 126, 13582-13583

OHOH HOOH OHOH HOOH

PhOH, AlCl3toluene, reflux

n-propyltosylate, Cs2CO3, DMF, 80°

OO

OO

OO

OONBS, MeOH

BrBr

Br Br

MgBrH3CO

OCH3

(PPh3)2PdCl2, THF OO

O

Ar

Ar

O

OCH3

H3CO

Ar

40

Blue

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

41

Outline

• Background • Industrial Applications• Chemical Applications

– Reactions and Catalysis– Scavengers– Receptors– Sensors

• Host Design• Conclusions

42

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

N OBn

HNO

HNO

N

N

HN

HN

O

O

N

N

O

NO2

O

NO2

2

2

43

New Host Design

NNN

N

O

O

OH

OH

N NH

NHN

O

O

R R

O

O

HN N

HN N

O

O

R R

R = n-heptylphenyl

• “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

OH

HO

OHOH

Pinane diol Guests

( ) ( )

44

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

t1/2 = 1 min

t1/2 = 1 min

t1/2 = 10-20 ht1/2 = 10-20 h Enantiomers

Matched Pair

Matched Pair

OH

HO

OHOH

Pinane diol Guests

45

Outline

• Background • Industrial Applications• Chemical Applications

– Reactions and Catalysis– Scavengers– Receptors– Sensors

• Host Design• Conclusions

46

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

47

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.

48

Acknowledgements

Blackwell Group Members

Matt BowmanQi LinBen GorskeDavid MillerJenny O’Neill Sarah JewellRachel WezemanGrant Geske

Brian Pujanauski Adam SiegelEmily Guerard

Jamie EllisChris ParadiseKatie AlfareKara Waugh

Professor Helen E. Blackwell