advances in host-guest chemistry megan jacobson university of wisconsin-madison april 21, 2005
TRANSCRIPT
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.
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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
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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]
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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
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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
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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
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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
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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
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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
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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.
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Outline
• Background • Industrial Applications• Chemical Applications
– Reactions and Catalysis– Scavengers– Receptors– Sensors
• Host Design• Conclusions
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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
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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
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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
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“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
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“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
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“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
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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