![Page 1: A Self-Supporting Strategy for Chiral Catalyst Immobilization · 4h: R = i-Pr, R' = Ph 0.5-1 h 91-99% yield 97.6% ee (R,S) 96.2% ee (R,S) 96.0% ee (R,S) 95.6% ee (R,S) 95.7% ee (R,S)](https://reader034.vdocuments.mx/reader034/viewer/2022050219/5f6503a55f06493c9a002710/html5/thumbnails/1.jpg)
A Self-Supporting Strategyfor Chiral Catalyst Immobilization
Kuiling Ding
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, China
ISCHIA ADVANCED SCHOOL OF ORGANIC CHEMISTRY
Ischia (Naples), September 27 - October 2, 2008
(50+10 min)
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• Selectivity: There is no given catalyst that is universal for all substrates. Catalyst diversity
• Reactivity and Efficiency : 1-10 mol% catalyst loading is not practical. 0.1-0.01% or less.
• Process chemistry: speed up the rate for catalyst discovery in customer synthesis.
• Catalyst recovery and reuse.
• Cost, energy, solvent, safety, and others…….
Some Challenges in Asymmetric Catalysis
Asy Catalysis
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Combinatorial Approach to Asymmetric Catalysis
Feature ArticleChem. Commun. 2008,909- 921.
Chem. Eur. J. 2004,10, 2872-2884.
Concept Article
ACIE 2001, 40, 544.ACIE 2003, 42, 5478.JACS 2002, 124, 10.JACS 2002, 124, 14866.JACS 2005, 127, 10488.JACS 2006, 128, 14212.JACS 2008,130, in press. CEJ 2002, 8, 5033.CEJ 2003, 9, 5989.CEJ 2008, 14, in pressASC 2005, 347, 1193.ASC 2006, 348, 1049.OL 2002, 4, 4349.OL 2003, 5, 1091.JOC 2004, 69, 146.EJOC 2006, 3606.EJOC 2008, 2248.
Modular Chiral Catalyst Library with m x n Members!
Chiral Ligand Library A with m Members
Ligand Library B with n Members (chiral, achiral or racemic)+ +
Related Conceptsmolecular recognition and assemblydynamic combinatorial chemistry
Mn+
High Throughput Screening (HTS) on Target Reactions
Highly Efficient and Enantioselective Catalysts
Related Conceptsasymmetric amplificationchiral poisoning asymmetric activation
HPLC-CD
Chemspeed Synthesizer
Brown (1986)Yamamoto(1989)Faller (1993)Mikami (1997)
Kagan Oguni, Noyori
Lehn (1999)
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Exceptionally Efficient Catalysts forEnantioselective Hetero-Diels-Alder Reaction
J. Long, K. Ding, et al., J. Am. Chem. Soc. 2002, 124, 10-11.
RCHO +
OMe
OSi CF3COOH
(1)
(2)
O
RO
OH
OH
L5
OH
OH
L6
L5/L5/Ti or L5/L6/Ti0.1-0.005 mol%
up to >99% yield99.8% ee
Highly efficient: 0.1% - 0.005% of cat. loading!Very high yield and enantioselectivityRoom temperature and solvent free
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Asymmetric HDA Reaction: A Facile Approach to Lactone Sub-unit of Chiral Drugs
O
O
OH
R O
O
HO
O
OHN
HNO
F
R = H, compactinR = Me, Mevacor Lipitor, $13.6 billion (2006)
lactone sub-unitlactone sub-unit
O
O
OHRRCHO +
OMe
OSi CF3COOH
(1)
(2)
Catalyst O
R O
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Exceptionally Efficient Catalysts for Quasi Solvent-Free Enantioselective Carbonyl-Ene Reaction
O
O
OEt+
1a: Ar = C6H51b: Ar = 4-ClC6H41c: Ar = 4-FC6H41d: Ar = 4-CH3C6H4
2 3
HAr Me ArOEt
OH
Osolvent-free
1
3a: Ar = C6H5 (98.2% ee)3b: Ar = 4-ClC6H4 (99.4% ee)3c: Ar = 4-FC6H4 (98.4% ee)3d: Ar = 4-CH3C6H4 (97.1% ee)
*
0.1-0.01% Cat
OH
OH
I
I
OH
OH
F3C
F3C
L1 L2
L1/L1/Ti orL1/L2/Ti
76-99% yield
Y. Yuan & K. Ding, Angew. Chem. Int. Ed. 2003, 42, 5478.
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Y. Yuan & K. Ding, Angew. Chem. Int. Ed. 2003, 42, 5478.
Exceptionally Efficient Catalysts for Quasi Solvent-Free Enantioselective Carbonyl-Ene Reaction
solvent-free(0.1-0.01mol %)
OH
OH
I
I
OH
OH
F3C
F3C
L1 L2
L1/L1/Ti orL1/L2/Ti
94-99% yield
O
O
OEt+
n = 0, 1
H OEtOH
O
H
n
n = 0 (91% ee)n = 1 (92% ee)
n *
n = 0
NN
O
O
HOHN
N
O
O
Trocade
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General Strategy for Chiral Catalyst Immobilization
★ Organic Polymers and Dendrimers;★ Inorganic Supports;★ Non-Conventional Media (such as water, fluorous inated liquids, ionic
liquids, and Sc CO2…)
Bonding PatternsBonding Patterns
Covalentbonding
Supports or MediaSupports or Media
Fan, Q.; Li, Y.-M.; Chan, A. S. C. Chem. Rev. 2002, 102, 3385. D. E. De Vos, I. F. J. Van Kelecom, P. A. Jacobs, Eds. Chiral Catalyst Immobilization and Recycling, Wiley-VCH, Weinheim, 2000.
Electrostatic interactions EntrapmentPhysisorption
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Microporous Metal-Organic Frameworks
O. M. Yahgi, et al. Nature, 2003, 423, 705; Science, 2003, 300, 1127.
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Coordination Network Material as A Zeolite-Like Heterogeneous Catalyst
M. Fujita & K. Ogura, et al., J. Am. Chem. Soc. 1994, 116, 1151-1152.
Me3SiCN5 (0.2 equiv.)
CH2Cl2, 40 0C24 h
R CN
OSiMe3R H
O
R = 2-MeC6H4, 3-MeC6H4, 1-naphthyl, 2-naphthyl.
19-84% yields
(4,4'-bpy)
Cd(NO3)2 N
(Counter ions are omitted for clarity)5
N N NCd N
Cd N N CdN
NCdN
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Microporous Homochiral Metal-Organic Frameworks
K. Kim et al., Nature, 2000, 404, 982.
OO
NHHOO O
N
Zn(NO3)2
H2O/MeOH
1 2
AcO NO2
O2N
+ HO NO2
O2N
+D-2
3 4
Ph
OH
Ph
OAc*
5, 8% ee 6
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Self-Supported Chiral Catalysts for Heterogeneous Enantioselective Catalysis
+
chiral ligand metallic ion
chiral metal-organic framworks
substrates
product
or chiral metal-organic coordination polymer
A bottom-up strategy
K. Ding et al. Chem. Eur. J. 2006, 12, 5188-5197.
A bottom-up strategy
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Self-Supported BINOL-Ti Catalysts for Carbonyl-Ene Reaction
O
OTi
HO
HOOiPr
OiPr
linkerOH
OH
HO
HO
linker
n
Ti(OiPr)4
catalysts for carbonyl-ene reaction:1 mol% of catalyst loadingup to >99% yield and 96.5% ee
O
O
OEt+ HPh Me PhOEt
OH
Oup to 99% yield96.5% ee
Catalyst 1 mol%
H. Sasai et al., Angew. Chem. Int. Ed. 2003, 42, 5711-5714.H. Guo, X. Wang et al, Tetrahedron Lett. 2004, 45, 2009-2012.X. Wang, H. Guo et al. Chem. Eur. J. 2005, 11, 4078-4088.
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Highly Stable and Enantioselective Heterogeneous Titanium Catalysts for Asymmetric Oxidation of Sulfides
n
1) 1 eq. Ti(OiPr)4, rt,12 h
1a-c
2a-c
linker: a
b
c single bond
2) 40 eq. H2O, rt,12 h
(H2O)m
m = 5 or 6
HO
HO
OH
OH
Linker
O
O
O
O
Linker
Ti
X. Wang, H. Guo, et al., Chem. Eur. J. 2005, 11, 4078-4088.
Kagan, Modena,
Uemura, Bolm
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Highly Stable and Enantioselective Heterogeneous Titanium Catalysts for Asymmetric Oxidation of Sulfides
SR'
RS
R'
O
R2a-c, 5 mol%
Oxidant ( 2 eq.) CCl4
3a: R = H, R' = Me3b: R = 4-Me, R' = Me3c: R = 4-Br, R' = Me3d: R = 4-F, R' = Me3e: R = 3-Br, R' = Me3f: R = NO2, R' = Me3g: R = H, R' = Et
3a-g 4a-g
up to >99.9% ee35-45% yield
3-4 days
Reused for 8 times,Life time > 1 month98.2->99.9% ee
Run 1 2 3 4 5 6 7Y (%) 39 34 42 39 30 38 32Ee (%) 98.2 99.1 99.2 99.2 99.0 99.1 >99.9
834
99.1
X. Wang, H. Guo et al., Chem. Eur. J. 2005, 11, 4078-4088.
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Heterogeneous Titanium Catalysts for Asymmetric Ring Opening of Expoide
Cf.Sagawa, S.; Inaba, T. J. Org. Chem. 1999, 64, 4962. H. Bao, Z. Wang & K. Ding et al., J. Am. Chem. Soc. 2008, in the press.
O
O O+ BnNH2
O O
OHBnHN
polymeric BINOL/Ti
recycled 12 times
>90% yield94-97% ee
(1 mol%)
linker = 1,4-phenylene linker = -CH2CH2CH2CH2-
OO Ti
OO
*
linker
npolymeric BINOL/Ti
HONH
OSPh
OHN
OHN
H
H
NelfinavirC4 unit
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The Impact of Bridging Spacers on the Self-Supported Catalysts
+
+
chiral unit metallic ion
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+
chiral unit metallic ion
The Impact of Bridging Spacers on the Self-Supported Catalysts
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Multitopic Ligands Containing BINOL Units with Various Bridging Spacers
= OHOH
spacer
single bondb
c
d
a
e
f
g
1a-g
spacer
1h 1i
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Self-Supported BINOL-La Catalysts with Various Bridging Spacers
+
+
+
(S)-BINOL
Self-supported BINOL/La catalyst
La(III)
Cf.M. Bougauchi, S. Watanabe, T. Arai, H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 1997, 119, 2329.K. Daikai, M. Kamaura, J. Inanaga, Tetrahedron Lett. 1998, 39, 7321-7322
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Self-Supported BINOL-La Catalysts for Epoxidation of Enones
single bondb
c
d
a
e
fg
1h
1i
97.6 (R,S)83.7 (R,S)
82.9 (R,S)
95.5 (R,S)
93.3 (R,S)
95.1 (R,S) 84.2 (R,S)
91.5 (R,S)
95.0 (R,S)
Ph Ph
O
CHMP 2a-i (5.0 mol%)
MS 4A, THF, RT Ph Ph
OO
α3a 4a
+ βPh3PO (15 mol%)
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Self-Supported BINOL-La Catalysts for Epoxidation of Enones
R'
O
CMHP (1.5 equiv.)
2a (5 mol%)Ph3P=O (15 mol%)
MS 4A, THF, RT R'
OO
123R R
4a: R = Ph, R' = Ph4b: R = 4-F-Ph, R' = Ph4c: R = 4-Cl-Ph, R' = Ph4d: R = 4-Br-Ph, R' = Ph4e: R = 4-NO2-Ph, R' = Ph4f: R = 4-NC-Ph, R' = Ph4g: R = Ph, R' = 4-MeO-Ph4h: R = i-Pr, R' = Ph
0.5-1 h 91-99% yield
97.6% ee (R,S)96.2% ee (R,S)96.0% ee (R,S)95.6% ee (R,S)95.7% ee (R,S)94.3% ee (R,S)95.0% ee (R,S)84.9% ee (R,S)
X. Wang, L. Shi, et al. Angew. Chem. Int. Ed. 2005, 44, 6362-6366.
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Recovery and Reuse of Self-Supported BINOL-La Catalysts
X. Wang, L. Shi, et al. Angew. Chem. Int. Ed. 2005, 44, 6362-6366.
Ph Ph
O
oxidant 2a (5.0 mol%)
MS 4A, THF, RTPh Ph
OO
α3a 4a
+ β
Run Ph3PO[mol%]
Time[h] Yield [%][b] Ee[c] [%]
(Config.)[d]
1 15 0.5 >99 96.5 (R,S)
2 10 0.5 >99 96.3 (R,S)
3 10 0.5 >99 95.8 (R,S)
4 10 0.5 >99 94.9 (R,S)5 10 0.5 95 94.5 (R,S)6 10 1 83 93.2 (R,S)
La leaching:<0.4 ppm
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Modular Monodentate Phosphorous Ligandsfor Rh(I)-Catalyzed Asymmetric Hydrogenation
Q. Zhou (2002)M. Reetz (2000)B. L. Feringa (2000)P. Pringle (2000)
K. Ding (2005)
OO
PO
OP X
N
N
O
OP NO
R
RR'
R'
3, DpenPhos1a X = OR1b X = alkyl or aryl1c X = NR2, MonoPhos
X
2a X = OR2b X = NR2, SpiroPhos
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MonoPhos/Rh Catalyst:from Homogeneous to Heterogeneous
Linker
single bondc:a: b:
=
O
O
O
O P
P
N
Nlinker
linkerO
OPN O
OP
N
[Rh]
n
B. L. Feringa, et al, J. Am. Chem. Soc. 2000, 122, 11539 Y. Liu & K. Ding, J. Am. Chem. Soc. 2005, 127, 10488-10499
+
O
O
P
O
O
P
+OO
OOP PN N
N
N
Rh+
Excellent catalyst for asymmetric hydrogenation
Rh+
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1 mol% of catalyst RR'
NHAc94-97% ee
NHAc
R'R
O
OPN O
OP
N
[Rh]
nself-supported catalyst
linker
H2
R = H, Ph, Me; R' = COOMe, H
X. Wang et al. J. Am. Chem. Soc. 2004, 126, 10524.
Self-Supported Catalysts for Heterogeneous Enantioselective Hydrogenation
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Catalyst Recycling
2c 1mol%, 40 atm H2CO2CH3
NHActoluene, rt, 10hNHAcOCH3
O
3a 4a
Run 1 2 3 4 5 6 7 8 9 10
Conv.(%)b >99 >99 >99 >99 >99 >99 >99 >99 >99 >99
E.e. (%)c 95.0 93.5 90.2 90.9 90.5 90.0 89.5 87.7 87.3 87.3
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Use of Hydrogen Bonds as the Bridging Linker: From Dimeric Supramolecules to Polymeric Chiral Catalyst
metallic ions
solvent
hydrogen-bonding unit
chiral ligand unit
n
dimeric supramolecules
polymeric chiral catalyst
L. Shi & K. Ding, Angew. Chem. Int. Ed. 2006, 45, 4108-4112
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Self-Supported MonoPhos/Rh(I) Catalyst
O
OP N
NH
NH
ONH
NO
SupraMonoPhos (1a)
NN
ON
NO
2
H
H HO
OP
N
N N
O N
N O
H
HH
O
OP
N[Rh]
n[Rh] = Rh(cod)BF4
CH2Cl2 or Toluene
[Rh(cod)2]BF4
L. Shi & K. Ding, Angew. Chem. Int. Ed. 2006, 45, 4108-4112
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Self-Supported MonoPhos/Rh(I) Catalystfor Enantioselective Hydrogenation
>99% conv.91% ee
>99% conv.93-96% ee
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High Enantioselectivity and Facile Recovery
Table 2. Recycling and reuse of the self-supported catalysts 2b in enantioselective hydrogenation of 3b.a
Run 1 2 3 4 5 6 7 8 9 10 11
conv.[%]b
>99 >99 >99 >99 >99 >99 >99 >99 >99 >99 96
Ee[%]c
95.7 95.7 95.2 94.7 94.3 94.5 94.6 94.5 92.9 92.0 91.5
2, 1 mol% H3CCO2CH3
NHAcH2, 40 atm,tolueneNHAc
OCH3
O
H3C
Rh leaching < 1 ppm
L. Shi & K. Ding, Angew. Chem. Int. Ed. 2006, 45, 4108-4112
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Schematic Representation of Continuous Flow Reaction System for Chiral Catalysis
Stainless Steel Cross
H2 Cylinder
H2 flow control
peek tube
reactioncolumn
check valve
A B C
PUMP
productGC analysis
self-supported catalyst
>100 hrwith >99% yield
96-97% ee
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Schematic Representation of the Strategy
+
+ +
n
n
Multitopic Ligands Metallic Ion
hetero-ligand polymer
homo-ligand polymer
P
PRu
Ar Ar
Ar Ar
Cl
Cl
Ph
PhNH2
H2N
Cf. R. Noyori, et al. J. Am. Chem. Soc. 1995, 117, 2675.
Programmed Assembly
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Self-Supported Noyori-Type Catalyst
1a Ar = C6H51b Ar = 3,5-(CH3)2C6H3 2H2N
OMe
OMe
O
n
1 + 2[(C6H6)RuCl2]2
DMF
3a Ar = C6H53b Ar = 3,5-(CH3)2C6H3
O
MeO
NH2
NH2
H2N
Ar2P
PAr2
H2N
NH2
Ru
Cl
Cl
PAr2
PAr2
Ar2P
Ar2P
O
Liang, Y. et al. J. Am. Chem. Soc. 2005, 127, 7694-7695.
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O
97.4% ee
O
97.5% ee
O
96.2% eeO
O
96.9% ee
F
OO
94.5% ee98.1% ee
O
94.2% ee (0.01 mol % of cat)
O
97.2% ee
Ar
O+ H2 Ar
OH
KOtBu, i-PrOH
0.1 mol% of Catalyst 3b
4a-h 5a-h
Br
O
Cl
96.2% ee
Self-Supported Noyori-Type Catalyst for Asymmetric Hydrogenation of Ketones
Run 1 2 3 4 5 6 7Y (%) >99 >99 >99 >99 >99 >99 97Ee (%) 97.4 97.6 97.3 96.5 95.6 96.1 95.4
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+ H2
O
RAr KOtBu, i-PrOH8a or 8b
RAr+ H2
9a or 9bMeOHR1 O
R2O O
R1 OR2
OH O
OH0.1-0.005mol%
1 mol%
up to >99% yield, 95% ee, 5 recycles
up to >99% yield; 99% ee, 8 recycles10 11
12 13
Zr
Zr
PP
Ph Ph
Ph Ph
Ru
Cl
Cl
P
PO OO
O O O
Zr
Zr
LL
8a L-L = (R,R)-DPEN9a L = DMF
Zr
Zr
Zr
PP
Ph Ph
Ph Ph
Ru
Cl
Cl
LL
Zr
POO
O
POO O
8b L-L = (R,R)-DPEN9b L = DMF
Lin, W. et al. J. Am. Chem. Soc. 2003, 125, 11490; Lin, W. et al. Anew. Chem. Int. Ed. 2003, 42, 6000.
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Summary and Outlook • Carbonyl-ene reaction• Epoxidation• Sulfoxidation• Ring Opening of Epoxide• Hydrogenation
• Carbonyl-ene reaction• Epoxidation• Sulfoxidation• Ring Opening of Epoxide• Hydrogenation
A Concept Article, see: K. Ding, et al. Chem. Eur. J. 2006, 12, 5188-5197.
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Acknowledgements
• Coworkers• Dr. Wang Zheng Dr. Christian A. Sandoval• Dr. Long Jiang Dr. Yuan Yu Dr. Yuxue Liang • Dr. Xisheng Wang Dr. Xingwang Wang Dr. Qing Jing• Dr. Yan Liu Mr. Lei Shi Dr. Baoguo Zhao
• Foundations• National Natural Science Foundation of China• Major Basic Research Development Program of China (973
Project) • Chinese Academy of Sciences• Science & Technology Commission of Shanghai Municipality