chiral counterions in asymmetric catalysisdongv/i/seminars/chiralcounterions.pdf · chiral...
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Chiral Counterions in Asymmetric Catalysis
Peter Dornan • Dong GroupPeter Dornan • Dong GroupMonday Night Seminar • April 13, 2009
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Asymmetric Catalysis
Chiral induction is typically achieved through strongly directional chiral catalyst – substrate interactions
N N
SR''
O
PhPhH
• Lewis Acid/Base Interactions• Hydrogen Bonds• Covalent Bonds• Coordination BondsN
HO
H
N
NR''2
R
N+B
OR
-H3B O
Ph
Me
• Coordination Bonds• Ion Pairing ?
N COOH
RPh
O
Chi lCatalyst
oror
N COOH
RR' Rh
ArPP
*
ChiralCounterion
Substrate
2
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Outline
1926: Introduction of the ‘Ion Pair’ Concept
1984: First example of Asymmetric Phase
2006: First example of chiral counterions
1900 1950
the Ion Pair ConceptTransfer Catalysis in organocatalysis
2000
2000: First example of chiral counterions in
1. Ion Pairingchiral counterions in transition metal catalysis
2. Phase Transfer Catalysis3. Transition Metal Catalysis4. Organocatalysis (Single Phase)
‐ Iminium Ion Catalysis
3
Iminium Ion Catalysis‐ Anion Binding
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Ion Pairing
Coulombic Interaction Energy:
Inversely proportional to the permittivityof the medium and the separation of charge
E = Energy εo = Permittivity of a vacuumq = Charge of the ionr = Separation of ions
oε = Dielectric constant of the medium
4Macchioni, A. Chem. Rev. 2005, 105, 2039
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Ion Pairing
Coulombic Interaction Energy:
Inversely proportional to the permittivityof the medium and the separation of charge
Solvent separated Solvent shared
+ ‐ + +
ion pair: ion pair: Contact Ion Pair:
+ + ‐ + ‐
5Macchioni, A. Chem. Rev. 2005, 105, 2039
Decreasing Ion Separation
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h f l iPhase Transfer Catalysis
6
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Enolate Alkylation – Pioneering Report
N
OH
N
N
CF3OCl
• Electron withdrawing groups at the para‐iti f th b l i i d th
OClCl
MeO
7Dolling, U.‐H. et al. J. Am. Chem. Soc. 1984, 106, 446
position of the benzyl ring improved the ee
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Cinchona Alkaloids
• Isolated from the bark of the Cinchona trees
• Quinine is a potent antimalarial (found in tonic water)
• Privileged scaffold for asymmetric catalysis
8Hoffmann, H.M.R. et al. Eur. J. Org. Chem. 2004, 4293
Dewick, P.M. Medicinal Natural Products Second Edition, John Wiley & Sons, 2001
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Asymmetric Phase Transfer Catalysis
Asymmetric Phase Transfer Catalysis involves a chiral ion which facilitatesmigration of a charged species into the organic phasemigration of a charged species into the organic phase.
O ONPh2C
Ot-Bu
O
NPh2COt-Bu
O
RBasic Aqueous Phase
Organic Phase
R'4NX*
+ RX
Two possible mechanisms: Interfacial and Extraction
9Maruoka, K. et al. Angew. Chem. Int. Ed. 2007, 46, 4222
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Interfacial Mechanism
O A* RX
NO
OMX
NPh2COt-Bu
NPh2COt-Bu
ROrganicPhase
NPh2COt-Bu
O
NPh C
OM
RX
NPh C
O
A* X
Interface
MOH H2O
NPh2COt-Bu
NPh2COt-Bu
R (+/ -)
Interface
AqueousPh
Th b i d d h i f
Phase
10Maruoka, K. et al. Angew. Chem. Int. Ed. 2007, 46, 4222
The substrate is deprotonated at the interface
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Extraction Mechanism
Th b d h i f
11Maruoka, K. et al. Angew. Chem. Int. Ed. 2007, 46, 4222
The substrate need not come to the interface
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Enolate Alkylation – Racemization Studies
NPh2COt-Bu
O50% aq NaOH
CH2Cl2
Conditions
NPh2COt-Bu
O
25 C, 1h
100% ee
Conditions ee (%)
No additives 100
1 (10 mol%) 30
1 (10 mol%) + BnBr (1 2 eq) 100
N
OH
N
Cl
1 1 (10 mol%) + BnBr (1.2 eq) 100
• Racemization was catalyzed by the free alkoxide
1
12
y y• In situ benzylation likely yields the active catalyst
O’Donnell, M.J. et al. Tetrahedron. 1994, 50, 4507
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Enolate Alkylation – Catalyst Modifications
Cl
N
O
1
NO
13Corey, E.J. et al. J. Am. Chem. Soc. 1997, 119, 12414 Maruoka, K. et al. J. Am. Chem. Soc. 1999, 121, 6519
1
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Enolate Alkylation – Catalyst Modifications
Cl BrAr
N
O
N
Ar
1
NO
Ar = 3,4,5-F3C6H22
Ar
14Corey, E.J. et al. J. Am. Chem. Soc. 1997, 119, 12414 Maruoka, K. et al. J. Am. Chem. Soc. 1999, 121, 6519
1
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Enolate Alkylation – Crown Ethers
OO
OO O
OOO
[18]crown-6
15Maruoka, K. et al. Angew. Chem. Int. Ed. 2005, 44, 625
Crown ether is proposed to extract KOH into the organic phase
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Michael Additions – Chiral Crown Ethers
16
Chiral crown ether complexes K+
Cram, D.J. et al. J. Chem. Soc. Chem. Commun. 1981, 625
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NOE Studies of Ion Pairing
NN
HOH
O Me
N
HOH
O Me
NO Me
1O Me
1
17Pochapsky, T.C. et al. J. Org. Chem. 1999, 64, 8794
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NOE Studies of Ion Pairing
N
HOH
O Me
NO Me
2
18Pochapsky, T.C. et al. J. Org. Chem. 1999, 64, 8794
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i i l l iTransition Metal Catalysis
19
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Chiral Borate Counterions
Design of a chiral counteranion for transition metal catalysts
OHOH
1. H2BBr·SMe2
2. Ag2CO3
O
OB
OO
O
CuCl
MeCN
Ag
MeCN
O
BO
OB
O
Cu(MeCN)4
Arndtsen, B. A. et al. Org. Lett. 2000, 2, 4165 20
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Chiral Borate Counterions
Design of a chiral counteranion for transition metal catalysts
Arndtsen, B. A. et al. Org. Lett. 2000, 2, 4165 21
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Chiral Borate Counterions
Ligand Sol ent Yield (%) ee (%)Ligand Solvent Yield (%) ee (%)
MeCN C6H6 86 7
2 C6H6 43 10
3 C6H6 90 2
MeCN CH2Cl2 97 4
MeCN MeCN 87 <1eC eC 8
M d i i d i b d i i idi i f l fiModest enantioinduction was observed in aziridinations of olefins
Arndtsen, B. A. et al. Org. Lett. 2000, 2, 4165 22
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Amino Acid Based Borate Counterions
+ N2CHCO2Et[Cu(MeCN)2]+[1]- (1 mol%)
CO2Et
PhC6H6
• A library of chiral counterions could be synthesized• The amino acid fragments had a greater effect on enantioinduction
trans: 20% (23% ee)cis: 16% (19% ee)
• The amino acid fragments had a greater effect on enantioinductionthan the tartrate fragments
Arndtsen, B. A. et al. Tetrahedron. Asymm. 2005, 16, 1789 23
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Asymmetric Gold Catalysis
Au(I) and Au(III) tend to adopt linear geometries
Asymmetric Induction is difficult when the chiral ligand is 180°from the substrate, however some examples are known:
24Toste, F.D. et al. J. Am. Chem. Soc. 2005, 129, 2452
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Phosphoric Acid Counterions
L X Solvent Yield (%) ee (%)
1 OPNB CH Cl 89 81 OPNB(6 mol% AgX)
CH2Cl2 89 8
dppm 2 CH2Cl2 76 65
PAr2
PAr2
1dppm 2 CH3NO2 60 18
dppm 2 C6H6 90 97Ar
Ar = 3,5-Me-C6H3
• Traditional chiral ligands failed• A chiral phosphoric acid counterion was successful in inducing chirality (97% ee)
OO
POO
25
successful in inducing chirality (97% ee)
Toste, F.D. et al. Science 2007, 317, 497
Ar
Ar = 2,4,6-(i-Pr)3-C6H2
2
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Chiral Counterions with Chiral Ligands
L X Yield (%) ee (%)
1 ‐OPNB 80 38
dppm 2 89 12
PPh2
PPh2
1 dppm 2 89 12
1 2 88 82
1
Ar
Together these two sources of chirality worked synergistically to give 82% ee.
OO
POO
26Toste, F.D. et al. Science 2007, 317, 497
Ar
Ar = 2,4,6-(i-Pr)3-C6H2
2
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l iOrganocatalysis
27
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Anion Binding Catalysis
• Effectively an asymmetric SN1 reaction• The term ‘Anion Binding Catalysis’ coined by Eric Jacobsen• Two possibilities:
28Jacobsen, E.N. et al. J. Am. Chem. Soc. 2007, 129, 13404
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Thiourea Catalyzed Anion Binding
N
O
N O
1 (10 mol%)TMSCl (2eq)
NH
NH
HO TBME, -55 C
90% yield97% ee
29Jacobsen, E.N. et al. J. Am. Chem. Soc. 2007, 129, 13404
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Thiourea Catalyzed Anion Binding
N
O
N O
1 (10 mol%)TMSCl (2eq)
NH
NH
HO TBME, -55 C
90% yield97% ee
30Jacobsen, E.N. et al. J. Am. Chem. Soc. 2007, 129, 13404
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Thiourea Anion Binding ‐Mechanism
• Reaction more effective for tertiary alcohol – supports an SN1 mechanism
A i ifi l d h lid ff b d• A significant solvent and halide effect was observed
Solvent Halide Conversion (%) ee (%)
TBME Cl 80 97
TBME Br 82 68
TBME I 75 <5
31
CH2Cl2 Cl >95 <5
Jacobsen, E.N. et al. J. Am. Chem. Soc. 2007, 129, 13404
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Thiourea Anion Binding ‐Mechanism
• Treatment of thiourea with a chloride source causes a 0.56 ppm shift of N‐H protons of the thiourea (Δppm : Cl‐ > Br‐ > I‐)
• DFT calculations (B3LYP/6‐31G(d)) indicate interactions between the thiourea and the chloridethiourea and the chloride.
• No minimum could be optimized with the thiourea bound to the N‐acyliminium ion
32Jacobsen, E.N. et al. J. Am. Chem. Soc. 2007, 129, 13404
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Thiourea Anion Binding ‐ Oxocarbeniums
N N
SR1 R2
O
N NHH
Cl
• An efficient DYKAT process involving oxocarbenium ions• 10 mol% n‐BuN4Cl was found to shut down the reaction
33Jacobsen, E.N. et al. J. Am. Chem. Soc. 2008, 130, 7198
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Silver Mediated Halide Abstraction Catalysis
AgA*R-XBH
g
R+A*-HA*
AgX(s)AgB(s)
NuHR-Nu
34Toste, F.D. et al. J. Am. Chem. Soc. 2008, 130, 14984
Effective chiral discrimination of a meso aziridinium ion
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Transfer Hydrogenation
• List coined the term ‘Asymmetric Counteranion‐Directed Catalysis’ (ACDC)
35List, B. et al. Angew. Chem. Int. Ed. 2006, 45, 4193 List, B. et al. J. Am. Chem. Soc. 2006, 128, 13368
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Transfer Hydrogenation Mechanism
36
Complementary to traditional iminium ion catalysis
List, B. et al. Angew. Chem. Int. Ed. 2006, 45, 4193
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Brønsted Acid versus Chiral Counterion
i-Pr
OO
i-Pr
i-Pr
N
O
O
P
i-Pr
O
O
Ar Me
i-Pri-Pr
Ion Pair Ion Pair or H‐bond?
I h di i i b B d A id d
37
In some cases, the distinction between Brønsted Acid and Chiral Counterion Catalysis can be difficult to distinguish.
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Organo‐ and Transition Metal Catalysis
Ph NH
Ph
(1 eq)
Ph CHO
Me (R)-TRIP (1.5 mol%),Pd(PPh3)4 (3.0 mol%)
MS 5A, MTBE, 40 C
H
Ph CHO
Me
(+/ -)85% Yield97% ee
• A novel combination of different modes of catalysis
• Secondary amine acts as a reagent and Seco da y a e acts as a eage t a da catalyst
• Role of the counterion?
38List, B. et al. J. Am. Chem. Soc. 2007, 129, 11336
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Organo‐ and Transition Metal Catalysis
O Ph
Me
CHO
+ RNH
Ph CHO
Me
RNH+
POR*
OR*HO
HR
Ph CHO
H2O H2O
OP
OR*OR*
OMe
N R
Ph
N OP
OR*OR*
O
RH
Ph Ph
OPd H
OP
OR**RO
R
Me
[Pd][Pd]
Pd HN
R
Me
Ph
39
Phosphoric acid acts as both a counterion and an anionic ligand
List, B. et al. J. Am. Chem. Soc. 2007, 129, 11336
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Conclusion
• Many examples of efficient chiral induction using chiral counterions:
Phase Transfer Catalysis Transition Metal Catalysis Organocatalysis
• We can expect more chemistry using chiral counterions in the future
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• More mechanistic information will be required for rational design
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Acknowledgements
Prof. Vy DongThe Dong Group
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The Dong Group
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Recyclable Phase Transfer Catalysts
42Maruoka, K. et al. Org. Lett. 2004, 6, 1429
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Recyclable Phase Transfer Catalysts
43Maruoka, K. et al. Org. Lett. 2004, 6, 1429
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Epoxidation with Chiral Anions
O
H1 (10 mol%)
t-BuOOH (1.1 eq)
O
HO
Ph Dioxane, 35 C, 72 h Ph
75% Yield>99:1 d.r.91% ee
• This strategy has been extended to epoxidation of α,β‐unsaturated aldehydes involving an iminium ionAr
CF3
F C aldehydes, involving an iminium ion with a chiral counterion
OO
POO
Ar
H2N
F3C
1
Ar
Ar = 2,4,6-(i-Pr)3-C6H2
F3C
CF
44List, B. et al. Angew. Chem. Int. Ed. 2008, 47, 1119
CF3
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Lewis Acid Catalyzed DYKAT
45Braun, M. et al. Angew. Chem. Int. Ed. 2004, 43, 514