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Chiral Counterions in Asymmetric Catalysis
Peter Dornan • Dong GroupPeter Dornan • Dong GroupMonday Night Seminar • April 13, 2009
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
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
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
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
h f l iPhase Transfer Catalysis
6
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
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
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
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
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
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
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
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
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
Michael Additions – Chiral Crown Ethers
16
Chiral crown ether complexes K+
Cram, D.J. et al. J. Chem. Soc. Chem. Commun. 1981, 625
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
NOE Studies of Ion Pairing
N
HOH
O Me
NO Me
2
18Pochapsky, T.C. et al. J. Org. Chem. 1999, 64, 8794
i i l l iTransition Metal Catalysis
19
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
Chiral Borate Counterions
Design of a chiral counteranion for transition metal catalysts
Arndtsen, B. A. et al. Org. Lett. 2000, 2, 4165 21
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
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
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
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
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
l iOrganocatalysis
27
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
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
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
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
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
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
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
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
Transfer Hydrogenation Mechanism
36
Complementary to traditional iminium ion catalysis
List, B. et al. Angew. Chem. Int. Ed. 2006, 45, 4193
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.
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
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
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
40
• More mechanistic information will be required for rational design
Acknowledgements
Prof. Vy DongThe Dong Group
41
The Dong Group
Recyclable Phase Transfer Catalysts
42Maruoka, K. et al. Org. Lett. 2004, 6, 1429
Recyclable Phase Transfer Catalysts
43Maruoka, K. et al. Org. Lett. 2004, 6, 1429
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
Lewis Acid Catalyzed DYKAT
45Braun, M. et al. Angew. Chem. Int. Ed. 2004, 43, 514
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