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Anion binding in Catalysis
Asymmetric and Non-Asymmetric Examples
Andy McNally
MacMillan Group Meeting
2/04/09
Chiral Anion Mediated Chemistry
! The use of 'cationic' counter-ion chemsitry far outweighs anion-binding
Introduction
SubstrateCounter-ion
!+ !–
SubstrateCounter-ion
!– !+
vs
! Ion-pair catalysis has been known for a very long time - phase transfer catalysis
! Ion-pairing involving a catalytic anionic component has only recently emerged
! New strategy for catalysis:
! Unexplored reactivity
! Enhanced reactivity vs ligand based approaches
! New asymmetric variants and entirely new transformations
Chiral Anion Mediated Asymmetric Chemistry
! The chiral pool provides a convenient source of enantiomerically pure anions
From Humble Beginings to New Strategies for Catalysis
–O2CCO2
–
OH
OH
Ph CO2–
OH
–O2CCO2
–
OCOPh
OCOPh
Me Me
OSO3
–
O
O
O
O
O
O
Sb
SbO
O
O
O
O
O
2–
Me Me
O
O
F3C
Eu
4
–
Review: Lacour, J. Chem. Soc. Rev. 2003, 32, 373-382.
Cl O
O
B
ClO
O
O
O
B
O
O
Me Me
MeMe
O
O
B
O
O
Me Me
O
OB
O
O
R
R
O
OB
O
OBB
O
O
P
O
O
O
O
P
O
O
O
O
Cl
Cl
Cl
Cl
Cl
ClCl
Cl
O
P
O
O
O
O
Cl
Cl
Cl
Cl
Cl
ClCl
Cl
O
Cl
Cl
Cl
Cl
Chiral Anion Mediated Asymmetric Chemistry
! Uses of chira anions: determination of enantiomeric purity
From Humble Beginings to New Strategies for Catalysis
N
N
Me
Me
Me
Me
Me
Me
NMe3
Me P
MeO
CD3
CH3
Mn(CO3
OMe
Me
S
Pht-Bu
Me
O
O
P
OO
OO
Cl
Cl
Cl
Cl
Cl
ClCl
Cl
Review: Lacour, J. Chem. Soc. Rev. 2003, 32, 373-382.
Chiral Anion Mediated Asymmetric Chemistry
! Uses of chira anions: purification and enantiomeric separation of cations
From Humble Beginings to New Strategies for Catalysis
O
P
OO
OO
Cl
Cl
Cl
Cl
Cl
ClCl
Cl
O
Cl
Cl
Cl
Cl
N N
Me
Me
Me
Me
X
(X = H or NMe2)
MeO OMe
O
Me
O
Me
MeO OMe N N
X
(X = H or Br)
Review: Lacour, J. Chem. Soc. Rev. 2003, 32, 373-382.
Chiral Anion Mediated Asymmetric Chemistry
! First transition metal-catalysed enantioselective transformation using chiral anions
From Humble Beginings to New Strategies for Catalysis
PhPhINTs
TsN
Ph
O
OB
O
OCu(MeCN)4
Benzene
Arndstsen, B. A. Org. Lett. 2000, 2, 4165-4168.
Chiral Anion Mediated Asymmetric Chemistry
! Aziridination under 'classical' conditions displays a pronounced counteranion effect
From Humble Beginings to New Strategies for Catalysis
PhPhINTs
TsN
Ph
10 mol% CuX, 0 ºC N
O
N
O
Me Me
t-Bu t-Bu
(11 mol%)
X % ee (benzene) % ee (MeCN)
OTf 66 2
ClO4 57 2
Cl 26 2
PF6 33 2
Arndstsen, B. A. Org. Lett. 2000, 2, 4165-4168.
Chiral Anion Mediated Asymmetric Chemistry
! Synthesis of copper-boronate catalyst
From Humble Beginings to New Strategies for Catalysis
O
OB
O
O
Cu(MeCN)4
OH
OH
1) H2BBrSMe2
2) Ag2CO3
Ag
O
OB
O
O
CuCl
MeCN
Arndstsen, B. A. Org. Lett. 2000, 2, 4165-4168.
Chiral Anion Mediated Asymmetric Chemistry
! Ion-pair crystal structure
From Humble Beginings to New Strategies for Catalysis
Cu-O, 2.16 A
Chiral Anion Mediated Asymmetric Chemistry
! Enantiocontrol from chiral boronate is low
From Humble Beginings to New Strategies for Catalysis
PhPhINTs
TsN
Ph
O
OB
O
OCu(MeCN)4
(1-3 mol% Cu-B(OR*)4)
1-3 mol% L
N
O
N
O
Me Me
t-Bu t-Bu
(S)-Cu-B(OR*)4
13% ee (R)
N
O
N
O
Me Me
t-Bu t-Bu
(R)-Cu-B(OR*)4
12% ee (R)
no ligand
(S)-Cu-B(OR*)4
7% ee (S)
no ligand
(R)-Cu-B(OR*)4
7% ee (R)
(R)-Cu-B(OR*)4
NN
10% ee (R)
Arndstsen, B. A. Org. Lett. 2000, 2, 4165-4168.
Chiral Anion Mediated Asymmetric Chemistry
! Enantiocontrol from chiral boronate is low
From Humble Beginings to New Strategies for Catalysis
PhPhINTs
TsN
Ph
O
OB
O
OCu(MeCN)4
(1-3 mol% Cu-B(OR*)4)
1-3 mol% L
N
O
N
O
Me Me
t-Bu t-Bu
(S)-Cu-B(OR*)4
13% ee (R)
N
O
N
O
Me Me
t-Bu t-Bu
(R)-Cu-B(OR*)4
12% ee (R)
no ligand
(S)-Cu-B(OR*)4
7% ee (S)
no ligand
(R)-Cu-B(OR*)4
7% ee (R)
(R)-Cu-B(OR*)4
NN
10% ee (R)
Arndstsen, B. A. Org. Lett. 2000, 2, 4165-4168.
Cu-O, 2.55A
Chiral Anion Mediated Asymmetric Chemistry
! Crystal structure of (bipy)Cu(H2C=CHPh)+(R)-B(OR*)4–
From Humble Beginings to New Strategies for Catalysis
Chiral Anion Mediated Asymmetric Chemistry
! Peptide derived chiral boranate cannot provide useful levels of enantioselectivity
From Humble Beginings to New Strategies for Catalysis
Ph Ph
Cu(MeCN)
1 mol%, CH2Cl2N2
O
OEt
O
B
O
O
O
NH
O
CO2Me
Me
Me
NH
O
CO2Me
Me
Me
HN
O
HN
O
CO2Me
CO2Me
Me
Me
Me
Me
CO2Et
Ph
CO2Et
max ee's 19% 34%
1:1 dr 3% yield
Arndstsen, B. A. Tetrahedron: Asymmetry 2005, 16, 1789-1799.
Braun, M. Angew. Chem. Intl. Ed 2004, 43, 514-517.
Titanium (IV) Catalysed Allylation
! Braun allylation of ethers is an overlooked reaction within this class
Anion Binding With Useful Levels of Selectivity
Me OTMS TMS Ti-cat. 10 mol%
–TMSOTMS
Me
96% 98.9% ee
Me OTMS(±)
Me
Me3SiOTiL*F2
Me
Me3SiOTiL*F2
ON
OPh
Ph
Ph
TiF2
t-Bu
t-Bu
Me
(S)
Me
(R)
Substrate
Gold Mediated Counteranion Catalysis
! Gold Catalysed enantioselective transformations were predicted to be difficult
The Toste Story
Au+Ligand
Large Distance
Short Reviews: Krause. Angew. Chem. Intl. Ed. 2008, 47, 2178-2181; Widenhoefer. Chem. Eur. J. 2008, 14, 5382-5391.
Gold Mediated Counteranion Catalysis
! Solution one: Development of bis(gold)-phosphine complexes
The Toste Story
O
O
O
O P
P
Au
Cl
Au
Cl
t-Bu
OMe
t-Bu
t-Bu
OMe
t-Bu
2
2
P
P
Au
Cl
Au
Cl
t-Bu
OMe
t-Bu
t-Bu
OMe
t-Bu
2
2
MeO
MeO
(R)-DTBM-SEGPHOS-(AuCl)2
(S)-DTBM-MeOBIPHEP-(AuCl)2
OPiv
Me Me
Ar Ar
Me
Me
PivO
2.5 mol% cat.
5 mol % AgSbF6
2.5 mol% cat.
5 mol % AgSbF6
2.5 mol% cat.
5 mol % AgSbF6
OH
PhPh n
O
PhPh
*
n = 0, 67%, 93% een = 1, 96%, 88% ee
TsN
Me
Me
NHTs Me
Me
99%, 99% ee
60-85%
76-94% ee
Substrate
Gold Mediated Counteranion Catalysis
! Chiral anion strategy may also overcome inherent proximity problem
The Toste Story
Au+Ligand
Large Distance
Counter-ion ShortDistance
Toste, D. F. J. Am. Chem. Soc. 2007, 129, 2452-2453.
Gold Mediated Counteranion Catalysis
! Counter-ion effects had already been identified in ligand controlled reactions
The Toste Story
P
P
Au
Cl
Au
Cl
2
2
(R)-xylyl-BINAP-(AuCl)2
TsNNHTs
Me
Me
Me
Me
P Au Cl
P Au Cl
*
P Au Cl
P Au
*
+ BF4–
P Au
P Au
*
2+ 2BF4–
3 mol% cat, 3 mol% AgBF4
81% 51% ee
3 mol% cat, 6 mol% AgBF4
82% 1% ee
Toste, D. F. Science 2007, 317, 496-499
Gold Mediated Counteranion Catalysis
! Initial investigations: ligand vs anion control
The Toste Story
PR2
PR2
OOH H3 mol% L(AuCl)2, 3 mol% AgX
PR2
PR2
O
O
O
O
AgBF4
Ag-CO2-4-(NO2)-C6H3
0-8% ee
CH2Cl2
Toste, D. F. Science 2007, 317, 496-499
Gold Mediated Counteranion Catalysis
! Initial investigations: ligand vs anion control
The Toste Story
OOH HLAuCl or L(AuCl)2, AgCat
L = PPh3 (5 mol%), 5 mol% (R)-Agcat
L = dppm (2.5 mol%), 5 mol% (R)-Agcat
CH2Cl2
O
OP
OAg
O
i-Pr i-Pr
i-Pr
i-Pr
i-Pri-Pr
L = dppm (2.5 mol%), 5 mol% (R)-Agcat
89% 48% ee
76% 65% ee
90% 98% ee
(benzene)
dppm = Ph2P PPh2
Toste, D. F. Science 2007, 317, 496-499
Gold Mediated Counteranion Catalysis
! Initial investigations: ligand vs anion control
The Toste Story
O
R1
R1
R1
R1
OH H2.5 mol% dppm(AuCl)2
benzene, 23 ˚C
n
R2 R2
R3 R3
R3
R3
R2R2
n
79-96% 90-99% ee
5 mol% Agcat.
SO2MesN
R1
R1
R1
R1
NHSO2Mes H5 mol% Ph(CH3)2PAuCl
benzene, 23 ˚C
R2 R2
R2R2
73-97% 96-99% ee
5 mol% Agcat.
Toste, D. F. Science 2007, 317, 496-499
Substrate
Gold Mediated Counteranion Catalysis
! Chiral amplification via ligand-counter ion relay
The Toste Story
Au+Ligand
Large Distance
Counter-ion ShortDistance
Toste, D. F. Science 2007, 317, 496-499
Substrate
Gold Mediated Counteranion Catalysis
! Chiral amplification via ligand-counter ion relay
The Toste Story
Au+Ligand
Large Distance
Counter-ionInteraction
ChiralAmplification?
Toste, D. F. Science 2007, 317, 496-499
Gold Mediated Counteranion Catalysis
! Chiral amplification vis ligand-counterion relay
The Toste Story
benzene, 23 ˚C
5 mol% Agcat.OH OH
O
OP
OAg
O
i-Pr i-Pr
i-Pr
i-Pr
i-Pri-Pr
Ph2P PPh2
dppm
2.5 mol% dppm(AuCl)2
96% 80% ee
Gold Mediated Counteranion Catalysis
! Chiral amplification vis ligand-counterion relay
The Toste Story
benzene, 23 ˚C
5 mol% Agcat.OH OH
O
OP
OAg
O
i-Pr i-Pr
i-Pr
i-Pr
i-Pri-Pr
P
(S,S)-DIPAMP
2.5 mol% [(S,S)-DIPAMP](AuCl)2
96% 92% ee
P
Ph
PhMeO
OMe
Toste, D. F. Science 2007, 317, 496-499
Toste, D. F. Science 2007, 317, 496-499
Gold Mediated Counteranion Catalysis
! Chiral amplification vis ligand-counterion relay
The Toste Story
OH
benzene, 23 ˚C
5 mol% Agcat.
O
OP
OAg
O
i-Pr i-Pr
i-Pr
i-Pr
i-Pri-Pr BINAP
dppm (R)-AgCat.
Me
MeO
O OMe
Me
H5 mol% L(AuCl)2
(R)-BINAP (R)-AgCat.
(S)-BINAP (R)-AgCat.
PPh2
PPh2
89% 12% ee (S)
91% 3% ee (R)
88% 82% ee (S)
Norton, J. R. J. Am. Chem. Soc. 2005, 127, 7805-7814
Chiral Couneranion-Aided Asymmetric Hydrogenation
! Imine hydrogenation via an ionic mechanism
Asymmetric Imine Reduction
N
R'R
M–H N
R'RH
M
M+
N
R'R
M–H
N
R'RH
H2
MH
H
N
R'RH
N
R'RH
H
Norton, J. R. J. Am. Chem. Soc. 2005, 127, 7805-7814
Chiral Couneranion-Aided Asymmetric Hydrogenation
! Imine hydrogenation via an ionic mechanism
Asymmetric Imine Reduction
N
R'R
M–H N
R'RH
M
M+
N
R'R
M–H
N
R'RH
H2
MH
H
N
R'RH
N
R'RH
H
N
Me
BF4–
N
MeH
2 mol %
CpRu(P-P)HPPh2
PPh2
(R,R)-Norphos50 psi H2
74% 54% ee
Xiao, J. J. Am. Chem. Soc. 2008, 130, 14450-14451
Chiral Couneranion-Aided Asymmetric Hydrogenation
! Ir(III)-Phosphoric acid system leads to high enantioselectivities via ligand-anion control
Asymmetric Imine Reduction
NR1
R3R2L
M
L
X*–
H2*
L
M
L* H
NR1
R3R2
HX*–
HNR1
R3R2
Chiral Couneranion-Aided Asymmetric Hydrogenation
! Ir(III)-Phosphoric acid system leads to high enantioselectivities via ligand-anion control
Asymmetric Imine Reduction
NR1
R3R2L
M
L
X*–
H2*
L
M
L* H
NR1
R3R2
HX*–
HNR1
R3R2
N
Me
OMe
[Ir] (1mol%)
H2 (20 bar), toluene, 20 ºC
HN
Me
OMe
Ph
Ph
N
NH
Ir
ArO2S
0% 0% ee
Ph
Ph
N
NH
Ir
ArO2S
30% 81% ee
Ph
Ph
N
NH
Ir
ArO2S
27% –3% ee
O
OP
O
OH
R
R
(R = 2,4,6-(2-C3H7)3C6H2)
Pacid (6mol%)
(Ar = 4-CH3C6H4)
Xiao, J. J. Am. Chem. Soc. 2008, 130, 14450-14451
Xiao, J. J. Am. Chem. Soc. 2008, 130, 14450-14451
Chiral Couneranion-Aided Asymmetric Hydrogenation
! Ir(III)-Phosphoric acid system leads to high enantioselectivities via ligand-anion control
Asymmetric Imine Reduction
NR1
R3R2L
M
L
X*–
H2*
L
M
L* H
NR1
R3R2
HX*–
HNR1
R3R2
N
Me
OMe
[Ir] (1mol%)
H2 (20 bar), toluene, 20 ºC
HN
Me
OMe
Ph
Ph
N
NH2
Ir
ArO2S
76% 97% ee 92% 97% ee
O
OP
O
OH
R
R
(R = 2,4,6-(2-C3H7)3C6H2)
Pacid (x mol%)
(Ar = 2,3,4,5,6-(CH3)5C6)
O
PO
OR*
OR*
Ph
Ph
N
NH2
Ir
ArO2S
O
PO
OR*
OR*
+ 1 mol%Pacid
Xiao, J. J. Am. Chem. Soc. 2008, 130, 14450-14451
Chiral Couneranion-Aided Asymmetric Hydrogenation
! Ir(III)-Phosphoric acid system leads to high enantioselectivities via ligand-anion control
Asymmetric Imine Reduction
N
Me
R1
H2 (20 bar), toluene, 20 ºC
HN
Me
R1
92-95% 84-97% ee
O
OP
O
OH
R
R
(R = 2,4,6-(2-C3H7)3C6H2)
(Ar = 2,3,4,5,6-(CH3)5C6)
Ph
Ph
N
NH2
Ir
ArO2S
O
PO
OR*
OR*
+ 1 mol%Pacid
R2 R2
NHPMB
MeNHPMB
Me
NHPMB
MeMe
Me NHPMB
MeMe
93% 91% ee 88% 95% ee
90% 92% ee 91% 94% ee
List, B. J. Am. Chem. Soc. 2007, 129, 11336-11337.
Chiral Counteranions in Transition Metal Catalysis
! Pd/Brønsted acid-catalysed direct allylation of aldehydes
Chiral Co-Catalysts - List
O
OP
O
OH
i-Pr
i-Pr i-Pr
i-Pr
i-Pr i-Pr(1.5 mol%)
5A MS, MTBE, 40 ºC, 8-24 hr
O
R1 = Ar: 40-89% 83-97% ee
Me
R1
O
MeR1
R2
Ph
NH
Ph R2
(1.0 equiv)
Pd(PPh3)4 3 mol%
˚
R1 = Alkyl: 45-65% 80-90%ee
Iminium Catalysis - An Alternative Approach
! Proposed mechanism
Chiral Co-Catalysts - List
O
MeH2O
NH
R
(R)-TRIP
R1
N
HR
R1Me
O
P
OR*O OR*
N
Me
R1
H R
P
O
OR**RO
O
Pd
Pd(0)
N
R1
Me
R
H
O
P
OR*O*RO
O
Me R1
(R)-TRIP
List, B. J. Am. Chem. Soc. 2007, 129, 11336-11337.
Chiral Anion Phase Transfer Catalysis
! Reverse of roles commonly associated in phase transfer systems
Chiral Borate Anions
R
R N
Cl
(±)
R
R
N
X–
R
R N
NucAnion cat. Nuc
O
O
B
O
O
Et3NH+
i-Pr i-Pr
i-Pr i-Pr
O
OP
O
OAg
i-Pr
i-Pr
2008 - Toste >90% ee2003 - Nelson <15% ee
ASYMMETRIC RING OPENING OF MESO-AZIRIDINIUM IONS
Chiral Anion Phase Transfer Catalysis
! Reverse of roles commonly associated in phase transfer systems
Chiral Borate Anions
R
R N
Cl
(±)
R
R
N
X–
R
R N
NucAnion cat. Nuc
O
O
B
O
O
Et3NH+
i-Pr i-Pr
i-Pr i-Pr
O
OP
O
OAg
i-Pr
i-Pr
2008 - Toste >90% ee2003 - Nelson <15% ee
ASYMMETRIC RING OPENING OF MESO-AZIRIDINIUM IONS
Chiral Anion Phase Transfer Catalysis
! Reverse of roles commonly associated in phase transfer systems
Chiral Borate Anions
Ph
Ph N
Cl
(±)
Ph
Ph
N
*B(OR)4–
Ph
Ph N
HN
50 mol% cat.
O
O
B
O
O
A+
ASYMMETRIC RING OPENING OF MESO-AZIRIDINIUM IONS
THF-Toluene100 ˚C
H2N PhPh
A+ Yield % ee %
Et3NH+
Et2NH2+
Ph NH3+
Me
(R)
Na+
25%
18%
12%
30%
15%
–6%
–7%
3% (R, R)
8% (S, S)
Nelson, A. Tetrahedron: Asymmetry 2003, 14, 1995-204.
Chiral Anion Phase Transfer Catalysis
! Ion-pairing NMR studies
Chiral Borate Anions
O
O
B
O
O
Nelson, A. Tetrahedron: Asymmetry 2003, 14, 1995-204.
N
Ph NH3+
Me
OTf
! Borate salt was found to be soluabalised but the aziridinium triflate in CDCl3
! Proton and carbon shifts vary linearly with amount of borate salt present
! Lack of spliting of enatiotopic protons in the aziridium salt indicates poor discrimination from the chiral anion
HA
HA
HB
HB
HC
HC
Chiral Anion Phase Transfer Catalysis
! Reverse of roles commonly associated in phase transfer systems
Chiral Phosphonate Anions
R
R N
Cl
(±)
R
R
N
X–
R
R N
NucAnion cat. Nuc
O
O
B
O
O
Et3NH+
i-Pr i-Pr
i-Pr i-Pr
O
OP
O
OAg
i-Pr
i-Pr
2008 - Toste >90% ee2003 - Nelson <15% ee
ASYMMETRIC RING OPENING OF MESO-AZIRIDINIUM IONS
Chiral Anion Phase Transfer Catalysis
! Halide abstraction method requires regeneration of chiral silver salt
Chiral Phosphonate Anions
Ph
Ph N
Cl
(±)
Ph
Ph
N
Cat.–
Ph
Ph N
NucCat.Ag Nuc
ASYMMETRIC RING OPENING OF MESO-AZIRIDINIUM IONS
–AgCl –Cat.H
! Addition of an achiral Ag(I) source must not introduce an interfereing counteranion
R-Hal
AgHalAgB
BH
NucHR-Nuc
AgCat.
R+ Cat.–HCat.
Halide
Abstraction
Chiral Anion Phase Transfer Catalysis
! Halide abstraction method requires regeneration of chiral silver salt
Chiral Phosphonate Anions
Ph
Ph N
Cl
(±)
Ph
Ph
N
Cat.–
Ph
Ph N
NucCat.Ag Nuc
ASYMMETRIC RING OPENING OF MESO-AZIRIDINIUM IONS
–AgCl –Cat.H
! Addition of an achiral Ag(I) source must not introduce an interfereing counteranion
R-Hal
AgHalAgB
BH
NucHR-Nuc
AgCat.
R+ Cat.–HCat.
Nucleophilic Addition
Chiral Anion Phase Transfer Catalysis
! Halide abstraction method requires regeneration of chiral silver salt
Chiral Phosphonate Anions
Ph
Ph N
Cl
(±)
Ph
Ph
N
Cat.–
Ph
Ph N
NucCat.Ag Nuc
ASYMMETRIC RING OPENING OF MESO-AZIRIDINIUM IONS
–AgCl –Cat.H
! Addition of an achiral Ag(I) source must not introduce an interfereing counteranion
R-Hal
AgHalAgB
BH
NucHR-Nuc
AgCat.
R+ Cat.–HCat.
PhaseTransfer
Use solid phase Ag(I)
solid-liquid PTC
Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984-14986.
Chiral Anion Phase Transfer Catalysis
! Suitability of silver(I) sources is crucial for the catalyst control
Chiral Phosphonate Anions
Ph
Ph N
Cl
(±)
Ph
Ph
N
Cat.–
Ph
Ph N
O15 mol% cat.
i-Pr i-Pr
i-Pr i-Pr
O
OP
O
OAg
i-Pr
i-Pr
ASYMMETRIC RING OPENING OF MESO-AZIRIDINIUM IONS
HO
Me
MeMe
Toluene, 50˚C
AgB
AgOTs
Ag2CO3
Ag2CO3
88% 56% ee
77% 94% ee
84% 94% ee(4A MS)
Me
MeMe
–
–
–
Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984-14986.
Chiral Anion Phase Transfer Catalysis
! Utility - alcohol and amine fucntionality
Chiral Phosphonate Anions
81% 92% ee
Ph
Ph N
O Me
Me OMe
Ph
Ph N
O
Me Me
OTBS
Ph
Ph N
O
OO
Ph
Ph N
O
MeMeMe
Ph
Ph N
O Me
Me OMe
Me
Me
Ph
Ph N
O Me
Me OMe
N
O
4-NO2-Ph
Ph
Ph N
OPh
Ph N
O Me
Me OMe
Me
67% 94% ee 85% 97% ee 50% 92% ee
86% 92% ee 70% 99% ee 76% 94% ee 80% 94% ee, 94% de
Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984-14986.
Chiral Anion Phase Transfer Catalysis
! Utility - alcohol and amine fucntionality
Chiral Phosphonate Anions
81% 92% ee
Ph
Ph N
O Me
Me OMe
Ph
Ph N
O
Me Me
OTBS
Ph
Ph N
O
OO
Ph
Ph N
O
MeMeMe
Ph
Ph N
O Me
Me OMe
Me
Me
Ph
Ph N
O Me
Me OMe
N
O
4-NO2-Ph
Ph
Ph N
OPh
Ph N
O Me
Me OMe
Me
67% 94% ee 85% 97% ee 50% 92% ee
86% 92% ee 70% 99% ee 76% 94% ee 80% 94% ee, 94% de
Chiral Anion Phase Transfer Catalysis
! Extention to meso-episulfonium ions uses a modified system
Chiral Phosphonate Anions
Ph
Ph SMe
O
(±)
Ph
Ph
SMe
Cat.–
Ph
Ph SMe
OR15 mol% cat.
i-Pr i-Pr
i-Pr i-Pr
O
OP
O
OH
i-Pr
i-Pr
ASYMMETRIC RING OPENING OF MESO-EPISULFONIUM IONS
ROH
Toluene, 23˚C
90-98% yield
CCl3HN
87-92%ee
! Mechanistically distinct from other phosphoric acid catalysed reactions enantioselectivity results from H-bonding to the electrohile
! Ring opening of the meso-episulfonium is the enantiodetermining step. Ion-pairing is responsible for the stereoselectivity
Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984-14986.
Hydrogen Bonding Mediated Counterion Catalysis
! Ureas and thioureas are proven motifs towards anion-binding using hydrogen bonding
Anion Recognition
Review: Schmidtchen, F. P. Chem. Rev. 1997, 97, 1609-1646.
Hydrogen Bonding Mediated Counterion Catalysis
! The stereoselectivity achieved by thiourea catalysts appears unusual
The Jacobsen Story
NH
NH2
RO
R'H
1) R'CHO, 3A MS˚
2) AcCl, 2,6-lutidine
Cat. (5-10 mol%)
Et2O, –30 to –60 ºC
NH
RNAc
R'
65-81%, 85-95%ee
Hydrogen Bonding Mediated Counterion Catalysis
! The stereoselectivity achieved by thiourea catalysts appears unusual
The Jacobsen Story
NH
NH2
RO
R'H
NH
RN
R'
1) R'CHO, 3A MS˚
2) AcCl, 2,6-lutidine
Cat. (5-10 mol%)
Et2O, –30 to –60 ºC
Me
O
Cl
N
N
S
t-Bu
N(i-Bu)2
O
N
Ph
Ph
H
H
NH
RNAc
R'
65-81%, 85-95%ee
! "The ability to activate a weakly Lewis basic N-acyliminium ion towards enantioselective transformations presents new opportunities for catalysis and raises intriguing questions as to the nature of this interaction."
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558-10559.
Hydrogen Bonding Mediated Counterion Catalysis
! H-Bond donor - anion binding catalysis is proposed in 2007
The Jacobsen Story
Cat. (10 mol%)
–55 ºC or –78 ºC
52-94%, 81-99%ee
! Alkylated derivatives react significantly faster than reduced compounds. SN1 mechanism.
NH
N
O
R4
HO
R1
R2
R3 n=1, 2NH
R1
R2
R3
N O
R4n=1, 2
TMSCl, TBME
! SN2 Mechanism
NH
N
O
RCl N
H
N O
R
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 127, 13404-13405..
Hydrogen Bonding Mediated Counterion Catalysis
! Two SN1-type mechanisms are likely
The Jacobsen Story
NH
N
O
RCl N
H
N O
RNH
N
O
R
Cl–
N
N
H
S
N
H
t-Bu
R
PhMe
N
N
O
Cl–N
H
S NH
R1
R2
R
spiro pathway
direct pathway
Hydrogen Bonding Mediated Counterion Catalysis
! Two SN1-type mechanisms are likely
The Jacobsen Story
NH
N
O
RCl N
H
N O
RNH
N
O
R
Cl–
N
N
H
S
N
H
t-Bu
R
PhMe
N
N
O
Cl–N
H
S NH
R1
R2
R
spiro pathway
direct pathway
! DFT calculations of fully ionised N-acyliminium ions interacting with thiourea derivatives failed to converge on any ground state structure.
Hydrogen Bonding Mediated Counterion Catalysis
! Two SN1-type mechanisms are likely
The Jacobsen Story
NH
N
O
RCl N
H
N O
RNH
N
O
R
Cl–
N
N
H
S
N
H
t-Bu
R
PhMe
N
N
O
Cl–N
H
S NH
R1
R2
R
spiro pathway
direct pathway
! Pronounced counter ion effect:
X– ee
Cl– 97%
Br– 68%
I– <5%
Hydrogen Bonding Mediated Counterion Catalysis
! Two SN1-type mechanisms are likely
The Jacobsen Story
NH
N
O
RCl N
H
N O
RNH
N
O
R
Cl–
N
N
H
S
N
H
t-Bu
R
PhMe
N
N
O
Cl–N
H
S NH
R1
R2
R
spiro pathway
direct pathway
! Pronounced solvent effect
solv ee
TBDME 97%
THF 34%
DCM <5%
see also: Jacobsen, E. N. Org. Lett,2008, 10,1577-1578.
Hydrogen Bonding Mediated Counterion Catalysis
! A versatile method for other highly reactive cationic species?
The Jacobsen Story
Cl–
N
N
H
S
N
H
t-Bu
R
PhMe
R3N
O
R4
R1 R2
Cl–
N
N
H
S
N
H
t-Bu
R
PhMe
O
Nuc
Nuc
ACYL-IMINIUM ION STABILISATION OXOCARBENIUM ION STABILISATION?
Hydrogen Bonding Mediated Counterion Catalysis
! A versatile method for other highly reactive cationic species?
The Jacobsen Story
Cl–
N
N
H
S
N
H
t-Bu
R
PhMe
R3N
O
R4
R1 R2
Cl–
N
N
H
S
N
H
t-Bu
R
PhMe
O
Nuc
Nuc
ACYL-IMINIUM ION STABILISATION OXOCARBENIUM ION STABILISATION?
! Cyclic oxo-carbenium ions are extremely unstable species (lifetime ~ 10-12 s)
! Enantioselective addtions to oxo-carbenium ions are extememly rare with only two examples reported (Braun: Angew. Intl. Ed. 2004, 43, 514-517 and Evans: JACS, 2005, 127, 10506-10507).
Hydrogen Bonding Mediated Counterion Catalysis
! Importance of catalyst structure
The Jacobsen Story
10 mol% cat.
ENANTIOSELECTIVE ADDITIONS TO OXOCARBENIUM IONS
TBDME, –78 ˚CO
Cl
R
OSIR3
OR1
R2
R2
OR
R2 CO2R1R2
70-96% 74-97%ee
NH
NH
St-Bu
N
O
F
CF3
CF3
Reactivity at low temp
3º amide important forreactivity and selectivity
Aryl group crucial forselectivity - engagesoxocarbenium ion in TS?
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130 ,7198-7199.
Hydrogen Bonding Mediated Counterion Catalysis
! Importance of catalyst structure
The Jacobsen Story
10 mol% cat.
ENANTIOSELECTIVE ADDITIONS TO OXOCARBENIUM IONS
TBDME, –78 ˚CO
Cl
R
OSIR3
OR1
R2
R2
OR
R2 CO2R1R2
70-96% 74-97%ee
O
CO2Me
O
CO2Me
O
CO2Me
O
CO2Me
Me
F MeO
87% 87% ee 71% 90% ee 70% 90% ee 96% 74% ee
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130 ,7198-7199.
Hydrogen Bonding Mediated Counterion Catalysis
! Importance of catalyst structure
The Jacobsen Story
10 mol% cat.
ENANTIOSELECTIVE ADDITIONS TO OXOCARBENIUM IONS
TBDME, –78 ˚CO
Cl
R
OSIR3
OR1
R2
R2
OR
R2 CO2R1R2
70-96% 74-97%ee
O
CO2Me
O
CO2Me
O
CO2Me
O
CO2Me
92% 92% ee 84% 94% ee 85% 92% ee 87% 93% ee
MeMe O
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130 ,7198-7199.
Iminium Catalysis - An Alternative Approach
! Explotation of ion-pair intermediate in iminium catalysis
Chiral Co-Catalysts - List
O
R2R1
NH
R
HX
N
R2R1
X
R
N
R2R1
NH HX*
X*
NH
R
HX*N
R2R1
X*
R
Amine ControlledStereoselectivity
Anion ControlledStereoselectivity
'Matched' Ion-PairControl
Iminium Catalysis - An Alternative Approach
! Reaction works across a range of aromatic aldehydes
Chiral Co-Catalysts - List
O
MeAr
O
OP
O
O–
i-Pr
i-Pr i-Pr
i-Pr
i-Pr i-Pr
NH2
O
(20 mol%)
NH
CO2MeMeO2C
H H
(1.1 equiv) O
MeArDioxane, 50 ˚C, 24 hr
63-90% 96-99% ee
List, B. Angew. Chem. Intl. Ed. 2006, 45, 4193-4195.
Iminium Catalysis - An Alternative Approach
! Achieving previously unatainable results - sterically unhindered aliphatic aldehydes
Chiral Co-Catalysts - List
O
Me
O
OP
O
O–
i-Pr
i-Pr i-Pr
i-Pr
i-Pr i-Pr
NH2
O
(20 mol%)
NH
CO2MeMeO2C
H H
(1.1 equiv)
O
Me
THF, r.t., 24 hr
71% 90% ee
Me Me Me Me
(E)-Citral (R)-Citronellal
N
NH
O Me
PhMe
Me
Me
TFA
N
NH
O Me
Me
Me
Me
TFA
58% 40% ee 82% 40% ee
List, B. Angew. Chem. Intl. Ed. 2006, 45, 4193-4195.
Iminium Catalysis - An Alternative Approach
! Extention to enone hydrogenation - matched-mismatched effects
Chiral Co-Catalysts - List
O
OP
O
O–
i-Pr
i-Pr i-Pr
i-Pr
i-Pr i-Pr
(20 mol%)
NH
CO2MeMeO2C
H H
(1.1 equiv)
Bu2O, 60 ºC, 24 hr
66% 54% ee 81% 94% ee
O
Me
O
Me
R
NH3+
CO2t-Bu
i-Pr
NH3+
CO2t-Bu
CF3COO–
NH3+
CO2t-Bu
(R)-TRIP
NH3+
CO2t-Bu
(R)-TRIP
i-Pr
NH3+
CO2t-Bu
(S)-TRIP
i-Pr
66% 48% ee 45% 16% ee
List, B. J. Am. Chem. Soc. 2006, 128, 13368-13369.
Iminium Catalysis - An Alternative Approach
! Extention to enone hydrogenation - substrate tolerance
Chiral Co-Catalysts - List
O
OP
O
O–
i-Pr
i-Pr i-Pr
i-Pr
i-Pr i-Pr
(5 mol%)
NH
CO2EtEtO2C
H H
(1.2 equiv)
Bu2O, 60 ºC, 48 hr
68-78% 96-98% ee 99% 96% ee
i-Pr
NH3+
CO2t-Bu
89-99% 90-98% ee R = CO2Et: 99% 90% ee
O
Rn
O
Rn
O
R
O
R
O
Me
Me
Me
O
R
R = Ph: 81% 70% ee
List, B. J. Am. Chem. Soc. 2006, 128, 13368-13369.
Iminium Catalysis - An Alternative Approach
! Extention to enal epoxidation
Chiral Co-Catalysts - List
O
OP
O
O–
i-Pr
i-Pr i-Pr
i-Pr
i-Pr i-Pr(10 mol%)
(1.1 equiv)
Dioxane, 35 ºC, 72 hr
R = Ar: 60-84%, 98:2->99:1 dr90-96% ee
O
R
O
R
t-BuOOH
NH2
F3C
CF3
CF3
F3C
O
R = n-hex: 67%, 94:6 dr70% ee (maj), 92% ee (min)
List, B. Angew. Chem. Intl. Ed. 2008, 47, 1119-1122.
Iminium Catalysis - An Alternative Approach
! Tri-substituted enals have proven to be elusive substrates
Chiral Co-Catalysts - List
O
OP
O
O–
i-Pr
i-Pr i-Pr
i-Pr
i-Pr i-Pr(10 mol%)
(1.1 equiv)
TBDME, 0 ºC, 24 hr
O
R2
O
R2
t-BuOOH
NH2
F3C
CF3
CF3
F3C
O
R1 R1
O
Me
O
Me
O
Et
O
Et
O
O
O
O
Me Me
Me
83% 94%ee 85% 94%ee 75% 90% ee85% 72:28 dr
76% ee (trans), 92% ee (cis)
List, B. Angew. Chem. Intl. Ed. 2008, 47, 1119-1122.
Iminium Catalysis - An Alternative Approach
! Proposed mechanism - unusual enantiodetermining step
Chiral Co-Catalysts - List
O
Me
t-BuOOH
Me
N
MeMe
Ar Ar
TRIP
N
Me
Ar Ar
TRIPMe
O Ot-Bu
H
N
MeMe
Ar Ar
TRIP
O
t-BuOH
H2O
Ar NH2
Ar
TRIP
Ar NH2
Ar
TRIP
List, B. Angew. Chem. Intl. Ed. 2008, 47, 1119-1122.
Weakly Coordinating Anions in Chemistry
! Non-coordinating anions – Fact or fiction?
Background to Carboranes
ClO4 BF4 PF6B(C6H5)4
> > >
decreasing coordinating ability
! Weakly coordinating anions or 'superweak anions': considerations
PF6
F– abstraction
S
O O
O CF3
Accessible
O– coordination
Prone to hydrolysis,and oxidation
B(C6H5)4
Krossing, I. Angew. Chem. Intl. Ed. 2004, 43, 2066-2090.
Weakly Coordinating Anions in Chemistry
! What should we look for in a weakly coordinating anion?
Background to Carboranes
(Or, how to make a very strong Brønsted acid)
! Low nucleophilicity
! Chemical inertness (especially to protonation!)
! Low redox activity
! Charge delocalisation
! Large size
! Peripheral atoms non-basic
! Solubility in nonpolar solvents
Krossing, I. Angew. Chem. Intl. Ed. 2004, 43, 2066-2090.
Weakly Coordinating Anions in Chemistry
! What should we look for in a weakly coordinating anion? Candidates:
Background to Carboranes
B
CF3
F3C
F3C
CF3 CF3
CF3
CF3
F3C
[B(C6F5)4]
[CB11H12]
Reviews: Strauss, S. H. Chem. Rev. 1993, 93, 927-942; Seppelt, K. Angew. Chem. Intl. Ed. 1993, 33, 1025-1027.
Weakly Coordinating Anions in Chemistry
! A brief introduction to carborane chemistry
Background to Carboranes
! Constructed of 2c-2e- and 3c2e- bonds
! Delocalised !-bonding (!-aromaticity)
! 3D-analogue of benzene
! Aromatic properties: delocalised bonding unusual stablilty propensity for substitution reactions
! Other idications: resonance energies geometries (bond order indices etc.) magnetic properties
! Very strong B-H bonds (103 kcal/mol)
Michl, J. Chem. Rev. 2006, 106, 5208-5249.
Weakly Coordinating Anions in Chemistry
! Carborane charge distribution
Background to Carboranes
Michl, J. Chem. Rev. 2006, 106, 5208-5249.
Weakly Coordinating Anions in Chemistry
! Carborane synthesis: B-H Insertion route
Background to Carboranes
B10H14 - commerciallyavailable but expensive
Michl, J. Chem. Rev. 2006, 106, 5208-5249.
NaB11H14 - 50% yield
Weakly Coordinating Anions in Chemistry
! Carborane synthesis: B-H Insertion route
Background to Carboranes
NaBH4 BF3 (OEt)+
! Carbon insertion route
NaH CHCl3
NaOEt
Michl, J. Chem. Rev. 2006, 106, 5208-5249.
Weakly Coordinating Anions in Chemistry
! Typical reactivity of carboranes
Background to Carboranes
! Electrophilic substitution
n-BuLi MeI
ICl, DME
65 ºC
I2, AcOH
25 ºC
ICl, 200ºC
Michl, J. Chem. Rev. 2006, 106, 5208-5249.
Weakly Coordinating Anions in Chemistry
! H(CHB11Cl11) - The strongest known Brønsted acid
Background to Carboranes
! "Strong yet gentle": Can protonate C60 and benzene to form isolable salts.
! Acidity only measurable by indirect (NMR) methods. Outranks HFSO3,
! HFSO3/SbF6 decomposes such molecules
! Exceptional anion stability (c.f. HSbF6 & [B(C6F5)4]–
! Stability due to weakly basic anion - large size, s-delocalisation, Cl-shielding
Reed, C. A. Angew. Chem. Intl. Ed. 2004, 43, 5352-5355 J. Am. Chem. Soc. 2006, 128, 3160-3161.
Reed, C. A. Chem. Commun. 2006, 7, 767-769 Chem. Commun. 2005, 13, 1669-1677..
Weakly Coordinating Anions in Chemistry
! Solution to an old problem: existence of a trialkylsilylium ion (R3Si+)
Background to Carboranes
! Three coordinate silicon prone to coordination by anions, solvent and even argon!
! Si-Cl bond length 2.334 Å
! Ave. C-Si-C = 116.5º
! Exceptional anion stability (c.f. HSbF6 & [B(C6F5)4]–
! 29Si NMR (115 ppm) therefore 'ion like'.
! Highly Lewis acidic silicon group
Reed, C. A. Chem. Commun. 2006, 7, 767-769 Chem. Commun. 2005, 13, 1669-1677..
Weakly Coordinating Anions in Chemistry
! Solution to an old problem: i-Pr3Si!+(CB11H6Cl6)!–
Background to Carboranes
! Three coordinate silicon prone to coordination by anions, solvent and even argon!
! Si-Cl bond length 2.334 Å
! Ave. C-Si-C = 117.6º
! Exceptional anion stability (c.f. HSbF6 & [B(C6F5)4]–
! 29Si NMR (115 ppm) therefore 'ion like'.
! Highly Lewis acidic silicon group
Weakly Coordinating Anions in Chemistry
! Uses of a R3Si+ cation: Hydrodefluorination reactions
Background to Carboranes
R F H H R H H F
catalyst
R F SiR3 H R H SiR3 F
catalyst
! Challenges:
C-F bonds are amongst the most passive functonalities in chemistry (C-F is the strongest single bond to carbon)
C-F bond strengths increase as the degree of flourination increases
C-F bonds are poor ligands and poor substrates for nuc substitution and oxidative addition
Short Review: Braun, T. Angew. Chem. Intl. Ed. 2009, 48, 2-6.
Short Review: Braun, T. Angew. Chem. Intl. Ed. 2009, 48, 2-6.
Weakly Coordinating Anions in Chemistry
! Uses of a R3Si+ cation: Hydrodefluorination reactions
Background to Carboranes
R F H H R H H F
catalyst
R F SiR3 H R H SiR3 F
catalyst
! Why do we need a hydrodefluorination reaction?
Despite the utility of fluorinated compounds (refridgerants, anesthetics, polymers, solvents, ligands, catalysts),
the high persistence of fluorocarbons is responsible for their contribution to global warming
Weakly Coordinating Anions in Chemistry
! Uses of a R3Si+ cation: Hydrodefluorination reactions
Background to Carboranes
Si-H
C-F
Si-F
C-H
favourable by~ 190 kJ / mol
Weakly Coordinating Anions in Chemistry
! Uses of a R3Si+ cation: Hydrodefluorination reactions
Background to Carboranes
Si-H
C-F
Si-F
C-H
favourable by~ 190 kJ / mol
Oserov, O. V. J. Am. Chem. Soc. 2005, 127, 2852-2853.
Max TON ~ 100
perfluorinated alkanes 0% conv
Weakly Coordinating Anions in Chemistry
! Uses of a R3Si+ cation: Hydrodefluorination reactions
Background to Carboranes
Si-H
C-F
Si-F
C-H
favourable by~ 190 kJ / mol
Oserov, O. V. J. Am. Chem. Soc. 2005, 127, 2852-2853.
Max TON ~ 100
perfluorinated alkanes 0% conv
Max TON ~ 30
perfluorinated alkanes 0% conv
alkane solvents only
Krossing, I. Tetrahedron Lett. 2007, 48, 8900-8903.
[i-Bu2-Al]+ [Al(C6F5)4]
–
[i-Bu2-Al]+ [Al{OC(CF3)3}4]
–
ori-Bu2AlH + Ph3C+M–
Weakly Coordinating Anions in Chemistry
! Uses of a R3Si+ cation: Hydrodefluorination reactions
Background to Carboranes
Ph3C[HCB11H5Cl6] Et3SiH Et3Si[HCB11H5Cl6] Ph3CH
CF3
F
F
F
F
F
CH3
F
F
F
F
F
CF3
F3C
F2C
CF2
F2C
CH2
CH3
CH3
Et3SiH
–Et3SiF
86%, 0.08 mol%TON = 1250
0%, 5% indaneremainder higher MW
28% 13%
10% <3%
>97% convTON = 200
>97% convTON = 780
Oserov, O. V. Science 2008, 321, 1188-1190.
Weakly Coordinating Anions in Chemistry
! Uses of a R3Si+ cation: Hydrodefluorination reactions
Background to Carboranes
Ph3C[HCB11H5Cl6] Et3SiH Et3Si[HCB11H5Cl6] Ph3CH
CF3
F
F
F
F
F
CF3
F3C
F2C
CF2
F2C
CH2
CH3
Et3SiH
–Et3SiF
28% 13%
10% <3%
>97% conv
TON = 200
F
F
F
F
F
53%
Cl
Cl
+ 26%
in o-C6H4Cl2 (>97% conv. TON = 1250)
76%
in benzene (>97% conv. TON = 780)
Anion Binding in Chemistry
! Area has promise for a general catalytic manifold
Conclusions
! Much work is needed towards mechanistic understanding
! Many new reactions to be discovered
! 4-years is a very short amount of time since breakthrough reactions
! Lots of scope for the design of new catalysts