Chiral Anions in Asymmetric Catalysis Hannah Haley
Burke Group Literature Seminar
13 April 2013
Key Ac2va2on Modes for Asymmetric Catalysis S
L
M
N
N
H
H
X
RX
R2
R1
R2
R1
Coordinative interaction
Double hydrogenbonding interaction
'Lewis acid catalysis'
'Hydrogen bonding catalysis'
Lewis acidic metal (M) and Lewis
basic ligand (L) form chiral net
Lewis acidic species
Directional H-bonds provide electrophilic
activation and stereodefined
environment
O
P
O
H
-O
+
XR
R1
R2
R1
P
O
XR2
R2
Single hydrogenbonding interaction
Electrostatic interaction
only
'Bronsted acid catalysis'
'Chiral anion catalysis'
High acidity of chiral phosphoric acid
and Bronsted basicity of phosphoryl O
activate electrophile and nucleophile
Ion pairing between fully protonated
substrate and phosphate counterion
Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4, 603.
Chiral Anion Catalysis X+ YNeutral
substrate
Neutral
product
Reagent
Modified
substrate+ Y-
§  Combina+on of achiral but cataly+cally ac+ve species (transi+on metal complex, Lewis base, Lewis acid) with chiral counterion §  In nonpolar media, species will exist as +ght ion pair and influence of counterion can be stereochemically significant §  Generalizable strategy as many reac+ons are known to proceed through ca+onic intermediates §  Most examples here: achiral ca2onic metal complex with chiral counterion Metal Catalysis with Chiral Counterions Generalized Strategy
TsHN
TsHN
achiral cationic Au(I)
•
•
chiral anion
Au+ L
AuL
*AnionH
H +
N Ts
H
*Anionchiral anion, not ligand, provides asymmetric induction
§  Chiral ions interact with metal only through electrosta2c interac+ons §  Tradi+onally chiral ligands which directly coordinate to metal center are used §  Phosphoric acid ligands regarded as highly dissociated compared to conven+onal ligands (eg phosphines) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4, 603.
NTs
Gold (I)-­‐Catalyzed Enan2oselec2ve Allene Hydroamina2on Original Methodology NOT a Chiral Anion Strategy Dinuclear Gold(I)-Phosphine Complexes
Silver activates gold complexes through formation of cationic gold species via halide extraction
P Au X
*
P Au Y
*
P Au 2+ X- Y*
B
catalytically
inactive
3 mol% *
•
Y-
P Au
A
NHTs
+
P Au X
P Au
C
catalytically active
P Au Cl
Ts
N
P Au Cl
PAr2AuCl
PAr2AuCl
6 mol% AgBF4
0.3 M DCE, 23 ˚C
Dicationic species assumed
82%, 1% ee
Ar = xylyl
Product formed with
no stereoselectivity
§ 
Phosphinegold(I) complexes known to be chemoselec+ve for ac+va+on of C-­‐C mul+ple bonds §  Useful for addi+ons to allenes, alkenes, alkynes § 
§ 
Few enan+oselec+ve Au(I) reac+ons known at the +me Silver ac+vates gold by forming ca+onic Au(I) via halide extrac+on LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452.
Gold (I)-­‐Catalyzed Enan2oselec2ve Allene Hydroamina2on Original Methodology NOT a Chiral Anion Strategy 3 mol% *
NHTs
•
P Au Cl
Ts
N
P Au Cl
PAr2AuCl
PAr2AuCl
AgBF4
0.3 M DCE, 23 ˚C
6 mol% AgBF4 (dication)
3 mol% AgBF4 (monocation)
82%, 1% ee
81%, 51% ee
Ar = xylyl
§  Increase in enan+oselec+vity with assumed monoca+onic species indicated that remaining coordinated counterion (Cl-­‐) was cri+cal for stereoinduc+on §  Hypothesized that replacing chloride with larger coordina+ng counterion may further enhance enan+oselec+vity LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452.
Gold (I)-­‐Catalyzed Enan2oselec2ve Allene Hydroamina2on Original Methodology NOT a Chiral Anion Strategy 3 mol% *
NHTs
•
3 mol% AgBF4
6 mol% AgOBz
6 mol% AgOPNB
6 mol% AgODNB
P Au Cl
Ts
N
P Au Cl
AgX
0.3 M DCE, 23 ˚C
81%, 51% ee
27%, 98% ee low equilib concentration of active species
76%, 98% ee EWG improves conversion
82%, 95% ee EWG improves conversion
OPNB = p-nitrobenzoate
ODNB = 3,5-dinitrobenzoate
§  Electronic and steric tuning of coordinated counterion possible with benzoates §  Must s+ll be able to form ac2ve ca2onic catalyst §  Results indicate that anionic counterion likely involved in discrimina+ng between diastereomeric transi2on states LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452.
Asymmetric Catalysis with Gold (I) Complexes long distance
*ligand
Au+
long distance
substrate
ligand
Au+
*counterion-
Gold(I) adopts bicoordinate linear geometry
Chiral information far from reaction center
substrate
short
distance
New Strategy
TsHN
TsHN
achiral cationic Au(I)
•
chiral anion
•
Au+ L
AuL
*AnionH
H +
N Ts
*Anion-
§  Asymmetric catalysis with gold(I) complexes is notoriously difficult §  Chiral counterion rather than chiral ligand strategy may lead to higher stereoselec+vity H
NTs
Gold (I)-­‐Catalyzed Enan2oselec2ve Allene Hydroalkoxyla2on Chiral Ligand Strategy Leads to Low Enan2oselec2vity Chiral phosphine ligand and achiral silver anion complex
HO
3 mol% *
•
P Au Cl
P Au Cl
Chiral gold complex
H
O
3 mol% AgX
CH2Cl2
AgBF4
AgOPNB
PAr2AuCl
PAr2AuCl
68%, 0% ee
89%, 8% ee
Ar = m-xylene
OPNB = p-nitrobenzoate
Achiral phosphine ligand and chiral silver anion complex
HO
2.5 mol%
Ph2P Au Cl
Chiral silver TRIP counterion
H
Ph2P Au Cl
•
O
O
P O
O Ag+
Solvent effect
60%, 18% ee
72%, 37% ee
THF
benzene
iPr
iPr
iPr
5 mol% (R)-AgTRIP
solvent
CH3NO2
acetone
O
83%, 76% ee
90%, 97% ee
iPr
iPr
iPr
§  At +me of publica+on, only gold(I) complexes had successfully promoted asymmetric allene hydroalkoxyla+on, but with limited scope Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496.
Gold (I)-­‐Catalyzed Enan2oselec2ve Allene Hydroalkoxyla2on Use of Chiral Ligand and Chiral Counterion is Produc2ve Strategy
(S,S) DIPAMP ligand
OMe
HO
2.5 mol% L(AuCl)2
5 mol% (R) or (S)-AgTRIP
•
H
benzene
H
H
H
H
challenging, unfunctionalized
substrate
O
P
Ph
Ph
P
MeO
(R)-AgTRIP counterion
iPr
iPr
dppm(AuCl)2, (R)-AgTRIP
96%, 80% ee
achiral gold ligand with chiral silver counteranion
[(S,S)-DIPAMP(AuCl)2, (S)-AgTRIP
96%, 92% ee
iPr
O
O
P O
O Ag+
iPr
chiral gold ligand AND chiral silver counteranion
iPr
Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496.
iPr
Chiral Anion Strategy for Asymmetric Tsuji-­‐Trost Allyla2on Achiral Ca2onic π-­‐Allyl Pd(II) Complex Ion Paris with Chiral Phosphoric Acid R1
R2
+
CHO
N
H
1.5 mol% (R)-TRIP
3 mol% Pd(PPh3)4
5 A MS, MTBE, 40 ˚C
R
R1
R2
then 2N HCl, Et2O
CHO
Mechanistic hypothesis
R1
CHO
+ H2NR
R2
iminium
hydrolysis
O
P O
HO
O
*
N
H
allylated
quaternary
center
R1
+
R2
CHO
H2O
H2O
O
R
H N+ - O P O
O
*
2
R
R1
R
acid catalyzed
allyl aminealdehyde
condensation
O
R
H
N+ - O P O
chiral
O
enammonium
* phosphate salt
1
2
R
R
Pd0
*
O O
-O P O
+Pd
H
R1
Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336.
R2
N
R
nucleophilic enamine
and cationic π-allyl Pd
with chiral counterion
Chiral Anion Strategy for Asymmetric Tsuji-­‐Trost Allyla2on Cataly2c Asymmetric Allyla2on of α-­‐Branched Aldehydes
R3
R1
R2
Ph
+
CHO
Ph
1.5 mol% (R)-TRIP
3 mol% Pd(PPh3)4
5 A MS, MTBE, 40 ˚C
N
H
then 2N HCl, Et2O
R3
R1
R2
CHO
H
H
Me
Me
H
Me
CHO
CHO
CHO
F
85%
98.5:1.5 er
85%
98:2 er
H
Me
Me
iPr
CHO
65%
85:15 er
40%
96:4 er
reaction run
at 110 ˚C
reaction run
at 60 ˚C
Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336.
(R)-TRIP counterion
iPr
Me
CHO
45%
95:5 er
iPr
O
O
P O
O
iPr
iPr
iPr
Chiral Anion Phase Transfer Catalysis Inversion of Tradi2onal PTC Uses Chiral Anionic Transfer Catalyst
Halocyclization
5 mol% chiral TRIPderived catalyst
1.25 equiv Selectfluor
1.1 equiv Proton Sponge
O
O
NH
C6H5F, -20 ˚C
Traditional PTC
Organic
phase
Reagent
Activated anionic substrate
Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. B. Science 2011, 334, 1681.
O
O
N
86%
92% ee
Inverted PTC
Organic
phase
Lipophilic chiral cation salt
(mediates reactivity)
Aqueous or
solid phase
F
Substrate
Lipophilic chiral anion salt
(mediates reactivity)
Aqueous or
solid phase
Activated cationic reagent
Chiral Anion Phase Transfer Catalysis Chiral Anionic Phase Transfer Catalyst Solubilizes Electrophilic Fluorine Source Solid
phase
Cl
2
*
NaHCO3
O
O
P
N+
2BF4N+
F Selectfluor
O
O- Na+
(insoluble)
Cl
Na2CO3
N+
N
NaBF4
iPr
iPr
2 NaBF4
BF4-
C8H17
iPr
Cl
O
P
O
*
-O
O
iPr
O
P
N+
N+
F
O
O-
iPr
antifluorocyclization
F
Organic
liquid
phase
O
chiral ion pair
(soluble)
C8H17
iPr
*
N+
N
O
O
P
O
OH
O
Ar
NH
O
Ar
N
Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. B. Science 2011, 334, 1681.
Cl
-O
O
P
O
O
Chiral Anion Phase Transfer Catalysis Chiral Anionic Phase Transfer Catalyst Solubilizes Electrophilic Fluorine Source Dihydropyran
substrates
R
O
5 mol% catalyst
1.25 equiv Selectfluor
1.1 equiv Proton Sponge
NH
O
F
R
O
O
N
C6H5F, -20 ˚C
F
F
F
O
O
O
Br
O
t-Bu
O
N
O
N
84%
95% ee
I
N
95%
95% ee
73%
9:1 dr
87% ee
Dihydronaphthalene
and chromene
substrates
R
O
X
NH
10 mol% catalyst
1.5 equiv Selectfluor
1.25 equiv Na2CO3
1:1 C6H5F/hexanes, 23 ˚C
X
F
O
R
N
(R)-TRIP derived catalyst
F
O
O
iPr
iPr
F
C8H17
O
iPr
I
N
71%
93% ee
O
O
P
O
OH
N
70%
92% ee
iPr
C8H17
Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. B. Science 2011, 334, 1681.
iPr
iPr