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Anita MattsonMarch 9, 2004
Contents:-Introduction -Mechanism-Alkylations-Micheal Additions-Darzens Reactions-Aldol Reactions-Epoxidations
References:-Dalko, P.I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726-3748.-Jones, R. Quaternary Ammonium Salts and Their Use as Phase Transfer Catalysts; Academic Press: New York, 2001.
Asymmetric Phase Transfer Catalysis: Cinchona Alkaloid Derived Quaternary Ammonium Salts
NH
N
HOH
R
N
H
N
HHOR
The General Principle of Phase Transfer Catalysis
Consider the Following Reaction:
Cl + Na+CN- CN + Na+Cl-
The 4-chlorobutane and sodium cyanide form two separate layers and the reaction between them is only able to take place at the interface of these layers.
Even reflux does not speed up the desired reaction significantly.
Addition of a phase transfer catalyst, such as a quaternary ammonium salt, is able to speed up the reaction.
A General Picture for the Process:
Organic Phase
Interfactial Region
Aqueous Phase
Cl + Q+CN- CN + Q+Cl-
Q+CN- Q+Cl-Cl- CN-+ +
Cinchona Alkaloid Derived Quaternary Ammonium Salts
NH
N
HOH
R
a) R=OMe, X=OH [(-)-quinine] $3.15/gb) R=H, X=OH [(-)-cinchonidine] $0.72/g
N
H
N
HHOR
a) R=OMe [(+)-quinidine] $5.50/gb) R=H [(+)-cinchonine] $1.20/g
-Chincona Alkaloids are a family of natural products that can be isolated from cinchona trees
-The following four are the most abundent and can be easily isolated from the bark of the trees: 1) Quinine
2) Cinchonidine 3) Quinidine
4) Cinchonine
R1R1
X X
Selected Catalysts for Enantioselective PhaseTransfer Reactions
F3C
NPh
Me Me Me
PhHOBr
N PhMeMe
Me
OH
Cl
NMe
OH
PhMe
Br
Ephedra Alkaloid Catalysts
N
R
RBr
H2NNH
OHN
NH
Bu
R RO
OR
Oligopeptides and Polymers
C2-Symmetric
Roberts et. al., Chem. Commun. 1997, 739.
Maruoka et al., J. Am. Chem. Soc. 1999, 121, 6519.
Phase Transfer Catalysis: Enantioselective Reactions
1) Alkylations
2) Michael Additions
3) Aldol and Related Condensations
6) Darzen Reactions
5) Epoxidations
•Several reactions have been done using cinchona alkaloid derived quaternary ammonium salts as asymmetric phase transfer catalysts.
•Reactions have been done in the following areas:
Phase Transfer Catalysis: Enantioselective Alkylations
First Example: Enantioselective Synthesis of (+)-IndacrinoneDolling et al, J. Am. Chem. Soc. 1984, 106, 446-447.
ClCl
H3CO
OCl
Cl
H3CO
O
CH3Cat. (10 mol %)
Br
Catalyst:
MeClNaOH (50%)PhCH3/H2O
Rationale:
N
H
OH
N CF3
N
H
OH
N CF3
OClCl
H3CO
δ
ClCl
O
O
CH3
HO
O95% yield92% ee20° C, 18h
Conlcusions of Kinetic and Mechanistic Studies:Hughes, Dolling et al, J. Org. Chem., 1987, 52, 4745-4752.
Step 1: Enolate Anion Formation Base concentration dependent, Rxn proceeds best in 50% NaOHStep 2: Anion Extraction into Organic Phase Catalyst could be working as a dimer? Ammonium Salts more soluble with bromide counterion.Step 3: Chiral Methylation in Organic Phase Higher ee's with less polar solvents Stirring has no effect on rate or ee.
Phase Transfer Catalysis: Enantioselective AlkylationsApplication to the Synthesis of Amino Acids
1) O'Donnell's Work
2) Corey's Work
3) Lygo's Work
NPh
PhOtBu
O
NPh
PhOtBu
O
R
Catalyst:
NH
OH
N
Cl
R-X10 mol% cat.
50% aq. NaOHCH2Cl2, 25°C
yields: 60-85%ee: 42-66%
O'Donnell et al., J. Am. Chem. Soc., 1989, 111, 2353.
Catalyst:
N
NO
Bryields: 68-91%ee: 92-99.5%
H
Catalyst:
N
NOH
Br H
Catalyst:
NH
OH
N
Br
yields: 40-86%ee: 67-91%
Corey et al., J. Am. Chem. Soc., 1997, 119, 12414.
Lygo et al., Acc. Chem. Res. ASAPLygo et al., Tetrahedron Lett. 1999, 40, 1389.Lygo et al., Tetrahedraon Lett. 1999, 40, 1385.
Phase Transfer Catalysis: The Mechanism of Imine Alkylation
NPh
PhCO2tBu
NPh
PhCO2tBu
K OH
NPh
Ph
OtBu
OK
NPh
Ph
OtBu
OQ
Q X
R X
NPh
PhCO2tBu
Ph
K OH
ORGANIC PHASE
AQUEOUS PHASE
INTERFACE
•Studies into the kinetics of phase transfer reactions indicate that the deprotonation most likely occurs one the interface of the two phases.
Lygo, B.; Andrews, B. Acc. Chem. Res. ASAP
•Steps: 1) Deprotonation of Substrate 2) Transfer of Substrate Anion 3) Alkylation in Organic Phase
Phase Transfer Catalysis: Enantioselective AlkylationsStereochemical Rationale
Lygo, B.; Andrews, B. Acc. Chem. Res. ASAP.
NHRON N
OO
cinchonidine derived
N HOR
NN
OO
cinchonine derived
R2 e.e. (%) Yield (%)Cyclohexyl 23 64CH3OCH2 10 66Ph 48 52Napthyl-1-yl 36 76Quinoin-4-yl 56 76
R1 e.e. (%) Yield (%)CH3 36 59n-Butyl 50 57PhCH2 48 64CH3OCH2 26 60PhCH2OCH2 30 50
R3 X e.e. (%) Yield (%)H I 8 67n-Propyl I 2 76Cyclohexyl Br 4 564-Nitrophenyl Br 38 664-Methoxyphenyl Cl 38 69Napthyl-1-yl Cl 52 67Napthyl-2-yl Br 40 67Anthracen-9-yl Cl 75 57Ph Br 2 73
Phase Transfer Catalysis: AlkylationsStructural Effects of the Catalyst
N
R3
HR1O
R2
X
Catalyst:Variation of R1:
Variation of R2:
Variation of R3:
Lygo et al, Tetrahedron, 2001, 57, 2391-2402.
Conclusions:-N-Anthracenylmethyl substituent substantially enhances enantioselectivity-1-Quinolyl group also is key in enantioselectivity
NPh
PhOtBu
ONPh
PhOtBu
O
R
10 mol% cat.50% aq. NaOHCH2Cl2, 25°C
Phase Transfer Catalysis: Michael Additions
BrCatalyst:
N
H
OH
N
O
CH3
ClCl
H3CO
+O
O
CH3
ClCl
H3CO
CH3
O
CF3
5.6 mol% cat.toluene/50% NaOH (5:1)
20°C, 18h80% ee, 95% yield
Conn et al., J. Org. Chem. 1986, 51, 4710.
-The yield and ee were best for the (S) enantiomer
-The (R) enantiomer was desired, but even after optimization only 52% ee -Same stereochemical rationale as in the alkylations
Phase Transfer Catalysis: Michael Additions
XCatalyst:
N
HN R
The Synthesis of (R)-Baclofen•HCl
O
Cl
+ CH3NO2
O
Cl
H
NO2
O
Cl
H
NO2
O
Cl
HN
O H
NH2
O
HO
Cl
HCl
OPh
H
10 mol% cat.CsF, toluene
-40°C, 36h89%
m-CPBA90%
70% ee95% ee after recrystalization
NiCl2/NaBH4
MeOH65%
5N HCl
Corey et al, Org. Lett. 2000, 2, 4257.
Phase Transfer Catalysis: Michael Additions
ClCatalyst:
N
NC
The Synthesis of Methyl-Dihydrojasmonate
OH3C
OH3C
CO2Me
11 mol% cat., K2CO3
30 equiv dimethyl malonate-20°C
then DMSO/H2O 190°C
H
OR
R'
Author's Rationale:
N
NC
H
O
R'
HO
CH3MeO
OMe
O
O
Plaquevent et al, Org. Lett. 2000, 2, 2959.
-trans-Dihydrojasmonates are constituents of commercial fragrances-The reaction fails if the hydroxyl group is protected-The dimethyl malonate is both a reagent and a solvent, the reaction fails with other solvents
Phase Transfer Catalysis: Aldol and Related Condensations
Shiori's Aldol
OTMS
R
CH3
PhCHO12 mol% cat
THF, -70°Cthen 1N HCl
O
R
PhCH3 OH Catalyst:
N
PhHN
OH
H
F
Corey's Aldol
NPh
PhOTMS
OtBu RCHO10 mol% Cat.
CH2Cl2/hexanesthen citric acid
RCO2tBu
OH
NH2
NH
H
HF2
N OBn
Catalyst:
Shiori et al, Tetrahedron Lett. 1993, 34, 1507.
Corey et al, Tetrahedron Lett. 1999, 40, 3843.
Phase Transfer Catalysis: Darzen Reaction
Catalyst:
NHN
OH
HBr
NH
HCl
N OH
Catalyst:
R
X
R1
O
R2+
O
OEtH R1
R2
OR
CO2Et
General Darzen's Reaction:
Asymmetric Darzens Reactions of Chloromethyl Phenylsulfone:
SO2PhCl ArCHO+10 mol% cat
KOH/TolueneRT
ArSO2Ph
O
CF3
CF3yields: 69-94%ee: 64-81%
Asymmetric Darzens Reaction with a-Chloro Ketones:O
Cl+ RCHO
10 mol% cat
LiOH•2H2OBu2O, 4°C
O
RO
Arai, Shiori et al, Tetrahedron Lett. 1998, 39, 8299.
Arai, Shiori et al, Tetrahedron 1999, 55, 6375.
yields: 67-99%ee: 59-86%
OEt
Phase Transfer Catalysis: Epoxidations
R1 R2
O
R1 R2
OO
Lygo, B.; Wainright, P. Tetrahedron 1999, 55, 6289.
BrCatalyst:
N
N
H
O
Ph
10 mol% Cat.
11% NaOClPhMe
RT, 4-48hrs
R2 %ee Yield(%)
Me
H3CO
O2N
Br
O
O
77
84
90
84
81
86
92
89
79
94
93
87
R2 %ee Yield(%)
O2N
Br
S
O
O
MeMe Me
86
88
83
85
89
85
90
99
85
82
95
40did not go to completion
R1=n-hexyl R1=phenyl
Phase Transfer Catalysis: Epoxidations
R
H
H
O
X
BrCatalyst:
N
Me
N
H
O
Ph
10 mol% Cat.
PhMe8M KOCl
-40°C, 12h
R
O
X
O
NNH
O
Ph
Me O
F
ClO
Stereochemical Model:
•The hypochlorite ion is contact ion-paired with the only accessible face of the charged nitrogen. •The enone is situated with the phenyl ring containing the halogen between the ethyl group and the quinuclidine ring. The carbonyl oxygen is as close to the charged nitrogen as possible.•In this arrangement, the hypochlorite ion oxygen is ready for nucleophilic attack at the β−carbon.
Corey, E.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
yields: 70-97%ee: 91-99%
Phase Transfer Catalysis: Conclusions
•There are a number of advantages that PTC offers over homogeneous alternatives: 1. Enhanced reactivity of the anion in the organic phase and increased reaction rates. 2. Generally more selective. 3. Wide variety of organic solvents can be used. 4. Simplifies product isolation. 5. Catalysts are inexpensive and biodegradable.
•Due to the "green" nature of the reactions, there are many industrial applications.
•The reaction can be applied to a wide variety of substrates with moderate to high selectivites. It is possible to make a wide variety of chiral starting materials.
•The reactions are relatively easy to perform.