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.