Quaternary Ammonium Salts as Chiral

Nonmetal-Based Asymmetric Catalysis :Quaternary Ammonium Salts as Chiral Catalysts

Evans Group Friday SeminarHemaka Rajapakse

March 16, 2001

Contents :• Introduction• Alkylations• Michael Additions• Darzens Reactions• Aldol Reactions• Epoxidations• Oxygenations

Leading References :

• O'Donnell, M., "Asymmetric Phase-Transfer Catalysis",

Catalytic Asymmetric Synthesis, Ojima ed., Wiley-VCH, 1993

• Shioiri, T., "Use of Chiral Quaternary Salts in Asymmetric

Synthesis", Phase-Transfer Catalysis : Mechanisms and

Syntheses, Halpern, ed., ACS Symposium Series, 1997.

01 Title Slide 3/15/01 9:33 AM

Introduction

• The most common chiral quaternary ammonium salts for asymmetric catalysis are derived from the chincona alkaloid family of natural products via simple N-alkylation.• The chinconine and chinconidine family of natural products are pseudo-enantiomeric.• Once N-alkylated, these alkaloids have a rather rigid structure, and tight-ion pairing can be made only on one sterically unhindered face of the alkaloid nitrogen.• Asymmetric catalysis with these ammonium salts have been documented in the literature since 1975. Early enantiomeric excesses were determined by rotation, and these results have been disputed since (see O'Donnell, M., "Asymmetric Phase Transfer Reactions", Catalytic Asymmetric Synthesis, Ojima ed., Wiley-VCH, 1993). Impurities from catalyst decomposition were thought to contaminate products, giving erroneous rotation values.• For the enantioselective syntheses of chincona alkaloid derivatives, see Lygo et al, Tetrahedron, 1999, 55, 2795.

N

H

HN

OH

R

R = H : Chinconine ($1.70/g)R = OCH3 : Quinidine ($8.80/g)

N

H

H

NOH

R

R = H : Chinconidine ($ 0.78/g)R = OCH3 : Quinine ($3.15/g)

02 Introduction 3/15/01 9:42 AM

Synthesis of (+)-Indacrinone

Dolling et al, J. Am. Chem. Soc., 1984, 106, 446

Cl

Cl

H3CO

OCl

Cl

H3CO

O

CH3

Cl

Cl

O

O

CH3

HO

O

CH3Cl, 10 mol% cat*

toluene/50% NaOH (5:1)

20 oC, 18h

92% ee, 95% yield

N

H

CF3

Br

Author's Rationale :

• CH3Cl was a superior electrophile to both CH3Br or CH3I.

• Increasing NaOH concentration improves selectivity.

• Catalyst N-benzyl substituent was critical for enantioselectivity,

with electron withdrawing substituents enhancing selectivity.

• A very rigid transition state is proposed, where the substrate is

bound to catalyst by a hydrogen bond as well as through

π-stacking.

• Tight-ion pairing shown is consistent with computational

modeling (J. Org. Chem., 1991, 56, 5181).

cat* =

HN

OH

N

H

CF3

H

O

H

N Cl

Cl

H3CO

O

H

δ-

(±)

03 Merck Alk-1c 3/15/01 9:49 AM

Kinetic and Mechanistic Considerations for Enantioselective Phase Transfer Methylation

Step 1 : Enolate Anion Formation - Base concentration dependent! • In 50% NaOH, deprotonation is interfacial, and enolate forms a separate solid phase, even in the absence of catalyst. The deprotonation is complete when 20% of indanone has been alkylated. • With 30% NaOH, indanone is much preferred to enolate at equilibrium.

Step 2 : Anion Extraction to Organic Phase - Dimeric or monomeric in catalyst? • In toluene, the catalyst exisits as a dimer with its zwitterionic oxide. Catalyst could extract indanone enolate from aqueous or solid phases, or zwitterion could deprotonate residual indanone in organic phase. • Tetraalkyl ammonium salts with a bromide counterion are 1000 times more soluble in organic solvents than with a hydroxide counterion.

Step 3 : Chiral Methylation in the Organic Phase • Stirring rate has no effect on rate or ee of reaction. • Higher ee's with less polar solvents such as toluene support tight-ion pair theory. Non-polar, non polarizable solvents such as hexane slows reaction and lowers ee due to poor solubility of indanone. • Under reaction conditions, catalyst can decompose to A and B. MeI can further alkylate decompositions adducts to give non- selective catalysts C and D.

N

H

H

Q

O

Ph

N

Ph

OQ

H

N

Ph

Q

H3CO

N

OQ

H

N

Q

H3CO

Me

Me

Ph

Ph

MeXthenbase

MeI

MeI

Hughes, Dolling et al, J. Org. Chem., 1987, 52, 4745

slow

Cl

Cl

H3CO

O Cl

Cl

H3CO

O

CH3cat*

MeCl

A

B

C

D

04 Merck Alk-2 Kin and Mech 3/15/01 10:38 AM

Amino Acid Synthesis : Early Examples

N

H

Clcat* =

HN

OH

OtBu

O

N

Ph

Ph

R-X

10 mol% cat*

50% aq. NaOH

CH2Cl2, 25 oC

OtBu

O

N

Ph

Ph

R

R-X

CH2=CHCH2Br

PhCH2Br

MeBr

n-BuBr

4-Cl-C6H4CH2Br

2-napthylCH2Br

equiv.

5

1.2

5

5

1.2

1.2

% ee (R)

66

66

42

52

66

54

Yield(%)

75

75

60

61

81

82

Time(h)

5

9

24

14

12

18

• tert-Butyl ester proved to be optimal for asymmetric induction

• N-benzyl catalyst shown above gave comparable results to the more expensive

N-(4-(trifluoromethyl))benzyl catalyst

• Discovers that O-protection with allyl or benzyl does not changes yields or

selectivities. Is the O-alkylated catalyst the actual "active species"?

(Tetrahedron, 1994, 50, 2353)

O'Donnell et al, J. Am. Chem. Soc., 1989, 111, 2353

OH

O

H2N

Cl

6.5 g prepared in >99% ee, two steps,50% overall yield from alkylation precursor Schiff base.

O'Donnell et al, Tetrahedron., 1994, 50, 235305 O'Donnell Alk-1 3/15/01 10:39 AM

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N

H

HN

OH

OtBu

O

N

Ph

PhO'Donnell's Stereochemical Rationale

• These models represent MM2 minimizations of substrate enolate fitting into catalyst binding region.

• Very little energy difference between Z and E enolates in the absence of small counterions.

• Z enolate was more consistent with experimental ee's.

Lipkowitz, O'Donnell et al, J. Org. Chem., 1991, 56, 5181

06 O'Donnell Alk model-2c 3/15/01 10:45 AM

N

H

Xcat* =

HN

OH

R2

R1

Asymmetric Alkylations of Oxindoles

N

O

CH3H3C

H3CO

N

O

CH3

H3CO

H3C

CN

N CH3

H3CO

N

H3C

H

CH3

10 mol% cat*

ClCH2CN

toluene

50% NaOH(5:1)

20 oC (-)-physostigmine

Wong et al, J. Org. Chem., 1991, 56, 872

R1

H

H

H

H

H

H

H

H

H

H

OCH3

OCH3

R2

H

2-CF3

3-CF3

4-CF3

3-Br

4-Br

4-Cl

3,4-Cl23,4-Cl22,6-Cl2

H

3,4-Cl2

X

Br

Br

Br

Br

Br

Br

Br

Br

Cl

Br

Br

Br

% ee

10

4

69

72

48

68

69

77

78

0

39

77

• Asymmetric induction is increased when N-benzyl group

is substituted at the 3 and 4 positions with electron

withdrawing groups.

• Little counterion effect observed

• Substitution at 2 and/ or 6 position of N-benzyl moiety severely

erodes selectivity.

• Increasing catalyst loading up to 50 mol% does not improve

enantiomeric excess

07 Wong Alk-1 3/15/01 10:47 AM

Corey's Amino Acid Synthesis Methodology N

H

H

Br

cat* =

NO

OtBu

O

N

Ph

Ph

R-X

10 mol% cat*

CsOH•H2O

CH2Cl2

OtBu

O

N

Ph

Ph

R

R-X

CH3I

CH3CH2I

CH3(CH2)4CH2I

Temp (oC), Time

-60, 28h

-60, 30h

-60, 32h

-60, 36h

-78, 22h

-78, 20h

-78, 18h

%ee

97

98

99.5

99

97

92

95

yield

71

82

79

75

89

91

68

Br

Br

Br

CH3

CH2BrTBS

Br

O

H3C

O

O

Br

OTBS

H3CO

TBSO

R-X

PhCH2Br

Ph2CHBr

Temp (oC), Time

-78, 23h

-78, 22h

-78, 24h

-78, 24h

%ee

94

99.5

97

96

yield

87

73

67

81

Corey et al, J. Am. Chem. Soc., 1997, 119, 12414

• Use of 50% aq. KOH at -20 oC gave slightly lower ee.

08 Corey Alk-1 3/15/01 10:49 AM

N

H

H

NO

Stereochemical Model for Alkylations :X-Ray Evidence

O N

O

O

Corey et al, J. Am. Chem. Soc., 1997, 119, 1241409 Corey Alk-2c 3/14/01 2:34 PM

N

H

H

NO

Stereochemical Model for Alkylations

tBuO N

Ph

Ph

O


10 Corey Alk-3c 3/14/01 2:37 PM

N

H

H

Br

NOH

N

H

Br

HN

OH

Lygo's Alkylations

OtBu

O

N

Ph

Ph

R-X

10 mol% cat

toluene/KOH

20 oC

OtBu

O

N

Ph

Ph

R

1. 2.

R-X

PhCH2Br

CH2=CHCH2Br

CH3I

CH3(CH2)3I

(β-naphthyl)CH2Br

cat

1

2

1

2

1

2

1

2

1

2

1

2

Time(h)

18

18

18

18

3

3

18

18

18

18

4

4

% ee (config)

89(R)

91(S)

88(R)

88(S)

86(R)

89(S)

87(R)

88(S)

82(R)

86(S)

67(R)

72(S)

Yield(%)

63

68

62

76

40

41

56

42

86

75

83

84

• Lygo also notes that the O-protected

catalysts give identical results, and also

suggests that the O-alkylated species

may be the active catalyst.

Lygo et al, Tetrahedron Lett., 1997, 38, 8595

tBuOI

O

11 Lygo Alk-1 3/16/01 11:02 AM

Synthesis of Chiral 1,3-Propane Diols N

H

H

Br

cat* =

NO

H

CO2tBu

(H3C)2N

(H3C)2N

H

CO2tBu

(H3C)2N

(H3C)2N

R

HOH2C CH2OTBS

R

R-X, 10 mol% cat*

CsOH•H2O

CH2Cl2/Et2O

(1:1)6 steps


R-X

CH3I

CH3(CH2)5I

Cl(CH2)3I

Cl(CH2)4I

PhCH2Br

Br

Ph

Br

Temp(oC), Time(h)

-50, 12

-45, 12

-45, 12

-45, 12

-65, 36

-65, 36

-65, 12

Yield(%)

68

73

71

62

76

83

81

% ee

98

95

95

94

96

94

98

• Strongly electron donating substituents on phenyl groups

of nucleophile required for high enantioselectivity.

• Use of bifunctionalized electrophiles make the synthesis

of chiral 3-susbtituted tetrahydrofurans and tetrahydropyrans

possible.

12 Corey Alk-4 3/15/01 10:54 AM

Synthesis of bis-α-Amino Acid Esters

N

R H

H

Br1 R = CH=CH22 R = CH2CH3

NOH

BrBr

Br

Br

OCH3

Br

O

Br

XCH2-R-CH2X, cat.

toluene/KOH

20 oC

then citric acid

OtBu

O

N

Ph

Ph

Br

Br

H3CO

H3CO

RtBuO

O

NH2 NH2

OtBu

O

XCH2-R-CH2X cat.

10 mol% 2

10 mol% 2

10 mol% 1

20 mol % 1

% de

82

75

80

80

Yield(%)

49

48

63

65

‡95% ee

• No explanation as to why the dihydro catalyst

2 was used in certain cases.

• One can control mono and bis alkylation by

varying the equivalents of bis-allyl bromide.

0.5 eqv. gives a 10:1 ratio of bis : mono

alkylation, 5.0 eqv. gives a 1:10 ratio.

• Useful methodology for the synthesis of

natural and unnatural dityrosine type

amino acids.

Lygo et al, Tetrahedron Lett., 1999, 40, 1385Lygo, Tetrahedron Lett., 1999, 40, 1389

13 Lygo Alk-2 3/16/01 11:10 AM

Asymmetric Alkylation of α-FluorotetraloneN

H

CH3

Brcat* =

HN

OH

H3C

H3C

CH3

CH3

O

FAr Br

10 mol% cat*

KOH/toluene

20 oC, 24h

OF

Ar

(±)

Arai et al, Tetrahedron Lett., 1999, 40, 6785

Ar

C6H5

2-Me-C6H4

3-MeC6H4

4-Me-C6H4

4-Br-C6H4

2,3,4,5,6-Me5-C6

β-Np

(E)-PhCH=CH

% ee

80

84

84

82

78

91

79

70

Yield(%)

71

60

45

58

83

44

60

33

• Reaction was optimized extensively for solvent and base.

RbOH•H2O/THF systems gave comparable results.

• Again, substitution and electronics at N-benzyl group of alkaloid

was critical to selectivity. In this case, electron withdrawing

substituents had a detrimental effect.

• Analogous alkylation of α-methyltetralone with benzyl bromide gave

a maximum of 55%ee and 18% yield with above catalyst.

N

H

H

O

H

N

CH3

CH3H3C

H3C

O

F

H

CH3

HAR Rationale :• Sterics of the N-benzyl group prevent the enolate from docking such that the re face is exposed.• Electron withdrawing substituents on the N-benzyl group will enhace π-stacking with enolate, again promoting binding with re face exposed.

14 Arai Alk-1c 3/15/01 10:58 AM

A C2-Symmetric Chiral Phase Transfer Catalyst for the Synthesis of Amino Acids N

Br

OtBu

O

N

Ph

Ph

R-X

1 mol% 3

50% aq. KOH

toluene

0 oC

OtBu

O

N

Ph

Ph

R

Maruoka et al, J. Am. Chem. Soc., 1999, 121, 6519

R-X

PhCH2Br

CH3I

CH3CH2I

Br

Br

Me

Br

Br

Me

Br

FBr

Temp (oC), Time

0, 0.5h

0, 8h

0, 10h

0, 1h

0, 1h

0, 1h

0, 0.5h

0, 1h

0, 1.5h

Yield(%)

95

64

41

84

82

90

80

81

60

%ee

96

90

95

94

93

95

96

96

96

R'

R'

1 R'=H2 R'=Ph3 R'= β-Np

• Rigid, chiral spiro ammonium salts required for high

enantioselectivity.

• R' substituent on catalyst critical for enentioselectivity, as 1 gives

79% ee and 2 gives 89% ee for the alkylation reaction with

PhCH2Br.

• The rate of reaction increases with the steric bulk of catalyst

substituent R' (For R-X being PhCH2Br, 1 takes 6h, 2 takes 30

min. at 0 oC). Solubility issue?

15 Maruoka Alk-1 3/15/01 11:02 AM

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Possible Rationalization of Observed Enantioselectivity

N

β-Np

β-Np

OtBu

O

N

Ph

Ph

"The conformation of the E-enolate.....makes a good match for the molecular pocket of chiral catalyst....." - Maruoka

(Chem3D models by HAR)16 Maruoka Alk. Chem3Dc 3/14/01 5:29 PM

Maruoka Catalyst SynthesisN

Br

Ar

Ar

OH

OH

Br

Br

OH

OH

Tf2O, Et3N

MeMgI, NiCl2(PPh3)2NBS, benzoyl peroxide

Br

Br

Allylamine

RhCl(PPh3)3, MeCN/H2ONH

Tf2O, Et3N

ArB(OH)2, Pd(OAc)2OTf

OTf

Ar

Ar

MeMgI, NiCl2(PPh3)2NBS, benzoyl peroxide

Ar

Ar

Br

Br

+

cat*

cat* =

• Synthetic route amenable to facile tuning of catalyst


K2CO3

17 Maruoka cat. prep 3/15/01 1:24 PM

Gram-Scale Synthesis of L-Dopa tert-Butyl Ester

N

Br

OtBu

O

N

Ph

Ph

1 mol% cat*

50% aq. KOH

toluene

(3:1)

0 oC, 3h

OtBu

O

N

Ph

Ph

Ar

Ar

cat* =

OBn

OBn

Br+ OBn

OBn

1M Citric Acid

THF

RT, 15h

OtBu

O

H2N

OBn

OBn

10% Pd/C, H2

THF

RT, 5h

OtBu

O

H2N

OH

OH

Maruoka et al, Tetrahedron Lett., 2000, 41, 8339

3.37g79% overall yield

98% ee

5.00g 7.77g

• L-Dopa esters and analogs are potential drugs for the

treatment of Parkinson's disease.

• Previously prepared from enzymatic resolution.

• 155mg of catalyst used for above reaction, and this

can be recovered in 72% yield after silica gel chromatography,

and reused without loss of yield or enantioselectivity.

Ar = 3,4,5-F3-Ph

18 Maruoka Alk-2 L-Dopa 3/15/01 1:25 PM

Synthesis of α, α Dialkyl α-Amino Acids N

Br

R

R

1 R = β-Np2 R = 3,4,5-F3-Ph

OtBu

O

Np-Cl-Ph

R2 -X, 1 mol% 2

CsOH•H2O

toluene

then citric acid

OtBu

O

H2N

R1R1R2

R1

Me

Me

Me

Me

Me

PhCH2

iBu

iBu

R2 -X

PhCH2Br

CH3CH2I

PhCH2Br

Br

tBuOBr

O

NBoc

Br

Br

Br

Temp (o C), Time

0, 0.5h

0, 0.5h

0, 0.3h

-20, 2h

-10, 0.7h

0, 0.5h

0, 0.5h

0, 1h

Yield(%)

85

73

71

60

78

71

64

70

% ee

98

98

99

93

91

97

92

93

• Solid/liquid phase transfer reaction increases reactivity as well

as selectivity.

• Enantiomerically pure starting material provide identical

reactivity and results.

• Tuning the electronic properties of the catalyst important, as 2

ffered significantly higher levels of enantioselectivity than 1.


(±)

19 Maruoka Alk-3 3/15/01 11:10 AM

Synthesis of α, α Dialkyl α-Amino Acidsvia a One Pot, bis-Alkylation Reaction

N

Br

R'

R'

1 R = β-Np2 R = 3,4,5-F3Ph

OtBu

O

Np-Cl-PhOtBu

O

H2N

R1R2

R1 -X then R2 -X

1 mol% 2

CsOH•H2O

toluene

then citric acid


Br

Br

Me

Br

R1-X

PhCH2Br

Br

Br

Br

Temp(oC), Time

-10, 3.5h

-10, 3.5h

-10, 3.5h

-10, 2h

R2 -X

PhCH2BrTemp (oC), Time

0, 0.5h

0, 0.7h

0, 0.5h

0, 0.3h

Yield

80

60

58

74

%ee(config.)

98(R)

97

96

92(S)

• Remarkable synthesis of α,α-dialkyl-α-amino acids!

• Either enantiomer can be prepared using the same

reagents, by just inverting the order of addition of

alyklating agents.

20 Maruoka Alk-4 3/15/01 11:11 AM

OtBu

O

N

Ph

Ph

R-X

10 mol% cat*

Conditions

CH2Cl2

OtBu

O

N

Ph

Ph

R

Organic Soluble Bases Can Also Be Used.......

PN

N

N

NEt2

tBu

CH3

H3C

BEMP pKa=16.2active halides

N

P

tBu

NN

N

BTPP pKa = 17.0non-active halides

R-X

CH3I

CH3CH2I

(CH3)2CHI

Br

Br

Me

Br

Br

O2N

Conditions

A

B

B

A

A

A

A

A

Yield(%)

92

98

93

96

91

89

88

93

% ee

94

89

97

90

94

56

91

89

A : 1.5 eqv. BEMP, -78 oCB : 5.0 eqv. BTPP, -50 oC

BuOtBr

O

O'Donnell et al, Tetrahedron Lett., 1998, 39, 8775

• Since both base and substrate are in the same phase,

reaction times are generally faster than phase transfer

reactions.

• No mention of base recovery in procedure.

• For Schwesinger base synthesis, see : Chem. Ber., 1994,

127, 2435.

pKa = 19.7

Time(h)

4

6

24

6

4

7

4

4

N

H

H

Br

cat* =

NO

21 O'Donnell Alk-2 3/16/01 11:15 AM

Cl

Cl

H3CO

OCl

Cl

H3CO

O

Cl

Cl

O

5.6 mol% cat*

toluene/50% NaOH (5:1)

20 oC, 18h

80% ee, 95% yield

N

H

CF3

Brcat* =

HN

OH

Michael Addition of Indanone to MVK

CH3

CH3

O

CH3

CH3

O

• The enantiomeric (R) adduct was the desired target.

• Use of the pseudo-enantiomeric chinconidium alkaloid catalyst

gave a maximum of 52% ee, despite attempts at tuning N-benzyl

substituent.

• The Michael addition is catalytic in base. Partitioning the catalyst

between toluene and aqueous base, followed by removal of

aqueous phase and running the reaction homogeneous in toluene

gives identical results.

• Stereochemical rationale identical to that proposed by Dolling (See

J. Am. Chem. Soc., 1984, 106, 406)

HO2C

Conn et al, J. Org. Chem., 1986, 51, 4710

CH3

O

+

22 Conn Michael-1 3/15/01 11:17 AM

Cyclopropanation via Michael Addition N

H

Brcat* =

HN

OH

OCH3R

O

Br10 mol% cat*

K2CO3

20 oC

NC CO2Bn

n

O

n

H

H

CN

CO2Bn

n

1

1

1

1

1

1

2

2

R

2,4-(CF3)22,4-(CF3)22,4-(CF3)2

4-CF3

2,4-(CH3)2F5

2,4-(CH3)22,4-(CF3)2

Solvent

toluene

1,2-dichloroethane

chlorobenzene

chlorobenzene

chlorobenzene

chlorobenzene

chlorobenzene

chlorobenzene

Time(h)

34

34

13

26

48

31

112

43

Yield(%)

76

74

74

82

96

62

51

60

% ee

31

44

45

25

15

24

6

83

• Both nitromethane and cyanomethylsulfone can be used as a nucleophile, but the enantioselectivity is lower.

• Substitution at 2 position of N-benzyl with an electron withdrawing group crucial to good enanioselectivity .

Arai, Shioiri et al, Tetrahedron Lett., 1999, 40, 421523 Arai Michael-1 3/15/01 11:18 AM

Corey's Michael Additions

OtBu

O

N

Ph

Ph10 mol% cat*

CsOH•H2O

CH2Cl2-78 oC

OtBu

O

N

Ph

Ph

N

H

H

Br

cat* =

NOEWG

R

+

R

EWG

OtBu

O

N

Ph

Ph

CN

85%, 91% ee

(reaction run at -55 oC)

OtBu

O

N

Ph

Ph

OCH3O

OtBu

O

N

Ph

Ph

EtO

OtBu

O

N

Ph

Ph

O

H

85%, 95% ee 85%, 91% ee 88%, 91% ee

dr = 96:4

Corey et al, Org. Lett., 2000, 2, 1097Corey et al, Tetrahedron Lett., 1998, 39, 5347

H3NCO2H

NH3

Cl

Cl(S)-ornithine hydrochloride

24 Corey Michael-1 3/15/01 11:20 AM

N

H

H

Br

NOH

Corey's Syntheses of Chiral 2-Cyclohexenones

10 mol% cat*

toluene/50% KOH

-10 oC, 36h

72%, 80% ee

cat* =

O

H3COO

H3CO

O+

O

NH

N

H3C

OH

Author's Rationale:

• No explanation given for why free hydroxyl on chinconidium salt is used.

Corey et al, Org. Lett., 2000, 2, 1097

CH3

O

OO

H3CO

25 Corey Michael-2c 3/15/01 11:21 AM

Synthesis of (R)-Baclofen N

H

H

Br

cat* =

NO

O

CH3NO2, 10 mol% cat*

CsF, toluene

-40 oC, 36h

89%

ONO2

70%ee, 95%ee after recryst. m-CPBA

90%

O

ONO2

NiCl2/NaBH4

MeOH

65%

HN

O

Cl

5N HCl

HO

O

NH2•HCl

Cl

Cl Cl

Cl


• (R)-baclofen hydrochloride is a therapeutically useful GABAB receptor agonist.

• Racemic baclofen is currently used to treat spasms caused by spinal chord injury or disease.

• Stereochemical model is identical to the Michael addition of acetophenone

(Corey et al, Org. Lett., 2000, 2, 1097).

26 Corey Michael-3 3/14/01 7:51 PM

O

Enantioselective Synthesis of Methyl Dihydrojasmonate

N

H

H

Cl

NOR

R'

1 R = R' = H

2 R = allyl, R' = H

3 R = H, R' = OMe

OH3C

11 mol% cat., K2CO3

30 eqv. dimethyl malonate

-20 oC

then DMSO/H2O 190 oC

OH3C

CO2Me

cat.

1

2

3

% ee

54

NR

90

Yield(%)

75

NR

91

N

H

H

ON

O

H3C

O

H

H3CO O

OCH3

O


• Both enantiomers of trans-dihydrojasmonate

are constituents of commercial fragrances.

• Unprotected hydroxyl group of catalyst

crucial to attain reactivity.

• Pseudo-enantiomeric quinidinium catalyst

catalyst gives 80% ee.

• Dimethyl malonate is used as a reagent and

also as a solvent. The use of any other solvent

completely inhibits the reaction.

Plaquevent et al, Org. Lett., 2000, 2, 2959

HAR Rationale :

N

H

H

ON

O

H3C

H

OCH3O

OCH3

CH3

O

27 Plaquevent Michael-1c 3/16/01 11:21 AM

Asymmetric Darzens Reactions of Chloromethyl Phenylsulfone

ArCHOCl SO2Ph + 10 mol% cat*

KOH/toluene

RT

ArSO2Ph

O

CHO

Br

CHO

Br

CHO

Me

CHO

tBu

CHO

Ph

CHO

ArCHO Time(h)

1

1.5

2

2

1.5

1

Yield(%)

80

69

84

70

71

94

% ee

64

71

78

81

72

68

Arai, Shioiri et al, Tehtrahedron Lett., 1998, 39, 8299

• The use of a non-polar solvent is critical for both yield

and enantioselectivity.

• Again, the electronics of the N-benzyl substituent

significantly influences enantioselectivity.

• Generally, metal mediated asymmetric Darzens reactions

are stoichiometric in chiral controller. For a chiral crown

ether catalyzed Darzens reaction, see Synlett, 1997, 291.

• For the synthetic utility of α,β epoxysulfones, see

J. Am. Chem. Soc., 1997, 119, 4557, and references

cited therein.

N

H

H

Cl

NOH

OCH3

CF3

cat* =

28 Shioiri Darzens-1 3/14/01 8:26 PM

N

H

CF3

Brcat* =

HN

OHO

Cl

RCHO+10 mol% cat*

LiOH•2H2O

Bu2O, 4 oC

Asymmetric Darzen's Reactions with α-Chloro KetonesO

R

O

RCHO

H

O

H3C

CH3

H

O

H3C

H3C

H

O

H

O

H

O

H3C

CH3H3C

Time(h)

61

84

252

62

43

Yield(%)

99

86

67

80

67

% ee

69

86

84

69

59

• Rare case where etherial solvent is optimal for asymmetric

induction.

• LiOH hydrate is the optimal base.

• Chloroenolate geometry is probably critical for enantioselectivity.

Phenacyl chloride gives lower ee's in reaction.

• More bulky aldehydes, such as pivaldehyde, do not react.

• O-protected catalyst gives almost racemic product.

Arai, Shioiri et al, Tetrahedron, 1999, 55, 637529 Shioiri Darzens-2 3/14/01 8:35 PM

Proposed Mechanism for Asymmetric Darzens Reaction

N

H

CF3

Brcat* =

HN

OH

Arai, Shioiri et al, Tetrahedron, 1999, 55, 6375

Ph

O

Cl

iPrCHO

+

iPr Ph

OOLi

Cl

iPr Ph

OOLi

Cl

iPr Ph

OOLi

Cl

iPr Ph

OOLi

Cl

+

+

iPr Ph

OO

cat*A

B C

D

• In a typical reaction, starting ketone is rapidly consumed, and aldol adduct

is consumed slowly.

• The syn:anti ratio of aldol adducts remains constant at 33:66 throughout the

reaction.

• Racemic syn and anti aldol adducts were separately subjected to reaction conditions.

• Does kinetic resolution of the aldol adducts determine enantioselectivity?

E

Substrates

B + C

D + E

%ee (yield) F

82(14)

69(21)

%ee D

47

17

A(% yield)

30

4

F

30 Shioiri Darzens-3 Mech 3/20/01 6:35 PM

N

H

Fcat* =

HN

OH

Shiori's Aldol

OTMS

CH3

R

PhCHO

12 mol% cat*

THF, -70 oC

then 1N HCl

O

R

Ph

OHCH3

Shiori et al, Tetrahedron Lett., 1993, 34, 1507

O

R

Ph

OHCH3

syn anti

R

Ha

Hb

OCH3b

Clb

Brb

Yield(%)

74

65

73

73

67

syn:anti

75:25

73:27

76:24

82:18

81:19

% ee syn

72

44

68

66

66

% ee anti

22

6

39

21

15

+

Catalyst preps : aAmberlite IRA-410 (fluoride form), then evaporation. bAmberlyst A-26 (hydroxide form), then HF, then evaporation.

31 Shioiri Aldol-1c 3/15/01 11:40 AM

Corey's Aldol Reaction

N

H3C H

H

HF2

cat* =

NO

OtBu

OTMSN

Ph

Ph

RCHO

10 mol% cat*

CH2Cl2/hexanes

then citric acidR

CO2tBu

OH

NH2

H3C

CHOH3C

CHO

H3C CHO

Cl CHO

CHO

H3C

H3CCHO

RCHO Temp(oC)

-78

-50

-78

-78

-78

-45

Time(h)

7

1

2

2

6

2

Yield(%)

70

81

79

48

64

61

syn/anti

86:14

93:07

75:25

50:50

50:50

75:25

% ee syn

95

88

89

82

72

76

%ee anti

83

46

91

86

86

70

Corey et al, Tetrahedron Lett., 1999, 40, 3843

• Bifluoride salt prepared from

passing bromide salt through

Amberlite A-26, then quenching

the hydroxide salt with 1N HF,

evaporation of solvent and

drying over P2O5.

• Silyl ketene acetal was a 7:1

E:Z mixture of isomers.

32 Corey Aldol-1 3/15/01 11:36 AM

Asymmetric Epoxidation of Chalcone-type Compounds

N

H3C H

H

Br

cat* =

O

R Ph

O

R Ph

OO

MeO

O

O

R % ee

86

82

83

82

77

Yield(%)

90

87

97

86

92

• Again, solvent efffects are dramatic, with non-polar solvents

giving superior results.

• Hydroxyl protected catalyst affords much higher selectivity.

• Hydrogen peroxide can also function as an oxidant, but product

is almost racemic.

Lygo et al, Tetrahedron, 1999, 55, 6289Lygo et al, Tetrahedron Lett., 1998, 39, 1599

10 mol % cat*

11% aq. NaOCl/toluene

20 oC, 4-48h

33 Lygo Epox-1 3/15/01 11:38 AM

N

H3C H

H

Br

cat* =

OR R'

O

R R'

OO10 mol % cat*

11% aq. NaOCl/toluene

20 oC, 4-48h

Br

O2N

H3C

H3CO

O

O

Br

O2N

S

O

O

H3C

H3C CH3

Lygo's Epoxidation : Full Scope

R = n-hexyl

R' % ee

77

84

90

84

81

86

Yield(%)

92

89

79

94

93

87

%ee

86

88

83

85

89

85

Yield(%)

90

99

85

82

95

40a

R'

R = phenyl

Lygo et al, Tetrahedron, 1999, 55, 6289

a reaction did not go to completion

34 Lygo Epox-2 3/15/01 11:42 AM

N

H3C H

H

Br

cat* =

NO

Corey's EpoxidationO

R

X

O

R

X

O10 mol% cat*

8M KOCl

toluene

-40 oC, 12h

O2N

Cl

H3CO

R % ee

93

94

94

92

95

93

Yield(%)

96

90

85

94

70

87

X = H

O2N

Cl

R % ee

98

95

95

99

91

Yield(%)

93

97

87

94

90

X = F

Corey et al, Org. Lett., 1999, 1, 128735 Corey Epox-1 3/15/01 11:42 AM

N

H3C H

H

Br

cat* =

NOCorey's Stereochemical Model

N

H3C

H

N

O

O

F OCl

• When aromatic ring attached to carbonyl group is forced

to be co-planar with the carbonyl σ-plane, low ee's are obtained.

• The described model is consistent with the observed sense

of induction, but has enone approaching over bridgehead!

• Substrate organization allows the chinconidium salt to stabilize

developing negative charge on enone oxygen, then as epoxide is

formed, provides a counterion for the chloride.

O

RR = CH3 76% eeR = Ph 61% ee



36 Corey Epox-2c 3/15/01 11:53 AM

Elaboration of Epoxy Ketone Derivatives

OO

O

OO

m-CPBA

81%

Zn, NH4Cl

68%

OOH

SmI264%

O

OOH

O

O

OH

H2/Pd-C

95%

Corey et al, Org. Lett., 1999, 1, 128737 Corey Epox-3 elab 3/15/01 11:57 AM

Synthesis of α-Hydroxy Ketones

N

H

CF3

Brcat* =

HN

OH

O

R1

R2 OR2R1

OH5 mol% cat*, O2

(EtO)3P

toluene/50% NaOH

R1

CH3

CH2CH3

CH(CH3)2CH(CH3)2

CH3

CH3

Ph

R2

H

H

H

H

CH3O

Cl

Cl

Time(h)

24

24

24

48

24

5

5

Yield(%)

95

98

59

87

93

95

95

% ee

70

72

77

56

27

79

48

Shioiri et al, Tetrahedron Lett., 1988, 29, 2835

N

Bn

CH3

CH3

CH3

OH

Br

N(CH3)2•HCl

NCH3

BnCH3

Br

A

B

• Triethyl phosphite is used to reduce the hydroperoxide in situ.

• Longer reaction times seem to decrease ee. Due to catalyst

decomposition?

• Other ammonium salts, derived from ephedrine (A) or cyclohexane

diamine (B) give <10% ee.

38 Oxygenation-1 3/14/01 9:54 PM

Conclusions...........

• Quaternary ammonium salts are capable of catalyzing a broad range of asymmetric reactions with moderate to high selectivities.

• N-alkylated chincona alkaloids stand out as the most effective natural product derived catalysts.

• While chincona alkaloids are difficult to tune structurally, a new class of even more effective axially chiral ligands are emerging.

• Generally, these reactions are not well understood. Hydrogen bonding may or may not be operative.

• The reactions themselves are generally user friendly, and do not require strictly anhydrous conditions.

• A broad variety of chiral starting material can be made using this methodology, with important industrial applications.

39 Conclusions 3/15/01 12:01 PM

Documents

Quaternary Ammonium Salts as Chiral