synthesis of optically active amino alcohols changyou yuan department of chemistry michigan state...

Synthesis of Optically Active Amino Alcohols

Changyou Yuan

Department of Chemistry

Michigan State University

-A survey of major developments after the year 2000

Ph

O

HOOC

NH2

NH OH

O

O

Ph

O

NMe

O

O

OH

Bestain Hapalosin

HN

NH

O

O OH

O

N

S

Ph

Ph

Saquinavir 1

HN O

O

NB O

Ph

Ph

Me

23

Important Free or Functionalized Amino Alcohols

Strategies Available for the Synthesis of Optically Active Amino Alcohols

R1

R2

OH

NH2

R1OH

NH2

O

Reduction of amino acids

R1R2

OH

OH

Substitution of 1,2 diols

R1

R2

O

NX2

Reduction reactions

O

R1 NX

R2+

Cross Coupling reactions

R1R2

Aminohydroxylations

N

R1

+R2

R3R-

or

R

Addition reactionR1

R2

Open epoxides, aziridines

X

R1R2

OH

NH2

Resolutions

OutlinePart 1: Addition reactions

Addition of Carbanions to IminesRadical Addition to Oximes, Hydrazones

Part 2: Reduction reactionsAsymmetric Hydrogenations of α-N-substituted β- Keto Esters

Part 3: Coupling ReactionsCross-Coupling of Ferrocenylideneamine and FerrocenecarboxaldehydesCross-Coupling of Benzylideneamines with AldehydesProline-Catalyzed Assemble of Aldehydes, Ketones, and Amine or Azodicarboxylic Acid Esters

Part 4: Kinetic Resolution of Racemic Epoxides

Conclusion

Lithiation of O-benzyl Carbamates–imine Addition

S.Arrasate, E.Lete, N.Sotomayor. Tetrahedron: Asymmetry, 2002, 13, 311–316.

O O

NiPr

MeO

MeO

O

NiPr

MeO

MeO

LiO

NN

N

Ph H

OMePh

OCONiPr2

NHPMP

MeO

MeO

PhOCONiPr2

NHPMP

MeO

MeO

4 (1RS, 2RS)

5 (1RS, 2SR)

s-BuLi, -78oC

TMEDA

72hr

64 % yield syn : anti > 95 : 5OMe

Li N

O

O

NiPr2

Li N

O

O

NiPr2

OMe

syn anti

A B

Asymmetric Lithiation of O-benzylCarbamates–imine Addition

Ph

MeO2C H

O NiPr2

O CO2Me

NiPr2

OH

Ph O

+

91% yield 57 : 43 ( 14% ee)

S R


1. CO2

2. CH2N2

Asymmetric Lithiation of O-benzylCarbamates–imine Addition

R1 R2 Temp Yield(%) D.R e.e. (%)

OCH3

OCH3

OCH3

H

-78oC 6h

-78oC 6h

84

67

>95:5

>95:5

56 (96)

76 (91)

MeO

Ph

OCONiPr2

NHPMP

MeO PhOCH2ONiPr2

NHPMP

MeO

MeO

4 (1R, 2R) major 4 (1S, 2S) minor


Addition of -Sulfinyl Carbanions to N-p-Tolylsulfinylketimines

Sulfoxide T (oC) Yield (%) De (%)

(S) – 1

(R) – 1

(S) – 1

(R) - 1

-78

-78

0

0

82

85

67

65

60

80

>98

>98

J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, 4454-4463. J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, 4513-4516.

Me Ph

N

SO

Tol

Me

S

Tol

O

(S)-1

Me

S

Tol

O

(R)-1

LDA

LDA

Ph

S

Tol

OMeTolSOHN

5A 5B

6A 6B

Ph

S

Tol

OMeTolSOHN

Ph

S

Tol

OMeTolSOHN

Ph

S

Tol

OMeTolSOHN

Major

Major

Addition of -Sulfinyl Carbanions to N-p-Tolylsulfinylketimines

Sulfoxide T (oC) Yield (%) de at C(2) (%)

(S) – 2

(R) – 2

(S) – 2

(R) - 2

-78

-78

0

0

77

75

73

70

70

20

80

54


C-1 C-2

(S)-sulfinyl ketimine (S)-(2)

(R)-(2)

R

S

S

S

Me Ph

N

SO

Ar

EtS

Tol

O

EtS

Tol

O

PhS

Tol

OMeTolSOHN

Me7A

8A

PhS

Tol

O

Me

TolSOHN Me

PhS

Tol

OMeTolSOHN

MePh

STol

OMeTolSOHN

Me

1 S

S S

S2 S R

R S

S

(S)-2

(R)-2

LDA

LDA

7B

8B

Major

Major


Addition of -Sulfinyl Carbanions to N-p-Tolylsulfinylketimines-Stereocontrol

Ph

STol

OMeTolSOHN

5A

6A

Ph

STol

OMeTolSOHN

Major

Major

S

S

Me Ph

N

SO

Tol

MeS

Tol

O

(S)-1

MeS

Tol

O

(R)-1

LDA

LDAor

S


Addition of -Sulfinyl Carbanions to N-p-Tolylsulfinylketimines - stereocontrol

Me Ph

N

SO

Ar EtS

Tol

O

A isomers

PhS

Tol

OMeArSOHN

Me

PhS

Tol

OMeArSOHN

Me

RS(R)-2

LDA

B isomers

Major minor

- 78oC 20 % de

0oC 54 % de

J.L.G.Ruano, J.Aleman, M.Prado, I. Fernandez. J. Org. Chem. 2004, 69, 4454-4463. J.L.G.Ruano, J.Aleman. Org. Lett. 2003, 5, 4513-4516. M.Crucianelli, P.Bravo, A.Arnone, E.Corradi, S.V.Meille, M.Zanda. J. Org. Chem. 2000, 65, 2965-2971.

Addition of -Sulfinyl Carbanions to N-p-Tolylsulfinylketimines – Demasking Steps

PhS

Tol

OMeTolSOHN TFA, 0oC

MeOH PhS

Tol

OMeH2N Boc2O, NEt3

CH3CN PhS

Tol

OMeBocHN

TFA, sym-collidine 1) NaBH4, KCO32) HCl, THF

Ph

MeClH3N

Ph

MeN

OOCCF3

BocS Tol

OH

1 2 3

4 5

Radical Addition of Hydroxymethyl and Vinyl Groups to C=N Bonds

G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, 863-875. G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2, 4237-4240.

R1R2

NH2 NX

R1R2

Stereocontrol

NX

SPhSiO

R

O Si

R

NHX

PhS

R

OSi Br

NX

Bu3Sn

OSi

NX

R

NX

R

OSi

O

NX

R

Si SPh

NHX

R

OH OH

NHX

R

OH

Atom Abstraction/Cyclization

Addition/Cyclization

Hydroxymethyl Addition to Oxime Ethers


NOBn

R1

OSi Br

Bu3SnH

O Si

R1

NHOBn

AIBN

ONOBnR1

OH

O

N

OO

OBnR1

OH O

R1

OH

O

NOBn

R1=Me: anti/syn=9:1 52%

1. ClCO2Me

2. KF, KHCO3, H2O2 THF, MeOH

1 2

cis-3 4 trans-3

anti=cis-3 + 4syn=trans-6

R1=Ph: no synthetically useful yields

Hydroxymethyl Addition to Hydrazones

R Me tBu iPr Ph

Anti-7:syn-7

Yield (%)

79:21

76

85:15

68

96:4

80

>98:2

57


NNPh2

R

OSi Br

Bu3SnH

O Si

R

NHNPh2

AIBN, PhH

KF, KHCO3, H2O2 THF, MeOH

5 6

R

OHOH

NHNPh2

anti-7

R

OHOH

NHNPh2

syn-7

Tandem Thiyl Addition-Cyclization: Vinyl Additionto Hydrazones

R Yield(%) Ratio (anti/syn)

Me 77 90:10

tBu 67 94:6

iPr 61 98:2

Ph 49 >98:2

G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, 863-875. G.K.Friestad, T.Jiang, G.M.Fioroni. Tetrahedron: Asymmetry, 2003, 14 , 2853–2856.

NNPh2

R

OSi

1. PhSH, AIBN, cyclohexane, refulx 2. KF, MeOH R

OH

NHNPh2

8 10

O Si

R

NHNPh2

9

SPh

Diastereocontrol in Radical Addition – CyclizationBeckwith-Houk Model

R

OHOH

NHNPh2

R

OH

NHNPh2

7 8

RA Value

(kcal/mol)

dr of 7 dr of 8

Me 1.6 79:21 90:10tBu 1.8 85:15 94:6iPr 2.2 96:4 98:2

Ph 2.9 >98:2 >98:2

G.K.Friestad, S.E.Massari. Org. Lett. 2000, 2, 4237-4240. G.K.Friestad, S.E.Massari. J. Org. Chem. 2004, 69, 863-875. G.K.Friestad, T.Jiang, G.M.Fioroni. Tetrahedron: Asymmetry, 2003, 14 , 2853–2856.

R

OHOH

NHNPh2

R

OH

NHNPh2

7 8

Comparison of the Addition Reactions

Me Ph

NS

O

Ar

S EtS

Tol

O

PhS

Tol

OMeTolSOHN

Me

SS

(R)-2

LDA

NNPh2

R

OSi

R

RR'

OH

NHNPh2

1 2

1: R = CH2Br; CH=CH22: R = CH2OH, CH=CH2

StereocontrolDe/ee (%)

Yield(%)

Anti

or syn

Chiral amine (additive)>95:5/

56-7667-84 syn

Sulfinylketimine and sulfinyl carbanions

60:40~

90:10 /-70-77 both

Substrate control and

Beckwith-Houk model

80:20~

>98:2/-50-80 anti

O O

NiPr

MeO

MeO

s-BuLi, -78oC

(-)-sparteinPh

OCONiPr2

NHPMP

MeO

MeO4 (1R, 2R)

NPh

H

OMe






Conclusion

C.Mordant, P.Dünkelmann, V.R,Vidal, J.P.Genet. Eur. J. Org. Chem. 2004, 3017-3026.

Asymmetric Hydrogenations of α-N-substituted β-keto esters - Preparation the Syn – Amino Alcohols

R OEt

O O

NHCOPh

R OEt

OH O

2 mol% [Ru(S)-SYNPHOSBr2]

H2 (120 bar), 80oC, 4days

CH2Cl2

3 (2R, 3S)-5

NHCOPh

O

O

O

O

PPh2

PPh2

(S)-SYNPHOS®

R Yield (%) de (%) ee (%)

C3H7 81 71 75

BnO-C4H8 53 93 >99

C5H11 77 98 99

C15H31

iPr

82

92

98

98

97

97

Asymmetric Hydrogenations of α-N-substituted β-keto esters - Preparation the Anti – Amino Alcohols

Substrate SYNPHOS configuration Yield (%) de anti (%) ee (%)

R = C3H7

R = BnO-C4H8

R = C5H11

R = C15H31

R = iPr

S

R

S

R

S

R

SR

S

R

90

90

94

93

85

90

83

85

90

96

86

86

92

93

93

93

96

98

99

97

92 (2S, 3S)

93 (2R, 3R)

92 (2S, 3S)

93 (2R, 3R)

91 (2S, 3S)

91 (2R, 3R)

96 (2S, 3S)

96 (2R, 3R)

97 (2S, 3S)

96 (2R, 3R)C.Mordant, P.Dünkelmann, V.R,Vidal, J.P.Genet. Eur. J. Org. Chem. 2004, 30173026.

R OEt

O O

NH2HCl

R OEt

OH O

NHCOPh

1. 2 mol% [Ru(S)-SYNPHOSBr2]

H2 (12 bar), 50oC, 24hr

CH2Cl2 + R'OH

2. (PhCO)2O, NEt3, CH2Cl24 (2S, 3S)-5






Conclusion

Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, 9227-9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838..

Cross-Coupling of N-TosylFerrocenylideneamine and Ferrocenecarboxaldehydes

Imine 2 ( X ) 3 yield(%) 4 yield(%) 5 yield(%)

Me

Bn

Ph

NMe2

NHSO2Ph

SO2Ph

Ts

Ms

0

0

0

0

0

92

88

94

95

96

96

98

92

Trace

Trace

trace

0

0

95

0

0

0

0

0

Cross-Coupling of Planar Chiral N-TosylFerrocenylideneamine and Ferrocenecarboxaldehydes

aldehyde 7 (% ee) imine 8 9 yield (%) %ee 9

R1=Me (95)

R1=Me

R1=I (95)

R1=Br (97)

R1= H

R1= HR1= H

R2=MeR2=I R2=IR2=Br R2=MeR2=IR2=Br

92

93

90

93

91

96

95

95

95

95

97

92

94

97

Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, 9227-9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838..

Reaction Mechanism of Cross-Coupling withN-Tosyl Ferrocenylideneamines

Y.Tanaka, N.Taniguchi, T.Kimura, M.Uemura. J. Org. Chem. 2002, 67, 9227-9237. Y.Tanaka, N.Taniguchi,M.Uemura. Org. Lett. 2002, 4, 835-838.

Reaction Mechanism of Cross-Coupling withN-Tosyl Ferrocenylideneamines

CpFe

CHO

R

7

R

R


CpFe

CHO

ent-7

R

92 % enantiopure

97 % enantiopure

Cross-Coupling of Benzylideneamines with Aldehydes

NX

R

CHO

R

CHOCr(CO3)

+ or

1. SmI2, THF, 0oC to rt

2. Ac2O, pyr3. hv-air ( for chromium complex)

R

NHX

OAc

29 11 14 30

imine aldehyde yield (%) Syn/anti

X=Ms

X=Ts

11 R=H, Me, OMe

14 R=H, Me, OMe

11 R=H, Me, OMe, Cl

14 R=H, Me, OMe, Cl

70-93

63-89

52-81

33-73

50/50 – 54/56

60/40 – 67/33

70/30 – 87/13

95/5 – 97/3


Cross-Coupling of Benzylideneamines with Aldehydes


NTs

Me

CHO

+


2. Ac2O, pyr

3. hv-air ( for chromium complex)

Me

NHTs

OAc

29b 17b 34Cr(CO3)

60%

>99% ee

NTs

Me

CHO

+


2. Ac2O, pyr

3. hv-air ( for chromium complex)

Me

NHTs

OAc

29b ent-17b ent-34Cr(CO3)

60%

>99% ee

Proline-Catalyzed Direct Asymmetric Mannich Reaction

B.List, P.Pojarliev, W.T.Biller, H.J. Martin. J. Am. Chem. Soc. 2002, 124,827-833.

Proline-Catalyzed Assemble of Aldehydes, Ketones, and Azodicarboxylic Acid Asters

N.S. Chowdari, D. B. Ramachary, C.F.Barbas. Org. Lett., 2003, 5 ,1685-1688.

R

O

R

O N

NCbz

Cbz

S-Proline (20 mol%)

CH3CN (0.33M)r.t. 96 h

++ N

O OH

R

N

O OHHNCbz

Cbz

HNCbz

Cbz

R

+


Yield(%)

Anti

or syn

Ferrocenylideneamines

Ferrocenecarboxaldehydes

>95/

92-9790-95 anti

planar chiral benzaldehyde chromium

complexes

90/

>9933-81 syn

Proline20-95/

60->9960-90 syn

Comparison of the Cross-Coupling Reactions

NXR

CHO

R

CHO

Cr(CO3)

R

NHX

OAc+

or

1. SmI2, THF, 0oC to rt2. Ac2O, pyr3. hv-air

RH R' R'

O O O

OH

NHR''ArNH2

or

N

N

Cbz

Cbz

R = H, OH

+ +Proline






Conclusion

Aminolytic Kinetic Resolution with Amines

G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, 2173-2176.

R1 R2 T (oC) t (h) Yield (%) Ee of 4 (%) Ee of 2 (%)

H

H

H

H

OMe

OMeOMe

H

H

OMe

OMe

H

HH

rt

-10

rt

0

rt

-10-10

18

36

18

24

12

2424

91

47

89

60

98

9393

86

>99

88

93

83

9494

30

80

81

PhPh

O

NH2

R1R2+

(+/-) 2

(R,R)-1 (5 mol%)

CH2Cl2

3

2 equiv 1 equiv

PhPh

NH

OH4

anti/syn > 99/1

R1R2

Aminolytic Kinetic Resolution with Amines

G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, 2173-2176.

G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, 3973-3975..

Aminolytic Kinetic Resolution with carbamates

(S,S)-catalyst (1.5 mol%)

Additive(3 mol%)

20h, rt / in air

R Cat. (M) Additive Solvent Conv (%) ee(%)

Boc

Boc

Boc

Boc

BocBoc

Cbz

COOEt

Fmoc

Cr(Cl)

Co(OAc)

Co

Co

CoCo

Co

Co

Co

None

None

AcOH

p-nitrobenzoic acid

p-nitrobenzoic acidp-nitrobenzoic acid

p-nitrobenzoic acid

p-nitrobenzoic acid

p-nitrobenzoic acid

CH2Cl2

CH2Cl2

CH2Cl2

CH2Cl2

TBMETBME

TBME

TBME

TBME

0

45

65

80

>95>95

95

>95

75

96

96

>99

9999

99.5

99

99.5

Aminolytic Kinetic Resolution with carbamates

G.Bartoli, M.Bosco, A.Carlone, M.Locatelli, M.Massaccesi, P.Melchiorre, L.Sambri. Org. Lett. 2004, 6, 3973-3975..

R Time (h) Yield (%) ee(%)

CH3,, 6a

(CH2)3CH3, 6b

(CH2)4CH=CH2, 6c

c-C6H11, 6d

CH2O(1-naphthyl), 6e

CH2Cl, 6f

C6H5, 6g

p-BrC6H4, 6h

o-NO2C6H4, 6i

24

24

24

24

24

24

36

48

48

99

99

99

84

95

87

90

76

62

99.3

99.2

99.7

99.9

99.5

99.9

99.9

99.8

99.8


Yield(%)

Anti

or syn

Chiral Cr(Salen)>99/

74-99.544-98 anti

Chiral Co(Salen)-/

>9962-99 -

Comparison of the Resulution Methods

NH2Boc RO

RNHBoc

OH

+

(+/-)2 equiv

chiral catalyst

1 equiv

R1 R2O+

(+/-)

2 equiv

PhPh

NH

OH

chiral catalyst

1 equiv

ArNH2

Conclusion

• Optically active amino alcohols have been prepared through: Addition of carbanions, free radicals to C=N.

Asymmetric hydrogenations of α-N-substituted β- keto esters

Coupling of imines and aldehyes

Kinetic resolution of racemic epoxides

• Much remains to be done:Scope of substrates

Relative and absolute stereochemisry

Acknowledgement • Dr. Hollingsworth

• Dr. Wulff

• Dr. Borhan

• Hollingsworth GroupXuezheng Carol

Chang Xiaoyu

Li Kun

Zhen Trevor

Joel Felica

Proline-Catalyzed Direct Asymmetric Three Component Mannich Reaction

B.List, P.Pojarliev, W.T.Biller, H.J. Martin. J. Am. Chem. Soc. 2002, 124,827-833.

Proline-Catalyzed assemble of aldehydes, ketones, and azodicarboxylic acid esters

N.S. Chowdari, D. B. Ramachary, C.F.Barbas. Org. Lett., 2003, 5 ,1685-1688.

C.Mordant, P.Dünkelmann, V.R,Vidal, J.P.Genet. Eur. J. Org. Chem. 2004, 30173026.

Asymmetric hydrogenations of α-N-substitutedβ-keto esters


Addition of -Sulfinyl Carbanions to N-p-Tolylsulfinylketimines - stereocontrol

synthesis of optically active amino alcohols changyou yuan department of chemistry michigan state...

Documents

hydroxymethyl addition

sulfinyl carbanions

iminesradical addition

n bondsg

ssulfinyl ketimines

azodicarboxylic acid

keto esterspart

vinyl groups