Asymmetric Synthesis Using Chiral Sulfinyl Groups 958... · Asymmetric Synthesis Using Chiral Sulfinyl Groups Yiqian Lian Department of Chemistry Michigan State University

Asymmetric Synthesis Using Chiral Sulfinyl Groups

Yiqian Lian

Department of Chemistry

Michigan State University

OUTLINE

I. Introduction

II. Some Examples of Chiral Sulfoxides in Asymmetric Reactions

III. Asymmetric Heck Reaction Using Chiral Sulfoxides

IV. Asymmetric Synthesis Using Chiral Sulfinimines

a) α-Branched and α,α-Dibranched Amines

b) α- and β-Amino Acids

c) Aziridines

d) α- and β-Aminophosphonic Acids

V. Application in Solid-Phase Synthesis

VI. Conclusions

Methods of Asymmetric Synthesis

1. Substrate-Controlled

2. Auxiliary-Controlled O

N OMe

O

Me PhLiN(iPr)2

PhCH2Br

O

N OMe

O

Me PhPh

3. Reagent-Controlled

4. Catalyst-Controlled

OB OH

Chiral L*

R1

R2

R1

R2HO

OHOsO4, NMO

OMe

H EtMgBrMe

H

OHEt

General Scheme for Auxiliary-Controlled Methods

A chiral auxiliary can be on either nucleophiles or electrophiles.

SA* S A* R P* A* - A* P*

recycle A*

bS

c

aSulfur-containing compounds

Sulfoxides

Sulfinimines

Distorted tetrahedron • Chiral • Configurationally stable

RS

N

R2

R1

O

RS

R1

O

Sulfinyl compounds bS

c

O

Preparation of Chiral Sulfoxides

1. Asymmetric Oxidation

2. Asymmetric Synthesis (Nucleophilic Substitution on Chiral Sulfur)

RS

R'R

SR'

O[O]

Ti(OiPr)4 / (+)-DET / tBuOOH

Ti(OiPr)4 / (+)-DET / PhC(CH3)2OOH

Ti(OiPr)4 / (+)-BINOL / tBuOOH

Cl

Cl

ON SO2Ph

R1S

OR*

OR2MgX

R1S

R2

O

HOR*OH =

O

O

O

O

O

HOorR1

SCl

OR*OH

Asymmetric Diels-Alder Reaction Using Chiral Sulfoxides

Takahashi, T.; Kotsubo, H.; oizumi, T. Tetrahedron Asymmetry 1991, 2, 1035-1039.

Arai, Y.; Hayashi, Y.; Yamanoto, M.; Takayema, H.; Koizumi, T. J. Chem. Soc. Perkin Trans. 1 1988, 3133-3141.

Alonso, Ines.; Carrentero, J. C.; Ruano, J. L. G. J. Org. Chem. 1994, 59, 1499-1508

O

SR'OO

Ar

X

R

+O

SR'OO

Ar

X = CH2, R = H;X = (CH2)2, R = H;X = O, R = MeO.

R' = Me, MenthylAr = 4-MeC6H4, 2-Py

Et2AlClX R

COOR'

S(O)Ar

86-99% de70-98% yield

Asymmetric Aldol Reaction Using Chiral Sulfoxides

Solladie, G.; Bauder, C.; Arce-Dubois, E.; Pasturel-Jacope, Y. Tetrahedron Lett. 2001, 42, 2923-2925.

Solladie, G.; Hamdouchi, C. Synthesis 1991, 979-982.

SOtBu

O Op-Tol 1) tBuMgBr, THF

2) RCHO OtBu

OH O

R

S

p-TolO

Al/Hg

OtBu

OH O

R

85-95% ee73-85% yield

R = alkyl, aryl, alkynyl

SNMe2

O Op-Tol 1) tBuMgBr, THF

2) RCHO NMe2

OH O

R

S

p-TolO

Al/Hg

NMe2

OH O

R

86-99% ee60-70% yield

R = Me, iPr, iBu, tBu

R

O

HH

S

O

p-Tol

OMg

Br

R'

Asymmetric Michael Additions Using Chiral Sulfoxides

Posner, G. H. Acc. Chem Res. 1987, 20, 72-78.

Iwata, C.; Fujita, M.; Hattori, K.; Uchide, S.; Imanishi, T. Tetrahedron Lett. 1985, 26, 2221-2224.

O

S

Op-Tol

n

n = 1 or 2R = Me, Et, tBu, CH2=CH, Ph, Ar

1) ZnBr2

2) RMgX3) Al/Hg

O

nR

80-98% ee67-90% yield

O

S

Op-Tol

n

M

** Carreno, M. C. Chem. Rev. 1995, 95, 1717-1760.

Catalytic Cycle of the Heck Reaction

H+ RX

R[Pd]

PdL2

R = aryl, alkenyl

R-X

RPdL2X

C C

H

XL2Pd R

HPdL2X

Et3N

Et3NHX

Pd(OAc)2 + 2 L + Pd(L)2 + + HOAc

HR

H OAc

Heck Reaction of α,β-Unsaturated Sulfoxides with Iodobenzene

Buezo, N. D.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 1998, 120, 7129-7130.

Buezo, N. D.; Rosa, J. C.; Priego, J.; Alonso, I.; Carretero, J. C. Chem. Eur. J. 2001, 7, 3890-3900.

Entry X R A:B ratio Yield, %

1 O Ph 77:23 68

2 O 2,4-Me2C6H3 78:22 80

3 O o-(MeO)C6H4 75:25 47

4 O o-(Me2N)C6H4 6:94 80

5 O t-Bu -a -

6 CH2 p-Tol 60:40 62

7 CH2 t-Bu -a -

8 CH2 o-(Me2N)C6H4 8:92 76

a. Complex mixture of products.

X

PhI[Pd(OAc)2]dppp, Ag2CO3DMF

X

S

O

+Ph

R

X

S

O

Ph

R

A B

S

O

R

Mechanistic Hypothesis for the stereoselectivity of the Heck Reaction



H

X

ArI[Pd(OAc)2]dppp, Ag2CO3 X

S

O

+Ar X

S

O

Ar

A B

NMe2 NMe2

Ar = C6H5

p-(MeO)C6H4

p-(O2N)C6H4

p-(MeO2C)C6H4

Steric controlX

S O

Me2N

ArPd+L2

insertionX

S O

Me2N

Pd+L2 HAr

β-H eliminationA

B

(Major)

Pd-N chelation control

XS

O

Pd NAr

LMe2

insertionX S

O

NPd+Ar L2

Me2

β-H elimination

S

NMe2O

+

Second Heck Reaction of α,β-Unsaturated Sulfoxides with Iodoarenes



Double Heck Reaction of α,β-Unsaturated Sulfoxides with Iodobenzene

Ar'I[Pd(OAc)2]dppp, Ag2CO3DMF

X

S

Ar

O

Me2N

X

S

Ar

O

Me2N

Ar'

Ar' = C6H5

p-(MeO)C6H4

p-(NO2)C6H4

One isomerYield: 70-84%

X

SO

Me2NPhI (excess)

[Pd(OAc)2]dppp, Ag2CO3DMF X

SO

Me2N

Ph

Ph X = O, 55% = CH2, 81%

Enantioselective Synthesis of Aryl-Substituted Five-Membered Ring


Ar = o-(Me2N)C6H4

SAr

O

PhIPd(OAc)2dppp, Ag2CO3

O

S

PhO

S

O

ArZn cat.

NH4Cl, THF O Ph

77%

PhI, Pd(OAc)2dppp, Ag2CO3

O Ph

83%

Raney Ni

EtOH O Ph

PhPh

ArO

SAr

O

PhIPd(OAc)2

dppp, Ag2CO3

SAr

O

Ph

1) mCPBA

2) Pd(acac)2, iPrMgBr Ph

Double Heckreaction

Pd(OAc)2dppp, Ag2CO3

SAr

O

Ph

76%

81%

Pd(acac)2, iPrMgBr

Ph

Ph

94% ee77% yield

PhI (excess)

Ph

90% ee55% yield

96% ee90% yield

96% ee51% yield

Asymmetric Intramolecular Heck Reaction Using α,β-Unsaturated Sulfoxides

Buezo, N. D.; Mancheno, O. G.; Carretero, J. C. Org. Lett. 2000, 2, 1451-1454

MeS

O

Pd(OAc)2

dppf, Ag2CO3

Me2N

1) LDA, THF2) ClPO(OEt)2

1) LDA, THF2) MeI

SO

PEtOEtO

O

Me

Ar

1) LDA

2)H

I EE O

E = CO2Et

Ar = o-(Me2N)C6H4

I

S

MeE

E

OAr

E

E

H

S

O

NMe2

72% (4 steps)

> 95% ee, 45% (3 steps)

1) mCPBA2) Zn, AcOH

E

E

H

SO2Ar

1) n-Bu3SnLi, THF2) SiO2, CHCl3

OsO4, Me3NO

E

E

H

S

O

NMe2

OH

OH

1) Ra Ni, EtOH2) NaIO4, CH2Cl2/H2O

81% 74%

E

E

E

EO

Et

85% yield> 95% ee

> 95% ee

77% yield> 95% ee

SO

PEtOEtO

O

Ar

Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; Jiang, Y.-Z.; Mi, A.-Q.; Jong, T.-T. J. Org. Chem. 1994, 59, 914-921. Davis, F. A,; Reddy, R. T.; Han, W.; Reddy, R. E. Pure Appl. Chem. 1993, 65, 633-640. Davis, F. A,; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992, 57, 6387-6387.

Preparation of Enantiomerically Pure Sulfinimines

1. Asymmetric Oxidation of Sulfenimines

OR1

SHNCS, NH3

CH2Cl2, -33 oC OR1

SNH2

PhCHO

CH2Cl2, -33 oC OR1

S

N

O

S

R1

O

H

O

O

C6H4Cl

OR1

S O

Ph

N

Ph

N

Ph

mCPBA

CH2Cl2, -78 oC

A)

R1 = (CH3)3CCH2, PhCH2, Hup to 98% de95-97% yield

ArS

N Ar'

R

+

Cl

Cl

NO

SO2Ph CCl4Ar

SN Ar'

RO

87-90% ee 89-96% yield (cryst. pure)

B)

Ar = C6H5, p-CH3C6H4Ar' = C6H5, o-CH3C6H4R = H, CH3

Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913-9914.

C)

Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268-269.

SS

OH

tBu

tBu

N OHH

tBu

VO(acac)2, H2O2, rt

SS

O

LiNH2

NH3, THF, -78 oCS

NH2

O

R1CHO

MgSO4, CH2Cl2

SN

O

R1 = Ph, 91 %R1 = i-Pr, 90 %R1 = Et, 96 %

H

R1

SN

O R1

R2

2.0 eq. Ti(OEt)4

O

R1

R2 THF, 60-70 oC

R1 = Me, R2 = i-Pr, 84%R1 = Me, R2 = Ph, 87%R1 = Bu, R2 = i-Pr, 66 %R1 = Bu, R2 = Ph, 77 %one isomer

Preparation of Enantiomerically Pure Sulfinimines 2. Asymmetric Iminolysis of Sulfinates

Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4-6. Davis, F. A.; �Reddy, R. E.; Szewczyk, J. M.; Portonovo, P. S. Tetrahedron Lett. 1993, 34, 6229-6232.

A)

B)

C)

Garcia Ruano, J. L.; Fernandez, I.; Prado Catalina, M. D.; Cruz, A. A. Tetrahedron: Asymmetry 1996, 7, 3407-3414.

p-MeC6H4S

O

O

p-MeC6H4S

N

O R

Ph+ N-M+

R

Ph

PhCN

RLi or RMgBr

p-MeC6H4S

O

OLiHMDS

THF p-MeC6H4S

N

O

TMS

TMS

R'CHO

p-MeC6H4S

N

O H

R'

> 95% ee57-90% yield

R = Me, 56%R = nBu, 70%

O

O

O

O

O

OS

O

tBu

1) LiHMDS

2) PhCHO/CsF BuS

N Ph

HO

t

one isomer70% yield

R = alkyl, aryl

Asymmetric Synthesis of α-Branched Amines - Method I

Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; Jiang, Y.-Z.; Mi, A.-Q.; Jong, T.-T. J. Org. Chem. 1994, 59, 914-921.

OR1

SHNCS, NH3

CH2Cl2, -33 oCOR1

SNH2PhCHO

CH2Cl2, -33 oC OR1

S

N

mCPBA CH2Cl2-78 oC

O

S

R1

O

H

O

O

C6H4Cl

OR1

SR2MgBr

O

OR1

S

HN

Ph

O

R2

H

1) Zn, TiCl42) HCl, MeOH

H2N

PhR2

H

Ph

N

Ph

N

Ph

R1 = (CH3)3CCH2, PhCH2, HR2 = allyl, alkyl

Reactions of Sulfinimines and Grignard Reagents

Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; Jiang, Y.-Z.; Mi, A.-Q.; Jong, T.-T. J. Org. Chem. 1994, 59, 914-921.

OR1

SR2MX

O

OR1

S

HN

Ph

O

R2

H

2) HCl, MeOH H2N

PhR2

H

N

Ph

1) Zn, TiCl4

Sulfinamide AmineEntry R1 R2MX

Yield, % % de Yield, % % ee

1 (CH3)3CCH2 CH2=CHCH2MgBr 96 > 98 80 99

2 (CH3)3CCH2 CH3MgI 96 > 97 56 > 99

3 (CH3)3CCH2 t-C4H9MgBr 60 > 98 80 > 98

4 PhCH2 CH2=CHCH2MgBr 84 > 98 80 > 98

5 PhCH2 CH3MgI 84 > 98 - -

6 PhCH2 t-C4H9MgBr 50 > 98 - -

Asymmetric Synthesis of α-Branched Amines -- Method II

Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913-9914.

SN

O H

R1 CH2Cl2

R2MgBr SNH

O R2

R1HCl

MeOH

R2

R1Cl H3N+-

Sulfinamide AmineEntry R1 R2

Yield, % dr Yield, % Config.

1 Et Me 96 93:7 97 S

2 Et i-Pr 97 92:8 92 R

3 Et Ph 100 96:4 90 R

4 i-Pr Me 99 98:2 97 S

5 i-Pr Et 100 97:3 93 S

6 i-Pr Ph 98 89:11 91 R

7 Ph Me 96 97:3 88 S

8 Ph Et 98 92:8 94 S

NM

S

H

R1O R2

Asymmetric Synthesis of α-Branched Amines - Method III

Annuniziata, R.; Cinqini, M.; Cozzi, F. J. Chem. Soc., Perkin Trans. 1 1982, 339-343. Hua, D. H.; Miao, S. W.; �Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4-6.

p-MeC6H4S

N

O R

Ph THF, -30 or 25 oC

[H]

R = Me, Et, n-Bu

p-MeC6H4S

NH

O R

PhH

DIBAL or LiAlH2(OMe)2: 88-92% de, 90-96% yield.

LiAlH4 and NaBH4 gave lower optical yield.

Optically pure amine then easily obtained from column chromatography with high yield.

p-MeC6H4S

N

O R

Ph

MH

HClMeOH

H2N

R

PhH

SN

O R1

R2

R3Li, Me3Al

TolueneS

NH

O R1

R2R3


Entry R1 R2 R3 Me3Al (eq.) Config. Yield, % dr

1 Me i-Pr Ph 0 R 65 94:6

2 Me i-Pr Ph 1.1 R 93 97:3

3 Me Ph Bu 0 S 26 99:1

4 Me Ph Bu 1.1 S 86 98:2

5 Me Bu Ph 0 R 67 63:37

6 Me Bu Ph 1.1 R 93 89:11

7 Bu Ph Me 1.1 R Quant. 99:1

8 Me i-Pr Bu 1.1 S 61 99:1

9 Bu i-Pr Me 0 R 54 82:18

10 Bu i-Pr Me 1.1 R 82 91:9

Asymmetric Synthesis of α,α-Dibranched Amines

Proposed Model Consistent with Observed Stereoselection


SNH

O Me

PhBu

MeOH

BzCl

Et3NHCl

Cl H3N

Me

Ph

Bu- +

NH

Me

Ph

BuPh

O

Quant. yield Quant. yield

NLiAl

S

RS

RL SNH

O RS

RL

R

O R

** First general method for the asymmetric synthesis of chiral acyclic α,α-dibranched amines.

Asymmetric Synthesis of α-Amino Acids - Method I

Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y. J. Org. Chem. 1996, 61, 440-441.

p-MeC6H4S

N

O H

R

R = Ph, tBui-PrOH

84-90% yield82-86% de (cryst. > 96% de)

p-MeC6H4S

NH

O H

RCN

6M HCl

H2N

H

RCO2H

Al

OEt

i-PrO

CS N

N

R

p-MeC6H4

Et2AlCN

70-86% yield> 95% ee

Davis, F. A.; Lee, S.; Zhang, H.; Fanelle, D. L. J. Org. Chem. 2000, 65, 8704-8708.

Asymmetric Synthesis of α-Amino Acids - Method II

Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J. Tetrahedron: Asymmetry 1995, 6, 349-352.

p-MeC6H4S

N

O Me

C(OEt)3

9-BBNTHF, 0 oC p-MeC6H4

SNH

O Me

C(OEt)3H

95 %

CH2=CHCH2MgBrEt2O, 0 oC

p-MeC6H4S

NH

O Me

C(OEt)3

1) TFA, MeCN, H2O

2) LiOH

H2N

Me

CO2H

p-MeC6H4S

NH

O Me

CO2EtH

H2N

Me

CO2EtH

95% ~100%

91%

Silica gel overnight

TFA, EtOH

91%

Asymmetric Synthesis of β-Amino Acids - Method I

Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4-6.

p-MeC6H4S

N

O R

Ph Et2O, 0 oC p-MeC6H4S

NH

O R

Ph

MgBr

1) TFA, MeOH

2) Ac2O, Et3N NH

R

PhCH3

O1) O3, -78 oC2) AgNO3, KOH3) HCl

H2N

R

PhCO2H

50-52% (5 steps)

R = Me, 98%, one diastereomerR = n-Bu, 84%, de = 82%

Mg

N Ph

RBr

S

O

p-Tol

Asymmetric Synthesis of β-Amino Acids - Method II

Davis, F. A,; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992, 57, 6387-6389.

p-MeC6H4S

N

O Me

Ph p-MeC6H4S

NH

O Me

PhCO2Me

TFA, MeOH

H2N

Me

PhCO2Me

>97% de 84% yield

LDA, THF

CH3CO2Me

85%

Asymmetric Synthesis of β-Amino Acids - Method III

Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12-13.

SN

O R2

OMe

O

R1

Ti(OiPr)3

-78 oC O NM

SO

R1

R2

MeO

SNH

O

R2CO2Me

R1

Entry R1 R2 Yield, % dr

1 Me H 94 99:1

2 i-Pr H 85 98:2

3 i-Bu H 80 98:2

4 Ph H 90 98:2

5 3-Pyr. H 70 95:5

6 i-Pr Me 85 99:1

7 Ph Me 89 98:2

Asymmetric Synthesis of Aziridine-2-Carboxylate Esters

Davis, F. A,; Zhou, P.; Reddy, G. V. J. Org. Chem. 1994, 59, 3243-3245.

Davis, F. A.; �Zhou, P. Tetrahedron Lett. 1994, 35, 7525-7528.

O

N

S

Li

O

R

HBr

OMe

p-MeC6H4S

N

O H

Rp-MeC6H4

SN

O

64-70% yield94-98% de

R = Ph, i-Pr, p-MeOC6H4

+OMe

OLi

Br

THF

H

H

CO2Me

R

C6H4Me-p O

N

S

Li

O

R

HBr

OMe

C6H4Me-p

-78 oC

Asymmetric Synthesis of α-Alkyl-β-Amino Acids Using Aziridines

Davis, F. A.; �Zhou, P. Tetrahedron Lett. 1994, 35, 7525-7528. Davis, F. A.; �Reddy, G. V.; Liang, C.-H. Tetrahedron Lett. 1997, 35, 5139-5142. Tanner, D.; Gautn, O. R. Tetrahedron 1995, 51, 8279-8288.

p-MeC6H4S

N

O H

Rp-MeC6H4

SN

O

76-84%R = Ph, Et

+ OMe

OLi

Me

THF

CO2Me

H

Me

R

-78 oC

LiAlH4

ether, 0 oC

Br

m-CPBACHCl3 N

TsCO2Me

MeR

H

96-99%

N

Ts

MeR

H

O

AlH2H-

R OH

NH-Ts

Me

90-95%

NaIO4

cat. RuCl3R

NH-Ts

Me

81-90%

48% HBr/PhOHor Na/liq. NH3

RCO2H

NH2

Me

> 97% ee79-95% yield

CO2H

Asymmetric Synthesis of α-Aminophosphonic Acids

Lefebvre, I M.; Evans, S. A. J. Org. Chem. 1997, 62, 7532-7533. Smith, A. B., III Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc. 1995, 117, 10879-10880.

p-MeC6H4S

N

O H

Ph

1) THF, -78 oCPRO

OM

RO

+

R = Et, i-PrM = Li, Na

2) sat. NH4ClPRO

O

RO

HN

SC6H4Me-p

OPh

93-97% de 80-82% yield

NS O

HP

O

OOLi

Me

NS

O

HO

OO

Li

Me

favored

TFAMeOH

PRO

O

RO

NH2

Ph

p-MeC6H4 OMe

O

+

disfavored

Asymmetric Synthesis of β-Aminophosphonic Acids

Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J.; Wieczorek, M. W.; Blaszczyk, J. Chem. Commun. 1996, 1503-1504.

p-MeC6H4S

N

O H

Ph

LiHMDS, THFPMeO

O

MeO

+-78 oC to r.t. p-MeC6H4

SNH

O H

CH2P(OMe)2Me Ph

82% de75% yield

TFAMeOH

HClHOAc

O

H2N

H

CH2P(OMe)2

Ph

O

H2N

H

CH2PPh

OOH

OHN

H

Ph SO p-Tol

Li

PO

RO

H2C

OR

-

78% 66%

Chiral Intermediates for Synthesis of Important Amine Derivatives

RS

N

O R1

R2

Sulfinimines

RS

NH

O R3

R2

RS

NH

O R1

R2

R3

RS

NH

O R1

R2

RS

NH

O CN

R2

RS

NH

O

OR4

R1 R2

R3

O

SN

O

R1R2

CO2Me

R

α-branched amines

α, α-dibranched amines

β-amino acids

α-amino acids

α-branched amines

aziridine-2-carboxylic acids

R3MgBr

R1 = H

Me3Al, R3Li

R3O M

OR4

- +

Et2AlCN

R1 = H

[H]

R1 = H

BrO M

OMe- +

R = t-BuR1 ≠ H

RS

NH

O R2

P

O

(OR3)2n

n = 0, α-aminophosphonic acidsn = 1, β-aminophosphonic acids

(R3O)2P(CH2)n

O-

R1 ≠ H

Synthesis of a Support-Bound tert-Butanesulfinamide

Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 10127-10128.

OH

2) Mg, THF, 72 oC

1) conc. HCl MgCl

then SOCl2

SO2, THF, -48 oC SCl

O +_

(S)-2-amino-1,1,2-triphenylethanol

cat. DMAP, i-Pr2EtN, THF, -78 oC

Dynamic Resolution

SNH

O

OH

Ph Ph

Ph

THF, -48 oC

Li, NH3, NH4Cl SNH2

O

9-BBN, THFthen bromopolystyrene5% Pd(PPh3)4, NaCO3, 72 oC

SNH2

O

76% 65%

Solid-Phase Synthesis of α-Branched Amines


Entry R Yield, % dr

1 i-Pr 95 97:3 (97:3)

2 Ph 95 88:12 (92:8)

3 Bn 90 89:11 (92:8)

4 pMeOPh 95 96:4 (99:1)

Note: Numbers in parentheses represent solution-phase results.

SNH2

O

2) EtMgBr, CH2Cl2, -48 oC

1) RCHO, Ti(OEt)4, THFS

NH

O

R

Et0.67 N HCl

1:1 CH2Cl2/nBuOH Cl H3N R

Et

- +

Pomeranz-Fritsch Synthesis of Pavine and Isopavine Alkaloids


N

RR1 R2

Pavine classes of alkaloids

R1 R2NR

Isopavine classes of alkaloids

NS

R1

R2

O

O

O

Solid-Phase Pomeranz-Fritsch Synthesis of Pavine and Isopavine Alkaloids


SNH2

O OMeTi(OEt)4, THF

CH2Cl2, -48 oC

+

OMe

H

OS

N

OOMe

OMe

SNH

OOMe

OMe

OMe

3-MeOPhMgBr 1) KOtBu, NMP, allyl bromide

2) m-CPBA, CH2Cl2/AcOH

1) 2.5 % OsO4/tBuOH, NMO, THF

2) Pb(OAc)4, 10:1 CH2Cl2/AcOHS

N

OMe

OMe

OMe

CHO

O OSN

OMe

OMe

OMe

O O

Solid-Phase Pomeranz-Fritsch Synthesis of Pavine and Isopavine Alkaloids


SN

OMe

OMe

OMe

CHO

O O

dilute HCl, CH2Cl2 3:1 CH2Cl2/HCO2H

N

RN

ROMe

OMe

MeO

OMe

OMeMeO

R = polymer

R = H

1) 0.1 N TfOH, OMeMeO

2) Sulfonic acid resin, then NH3/MeOH

45% overall yield86:14 enantiomeric ratio

47% overall yield86:14 enantiomeric ratio

Synthesis of Polymer-Bound Chiral 3-Phenyl β-Alanine Building Block

Lee, Y.; Silverman, R. B. Org. Letter 2000, 3, 303-306.

Br

OHC

Si

2) t-BuLi, THF, 78 oC

SiClthen

OH

OH

1) , p-TsOHbenzen, reflux

O

O

acetone

p-TsOH

Si

OHC

SNH2

O

SN

O

Si then Ti(OiPr)3Cl

CH3CO2Me, LDA

SNH

O

OMe

O

Si

then bromopolystyreneDMF, Pd(PPh3)4, Na2CO3

9-BBN, THF

86% 86%

68%> 98% de79% yield

SNH

O

OMe

O

Si

Solid-Phase Synthesis of Chiral 3-Aryl β-Amino Acid Containing Peptides

Lee, Y.; Silverman, R. B. Org. Letter 2000, 3, 303-306.

2) Fmoc-Ala-OH, EDC, HOBT, TEA, DMF

1) 50% TFA/CH2Cl2

SNH

O

OMe

O

Si

3) 20% piperidine/DMF4) benzoic acid, EDC HOBT, TEA, DMF N

HOMe

O

Si

HN

O

CH3O

1) LiOH, THF/H2O

2) NH2-Gly-OEt, EDC HOBT, TEA, DMF

NH

NH

O

R

HN

O

CH3O

OEt

O

cleavage reagent

CH2Cl2

NH

NH

OHN

O

CH3O

OEt

O

Si

Reagent R Yield (%) Purity (%)50% TFA H 88 > 95Br2 Br 95 > 95ICl I 95 > 95

Conclusions •  Chiral sulfoxides have been used in a variety of stereoselective carbon-carbon bond-

forming reactions, such as Aldol reaction, Diels-Alder reaction and Michael additions.

•  Chiral sulfoxides can be used in asymmetric Heck reaction as stereochemical controllers, by the coordination of Pd to an amino group tethered to the sulfoxides, rather than by direct steric control. This chiral auxiliary-based procedure constitutes an alternative to the use of chiral bidentate ligands in asymmetric Heck reaction.

•  Sulfinimines are being utilized as versatile chiral nitrogen intermediates for the preparation of a range of chiral amines, including α-branched and α,α-dibranched amines, α- and β-amino acids, aziridines and α- and β-amino phosphonic acids.

•  Solid-phase asymmetric synthesis of amine and amino acid containing molecules has also been studied. These studies should provide for the generation of combinatorial libraries.

Preparation of Chiral Sulfoxides

1. Asymmetric Oxidation

2. Asymmetric Synthesis (Nucleophilic Substitution on Chiral Sulfur)

R1S

R*

OR2MgX

R1S

R2

O

OR* =

O

O

O

O

O

OS

O

tBu

or

RS

R'R

SR'

O[O]

Ti(OiPr)4 / (+)-DET / tBuOOH

Ti(OiPr)4 / (+)-DET / Ph(CH3)2OOH

Ti(OiPr)4 / (+)-BINOL / tBuOOH

Cl

Cl

ON SO2Ph

O

O

O

O

O

OS

O

tBu

1) LiHMDS

2) RCHO/CsF BuS

N R

HO

t

Asymmetric Iminolysis of Sulfinates

Garcia Ruano, J. L.; Fernandez, I.; Prado Catalina, M. D.; Cruz, A. A. Tetrahedron: Asymmetry 1996, 7, 3407-3414.

Attempted Enantioselective Synthesis of α,β-Unsaturated Sulfoxides by Asymmetric Oxidation



O

S

O

SAr

O

Ar

(S)

[Ti(OiPr)4], (R,R)-DETPhC(CH3)2OOH

CH2Cl2, -20 oC

26% ee

O

S

O

SAr

O

Ar

(S)

CH2Cl2, r.t.

62% ee

ClClN

O

SO2Ph

Ar = o-(Me2N)C6H4

Asymmetric Synthesis of α,β-Unsaturated Sulfoxides Using Enantiomerically Pure Sulfoxides


Ar = o-(Me2N)C6H4

SOO

PhPhMe

O

Li

NMe2

Et2O, -78 oC SO

PhPhMe

O

OH

Ar

MgBr

THF

SAr

O

61% > 97% ee85% yield

MeS

Ar

O 1) LDA, Et2O

2) O

HO SAr

O 1) LDA, Et2O

2) HCO2Et

72%

> 96% ee77% yield

O

S

O

Ar

OH

MsCl, Et3N

CH2Cl2

80%

O

S

O

Ar

SN

O R1

R2

2.0 eq. Ti(OEt)4

O

R1

R2S

NH2

O

+THF, 60-70 oC

Asymmetric Synthesis of α,α-Dibranched Amines


Condensations of Ketones with Sulfinamide

Entry R1 R2 Yield, % (E:Z)

1 Me i-Pr 84 One isomer

2 Me Ph 87 One isomer

3 Bu i-Pr 66 One isomer

4 Bu Ph 77 One isomer

5 Me Bu 77 5:1

Pummerer Rearrangement

Marino, J. P.; Pradilla, R. F.; Laborde, E. Synthesis 1987, 1088-1092.

** Carreno, M. C. Chem. Rev. 1995, 95, 1717-1760.

Me

Ar S

p-Tol

OO

Cl

ClS

O

Cl

Clp-Tol

Ar

O-

S -Op-Tol

Ar

O

+ +

Cl

Cl

O

Cl

Cl

O

Ar

p-TolS1) Al/Hg (73%)

2) Ra Ni (60%)

OMeO

MeO

O

OMeO

MeOO

Porosin

Ar = OMe

OMe

OMe

Asymmetric Synthesis of β-Amino Acids - Method IV


SNH

O

H CO2MePyr

SN

O

CO2MeH

N

LiOH

MeOH, H2OS

N

O

CO2HH

N

β-Ala-OEt.HCl

DCC, HOBt, CH2Cl2S

N

O

H

N

N

CO2Et

O

H

HCl, EtOH

NH

N

N

CO2Et

O

Hthen 4-cyanophenylisocyanate, i-Pr2NEt, DMF

N

O

H

NC

HCl, EtOH

NH

N

N

CO2Et

O

Hthen NH4OH, NH4Cl N

O

H

H2N

NH

Asymmetric Synthesis of β-Amino Acids - Method IV


Zimmerman-Traxler Transition State

SN

OO Ti(OiPr)3

O NM

SO

CH3

H

MeO

SNH

O

CO2MeH3C

OMeTHF, -78 oC

CH3

Asymmetric Synthesis of Aziridines and Its Application

Davis, F. A.; �Zhou, P. Tetrahedron Lett. 1994, 35, 7525-7528.

Davis, F. A,; Zhou, P.; Reddy, G. V. J. Org. Chem. 1994, 59, 3243-3245.

p-MeC6H4S

N

O H

Arp-MeC6H4

SN

O

60%Ar = p-MeSC6H4

+OMe

OLi

Br

THF

H

H

CO2Me

Ar

-78 oC

3 eq. LiAlH4

ether, 0 oC p-MeC6H4S

N

O

H

H Ar

OH

TsOH

87%

Ar OH

NH2

OH

one isomer93% yield

Cl2CHCOClAr OH

HN

OH

H2O/THF

Et3Nm-CPBA

THF

CHCl2

O

OH

HN

OH

CHCl2

O

CH3SO2

(+)-thiamphenicol 88% 94%

Asymmetric Synthesis of β-Amino Acids - Method III

Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett. 1996, 37, 3881-3884.

p-MeC6H4S

N

O H

O O+

OtBu

OM

THF, HMPAM = Li

THF

p-MeC6H4S

NH

O H

O O

CO2tBu

p-MeC6H4S

NH

O H

O O

CO2tBu

(SS)

(SS, R) 92% de 89% yield

M = Ti(OiPr)3

TFAO O

CO2H

NH2

70%

N

(SS, S) 96% de 68% yield

RH

O

p-Tol

Nu-

M

O

N

SO p-Tol

OtBu

H

OO

NO

S

MO

p-Tol

BuOt

HO

O

si face attackre face attack

1) α-Branched Amines α,α-Dibranched Amines

2) α-Amino Acids β-Amino Acids

3) Aziridine Derivatives

4) α-Amino Phosphonic acids β-Amino Phosphonic acids

Asymmetric Synthesis Using Sulfinimines

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Asymmetric Synthesis Using Chiral Sulfinyl Groups 958... · Asymmetric Synthesis Using Chiral Sulfinyl Groups Yiqian Lian Department of Chemistry Michigan State University