catalytic asymmetric pauson-khand reaction asymmetric pauson-khand reaction won-jin chung 02/25/2003...

Catalytic Asymmetric Pauson-Khand Reaction

Won-jin Chung02/25/2003

U. Khand; G. R. Knox; P. L. Pauson; W. E. WattsJ. Chem. Soc. Chem. Commun. 1971, 36

The General Pattern of the Pauson-Khand Reaction

R

OR Co2(CO)8

D

Schore, N. E.; Croudace, M. C.J. Org. Chem. 1981, 46, 5436

• Formal [2+2+1] cycloaddition• Stoichiometric amount of the metal• Long reaction time

R1

R2 Co2(CO)6 (OC)3Co Co(CO)3C C

R2 R1

=

Improved Reaction Conditions

Promoters

• Tertiary amine N-oxides - Room temperature - Generate free coordination sites at cobalt by oxidative removal of CO ligands Shambayati, S.; Crowe, W. E.; Schrieber, S. L. TL 1990, 31, 5289 Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991, 204

• Primary amines as solvent

- Few minutes

Sugihara, T. et al. ACIEE 1997, 36, 2801

PhCo2(CO)6 +

n-Bu S CH3

ClCH2CH2Cl

83oC, 30 min, 79%

O

Ph

Improved Reaction Conditions

• Sulfides - Mild condition

NHp-TsN Co2(CO)6p-Ts83oC, 30 min, 15%

NH2

N Op-TsN Co2(CO)6p-Tsn-Bu S CH3

ClCH2CH2Cl

83oC, 30 min, 79%

Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett 1991, 204

Catalytic Pauson-Khand Reactions – Cobalt Catalyzed

• High CO pressure, high temperatureRautenstrauch, V.; Megard, P.; Conesa, J.; Kuster, W. ACIEE 1990, 29, 1413

Co2(CO)8 (3 mol%)

CO (1 atm), DME120oC, 82%

P(OPh)3 (10 mol%)EtO2C

EtO2CO

EtO2C

EtO2C

• The ligands stabilize the active cobalt intermediates.Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. JACS 1994, 116, 3159

C5H11

ethylene/CO (310-360 bar)Co2(CO)8 (0.22 mol%)

150oC, 16h, 48%

O

C5H11


(ind)Co(COD) (2 mol%)

DME, 100oC, 64%

CO (15 atm)EtO2C

EtO2CO

EtO2C

EtO2C

Lee, B. Y.; Chung, Y. K.; Jeong, N.; Lee, Y.; Hwang, S. H. JACS 1994, 116, 8793

Co2(CO)8 (5 mol%)CO (1 atm)

hv = 95%D = 83%

EtO2C

EtO2CO

EtO2C

EtO2CDME, 50-55oC

• Photochemical – 8% starting enyne remaining after 14h• Thermal – 15 % starting enyne remaining after 14hPagenkopf, B. L.; Livinghouse, T. JACS 1996, 118, 2285Belanger, D. B.; O’Mahony, D. J. R.; Livinghouse, T. TL 1998, 39, 7637

Co2(CO)8 (2.5 mol%)CO (30 atm), CO2 (112 atm)EtO2C

EtO2CO

EtO2C

EtO2C90oC, 82%


• Super critical fluids promote the reaction.Jeong, N.; Hwang, S. H.; Lee, Y. W.; Lim, J. S. JACS 1997, 119, 10549

Co2(CO)8 (1 mol%)additiveMeO2C

MeO2CO

MeO2C

MeO2CCO (7 atm), toluene120oC

additive yieldDME (4 mol%) 94%H2O (4 mL) 97%

• Hard Lewis BasesSugihara, T.; Yamaguchi, M. Synlett 1998, 1384


Co(acac)2 (5 mol%)NaBH4 (10 mol%)EtO2C

EtO2CO

EtO2C

EtO2CCO (30-40 atm), CH2Cl2100oC, 66%

Lee, N. Y.; Chung, Y. K. TL 1996, 37, 3145

Co4(CO)12 (1 mol%)EtO2C

EtO2CO

EtO2C

EtO2CCO (10 atm), CH2Cl2150oC, 92%

Kim, J. W.; Chung, Y. K. Synthesis 1998, 142

Co3(CO)9(m3-CH) (1 mol%)MeO2C

MeO2CO

MeO2C

MeO2CCO (7 atm), toluene

120oC, 98%

O

R

R

CoBr2 (0.4 eq)

CO (1 atm), 110oC

toluene/t-BuOH

+Zn (0.43 eq)


Sugihara, T.; Yamaguchi, M. JACS 1998, 120, 10782

• In situ generation of the alkyne-Co2(CO)6 complexRajesh, T.; Periasamy, M. TL 1999, 40, 817

TitanoceneO O N

benzene, 45oCPh Me3SiCN

Ph

TMS H3O+

O O

Ph

catalyst mol% yieldCp2Ti(PMe3)2 10 80%Cp2TiCl2 / n-BuLi 10 82%Ni(COD)2 / Ligand 5 60%

catalyst (5 mol%)O

toluene, 90oCPh CO (18 psig)

O O

PhTi CO

OC

catalyst yield eeCp2Ti(CO)2 92% -

85% 96%

Catalytic Pauson-Khand Reactions – Titanium Catalyzed

Berk, S. C.; Grossman, R. B.; Buchwald, S. L. JACS 1993, 115, 4912Berk, S. C.; Grossman, R. B.; Buchwald, S. L. JACS 1994, 116, 8593

Hicks, F. A.; Buchwald, S. L. JACS 1996, 118, 11688Hicks, F. A.; Buchwald, S. L. JACS 1999, 121, 7026

11 solvent yieldMurai dioxane 86%Mitsudo DMAc 78%

Catalytic Pauson-Khand Reactions – Ruthenium Catalyzed

Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. JOC 1997, 62, 3762Kondo, T.; Suzuki, N.; Okada, T.; Mitsudo, T. JACS 1997, 119, 6187

Ru3(CO)12 (2 mol%)EtO2C

EtO2CO

EtO2C

EtO2CCO (10-15 atm)

solvent, 140-150oC

[RhCl(CO)2]2 (1 mol%)EtO2C

EtO2CO

EtO2C

EtO2CCO (1 atm), dibutyl ether

130oC, 94%Ph

Ph

trans-[RhCl(CO)(dppp)]2 (2.5 mol%)EtO2C

EtO2CO

EtO2C

EtO2CCO (1 atm), toluene

110oC, 99%Ph

Ph

Catalytic Pauson-Khand Reactions – Rhodium Catalyzed

Koga, Y.; Kobayashi, T.; Narasaka, K. CL 1998, 249

Jeong, N.; Lee, S.; Sung, B. K. Organometallics 1998, 17, 3642

SR

O

SHR

O-CO (D), N2

+CO (CO)CoCo

CO

OC

CO

COOC

CO

CoCo

COCO

CO

COOC

Asymmetric Pauson-Khand Reactions – Chiral Auxiliary Approach

• The sulfur ligated complex can be isolated.• The equilibrium can be controlled.• Maximum concentration of complex A - 40% de• Maximum concentration of complex B - 92% de - Could not be used with less reactive olefins


S

O O

O*R

1. Co2(CO)62. NMO

rt, 44h

H(+)-15-nor-pentalenene

dr 9:1

Tormo, J.; Moyano, A.; Pericas, M. A.; Riera, A. JOC 1997, 62, 4851

OS

O

R*S

*

1. Co2(CO)8

2. 65oC, 42hhexanes

OS R*S

O

*

CoCoOC

OC COCO

COCO

*

NMO (6 eq)

CH2Cl2, -20oC28h

4.6 : 1


• In the absence of the chelating sulfur moiety : low diastereoselectivityPericas, M. A.; Riera, A. et al. Tetrahedron 1997, 53, 8651

1.4 : 1

NO2S

O

Co

Co

OC

COOC

COOCOC

R

toluene25-45 oC

orNMO H2O (6 eq)

CH2Cl2

OR

Xc

O


• Thermal conditions - dr 523:1• Oxidative conditions - dr 800:1Pericas, M. A.; Riera, A. et al. JACS 1997, 119, 10225

CoCo

R

S OC COCOCO

OC CO

O

SO

O

R SO

R

O

**

*

*

+

+


• Close proximity• Low reactivity• Low selectivity• The dicobalthexacarbonyl alkynyl sulfoxide complex is configurationally unstable.Pericas, M. A.; Riera, A. et al. TA 1999, 10, 457

SO Co2(CO)8

CH3CN, 80oC44% O

H SO

O

HZn, NH4Cl

THF, rt96% ee


• The chiral sulfoxide moiety was attached to the olefin.• cis and trans vinyl sulfoxides afforded only one isomer upon cyclization.Adrio, J.; Carretero, J. C. JACS 1999, 121, 7411

Co CoP P

OCOC

COCO

Ph H

EXX

XX

OPhtoluene

80oC+

5 eq

Asymmetric Pauson-Khand Reactions – Chiral Complex Approach

• E=NMe : 3-5 days, 90-98% yield• E=(-)-a- methyl-benzylamine : 16% eeGreene, A. E. et al.JOC 1999, 64, 3492

N N O

HR 10-15 mol% (S,S)-(EBTHI)TiMe2

14 psig CO, toluene, 12-45 h, 95oCR


• Chiral mixed metal complex• Thermally stableRutherford, D. T.; Christie, S. D. R. TL 1998, 39, 9805

OCo

Mo

OC COOC

H

COCO

toluene61%

O

O

100% de

Sturla, S. J.; Buchwald, S. L. JOC 1999, 64, 5547


Jeong, N.; Sung, B. K.; Choi, Y. K. JACS 2000, 122, 6771


Shibata, T.; Takagi, K. JACS 2000, 122, 9852

Asymmetric Pauson-Khand Reactions – Chiral Promoter Approach

Co CoOC CO

OC CO

OC CO

RH

• Chiral promoter should be able to differentiate between the enantiotopic ligands.• Chiral N-oxides were used.• Maximum ee 33%Kerr, W. J.; Kirk, G. G.; Middlemiss, D. Synlett 1995, 1085Derdau, V.; Laschat, S.; Jones, P. G. Heterocycles 1998, 48, 1445

TMS

Cr(CO)3MeO

TMSLi

Br

1.

2.

3. TsOH

TMSO

TMS

OO

TMS

HH

H

1. Co2(CO)8

2. NMO (10 eq)88%

Asymmetric Pauson-Khand Reactions – Chiral Precursor Approach

Quattropani, A. et al. JACS 1997, 119, 4773

OMeOMe

O

O

HO

HO

OO

OHHO

HO

HO

or R2

R1O

R1O

O

R2

R1O

R1O

H

O

R2

R1O

R1O

H1. Co2(CO)8

2. D or TMANO or NMO


• Depending on R groups, yields ranged from 0 to 96%.• The product ratio ranged from 1:1 to 100:0.Mukai, C.; Hanaoka, M. et al. JCS PT1 1998, 2903Mukai, C.; Hanaoka, M. et al. TL 1998, 39, 7909

OEt

O

TMSH

H

H

HCo

Co

OC COCO

CO

COCO

OH

1. Co2(CO)8

2. Et2AlCl, -78oC82% 2 steps

O

O

H

H

H

HO

H

H

H

H

H

H

CH3CN, airreflux, 15 min

85% (5:1)

NMO, CH2Cl270% (11:1)

ultrasoundCH3CN, 40oC

45% (3:1)

or

or

(+)-epoxydictymene


Schreiber, S. L. et al. JACS 1994, 116, 5505Schreiber, S. L. et al. JACS 1997, 119, 4353

Pauson-Khand reaction - Mechanistic Studies

• The currently accepted mechanistic pathwayMagnus, P.; Principe, L. M. TL 1985, 26, 4851

• Beyond the fact that a hexacarbonyldicobalt-alkyne complex is involved, little is actually known about the mechanism.• No group has observed any of the proposed intermediates.

Co CoOC CO

R R'

COCO

OCOC

R''Co CoOC CO

R R'

COOCOC R''

Co CoOC

OC

RR'

COCO

OC R''

Co CoOC

OC

RR'

COOC

O

R''CoOC

OC

RR'

OCR''

CoCOO

R''R

R'

-Co2(CO)5

O

OC OC

OCCO

CoCo

R

OCOC

CO

COCO

CO CoCo

R

OC CO

COCO

CO CoCo

R

OC CO

COCO

CO

CoCo

R

L CO

COCO

CO

OO

Co

R

CO

COCo

LCO

L

CO

OR

-CO

O2

Pauson-Khand reaction - Mechanistic Studies

• The reaction was interrupted by exposing the reaction mixture to an oxygen containing atmosphere.Krafft, M. E. et al. JACS 1996, 118, 6080

Pauson-Khand reaction - Summary

• The P-K reaction allows for a rapid increase in molecular complexity from relatively simple starting materials.• Several promoters can make the reaction efficient.• Many kinds of metal complexes can be used as catalysts.• High levels of enantioselectivity can be achieved.• The reaction mechanism is not clear.

catalytic asymmetric pauson-khand reaction asymmetric pauson-khand reaction won-jin chung 02/25/2003...

Documents