Catalytic Asymmetric Intramolecular Pauson-Khand …scs.illinois.edu/burke/files/group_meetings/SGB_535ppt.pdfPauson-Khand Reaction Promoters Support for Proposed Mechanism Co Co OC

Catalytic Asymmetric Intramolecular Pauson Khand and Pauson Khand TypePauson-Khand and Pauson-Khand-Type

Reactions

Steven BallmerCHEM 535 S iCHEM 535 Seminar

October 9, 2008University of Illinois at Urbana-Champaign

Copyright © 2008 by Steven Ballmer

Synthetic Challenges

Co-Mediated [2+2+1] Cycloaddition1

Co Co

R1 R2

OC

OC

OCCO

CO

COO

HH

R2R1

+60-70 °C, 4 h

tolueneR2R1

Co2(CO)8

H H Ph EtH

hexacarbonyldicobaltalkyne complex

cyclopentenone

OHH

MeH

OHH

PhH

OHH

PhPh

OHH

EtEt

OHH

HH

43% 33% 45% 28% 23%

Co Co

OC CO

COR2

R1

R1

Side Products

CO

COOC

Co Co

OC

C COOC

CoOC CO

cyclopentadienylcobalt

(retro Diels Alder)norbornadiene

complexesO

HH

R2R1

O

OHH O

HR2

HHR2

diketones

Pauson and coworkers J. Chem. Soc., Perkin Trans. 1 1973, 977.

Pauson and coworkers J. Chem. Soc., Perkin Trans. 1 1973, 975.

CO

COOC(retro Diels-Alder) complexesHH H R1

Proposed Mechanism

Co Co

OC

C

COCO

CO

OCOC

OCCo Co

R1

OC

OC COCo Co

R1

OCCO

COdissociationX

R1 XR

XR

alkynecomplexation

CO

COOC OCOC

COCO OC CO

CO

R1

R

X X

COenyne

2CO

Co Co

R1

OCOC

CO

CO

CO

RCo Co

R1

OCOC

CO

CO

CO

RCo Co

R1

OC

OCCO

CO

COR

alkenecoordination isomerization

alkeneinsertion

X

OC OC CO

R1 Co(CO)3CO reductive

li i tireductive

lialkyl

XXX

Co Co

R

OCCO

CO

CO

R

OO

R R1

OC

OC

O

R R1

Co( )3

COCO

Co2(CO)6

eliminationcouplingmigration

+ CO

bicyclicc clopentenone

Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851.

Magnus and coworkers Tetrahedron 1985, 41, 5861.

cyclopentenone

Mechanistic Calculations

DFT (VWN/PW91xc) methodology

ethylenecoordination

acetylenecomplex

Pericàs and coworkers Pure Appl. Chem. 2002, 74, 167.

Pauson-Khand Reaction Promoters

Support for Proposed Mechanism

Co CoOC

OCCO

CO

CO

SMe OC

bishomopropargylic sulfide complexMixed Ar/N2 Matrix

bishomopropargylic sulfide complex

NMO H2O,DCM, rt, 5 d

Co CoOC

S

CO

CO

CO

Me

10-6 mbar12 K

OC CO

isolable pentacarbonyl complex

O

SMe

Gordon and coworkers J. Organomet. Chem. 1998, 554, 147.Krafft and coworkers J. Am. Chem. Soc. 1993, 115, 7199.

bishomoallylic sulfide

MS Support for Proposed MechanismH Ph

ESI collision-activated reaction (CAR) MS/MS- CO dissociation occurs first

Co CoOC

Ph2PCO

CO

PPh2

OC

H Ph

m/z = 716.0Idppm

Co Co

H Ph

OC CO

CO

Co CoOC

Ph2PCO

CO

PPh2 Ea = 34 kcal/molPh2P PPh2

m/z = 781.1

H Ph

[Idppm - H - CO]-

DFT calculations(B3LYP/LANL2DZ*)

Co CoOC

Ph2PCO

CO

PPh2

[Idppm - H - 2CO]-Ea = 12 kcal/mol

Gimbert and coworkers Org. Lett. 2003, 5, 4073.

X-Ray Crystal Support for Mechanism

OHOH

Co

Co

OCCO

OCOC

OCCo Co

OC CO

CO COOC

CO

hexacarbonyl alkyne complex η2-alkene pentacarbonyl alkyne complex

COCC

COH

Ph

HO Ph

Co2(CO)8

THF, rt, 15h

CoOC CO

OC

COPh O Ph

Evans and coworkers Angew. Chem. Int. Ed. 2007, 46, 2907.

η2-alkene pentacarbonyl alkyne complex (viewed down Co-Co bond)

Pauson-Khand Regioselectivity

Catalytic and Intramolecular Pauson-KhandFirst Intramolecular

First Catalytic

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

Jeong and coworkers J. Am. Chem. Soc. 1994, 116, 3159.

Asymmetric Catalytic CycleCO

RO Cl M

P

OC MPP

CO

Cl

reductive*

*

chiralcatalyst

metallacyclohexenone+ CO

- CO

R

MX

PP

Cl

R

Cl MPelimination

-

*

* *

carbonX O

R R

XCOinsertion

complexationCO * enyne

bicycliccyclopentenone

monoxide

X MPP

Cl

RX M P

PCl

RX

oxidativeaddition

*

**

*

catalyst/enynecomplex

metallacyclpentene

+ CO

- COX M P

COCl

P*complex

CO pressure-dependenceti t d ith i d CO-reaction rate decreases with increased CO pressure

-enantioselectivity decreases with increased CO pressure

Reagent-Directed StereocontrolR

P filledfilled

open

open

Ph Ph

Co

COCOCO

CO

Open/ClosedQuadrantsP

P

Ph Ph

Ph

CoCo

XH

((S)-BINAP)Co2CO6

P filled open

PhPh

Co

COCO

CO

PhP P

PhCo Co

PhPhCO ligandsnot shown

CO ligands not shown

X O

R

X O

R

Ph Ph COCO

HHR isomer S isomer

Co CoP PPh

Ph

P

P

PhPh

Co

Co

CO

COCO

CO

filledfilledopen

open

Open/ClosedQuadrants

((R) BINAP)Co CO P

Ph PhR

CO ligandst h

Ph

CO ligands not shownfilledopen((R)-BINAP)Co2CO6 P

P

Ph Ph

CoCo

not shown

HX

Substrate-Directed StereocontrolH

CoR1R2

H H

(CO)3 R2

R1

O

R

H

R1R2

H H

RCo2(CO)8

R1

HH H

HH

Co

H

R

R(CO)2

O

R

H

R1

R2H

RR2

RH

chairconformer

favoredolefin rotamer

R isomerR

R1

R2

olefin rotamer

R2

R1

O

R

H

R1R2

H

H

disfavoredolefin rotamer

Co1

H

(CO)3

Co2(CO)8

R1H H

H

O

RR1

R2

H

R RR

H

Co

H

R1R2

R(CO)2

HCo2(CO)8H

R2 Rchairconformer

H

H

H

HS isomer

Development of Cobalt Catalysts

RX

20 mol %((S)-BINAP)Co2CO6 X O

R

DME, reflux,1 atm CO H1 atm CO

14 h 24 h 24 h 15 h60% i ld

14 h

O

H

HMeO2CMeO2C

O

H

MeMeO2CMeO2C

O

Me

MeMeO2CMeO2C TsN O

H

H

TsN O

H

Me

14 h53% yield90% ee

31% yield63% ee

90% yield0% ee

60% yield93% ee

13% yield62% ee

P

Ph PhR

HPh Ph

R

R

H Me Me

R P

P

PhPh

CoCo

CO ligandsnot shown

X

HP

P

PhPh

CoCo

XX O

H

favored

H

disfavoredX O

R

H

Hiroi and coworkers Tetrahedron Lett. 2000, 41, 891.Hiroi and coworkers Tetrahedron: Asymmetry 2000, 11, 797.

Development of Rhodium Catalysts

Jeong and coworkers J. Am. Chem. Soc. 2000, 122, 6771.

Development of Iridium Catalysts

Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852.

Development of Titanium Catalysts

Buchwald and coworkers J. Am. Chem. Soc. 1996, 118, 9450.Buchwald and coworkers J. Am. Chem. Soc. 1996, 118, 11688.

Expansion of Substrate Scope

XR

•

X

RR1

R

MeO2C

MeO2C

R2R1

allenynes dienenesdienynes

X O

R

X

R

OX O

H

HR

R1X O

H

HR

R1

MeO2CMeO2C

R

O

HR2

R1

dienylcyclopentenones

-methylenecyclopentenones

R1R2

vinylcyclopentenones

vinylcyclopentanones

-methylenecyclopentanones

X

• R2

R3

X O

R3R2

H

H

X•

PhO2S

OX

SO2Ph

RRH H

-methylene vinylcyclopentanones

allenenes cyclopenteonesdiene-allenes

Bicyclic Dienones from Allenynes

XR

•

XR

•MM X

R

•XX

R

O O

RCOCO M M

bi li di ll

non-catalyticnon-asymmetric

bicyclic dienone -methylenecyclopentenone

allenyne

non asymmetric

X•

MeS

X O

MeS

Fe(CO)5, TMANO, THF

rt, h (100 W)

O O OHO Ph Ph

O

MeS 60%

O

SMe

OO

SMeSMe

O

SMe45%15% 30%19%

Fe(CO)3

cyclopentadienoneiron complex

Narasaka, K.; Shibata, T. Chem. Lett. 1994, 315.

iron complex

α-Methylene Cyclopentenones from Allenynesy

XR

•

XR

•MM X

R

•XX

R

O O

RCOCO M M

non-catalytic

bicyclic dienone -methylenecyclopentenone

allenyne

non-asymmetricMo(CO)6 (1.2 equiv), DMSO

PhMe, 100 °C, 3 hX O

TMS

XTMS

•

triquinane sesquiterpenesmethylenomycin antitumor agents

O

TMS

O

TMS

O

TMS

O

TMS

MeMe

HO Me68% 47% 30% 0%

no cycloaddition

TMS

•

Me

Brummond and coworkers Tetrahedron Lett. 1995, 36, 2407.

-no cycloaddition-starting material decompostion

Vinyl Cyclopentenones from DienynesRR

MeO2C

MeO2C

R2

[RhCl(CO)(PPh3)2], AgSbF6

DCE, CO

R1

MeO2CMeO2C

R

O

HR2

R1

MeO2C

Me

OMeO2C

TMS

OMeO2C

O

89% 85% 43%1 mol% Rh, Ag1 atm COrt, 14 h

2 mol% Rh, Ag2 atm COrt 12 h

1 mol% Rh, Ag1 atm COrt, 40 h

MeO2CO

HMeO2C

O

HMeO2C

O

Hi-Pr i-Pr i-Pr

rt, 12 h

5 l% Rh A 1 mol% Rh Ag

MeO2CMeO2C

Me

O

H

MeO2CMeO2C

O

H

96% 45% 42%MeO2CMeO2C

O

H Me

1 mol% Rh, Ag1 atm COrt, 24 h

5 mol% Rh, Ag1 atm COrt, 32 h

1 mol% Rh, Ag1 atm COrt, 30 h

MeO2CM O C

Me

O MeO2C

Me

OMeO2C

Me

O

86% 90% 96%2.5 mol% Rh, Ag2 atm CO40 °C, 12 h

2.5 mol% Rh, Ag1 atm CO40 °C, 12 h

2.5 mol% Rh, Ag2 atm CO40 °C, 10 h

Wender and coworkers Angew. Chem. Int. Ed. 2003, 42, 1853.

MeO2CH

MeO2CH

MeO2CHMe Me

Vinyl Cyclopentanones from Dienenes

Wender and coworkers J. Am. Chem. Soc. 2004, 126, 5948.

α-Methylene Cyclopentanones from Diene-Allenes

Wender and coworkers Angew. Chem. Int. Ed. 2006, 45, 2459.

Bicyclo[5.3.0]decenones from AllenenesPhO2S

SO PhSO Ph

X•

OX

SO2Ph

OX

SO2Phisomerization to, -unsaturated

ketone

[RhCl(CO)2]2, CO

PhMe, 120 °C

H

OO

H

SO2PhSO2Ph

MeO2CMeO2CPhO2S

PhO2S49%36%

73%25:75

5 mol% Rh10 atm CO

82%35:65

10 mol% Rh10 atm CO

47%60 40

10 mol% Rh10 atm CO

H H

SO2Ph SO2PhSO2Ph

49%15:85

cis:trans

36%60:40

cis:trans2.5 mol% Rh5 atm CO

5 mol% Rh10 atm CO

25:75cis:trans

35:65cis:trans

60:40cis:trans

TsN OO OO

H HH

SO2Ph SO2Ph2

33%93:7

cis:trans

73%80:20

cis:trans

30%100:0

cis:trans

10 mol% Rh10 atm CO10 mol% Rh

10 atm CO10 mol% Rh10 atm CO

SO2Ph

cis:trans10 atm CO

•PhO2S

MeO2CM O C

•PhO2S

MeO2CM O C

[2+2]adduct

5 mol% [RhCl(CO)2]2,5 atm CO

Mukai and coworkers Org. Lett. 2006, 8, 1217.

MeMeMeO2C

MeO2C

68%Me

MeO2C

Me

MeO2CMe

adductPhMe, 120 °C

olefin isomerizationRh

Applications in Synthesis

Synthesis of Isocarbacyclin

OO

MeMe

1 atm CO,5 mol% (CO)6Co2-(2-methyl-3-butyn-2-ol)

OO

H

MeMe

10 mol% Et3SiH 10 mol% CyNH21+

O O

OHHO

H

OHHO

TMS O

TMS

H10 mol% Et3SiH, 10 mol% CyNH2,DME, 65 °C, 15 min;

1, reflux, 6 h

(CO) C (2 th l 3 b t 2 l)

1

51%

33%OHHO

L-ascorbic acid

Livinghouse conditions(CO)6Co2-alkyne complexes

as Co2(CO)8 surrogates

(CO)6Co2-(2-methyl-3-butyn-2-ol)

HO MeMe

(OC)6Co2

H H Me

CO2H

4

3Me

HMe

(CO)3Me

(CO)3

OHOH

isocarbacyclinCo

Co

H

O

O HMe

TMS(CO)2

Co

Co

H

O

OMe

TMS(CO)2

H

Saito and coworkers J. Org. Chem. 2004, 69, 8133.

-Prostacyclin (PGI2) analogue-metabolically stable

Synthesis of Steroidal Skeletons

Chung and coworkers J. Org. Chem. 2006, 71, 8264.

Synthesis of (-)-Pentalenene

-unnatural enantiomer of triquinane

Fox and coworkers Org. Lett. 2007, 9, 5625.

natural product-bio precursors to pentalenolactone

antiobiotics

Synthesis of Tricyclic Sesquiterpenoids

MeTBSO

MOMO•

CO Me

O

MeTBSO

MOMO5 mol% [RhCO(dppp)2]Cl,

1 atm CO, PhMe,reflux, 1 h

74%

HOHO

Me

H

MOMO CO2Me CO2Me

H RhLO

H H

H

H

H

Me CO2Me

MOMOTBSO

RhLn

O

O

HO

OMeMeMe

equatorial chair

MOMO HMe MeH

AcO

Ac2O, TEA, DMAP,DCM, 0 °C to rt

HOO

equatorial, chair

H

MeO2COTBS

RhLn

H

MOMORhLnTBSO

CO2Me

AcOMe

H H

H

dimethylD-tartrate

HO

HO

OMeOMe

Oaxial, chair equatorial, boat

Mukai and coworkers Org. Lett. 2008, 10, 2385.

isolated from Jatropha neopauciflora

Conclusion and Future Directions

Conclusion and Future Directions

• The Pauson-Khand reaction is a highly versatile and efficient transformation for the synthesis of cyclopentenones.

• The Pauson-Khand reaction enables construction of complex molecules in a convergent and atom economic fashion from structurally simple precursors.

• The catalytic, asymmetric, intramolecular variant is highly enabling for the synthesis of stereodefined bicyclic cyclopentenones.

• Reagent-directed stereocontrol absent in context of complex g pmolecule synthesis.

• Further research must seek out more general conditions for the catalytic, asymmetric, intramolecular Pauson-Khand reaction.y , y ,

Acknowledgements

Prof. Scott E. DenmarkCHEM 535 class

Prof. Martin D. BurkeBurke Group