1 applications of palladium-catalyzed aerobic oxidative kinetic resolution of alcohols in the...

11

Applications of Palladium-Catalyzed Applications of Palladium-Catalyzed Aerobic Oxidative Kinetic Resolution of Aerobic Oxidative Kinetic Resolution of

Alcohols in the Preparation of Alcohols in the Preparation of Pharmaceutical CompoundsPharmaceutical Compounds

Roch LavigneMarch 2nd 2006

22

Inspiration from Nature : Inspiration from Nature : OxidasesOxidases

EC 1. Oxidoreductase 1.1. Acting on the CH-OH group donors 1.1.3. With oxygen as acceptor 1.1.3.6 Cholesterol oxidase

HO

H

H HO

H

H H

FADH2FAD

O2H2O2

33

On the Footsteps of Mother NatureOn the Footsteps of Mother Nature

nC7H15

OH

nC7H15

OTEMPO (0.01 eq) NaOCl (1.25 eq)

aq KBr (0.1 eq)r.t., DCM 98%

• Oxidation with a stochiometric amount of reagent

• Oxidation with a catalyst and a stochiometric amount of terminal oxidant

Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.De Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153.

OH Dess-Martin Periodinane (1.1eq)

r.t., DCM

O

89%

44

Evolution of OxidationEvolution of Oxidation

• Oxidation with a catalyst and O2 as the terminal oxidant

OH PdCl2 (10 mol%)NaOAc (50 mol%)

O2, Ethylene Carbonate38°C

O

92%

nC8H17

OH Pd(OAc)2 (3 mol%)Et3N (6 mol%)O2, THF/Toluener.t.

nC8H17

O

97%

Blackburn, T. F.; Schwartz, J. J. Chem. Soc., Chem. Commun. 1977, 157.Schultz, M. J.; Hamilton, S. S.; Jensen, D. R.; Sigman, M. S. J. Org. Chem. 2005, 70, 3343.

55

Towards Oxidases ActivityTowards Oxidases Activity

• Ideal cases of enantioselective oxidation with a catalyst and O2 as the terminal oxidant

R1

OH Chiral catalyst

O2, Solventr.t.

R2 R1

OH

R2

50 %99.9 % ee

+R1

O

R2

50 %

OH

R2R1

HO Chiral catalyst

O2, Solventr.t.

O

R2R1

HO

quant.99.9 % ee

66

Presentation OutlinePresentation Outline

• Resolution background

• The first reported systems

• Catalytic cycle

• Origins of the enantiodifferentiation

• Improvement of these systems

• Total synthesis of (S)-fluoxetine and (R)-tomoxetine

• Application to the preparation of Singulair© and an h-NK1 receptor antagonist

77

• Three methods :Chiral pool : most useful method when available

Enantioselective synthesis : most elegant method, but sometimes expensive, requires additional steps or substrate-dependent

Resolution : racemates are easier and less expensive to access but 50% of the material is lost

Preparation of Enantioenriched Compounds

88

About ResolutionAbout Resolution

• Three classes of resolution

A. Classical resolution : especially useful in salt formation with carboxylic acids and amines B. Chiral chromatography : principally for analytical or preparative scaleC. Kinetic resolution : particularly attractive when catalytic because of the need for only small amounts of chiral resolving agent

99

Selectivity FactorSelectivity Factor

• Efficacy of catalytic kinetic resolution is measured by the selectivity factor (s)

s = e∆∆G≠/RT = krel = kfast/kslow = ln[(1-c)(1 - ee)] ln[(1-c)(1+ ee)]where c = conversion

SS SRPS PR

chiral catalyst

kR = kfast

chiral catalyst

kS = kslow

Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5.

1010

Selectivity FactorSelectivity Factor

• The ee obtained is a function of conversion

Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5.

kkrelrel11

∆∆G≠

(kcal/mol)

1.51.5 0.240.24

22 0.410.41

55 0.950.95

1010 1.351.35

5050 2.312.31

100100 2.722.72

500500 3.663.661 1 at room temperature

• Enantioselective reaction of a prochiral substrate 5:1 ratio of products Therefore 67% ee

1111

The First Step Towards Palladium The First Step Towards Palladium Enantioselective Aerobic OxidationEnantioselective Aerobic Oxidation

• Uemura Conditions

OH

Pd

Py Py

AcO OAc

OPd(OAc)2 (5 mol%)Pyridine (20 mol%)

O2, MS 3ÅToluene 80°C

Active Catalyst

quant.

Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750.

1212

First reported Palladium First reported Palladium Enantioselective Aerobic OxidationEnantioselective Aerobic Oxidation

• Sigman, M. S. et al. J. Am. Chem. Soc. 2001, 123, 7475.

• Stoltz, B. M. et al. J. Am. Chem. Soc. 2001, 123, 7725.

OH OHPd(OAc)2 (5 mol%)(-)-sparteine (20 mol%)

O2, DCE 60°C, 24h

O

+

34 %98.2 % ee

66 %

OH OHPd(nbd)Cl2 (5 mol%)(-)-sparteine (20 mol%)

O2, MS 3Å, Toluene80°C, 96h

O

+

40 %98.7 % ee

60 %

s = 13

s = 23

1313

The Catalyst StructureThe Catalyst Structure

OH OHPd(MeCN)2Cl2 (5 mol%)(-)-sparteine (20 mol%)

O2, DCE 70°C, 24h

O

+

46 %86.9 % ee

54%

s = 17

Sigman M. S. et al. J. Am. Chem. Soc. 2001, 123, 7475.

N N

Pd

Cl Cl

Pd[(-)-sparteine]Cl2

1414

Pd(II) Catalytic CyclePd(II) Catalytic Cycle

HX

R OH

O R

HX

HX

R'

RR'

R-X

H2O2

O22 HX

LnPd0

Oxidation AlcoholBinding

-HydrideElimination

Reductive Elimination

LnPd0

MigratoryInsertion

-HydrideElimination

Oxidative AdditionLnPdIIR

XLnPdII

X

X

LnPdII

X

RR'

H

LnPdIIH

XLnPdII

H

X

LnPdIIO

X

R

H

Pd0 cycle PdII cycle

1515

Concerning the Alcohol BindingConcerning the Alcohol Binding


Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 4482.

AgSbF6 (1 equiv.)Pyridine (1 equiv.)DCM 23°C

N N

Pd

Cl Py

Exclusively

N N

Pd

Py Cl

Not Observed

N N

Pd

Cl Cl

Pd[(-)-sparteine]Cl2

N N

Pd

Cl

+ Cl -

DCE

+ SbF6- + SbF6

-

OH Pd[(-)-sparteine]Cl2 (5 mol%) No baseO2, DCE

OHPd[(-)-sparteine]Cl2 (5 mol%)(-)-sparteine (10 mol%)O2, DCE

O

+

46 %86.9 % ee

54%

s = 17

No Oxidation

1616

Alcohol Binding MecanismAlcohol Binding Mecanism

PdN N

Cl

* + Cl-

PdN

O

N

Cl

*

R R'

H

+ Cl-

R R'

OH

PdN

O

N

Cl

*

R R'

PdN

Cl

N

Cl

*

(-)-sparteine

(-)-sparteine HCl

LigandDissociation

AlcoholBinding

Deprotonation

AlcoholOxidation

1717

β - Hydride Elimination

• Looking at (-)-sparteine from a ligand point of vue

NNPd OClH R'

R

NNPd OH

R'

R

Cl

NNPdH O

R'R

N N

Pd

Cl

R R'

O

+ Cl -

NNPd ClH

N N

Pd0

ReductiveElimination

HClO

R

R'


1818

Pd (II) Regeneration MechanismPd (II) Regeneration Mechanism

• A direct hydroperoxide species formation is proposed

• Evidences for the peroxopalladium species

NNPd

O O

PhPh

2 HX NNPd

X X

PhPh

X = OAc, SO4

quant.

Uemura, S. et al. J. Org. Chem. 1999, 64, 6750.Stahl, S.S. et al. J. Am. Chem. Soc. 2001, 123, 7188.

LnPdIIH

X

O2 LnPdIIOOH

X

R OH H2O2

LnPdIIO

X

R

H

1919

Pd (II) RegenerationPd (II) Regeneration

HX

H2O2LnPdII

X

X

R OH

OR + 2 HX

HXLnPdII

O

O

O2

Substrate Oxidation

LnPd0 [Pd0] m- nL

MS 3ÅH2O + ½ O2

LnPdIIOOH

X

Oxygenation

Stahl, S.S. et al. J. Am. Chem. Soc. 2001, 123, 7188.

2020

HX

[O]

LnPdIIH

X

LnPdIIX

X

R OH

O R

LnPdIIO

X

R

H

HX

LnPd0

Oxidation AlcoholBinding

ß-HydrideElimination

ReductiveElimination

Rate Determining StepRate Determining Step

[O]

R OH

HX

Regenaration ofthe Catalyst

AlcoholBinding

Deprotonation-HydrideElimination

+ X -

Base

LnPdIIX

X

LnPdIIO

X

R

H

H

LnPdIIO

X

R

H

LnPdIIH

X

O R

ParameterParameter ResultsResults

[alcohol][alcohol] first orderfirst order

[(-)-sparteine] [(-)-sparteine] saturationsaturation

Hammett Hammett correlationscorrelations

= -1.41= -1.41

++ = -1.00= -1.00

KIEKIE 1.311.31

• The β-hydride elimination would be the rate determining step.


LnPdIIO

H

OMe

LnPdIIO

H

OMe

LnPdIIO

X H

HOMe

HO

D

+

+

+

2121

About SparteineAbout Sparteine

N NN

N

H

H

NN

I

II III

IV

• Lupin alkaloid• (-)-sparteine isolated from certain papilionaceous plants

such as Scotch broom• (-)-sparteine is commercially available (2.73 $/g)

• C1 symmetric ligand


I

II III

IV

2222

Enantioselectivity OriginsEnantioselectivity Origins

• Aromatic group prefers to rely in quadrant IV


N N

Pd

Cl Cl

Ph CF3

OH

N N

Pd

Cl

Ph CF3

O

NNPd OCl H

CF3

(1 equiv.)NaH (1 equiv.)

THF 23°C

I

II III

IV

2323

Enantioselectivity OriginsEnantioselectivity Origins


SPh

OH

NNPd OCl

H

RPh

OH

NNPd OH

Cl

NNPd OCl H

NNPd OH

Cl

NNPd OH

Cl

ONN

PdHPd[(-)-sparteine]Cl2

I

II III

IV

2424

Another Factor AffectsAnother Factor AffectsEnantioselectivityEnantioselectivity

Ph

OH

R

Ph

OH

S

kR

ks

Ph

O

Ph

O

Intrinsic krel = kR = 11 ks

Ph

OH

RPh

OH

S

+ Racemate krel = s = 25KineticResolution Ph

O


2525

Another Factor AffectsAnother Factor AffectsEnantioselectivityEnantioselectivity

Ph

OH N N

Pd

Cl

Ph

OH

N N

Pd

Cl Cl

R

N N

Pd

Cl

Ph

O

Ph

O*

* + Cl - *

k2R

(-)-sparteine (-)-sparteine HCl

k 1R

k -1R


Ph

OH

S

N N

Pd

Cl

Ph

OH

N N

Pd

Cl

Ph

O

* + Cl - *k2S

k 1S

k -1S



k -1R

k 2R= 170

k -1S

k 2S= 240

k 2R

k 2S= 11

2626

LimitationsLimitations

• R1 needs to be aromatic • R2 needs to be a methyl or a methylene• Long reaction times (>24h)• Need to be heated (>50OC)• Oxygen source need to be pure• Relativily high equivalents of (-)-sparteine are requiered (~20 mol%)• Sparteine is only easily available as a single antipode

N

N

H

H

N

NH

(-)-sparteine (+)-sparteine

H

(-)-sparteine

R1 R2

OH

O2, MS 3Å R1 R2

OH+

R1 R2

OPdII

2727

(+)-Sparteine Surrogate(+)-Sparteine Surrogate

• (+)-sparteine needs resolution to obtained from natural sources• Only one total synthesis of (+)-sparteine reported (15 steps, 16% yield)• Gram-scale quantities of diamine (+)-1 can be prepared in 3 steps with 79% overall yield.

Aubé, J. et al. Org. Lett. 2002, 4, 2577. O’Brien, P. et al. J. Am. Chem. Soc. 2002, 124, 11870.

OH

N

N

H

H

N

NH

OH

OHPd(nbd)Cl2 (5 mol%)(-)-sparteine (20 mol%)


25% 98%ee s = 8.9

59% 44%ee s = 6.8diamine (+)-1 (20 mol%)

(-)-sparteine (+)-1

2828

Resolution of Non-Benzylic Resolution of Non-Benzylic AlcoholAlcohol

RR11% %

conversionconversion % ee% ee

Selectivity Factor Selectivity Factor (s)(s)

ttBuOHBuOH DCEDCE

tBu 60.960.9 97.297.2 1717 7.17.1

cyclopropylcyclopropyl 59.059.0 82.682.6 9.19.1 5.55.51-1-cyclohexenylcyclohexenyl 67.967.9 95.495.4 9.09.0 7.07.0

• Using tBuOH increases both reactivity and enantioselectivity

Sigman, M. S. et al. J. Org. Chem. 2003, 68, 4600.

Pd[(-)-sparteine]Cl2 (5 mol%)(-)-sparteine (20 mol%)

O2, tBuOH65°C, 20h

R1

OH

R1

O+

R1

OH

2929

Use of an Achiral Exogenous Use of an Achiral Exogenous BaseBase

RR11% %

conversionconversion % ee% eeSelectivity Factor (s)Selectivity Factor (s)

NaNa22COCO33(-)-(-)-

sparteinesparteine

Ph 59.059.0 96.696.6 2020 1616tBu 42.342.3 51.251.2 9.39.3 1717

cyclopropylcyclopropyl 59.159.1 86.086.0 1010 9.19.11-1-cyclohexenylcyclohexenyl 68.168.1 92.392.3 7.67.6 9.09.0

• Carbonate bases can be used to form the alkoxide

Sigman, M. S. et al. J. Org. Chem. 2003, 68, 7535.

Pd[(-)-sparteine]Cl2 (5 mol%)Na2CO3 (50 mol%)

O2, MS 3Å, tBuOH65°C, 24h

R1

OH

R1

O+

R1

OH

3030

Oxidation with Air and at Room Oxidation with Air and at Room TemperatureTemperature

RR11 Time (h)Time (h) % conversion% conversion % ee% eeSelectivity Factor Selectivity Factor

(s)(s)AirAir OO22

24 62.362.3 99.899.8 2525 2727

24 56.756.7 93.093.0 2020 2323

1616 60.260.2 99.699.6 2828 2828

Pd(nbd)Cl2 (5 mol%)(-)-sparteine (12 mol%)

Cs2CO3 (0.4 equiv)Air, MS 3Å, CHCl3, r.t.

R1 R2

OH

R1 R2

O+

R1 R2

OH

• Tremendous reactivity using CHCl3 as solvent

Stoltz, B. M. et al. Angew. Chem. Int. Ed. 2004, 43, 353.

MeO

OH

F

OH

OH

3131

Other Aerobic Oxidative Kinetic Other Aerobic Oxidative Kinetic Resolution SystemsResolution Systems

O

N

PhO

N

Ph

Ru

NO

Cl

(R)

(R)1

RR11 SolventSolvent % conversion% conversion % ee% ee ss

chlorobenzene 64.764.7 94.994.9 1111

chlorobenzene 60.760.7 90.690.6 1111

toluenetoluene 57.857.8 82.182.1 1111

R1 R2

OH

R1 R2

O+

R1 R2

OHComplex 1 (2 mol%) h

• Photoactivated Ruthenium-Catalyzed Asymmetric Oxidation

Katsuki, S. et al. Chem. Rec. 2004, 4, 96.

OH

OH

OH

3232

RR11 RR22 Time (h)Time (h) % conversion% conversion % ee% ee ssPh EtEt 1010 5151 9999 >50>50

Bn 1616 5757 9292 1818i-Bu i-Pr 9090 5555 9898 3030TBSOCHTBSOCH22CHCH

22MeMe 144144 5151 9090 4242

R1

OHOR2

OR1

OOR2

O

R1

OHOR2

O tBu

tBu

OH

N OH

tBu

VO(OiPr)3 (5 mol%)

Ligand 2 (5.5 mol%)O2, Acetone, r.t.

+

2

Toste, F. D. et al. J. Am. Chem. Soc. 2005, 127, 1090.

• Vanadium-Catalyzed Asymmetric Oxidation of –Hydroxy Esters

Other Aerobic Oxidative Kinetic Other Aerobic Oxidative Kinetic Resolution SystemsResolution Systems

3333

Application of Oxidative KineticApplication of Oxidative KineticResolutionResolution

NHR HCl

O

CF3

NHMe HCl

O

NHMe HCl

O

MeO

CF3F3C

OF

MeN NNH

HNO

NCl S

CO2-Na+

HO

R = Me (S)-Fluoxetine (Prozac)R = H (S)-Norfluoxetine

(R)-Tomoxetine (R)-Nisoxetine

Montelukast Sodium (Singulair) Merck's h-NK1 receptor antagonist

3434

Formation of the Benzyl AlcoholFormation of the Benzyl AlcoholO

BrO

OEt

OH

OH

NHMe HCl

O

CF3

OH

OEt

O

NHMe HCl

O

OH

OTs

(R)-Tomoxetine

ZnBenzene

LiAlH4THF

85%

TsCl, Et3NDCM

-10 to 0°C

95%

85%

(S)-Fluoxetine

Ali, I. S.; Sudalai A. Tett. Lett. 2002, 43, 5435.

3535

Oxidative Kinetic ResolutionOxidative Kinetic Resolution

Ali, I. S.; Sudalai A. Tett. Lett. 2002, 43, 5435. Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081.

O

OTs

OH

OTs

OH

OTs

OH

NHMeaq. MeNH2THF, 65°C

95%

Pd(OAc)2 (5 mol%)(-)-sparteine (20 mol%)

O2, Toluene80°C, 36h

+

45% 47%95% ee

1. o-cresol, PPh3 DEAD, ether

-10 to 0°C

2. HCl (gas), etherNHMe HCl

O

1. NaH, DMAC, 90°C 2. p-chlorobenzotrifluoride 105°C3. HCl (gas), ether NHR HCl

O

CF3

(R)-Tomoxetine

(S)-Fluoxetine

94%

75%

s = 43

90% ee 23% overall yield

84% ee 29% overall yield

3636

Oxidative Kinetic Resolution for Oxidative Kinetic Resolution for AntidepressantsAntidepressants

Capsi, D.D.; Edner, D. C.; Bagdanoff, J. T.; Stoltz, B. M. Adv. Synth. Catal. 2004. 346, 185.

OH

NHBoc

NHMe

OH

O

NHBoc

NHBoc

OH

O

NHBoc

OH

NHBoc

OH

NHBoc

NH2

OH

TFAH2O

68%

LiAlH4THF,

78%

NaBH4EtOH

quant.



+

43%93% ee

FluoxetineTomoxetineNisoxetine

Norfluoxetine

s = 18

3737

Oxidative Kinetic ResolutionOxidative Kinetic Resolutionfor Singulairfor Singulair


HOOH

BrHOO

Br NaBH4EtOH, CH2Cl2

75%


Cs2CO3 (0.5 equiv.)O2, MS 3Å, tBuOH

+

29%99.9% ee

HOOH

Br

60°C, 4.5h

HOO

Br HOOH

Br

s = 15

HOOH

BrPd(OAc)2, P(o-tolyl)3Et3N, DMF, 100°C

Ar

90%

NClHO

OH

3838

Achievement of the Synthesis Achievement of the Synthesis of Singulairof Singulair

NClHO

OH

HSO

OMe

S

CO2-Na+

NClHO

Montelukast Sodium (Singulair)

1. MsCl, Et3N, Toluene -20°C2. Cs2CO3, MeCN

3. NaOH, H2O-MeCN

Zamboni, R.J. et al. J. Org. Chem. 1996. 61, 3398.

3939

Oxidative Kinetic Resolution for Oxidative Kinetic Resolution for Merck’s h-NK1 receptor antagonistMerck’s h-NK1 receptor antagonist


OHF

MeO2C

OF

MeO2C

OHF

MeO2C

OF

MeO2C

OHF

MeO2C

CF3F3C

OF

MeN NNH

HNO

OHF

MeO2C

Merck's h-NK1 receptor antagonist

NaBH4CeCl3 7H2O

EtOH, CH2Cl2

82%


Cs2CO3 (0.5 equiv.)O2, MS 3Å, tBuOH

+

45%99.5% ee

60°C, 1h

s = 51

4040

ConclusionConclusion

• Molecular oxygen, a readily-available and environmentallly friendly co-

oxidant can be used for oxidative kinetic resolution

• Sparteine possesses a unique ability for the enantiodifferentiation due to its

C1-symmetry

• Palladium-catalyzed oxidative kinetic resolution is a very practical

system where the reagents are very inexpensive and accessible

• Tuning the solvent and adding carbonate bases allowed resolution of allylic

and aliphatic alcohols and the usage of air as the oxygen source Pd(nbd)Cl2 (5 mol%)(-)-sparteine (12 mol%)

Cs2CO3 (0.4 equiv)Air, MS 3Å, CHCl3, r.t.

R1 R2

OH

R1 R2

O+

R1 R2

OH

4141

ConclusionConclusion

• Resolution can be useful when the racemates are obtained in few

steps and good yields

• This system can be employed for the enantioselective preparation of

a variety of pharmaceutical compounds

NHR HCl

O

CF3

NHMe HCl

O

NHMe HCl

O

MeO

CF3F3C

OF

MeN NNH

HNO

NCl S

CO2-Na+

HO

R = Me Fluoxetine (Prozac)R = H Norfluoxetine

Tomoxetine Nisoxetine

Montelukast Sodium (Singulair) Merck's h-NK1 receptor antagonist

4242

AcknowledgementsAcknowledgements

Prof. Louis BarriaultSteve Arns

Louis MorencyMélina GirardinMaxime Riou

Christiane GriséEffie Sauer

Rachel BeingessnerPatrick Ang

Nathalie GouletGuillaume Tessier

…and you!

1 applications of palladium-catalyzed aerobic oxidative kinetic resolution of alcohols in the...

Documents

cycle slide

ee slide

terminal oxidant slide

cholesterol oxidase

single antipode slide

alcohol binding mecanism

sparteine needs resolution

enantioselectivity sigman