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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
Sigman M. S. et al. J. Am. Chem. Soc. 2005, 127, 14817.
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'
Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 7971.
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.
Sigman M. S. et al. J. Am. Chem. Soc. 2003, 23, 7005.
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
Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 4482.
I
II III
IV
2222
Enantioselectivity OriginsEnantioselectivity Origins
• Aromatic group prefers to rely in quadrant IV
Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 4482.
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
Stoltz B. M. et al. J. Am. Chem. Soc. 2004, 126, 7971.
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
Sigman M. S. et al. J. Am. Chem. Soc. 2005, 127, 14817.
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
(-)-sparteine (-)-sparteine HCl
Ph
OH
S
N N
Pd
Cl
Ph
OH
N N
Pd
Cl
Ph
O
* + Cl - *k2S
k 1S
k -1S
(-)-sparteine (-)-sparteine HCl
Sigman M. S. et al. J. Am. Chem. Soc. 2005, 127, 14817.
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%)
O2, MS 3Å, Toluene60°C, 54h
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.
Pd(nbd)Cl2 (5 mol%)(-)-sparteine (20 mol%)
O2, MS 3Å, Toluene80°C, 24h
+
43%93% ee
FluoxetineTomoxetineNisoxetine
Norfluoxetine
s = 18
3737
Oxidative Kinetic ResolutionOxidative Kinetic Resolutionfor Singulairfor Singulair
Capsi, D.D.; Edner, D. C.; Bagdanoff, J. T.; Stoltz, B. M. Adv. Synth. Catal. 2004. 346, 185.
HOOH
BrHOO
Br NaBH4EtOH, CH2Cl2
75%
Pd(nbd)Cl2 (5 mol%)(-)-sparteine (20 mol%)
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
Capsi, D.D.; Edner, D. C.; Bagdanoff, J. T.; Stoltz, B. M. Adv. Synth. Catal. 2004. 346, 185.
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%
Pd(nbd)Cl2 (5 mol%)(-)-sparteine (20 mol%)
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!