1 Applications of Palladium- Applications of Palladium- Catalyzed Aerobic Oxidative Catalyzed Aerobic Oxidative Kinetic Resolution of Kinetic Resolution of Alcohols in the Preparation Alcohols in the Preparation of Pharmaceutical Compounds of Pharmaceutical Compounds Roch Lavigne March 2 nd 2006
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1 Applications of Palladium-Catalyzed Aerobic Oxidative Kinetic Resolution of Alcohols in the Preparation of Pharmaceutical Compounds Roch Lavigne March.
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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
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
• 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.
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