dynamic kinetic resolution: a powerful approach to...
TRANSCRIPT
Dynamic Kinetic Resolution: A Powerful Approach toAsymmetric Synthesis
OCO2EtMeO
Ru(II)(R)-BINAPOH
CO2EtMeOH2
OHCO2EtMeORu(II)(S)-BINAP
H2
Rhizopus arrhizus
Baker's yeast
100% yield97% de, 96% ee
93% yield93% de, 86% ee
OHCO2EtMeO
OHCO2EtMeO
98% yield98% de, 99% ee
70% yield98% de, 95% ee
Erik AlexanianSupergroup Meeting
March 30, 2005
For leading references, see: Pellissier, H. Tetrahedron 2003, 59, 8291Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247
Methods for Asymmetric Synthesis
Catalytic enantioselective organic reactions
- Chemocatalysis - metal-mediated, Lewis acid-mediated, organocatalysis- Biocatalysis - enzymes (hydrolases)
Resolution
Synthesis utilizing existing stereogenic centers (chiral substrates or auxiliaries)
- Conventional separation procedures- Kinetic resolution
SRkR PR
kSSS PS
Problems associated with standard kinetic resolutions:
- Theoretical yield = 50%
- Separation of product from remaining substrate required
- In the majority of processes, only one stereoisomer is desired
- Drop in enantiomeric purity as process nears 50% conversion
100
50
00 50 100
% ee
% conversion
E = kfast/kslow = 10
ee P
ee S
Dynamic Kinetic Resolution
SRkR PR
kSSS PS
100
50
00 50 100
% ee
% conversion
E = kfast/kslow = 10
ee Pee S
SRkR PR
kSSS PS
Classic Resolution Dynamic Resolution
ee P DKR
kinv
PRPS
SR
SS
kinv
kS
kR ∆∆G
If racemization can occur concurrently with kinetic resolution, then theoretically 100% of the racemic mixture can be converted to one enantiomer. This process is known as dynamic kinetic resolution (DKR).
DKR is an example of a Curtin-Hammett system in which the composition of products is controlled by the free energies of the transition states and not the composition of the starting materials.
Guidelines for Dynamic Kinetic Resolution
SRkR PR
kSSS PS
Dynamic Resolution
kinv
In order to design a successful DKR, both the inversion and resolution steps have to be carefully tuned. Here are a few established general guidelines for an efficient DKR:
(1) The kinetic resolution should be irreversible in order to ensure high enantioselectivity.
(2) The enantiomeric ratio (E = kR/kS) should be at least greater than ~20.
(3) To avoid depletion of SR, racemization (kinv) should be at least equal or greater than the reaction rate of the fast enantiomer (kR).
(4) In case the selectivities are only moderate, kinv should be greater than kR by a factor of ~10.
(5) Obviously, any spontaneous reaction involving the substrate enantiomers as well as racemization of the product should be absent.
Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry 1999, 10, 107
Examples of Racemization
1) Acid or base catalyzed racemization
2) Enzyme catalyzed racemization
The racemization/inversion step is key to a successful DKR. Following are a number of common techniques used for this step.
NO
R
O
Ph
CALBNEt3, R'OH
HN
OPh
R
COOR'
up to 96% yieldup to 98% ee
R1 R2
OHDehydrogenase
(reversible)
NAD(P)+ NAD(P)H
R1 R2
ORedox-Enzyme
(irreversible)
R1 R2
OH
Examples of Racemization (Cont'd)3) Schiff base-mediated racemization
4) Racemization via sp2 intermediates (redox, addition/elimination)
H2N CO2R
R1 Alcalase
t-BuOH/H2O (19:1) H2N CO2H
R1
90-98% ee, 87-95% yield
pyridoxal 5-phosphate
NCO2R
R1
CH
NCO2R
R1
CH2NH+
OH
O H
OPO
OO
pyridoxal 5-phosphate
R
OH
X
High pH
R
O
X
Lipase
Acyl donorR
OAc
XX = SR', OR', NHR', CN
R1 R2 R1 R2
XH
[M]R1 R2
X
[M]HH
+X
H[M]H
H
Examples of Racemization (Cont'd)5) Anionic interconversion
6) Racemization via π-allyl intermediates
O N
Ets-BuLi
(-)-sparteine
ONLi L
ONLi L E
ONE
R2R1
Nu
[ M ] R2R1
MNu R2R1
Nu
7) Racemization via SN2 processes
CO2Me
BrC. rugosa
PPh3 BrCO2H
Br
79% ee, 78% yield
The "Catalytic Triad" - Reaction Mechanism of CALB
N N
His224
H
Asp187
O O
Ser105OHO
O
R2R1
N N
His224
H
Asp187
O O
Ser105OH
OO
R2
R1
O
O
R2
R3
R4
N N
His224
H
Asp187
O O
Ser105OH
OO
R2
R3
R4
R3 R4
OHR1OHN N
His224
H
Asp187
O O
Ser105OH
O
R2O
R1
Pamies, O; Backvall, J-E. Chem. Rev. 2003, 103, 3247
Enzymatic Methods - Reductions of β-Ketoesters
Pellissier, H. Tetrahedron 2003, 59, 8291
H3C
OH O
OEt H3C
OH O
OEt
OHCO2Et
OHCO2Et
OHCO2Et
OMe
OHCO2Et
O
OH
O OO
OHCO2EtBocN
OHO
MeOS
OH O
OMe
1 2 3 4 5
6 7 8 9 10Product Microorganism Yield (%) de (%) ee (%)
1
2
3
4
5
6
7
8
9
10
G. candidum
Baker's yeast
M. racemosus
Saccharomyces sp.
Baker's yeast
K. magna
Y. lipolytica
Dipodascus sp.
Baker's yeast
Baker's yeast
80
94
75
95
72-85
80
95
80
74
71
Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475
98
92
98
98
99
100
-
-
98
-
98
99
99
98
99
94
95
99
98
85
Enzymatic Methods - Other Selected Reductions
Pellissier, H. Tetrahedron 2003, 59, 8291
1 2 3 4
5
Product Microorganism Yield (%) de (%) ee (%)
1
2
3
4
5
6
7
8
Baker's yeast
Baker's yeast
Baker's yeast
S. montanus
Baker's yeast
R. arrhizus
M. isabellina
M. isabellina
88
82
76
89
95
97
92
100
100
76
-
-
96
98
72:28 dr
92
96
99
80
97
98
99
99
99
OH O
SEt
OHCN
OHSO2Ph
S
OH OH
C5H11
OHCO2Et
OH
OH O
NH2
OH O
NHBn
OH
CN
6 7 8
MeO
Enzymatic Methods - Hydrolysis
H2N CO2R
R1 Alcalase
t-BuOH/H2O (19:1)H2N CO2H
R1
90-98% ee, 87-95% yield
pyridoxal 5-phosphate
NH+
OH
O H
OPO
OO
pyridoxal 5-phosphate
Amino acid synthesis
S N
NH2
CO2HP. thiasolinophilum CO2HHS
NH2
100% ee, 100% yield
N O
Ph
OLipozyme
Et3N/BuOHToluene N
HCO2Bu
O
Ph H2N CO2HL-(S)-tert leucine99.5% ee, 94% yield
Many other useful hydrolysis systems
ON
CO2Et S. griseusbuffer pH 9.7
ON
CO2H
(S) - keterolac85% ee, 92% yield
Stecher, H.; Faber, K. Synthesis 1997, 1
Enzymatic Methods - EsterificationsDKR of Hemiacetals, cyanohydrins, and derivatives
Many other esterifications
Taniguchi, T.; Ogasawara, K. Chem. Commun. 1997, 1399
R
OH
X
High pH
R
O
H
Lipase
Acyl donorR
OAc
XX = SR', OR', NHR', CN
OH
SBuO
MeO P. cepacia
OAc TBME,
SiO2
OAc
SBuO
MeO
> 95% ee, 63% yield
OH
OH O
OHH
O
OAcH
97% ee, 75% yield
fastslow
O
HO H
O
AcO H
Conditions: Lipase, vinyl acetate, Et3N
Other Enzymatic Methods via DKRDKR applied to microbiological Baeyer-Villiger oxidation
O
OBn O
O
OBn
O
OBnO
O
OBn
fastslow
recombinantE.coli, pH 9
96% ee, 85% yield
Chemoenzymatic DKR of Phenylglycine Methyl Ester
O
OMeNH2 CALB (Candida antarctica lipase B)
NH3, tert-butanolN
HOOH
OOH
O or
O
NH2
NH2
88% ee, 85% yield
DKR combining enzyme and racemization via SN2 displacement
O
OEtCl
C. cylindracea lipaseR'NH2, PPh3 Cl
O
NHR'Cl
up to 86% ee, up to 92% yield
Berezina, N.; Alphand, V.; Furstoss, R. Tetrahedron: Asymmetry 2002, 13, 1953Wegman, M. A.; Hacking, A. P. J.; Rops, J.; Pereira, P.; van Rantwijk, F.; Sheldon, R. A. Tetrahedron: Asymmetry 1999, 10, 1739Badjic, J. D.; Kadnikova, E. N.; Kostic, N. M. Org. Lett. 2001, 3, 2025.
Combination of Enzymes and Transition Metals in DKR
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247
Question: Why use anything other than simple enzymes and nonmetallic racemization methods?
Answer: These DKR approaches are mainly limited to substrates that possess a stereogenic centerwith an acidic proton.
R2R1
Nu
[ M ] R2R1
MNu R2R1
Nu
R1 R2 R1 R2
XH
[M]R1 R2
X
[M]HH
+X
H[M]H
H
A Possible Solution: Transition Metal-Catalyzed Racemizations
Shvo's Catalyst - Mechanism of Action
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247
Ph
PhPh
Ph
O
Ru HOC
OC
Ph
PhPh
Ph
O
RuCO
CO
H
Shvo's Catalyst
OHPh
Ph Ph
Ph
RuOC
OCH
OPh
Ph Ph
Ph
RuOC
OC
+
OPh
Ph Ph
Ph
RuOC
OC
OH
R H*R'
OHPh
Ph Ph
Ph
RuOC
OCH*
R R'
OOPh
Ph Ph
Ph
RuOC
OC
OH
R R'H*
+ + +
Combination Enzyme-Metal Catalysis - DKR of Alcohols/Diols
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247
R1
OH
R2
CALBp-Cl-C6H4-OAc (3 equiv)
Shvo's Ru Cat. (2 mol%)PhCH3
R1
OAc
R2
78-92% yield91- >99% ee
OAc OAc OAcOAcO
OAc OAcOAc
5
80%, >99% ee 80%, 98% ee 77%, >99% ee 88%, >99% ee 79%, >99% ee 65%, >99% ee 90%, >97% ee
OH
OH
CALBp-Cl-C6H4-OAc (3 equiv)
Shvo's Ru Cat. (4 mol%)PhCH3
OH
OH
OH
OH
+
(R,R)-product meso-product
86 14:
63%, >99% ee
OAc OAc
OAc OAc
OAc
OAc
OAcAcO
NOAcOAc
NBn OAcOAc
90%, >99% ee(R,R:meso)
(38:62)
63%, >97% ee(90:10)
43%, >99% ee(74:26)
78%, >99% ee(100:0)
77%, >99% ee(98:2)
64%, >96% ee(89:11)
Enzyme-Metal Catalysis - DKR of Hydroxy Acid Derivatives
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247
3) P. cepacia lipase
p-Cl-C6H4-OAcShvo Cat. (6 mol%)
TBME, 60 oC, 6d
O
R H
O
OEt+
1) LDA/THF2) NH4Cl sat. 2 equiv.
R OEt
OAc O
up to 82% yieldup to 99% ee
O
R H
OLi
OEt
C-C bond
formation
R OEt
OH O
R OEt
OH O
R OEt
OAc O
R OEt
OAc O
EnzymeAcyl donor
Fast
EnzymeAcyl donor
Slow
+
Minor
MajorRu - catalyzedracemization
R
OH
CO2R'
P. cepacia lipaseShvo Cat. (2 mol%)
p-Cl-C6H4-OAc (3 equiv)Cyclohexane
R
OAc
CO2R'
R = alkyl, arylR' = Me, Et
60-80% yield30-98% ee
Tandem Aldol Reaction/DKR
DKR of Racemic α-Hydroxy Esters
Huerta, F. F.; Backvall, J.-E. Org. Lett. 2001, 3, 1209
Enzyme-Metal Catalysis - Other Alcohol DKRs
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247
Azido Alcohols
Hydroxy Nitriles
Halo Alcohols
Allylic Alcohols
N3
OH CALBShvo's catalyst (4 mol%)
p-Cl-C6H4-OAc (3 equiv)PhCH3
N3
OAc
86%, >99% ee
CNOH
7
CALBShvo's catalyst (4 mol%)
p-Cl-C6H4-OAc (3 equiv)PhCH3
CNOAc
7
93%, 92% ee
ClOH
CALBShvo's catalyst (4 mol%)
p-Cl-C6H4-OAc (3 equiv)PhCH3
ClOAc
74%, 91% ee
Pr
OH
Pr
OAc
83%, 95% ee
P. cepacia lipaseRu catalyst (4 mol%)
p-Cl-C6H4-OAc, Et3NCH2Cl2
RuCl Cl
HRuCl
Enzyme-Metal Catalysis Utilizing Palladium
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247
PhOAc
PF lipase37-40 oC, pH 7.0
0.1M phosphate bufferPdCl2(MeCN)2 (5 mol%)
19 days
PhOH
81%, 96% ee
DKR of Allylic Acetates
DKR of Amines
NH2Pd/CCALB
Et3N, EtOAc
NHAc
64%, 99% ee
NH2
Ph+ Pd NH
Ph
HPdH
PdH2NH
Ph
Ph
NH2HN
PhN
Ph
PhNH
Ph
Ph+Pd
+
- NH3PdH2
Challenges w/Enzymatic DKR
Question: Why use anything other than enzymatic systems with DKR?
Answer: There are currently a number of serious drawbacks towards applications of this technology.
Since enzymes and chemical catalysts usually work in different environments, their combinationin a one-pot transformation in far from straightforward.
For instance, with lipase catalyzed DKRs with transition-metal catalysts, solvents, metal, acyl donor,and temperature all need to be optimized.
The necessary chiral recognition by enzymes can place significant constraints on substrate scope.
M L
OHH
Finally, the achilles' heel: in many cases only one enantiomer is accessible.
Potential Solution: Enzyme-free DKR!
Using Chiral Auxiliaries in DKR
SRkR PRR
kSSS PSR
kinv
PSS
+
+
PRS
R*
O
X
Nuslow R*
O
Nu
R*
O
X
addition-inducedepimerization
NuFast R*
O
Numajor
O
OHO
H3CN N
O
CO2tBu
NSO2
N
O
Me
O
H3CN N
O
PhMe
R* =Durst Nunami
Ward
Devine
Caddick & Jenkins
N N
O
PhMe
OMe
Br
MeN N
O
PhMe
OMeMe
CH(CO2Me)2
N N
O
PhMe
OMeMeNaCH(CO2Me)2
TBAITHF
BnNH2
TBAIEt3N / THF
100%, 74% de
NHBn
78%, 40-60% de
Caddick, S.; Afonso, C. A. M.; Candeias, S. X.; Hitchcock, P. B.; Jenkins, K.; Murtagh, L.; Pardoe, D.; Gil Santos, A.; Treweeke, N.; Weaving, R. Tetrahedron 2001, 57, 6589
DKR Utilizing Configurationally Labile Anions
Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J. Am. Chem. Soc. 1999, 121, 9522
Ph
NArBoc
n-BuLi / (-)-sparteine
PhCH2Br NBocArPh
HPh
84%, 96% ee
R
NArBoc
LiL*
R
NArBoc
LiL*
R
NArBoc
LiL*
R
NBocAr
HH
NBocAr
E
HRenantioenriched
E
E
asymmetricsubstitution
asymmetricdeprotonation
RLi / L*
RLi / L*
Ratio of products identical with racemic or enatiomerically pure electrophile
Ph Me
Li Ph
O
HNBn2
+ Ph
OH
NBn2
PhPh
OH
NBn2
PhPh
OH
NBn2
PhPh
OH
NBn2
Ph
60% 21% 13% 6%
Hoffmann, R. W.; Ruhl, T.; Chemla, F.; Zahneisen, T. Liebigs Ann. Chem. 1992, 719
DKR with Boron Electrophiles
Sturmer, R. Angew. Chem. Int. Ed. Engl. 1990, 29, 59Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475
ClMg OPrOB
O Cy
Cyi
B O
OCy
Cy PhCHOPh
OH
71%, 94% ee89%, 94% de
O N
O O
O N
O OLi
O N
O O BOOB
OO
BrLDANaI (cat), 18-Crown-6
100%, >97% de
Ruthenium-Catalyzed Hydrogenation of β-Ketoesters
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995 68, 36
Ru-catalyzed DKR has been developed into a powerful transformation of very broad scope
O O
OMe
NHBz
[RuCl2((R)-BINAP)]2Et3N
H2 , 100 atm
syn:anti = 94:698% ee
OH O
OMe
NHBz100% conv.
N
OH
O
SR
CO2Hcarbapenems
O
OO[RuCl((R)-BINAP)(C6H6)]Cl
H2 , 100 atm O
O
H
OH
96% de, 94% ee
OO
H
O
H3C
Ru
X
H
[(R)-binap]
Cl
CO2H
BnO
ClBnO
O
CO2MeAcHN
ClBnO
OH
CO2MeAcHN
(R)-MeO-BIPHEPRuBr2H2 , 140 bar
100% yield, 95% de, 80% ee(enantiomerically pure after
two recrystallizations)
Ph
O O
OEtCl
[(R)-BINAP]Ru(II)
H2 , 80 bar Ph
OH O
OEtCl
90% de, 88% ee
diltiazem (a potent channel blocker)
Ruthenium-Catalyzed Hydrogenations (Cont'd)
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995 68, 36
[(S)-BINAP]Ru(II)O
P(OCH3)2
O
Br
H2
MeOH
OHP(OCH3)2
O
Br O
PH3CO
OHOH
HH
fosfomycin80% de, 98% ee
O
PhO
Ph
Ph
Ph
TsN
NTs
RuCl
H2, HCO2H, Et3N
OH
PhOH
Ph
100%, 97% de, >99% ee
O O
NOMe
Ru(S-C3-Tunephos)
MeOH, 50oC100 bar
OH O
NOMe
>99% ee, anti:syn >97:3
PPh2
PPh2
O
On
(S)-Tunephos
Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004 126, 1626
DKR via Cross-Coupling
Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475
Ph
MgClBr
cat. NiCl2 / L* PhL* =
PPh2Me2N
R
(R = iPr, sBu, tBu)
H
>95%, >80% ee
MgCl
Ph CH3H
MgCl
Ph HCH3
NiLL
Ph HCH3
Ni(L2)(Br)NiLL
Ph CH3H
Ph CH3H Ph H
CH3
BrBr
MgBrCl MgBrCl
Pd
DKR via Pd-Catalyzed Allylic Substitution
Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543
OBocO O
O
OEtO O
I
H3CO OH
O OROH
OO
O
O O
H3CO
H
H
6 steps
Aflatoxin B
+ R OH
2.5 mol% Pd2dba37.5 mol% L*
30 mol% Bu4NCl
R = HNNHOO
PPh2 Ph2P
L* =
O OOR
O
O O
LLPd
O O
LL
O OPdL2 O ONuNu
racemization via η3-η1 complexes
Pd
L*
89%, >95% ee
DKR via Asymmetric Conjugate Reduction
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 2892
OR
R'
10 mol% CuCl/(S)-p-tol-BINAPNaOt-Bu (1.7 equiv)
tBuOH (5.0 equiv), PMHS (2.2 equiv)PhCH3, 26 h, then TBAF
OR
R'R = alkylR' = alkyl, aryl de = 82-93%, ee=91-94%
OR
R'
OR
R'
OTMSR
R'
OTMSR
R'
OR
R'
OR
R'
very fastNaOR, ROH
[H]fast
F
F[H]slow
DKR Utilizing Organocatalysts
Berkessel, A.; Cleemann, F.; Mukherjee, S.; Muller, T. N.; Lex, J. Angew. Chem. Int. Ed. Engl. 2005, 44, 807
DKR of azlactones using urea-based bifunctional organocatalysts
RNH
O
NH
NR2
NO
O
R1
H
R2
H-bond donor
* chiral spacer
Bronsted base
RNH
O
NH
NR2
NO
O
R1
H
R2
H-bond donor
* chiral spacer
Bronsted base
OR3
H
NO
O
Ph
R catalyst (5 mol%)allyl alcohol (1.5 equiv)
PhCH3, RT, 48 h Ph NH
Oallyl
O
O
R H
R = PhCH2, Me, iPr, iBu, tBu, Ph 43-96% conversion, 72-87% ee
NMe2
NH
O
NH
CF3
F3C
urea-based catalyst
DKR Utilizing Organocatalysts
Tang, L.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2870
Asymmetric Synthesis of α-Hydroxy Carboxylic Acids
OO
O
O
RO
OEtOH
R (DHQD)2AQN (10 mol%)
EtOH (1.5 equiv), Et2O
R = aryl61-85% yield60-96% ee
HNR3* OO
O
O
R+
OO
O
O
HR
OO
O
O
HR
O
OR'OH
R
O
OR'OH
R
R'OH, NR3*
R'OH, NR3*
fast
slow
Racemization rate with R=alkyl was too slow to allow for efficient DKR