dynamic kinetic resolution: practical applications in synthesis valerie keller november 1, 2001
TRANSCRIPT
Dynamic Kinetic Resolution:Practical Applications in
Synthesis
Valerie Keller
November 1, 2001
Outline
• Types of resolution reactions– Kinetic Resolution (KR)– Dynamic Kinetic Resolution (DKR)– Dynamic Thermodynamic Resolution
• Types of DKR
• Case study of KR vs. DKR
Kinetic Resolution
• Assume R is fast reacting enantiomer
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330.
S R
PSPR
kSR=kRS=0
ΔΔG++
kSkR
energy diagramS
R PR
PS
kR
kS
Kinetic Resolution• ee of SM increases as time
increases, ee of product decreases as time increases
• Only when kR>>kS does the yield approach 50% and ee approach 100%
• In practice, one cannot maximize both high yield and high ee
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330.Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5-27.
%eeremainingstarting material
% conversion
∞
1002510
5
2
relative rateln[(1-C)(1+ee)]
ΔΔG /RT++
= =[(1- )(1- )]ln C ee kR= e
kS
Kinetic Resolution by Sharpless Asymmetric Epoxidation
Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ideda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981,103, 6237-6240.
OH Ti(OiPr)4, L-(+)-DIPT,tBuOOH
OH
OH
+
O
(fast)
Ti(OiPr)4, L-(+)-DIPT,tBuOOH
(slow)
OHO
= kR/kS = 13855% conversion>96% ee
ln[(1-C)(1-ee)]ln[1-C)(1+ee)]
%eeunreacted
alcohol
60% conv.
Dynamic Kinetic Resolution
• Assume R is fast reacting enantiomer
• Rates are pseudo 1st order
• S and R racemize at the same rate
• Reaction is irreversible
• Products do not racemize under reaction conditions
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36-56.Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
R
S
PR
PS
kR
kS
kinv kinv
r. d. s.
ΔΔG++
PS
S R
PR
kSkR
kinv
energy diagram
Dynamic Kinetic Resolution
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
SEL(t) = PRR(t)
PRR(t) + PRS(t) + PSR(t) + PSS(t)
SEL100
kinv/kR kR/kS
R
S
PRR
PSR
kR
kS
kinv kinv
+
+
PRS
PSS
favoredfast
slow
Dynamic Kinetic Resolution
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
SEL(t) = PRR(t)
PRR(t) + PRS(t) + PSR(t) + PSS(t)
SEL100
R
S
PRR
PSR
kR
kS
kinv kinv
+
+
PRS
PSS
favoredfast
slow
kinv/kR kR/kS
SEL100
Dynamic Kinetic Resolution
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
SEL(t) = PRR(t)
PRR(t) + PRS(t) + PSR(t) + PSS(t)kR/kSkinv/kR
SEL100
R
S
PRR
PSR
kR
kS
kinv kinv
+
+
PRS
PSS
favoredfast
slow
kinv and kR
• kR/kS = 6.14 (relative rate)
• If kinv>>kR, the S/R ratio remains steady
• If kinv < kR, R is consumed faster than it is replaced
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
% conversion
%eeofproduct
100 10
1
0.1
0.01kinv/kR
Hoffmann Test
Hirsch, R.; Hoffmann, R. W. Chem. Ber. 1992, 125, 975-982.
ΔΔG++
PS
S R
PR
kSkR
kinv
energy diagram
R R'
X
R R'
X
kinv kinv
kR
kS
ER + EP
ER + EP
R R'
ER
R R'
ER
PRR
PSR
R R'
ES
R R'
ES
PRS
+
+
PSS
PRR + PRS
PSR + PSS
ΔΔG /RT++
=kR ekS
=
First Published Example of Chemical DKR
Noyori, R.; Ideda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Sayo, N. Saito, T.; Taketomi, T.;Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134-9135.
R1, R3 = Me, R2 = CH2NHCOMe, (R)-BINAP-Ru major product is synSR 98% de and ee
R1 OR3
O O
R2
R1 OR3
O O
R2
R1 OR3
OH O
R2R1 OR3
OH O
R2
R1 OR3
OH O
R2R1 OR3
OH O
R2
+
+
H2BINAP-Ru
H2BINAP-Ru
R
S
antiRR synRS
synSR antiSS
Labeling Experiment
Noyori, R.; Ideda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Sayo, N. Saito, T.; Taketomi, T.;Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134-9135.
O
O
O
OMe
O
D NHCOMe
O
O
OH
OMe
O
D NHCOMe
O
O
O
OMe
O
NHCOMe
1.3% conversion
H2, 100 atm(R)-BINAP-Ru
80% deuterium
0% deuterium
70% deuteriumin recoveredstarting material
D
Solvent Effects• Hydrogenation in
CH2Cl2 is much slower than in MeOH
• In MeOH, kinv/kR = 0.04
• In CH2Cl2, kinv/kR = 0.44
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
O
OMe
O
OMe
OOHH2, 100 atm
(R)-BINAP-Ru
solvent
major product
SEL100
% conversion
CH2Cl2
MeOH
Stereochemical Rationale
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36-56.
enantiomerpreference
diastereomerpreference
O
O
R1 H
NO
Ru
X
PP
HR2
O
HO
O
HOMeRu
X
PP
H
nn = 1,2,3
Dynamic Thermodynamic Resolution
• First equilibrate to thermodynamically favored enantiomer
• Second rely on kinetic differences to enhance selectivity
• Rates of equilibration are not equal
• kR>>kS>>kSR, kRS
Beak, P.; Anderson, D. R; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715-727.
kSR,kRS > 0
kS
kR
SR
PS PR
energy diagram
R
S
PR
PS
kR
kS
kRS kSR
Dynamic Thermodynamic Resolution
Li*sparteine complex stable at -78oC, but equilibrates at -25oC
Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718-5719.
1. -25oC, 45 min
2. -78oC, 30 min, 0.45 eq. TMSCl
3. -25oC, 45 min
4. -78oC, 30 min, 0.45 eq. TMSCl
PivNH TMS72% yield94% ee
PivNLi Li.1
PivNLi Li.1
N N
1
Summary of Resolution Reactions
Kinetic Resolution
DynamicKinetic Resolution
DynamicThermodynamicResolution
kSR,kRS > 0
kS
kR
S
R
PS PR
S R
PSPR
kSR=kRS=0
kSkR
PS
S R
PR
kSkR
kinv
no equilibration equilibration rate fastcompared to reaction
equilibration rate slowcompared to reaction
Outline
• Types of resolution reactions
• Types of DKR– Enzymatic DKR– Substrate controlled DKR– Reagent controlled DKR– Catalyst controlled DKR
• Case study of KR vs. DKR
Enzymatic DKR
Huerta, F. F.; Bäckvall, J.-E. Org. Lett. 2001, 3, 1209-1212.
O
NCO2Et
O
NCO2H
protease fromStreptomycesgriseus
pH 9.7
92% yield85% ee
Fülling, G.; Sih, C. J. J. Am. Chem. Soc. 1987, 109, 2845-2846.
RuRu
R H
O
OR'
OLi+
R OR'
OOH
R OR'
OOH
R OR'
OOAc
R OR'
OOAc
Ru(II)
EnzymeAcyl donor
EnzymeAcyl donor
fast
slow
O OHPh
Ph
Ph
PhPhPh Ph
PhH
OC COCO OC
69% yield99% ee Ru(II) =
Nunami Chiral AuxiliarySubstrate Controlled DKR
O’Meara, J. A.; Jung, M.; Durst, T. Tetrahedron Lett. 1995, 36, 2559-2562.O’Meara, J. A.; Jung, M.; Durst, T. Tetrahedron Lett. 1995, 36, 5096
• Chiral auxiliary must be removed• Starting material takes several steps to synthesize
BnNH2
Et3NTHF
87% yield>98% deN NMe
OBr O
BrCO2
tBu
N NMe
OBr O
BrCO2
tBu
N NMe
OO
NBnCO2
tBu
Bu4NI
BnNH2
Et3NTHF
N NMe
OO
NBnCO2
tBu
(fast)
(slow)
Reagent Controlled DKR
DAGOH = diacetone-D-glucose
Stereochemistry controlled by base used
Khiar, N.; Alcudia, F.; Espartero, J.-L.; Rodríguez, L.; Fernández, I. J. Am. Chem. Soc. 2000, 122, 7598-7599.
O
HOO
O
O
O
ClS
SCl
O
O
DAGOH
DAGOH
iPr2NEt
toluene, -78o
pyridine
THF, -78oDAGO
SS
ODAG
DAGOS
SODAG
O
O
O
O
tBuO2CCH2Li
tBuO2CCH2Li
toluene
toluene RS
SR
O
O
RS
SR
O
O
60% yield>98% de>98% ee
70% yield>98% de>98% ee
(S,S)
(R,R)
(R,R)
(S,S)
Effect of Base on Stereochemistry
Fernández, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem. 1992, 57, 6789-6796.Khiar, N.; Alcudia, F.; Espartero, J.-L.; Rodríguez, L.; Fernández, I. J. Am. Chem. Soc. 2000, 122, 7598-7599.
ClS
SCl
O
ON+ S
SN+
O
O
+ +N+ S
SN+
O
ON+ S
SN+
O
O
SS
N+
OH
OH
N+DAGOODAG
SS
N+
ODAG
ODAG
N+HOOH
- N
- N
DAGOS
SODAG
O
O
DAGOS
SODAG
O
O
+ N
- N
N = pyridine
N = iPr2NEt
(R,R)
(S,S)
DAGOH
DAGOH
Reagent Controlled DKR
Tunge, J. A.; Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1999, 121, 4520-4521.
Cp2ZrN R'
R
Cp2ZrN R'
R
kinvkinv
kR
(fast)
kS(slow)
OO
O
Ph Ph
Carbonate =
carbonate
carbonate
Cp2ZrO
R'N
O
O
R
Ph
Ph
Cp2ZrO
R'N
O
O
R
Ph
Ph
HClHO O
NHR'
O
RPhPh
MeONHR'
O
HO OH
R
PhPh
+
cat. NaOH, MeOH
Kinetic Studies
Tunge, J. A.; Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1999, 121, 4520-4521.
Cp2ZrN R'
R
Cp2ZrN R'
R
RSSSRR
RRRSSS
O O
O
PhPh
O O
O
PhPh
O O
O
PhPh
O O
O
PhPh
kslowkslow
kfastkfast
(S,S)
(R,R)(S,S)
(R,R)
kfast
kslow=
SSS + RRRSRR + RSS
complexcalculated
de (%)relative
rate
1a
1b
1c
1d
76
90
7.3
19
1a R' = R = Ph1b R' = TMS, R = Ph1c R' = TMS, R = iPr1d R' = R = CH2Ph1e R' = TMS, R = CH2
iPr
21 1.5
(R)-1 (S)-1
observedde (%)
76
90
18
relative rate =
74 6.7 71
1e 82 10.1 77
Catalyst Controlled DKR
Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195-2198.
Ph
MgClH
Ph
HClMg
Br
Br
Ph
H
Me2N PPh2
R HNiCl2, L*0oC(fast)
NiCl2, L*0oC(slow)
L* =
>95% yield>80% ee
R=iPr, sBu, tBu
H
Ph
Catalytic Cycle
Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195-2198.
NiBrN
Me2
Ph2P Ni
Br
Ph2P
Me2N
MgCl
NiNMe2
Ph2P
PhHMgBrCl
Ph
>95% yield81% ee
BrH
NiCl2L*
+
Br
HPh
Catalyst Control of DKR
Schaus, S. E.; Jacobsen, E. N. Tetrahedron Lett. 1996, 37, 7937-7940.
NN
tBu tBuO O
tBu tBu
H H
Cr
N3
ClO
0.5 eq. TMSN3, 16 hr.
(S,S)-11. 0.2 eq.
2. 0.5 eq. TMSN3 slow addition, 16 hr.
(+)
Cl N3 Cl Cl N3 N3
OTMS OTMSOTMS
+
76% yield97% ee
12% yield 12% yield
+
Salen Catalytic Cycle
Schaus, S. E.; Jacobsen, E. N. Tetrahedron Lett. 1996, 37, 7937-7940.
ClO Cr
Cr
CrCr
N3
Cl N3
O
Cl N3
OTMS
Cl Cl
O
Cl
TMSN3
N3O
ClO
(S,S)-1
reaction cycle racemization cycle
DKR in Small Library Synthesis
Peukert, S.; Jacobsen, E. N. Org. Lett. 1999, 1, 1245-1248.
BrO
Br O
OH
R1
OR1
O
N O
OH
R1
O O
OH
R1 R2
R3
R1'
OH
R1
(R,R)1, F9-tBuOH,CH2Cl2, 4o-25o KOH, ether
R2R3NH
Yb(OTf)3
(or Cu(OTf)2)
CH2Cl2
(S,S)1, F9-tBuOH,CH2Cl2, 4o-25o
OH
R1'
83 - 96% yield>99% ee
81-87% yield98% ee
85-99% ee
NN
tBu OO O
tBu tBu
H H
Co
OAc
=polystyrene resin
(R,R)1
O
O
KR vs. DKR
OMe
OMeMe
OO
OMe O
O
OMe
OMeOMe
OMe
OH
OHOH
OH
Mastigophorene B
DynamicKinetic Resolution
KineticResolution
Mastigophorene B: Kinetic Resolution
Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P,; Peters, K.; Peters, E.-M. Synthesis 2001, 155-167.
OO
OMeOMe
OMeOMe
OO
OMeOMe
OMeOMe
HO
OMeOMe
OMeOMe
OH
OHOH
OHOH
NB
O
Me
H PhPh
Mastigophorene B
unreacted isomer96% de
BH3.THF
(M) (P)58:42
recycle
(P)46% yield30% de
slow reacting fast reacting
(M)
Mastigophorene B: Dynamic Kinetic Resolution
Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J.; Peters, K.; Peters, E.-M.; Rycroft, D. S.; Connolly, J. D. J. Am. Chem. Soc. 2000, 122, 9127-9133.
OMeOMe
Me
OMeOMe
Me
OO OO
OMe OMe
rapidN
BO
Me
H PhPh
OHOH
OHOH
Mastigophorene B
OMeOMe
OHOMe
HO
61% yield94% de
(M) (P)
BH3.THF
slow reactingfast reacting
(M)
Kinetic vs. Dynamic Kinetic Resolution
Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J.; Peters, K.; Peters, E.-M.; Rycroft, D. S.; Connolly, J. D. J. Am. Chem. Soc. 2000, 122, 9127-9133.
Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P.; Peters, K.; Peters, E.-M. Synthesis 2001, 155-167.
Kineticresolution
DynamicKinetic resolution
OO
OMeOMe
OMeOMe
OMeOMe
Me
OOOMe
1% yield24 steps
4% yield17 steps
OHOH
OHOH
Mastigophorene B
CHO
IOH
OMe
50% yield2 steps62% de(no recycles)
52% yield5 steps84% de
(M) (M)
Conclusions
• In situ racemization of dynamic kinetic resolution can compensate for limitations of kinetic resolution
• Ratios of kinv, kR, and kS important for ee of products
• Wide variety of reactions possible
Thank youLei Jiang John Herbert
Bill Lambert Jen Slaughter
John Campbell Whitney Erwin
Eric Voight Margaret Biddle
Greg Hanson Jason Adasiewicz
Melissa Feenstra Belshaw Group
Joe Martinelli Tolga Gulmen
Susie Martins Lisa Jungbauer
Jason Pontrello