Transcript Dynamic Kinetic Resolution

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
kSR=kRS=0
• Assume R is fast
reacting enantiomer
kS
kR
kR
+
+
G
S
PR
R
R
kS
PR
PS
S
energy diagram
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330.
PS
Kinetic Resolution
100
%ee
remaining
starting
material
25
10
5
∞
2
• 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
% conversion
ln[(1-C)(1-ee)]
kR
relative rate =
=
ln[(1-C)(1+ee)]
kS
+
+
= e G /RT
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.
Kinetic Resolution by Sharpless
Asymmetric Epoxidation
OH
Ti(OiPr)4,
L-(+)-DIPT,
t
BuOOH
(f ast)
O
OH
%ee
unreacted
alcohol
+
OH
55% conversion
>96% ee
Ti(OiPr)4,
L-(+)-DIPT,
t
BuOOH
(slow)
O
OH

60% conv.
ln[(1-C)(1-ee)]
ln[1-C)(1+ee)]
= kR/kS = 138
Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ideda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981,
103, 6237-6240.
Dynamic Kinetic Resolution
kS
kR
G
kinv
S
PS
R
energy diagram
PR
kR
R
kin v
r. d. s.
PR
kin v
+
+
• 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
kS
S
PS
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.
Dynamic Kinetic Resolution
kR
fast
R
kin v kin v
SEL100
kinv/kR
kR/kS
S
SEL(t) =
kS
slow
PRR + PRS
favored
PSR + PSS
PRR(t)
PRR(t) + PRS(t) + PSR(t) + PSS(t)
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
Dynamic Kinetic Resolution
kR
fast
R
kin v kin v
SEL100
SEL100
kinv/kR
kR/kS
S
SEL(t) =
kS
slow
PRR + PRS
favored
PSR + PSS
PRR(t)
PRR(t) + PRS(t) + PSR(t) + PSS(t)
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
Dynamic Kinetic Resolution
kR
fast
R
kin v kin v
SEL100
kinv/kR
kR/kS
S
SEL(t) =
kS
slow
PRR + PRS
favored
PSR + PSS
PRR(t)
PRR(t) + PRS(t) + PSR(t) + PSS(t)
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
kinv and kR
1
%ee
of
product
100
10
kinv/kR
% conversion
0.1
0.01
• 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.
Hoffmann Test
kS
kR
G
kinv
+
+
PS
R
R'
PR
kR
R
ER + EP
X
R
R'
kS
R
R'
PRR
PRS
ER
ES
+
R'
kS
R
R'
PSR
kR
ES
kinv
kinv
energy diagram
ER
+
R
S
ER + EP
X
+
+
PRR + PRS
G
/RT
=
= e
PSR + PSS
Hirsch, R.; Hoffmann, R. W. Chem. Ber. 1992, 125, 975-982.
R
R'
PSS
First Published Example of
Chemical DKR
O
H2
BINAP-Ru
O
3
1
R2
O
H2
BINAP-Ru
O
OR3
R2
S
R2
synRS
OH O
R1
OR3
R1
R2
antiRR
R
R1
OH O
+
OR3
R1
OR
R
OH O
OH O
+
OR3
R2
synSR
OR3
R1
R2
antiSS
R1, R3 = Me, R2 = CH2NHCOMe, (R)-BINAP-Ru
major product is synSR 98% de and ee
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.
Labeling Experiment
0% deuterium
O
O
O
O
OMe
D NHCOMe
70% deuterium
in recov ered
starting material
O
1.3% conv ersion
O
O
O
O
OH O
H2, 100 atm
(R)-BINAP-Ru
D
OMe
D NHCOMe
80% deuterium
O
OMe
NHCOMe
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.
Solvent Effects
SEL100
CH2Cl2
MeOH
% conversion
O
O
H2, 100 atm
OMe (R)-BINAP-Ru
solv ent
• Hydrogenation in
CH2Cl2 is much
slower than in MeOH
• In MeOH, kinv/kR =
0.04
• In CH2Cl2, kinv/kR =
0.44
OH
O
OMe
major product
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144-152.
Stereochemical Rationale
enantiomer
preference
diastereomer
preference
P
P
X
Ru
H
O OMe
O
H
n = 1,2,3
P
P
X
Ru
O
O
O
H
n
R1
H
N
H
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36-56.
R2
O
Dynamic Thermodynamic
Resolution
kSR,kRS > 0
kS
kR
S
R
PR
PS
energy diagram
kR
R
kRS
kSR
S
kS
PR
PS
• 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.
Dynamic Thermodynamic
Resolution
PivNLi Li.1
1. -25oC, 45 min
PivNH TMS
2. -78oC, 30 min, 0.45 eq. TMSCl
72% yield
94% ee
3. -25oC, 45 min
4. -78oC, 30 min, 0.45 eq. TMSCl
N
N
.
PivNLi Li 1
1
 Li*sparteine complex stable at -78oC,
but equilibrates at -25oC
Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718-5719.
Summary of Resolution
Reactions
Dynamic
Thermodynamic
Resolution
Dynamic
Kinetic
Resolution
Kinetic
Resolution
no equilibration
equilibration rate fast
compared to reaction
equilibration rate slow
compared to reaction
kSR,kRS > 0
kSR=kRS=0
kS
kR
kS
kR
kS
kR
kinv
S
S
S
R
R
PS
PS
R
PR
PR
PS
PR
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
protease from
Streptomyces
griseus
CO2Et
N
92% yield
85% ee
CO2H
N
pH 9.7
O
O
Fülling, G.; Sih, C. J. J. Am. Chem. Soc. 1987, 109, 2845-2846.
OH O
R
O
R
+
H
OR'
Enzyme
OAc O
69% yield
Acyl donor
R
OR' 99% ee
fast
OLi
Ru(II)
OR'
Enzyme
Acyl donor
OH O
R
OR'
slow
OAc O
R
Ru(II) =
Ph
O
Ph
Ph
Ph
Huerta, F. F.; Bäckvall, J.-E. Org. Lett. 2001, 3, 1209-1212.
OC
O
Ph
H
Ru
OR'
H
Ru
CO OC
Ph
Ph
CO
Ph
Nunami Chiral Auxiliary
Substrate Controlled DKR
Br
O
O
N
BnNH2
NMe
Br
CO2tBu
Et3N
THF
(fast)
O
O
N
NMe
87% yield
>98% de
NBn
CO2tBu
Bu4NI
Br
O
O
N
BnNH2
NMe
Br
CO2tBu
Et3N
THF
(slow)
O
O
N
NMe
NBn
CO2tBu
• Chiral auxiliary must be removed
• Starting material takes several steps to synthesize
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
Reagent Controlled DKR
DAGOH
Cl
O
S
S
O
Cl
O
pyridine DAGO S
(R,R)
THF, -78o
S
ODAG
DAGO
P r2NEt
toluene, -78o
toluene
t
S
(S,S)
BuO2CCH2Li
O
O
DAGOH
i
t
S
ODAG
S
R
(S,S)
O
BuO2CCH2Li
toluene
O
60% yield
R >98% de
S
>98% ee
O
O
R
S
(R,R)
O
70% yield
R >98% de
S
>98% ee
O
DAGOH = diacetone-D-glucose
O
HO
O
O
O
Stereochemistry controlled by base used
Khiar, N.; Alcudia, F.; Espartero, J.-L.; Rodríguez, L.; Fernández, I. J. Am. Chem. Soc. 2000, 122, 7598-7599.
Effect of Base on
Stereochemistry
N = py ridine
N+
S
ODAG
OH
OH
S
DAGO N+
-N
DAGO
O
S
ODAG
S
(R,R)
O
DAGOH
Cl
O
S
+N
S
O
Cl
+
-N
N
O
S
+
S
N
O
+
+
N
+
S
N
S
O
O
+
+
N
O
S
N+
S
O
DAGOH
N = iPr2NEt
N+
ODAG S
OH
S
ODAG
HO N+
O
-N
DAGO
S
ODAG
S
O
(S,S)
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.
Reagent Controlled DKR
Cp2Zr
carbonate
N R'
R
kin v
R'
N
Cp2Zr
kR
R
Ph
O
(fast)
Ph
kin v
N R'
HCl
O
O
R'
N
Cp2Zr
O
R
carbonate
O
Ph
Ph
NHR'
R
cat. NaOH, MeOH
O
R
Cp2Zr
O
O
Ph
O
kS
(slow)
HO
Ph
NHR'
MeO
+
R
HO
OH
Ph
Ph
O
Carbonate = O
Ph
O
Ph
Tunge, J. A.; Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1999, 121, 4520-4521.
Kinetic Studies
kslow
O
O
RSS
SRR
kslow
O
O
O
Ph
Ph
(R,R)
O
Ph
Ph
(S,S)
Cp2Zr
Cp2Zr
N R'
R (R)-1
N R'
R (S)-1
O
O
calculated relative observed
rate
de (%)
complex de (%)
O
O
Ph
Ph
(S,S)
O
RRR
SSS
kfast
relative rate =
kfast
kfast SSS + RRR
=
kslow SRR + RSS
1a
76
7.3
76
1b
90
19
90
1c
21
1.5
18
1d
74
6.7
71
1e
82
10.1
77
O
Ph
Ph
(R,R)
1a R' = R = Ph
1b R' = TMS, R = Ph
1c R' = TMS, R = iPr
1d R' = R = CH 2Ph
1e R' = TMS, R = CH 2iPr
Tunge, J. A.; Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1999, 121, 4520-4521.
Catalyst Controlled DKR
H MgCl
Ph
ClMg H
Ph
Br
NiCl2, L*
0oC
(f ast)
H
Ph
>95% y ield
>80% ee
R H
L* =
Me2N
PPh2
R=iPr, sBu, tBu
Br
NiCl2, L*
0oC
(slow)
Ph
H
Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195-2198.
Catalytic Cycle
NiCl2L*
Ph2
P
Ni
Ph2
P
Ni
N Br
Me2
+
Br
H
Ph
>95% y ield
81% ee
Br
Me2N
MgCl
Ph H
Br
Ph2
P
Ni
N
Me2
MgBrCl
H Ph
Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195-2198.
Catalyst Control of DKR
H
N
H
N
Cr
t
Bu
O
Cl
t
1. 0.2 eq.
t
O N3 O
t
Bu
Bu
Bu
(S,S)-1
(+)
0.5 eq. TMSN3, 16 hr.
2. 0.5 eq. TMSN3
slow addition, 16 hr.
Cl
OTMS
N3
76% y ield
97% ee
+ Cl
OTMS
Cl + N3
12% y ield
OTMS
N3
12% y ield
Schaus, S. E.; Jacobsen, E. N. Tetrahedron Lett. 1996, 37, 7937-7940.
Salen Catalytic Cycle
reaction cy cle
Cl
N3
Cr
O
racemization cy cle
Cl
OTMS
N3
(S,S)-1
Cl
Cr
O
Cr
O
Cl
O
Cl
O
Cl
Cr
N3
TMSN3
N3
Schaus, S. E.; Jacobsen, E. N. Tetrahedron Lett. 1996, 37, 7937-7940.
Cl
DKR in Small Library Synthesis
Br
(R,R)1, F9-tBuOH,
CH2Cl2, 4o-25o
Br
OH
O
R1 KOH, ether
O
R1
O
OH
O
85-99% ee
R1
H
N
H
N
Bu
O
t
Bu
O
OAc
t
R1'
O
Co
t
R2R3NH
Y b(OTf )3
(or Cu(OTf )2)
CH2Cl2
(S,S)1, F9-tBuOH,
CH2Cl2, 4o-25o
OH
O
O
Bu
=poly sty rene resin
(R,R)1
83 - 96% y ield R1'
>99% ee
R1
O
O
R2
N
R3
OH
Peukert, S.; Jacobsen, E. N. Org. Lett. 1999, 1, 1245-1248.
R1
O
OH
81-87% y ield
98% ee
KR vs. DKR
O
OMe
O
O
O
OMe
OMe
OMe
Me
OMe
OMe
OMe
Dynamic
Kinetic
Resolution
Kinetic
Resolution
OH
OH
OH
OH
Masti goph ore ne B
Mastigophorene B: Kinetic
Resolution
O
unreacted isomer
96% de
O
O
O
H Ph
Ph
OMe
OMe
OMe
OMe
OMe
OMe
(M)
slow reacting
58:42
OMe
N
OMe
(P)
fast reacting
O
B
Me
BH3.THF
OH
HO
OH
OH
OH
(M)
OH
Mastigophorene B
recycle
OMe
OMe
OMe
OMe (P)
46% yield
30% de
Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P,; Peters, K.; Peters, E.-M. Synthesis 2001, 155-167.
Mastigophorene B: Dynamic
Kinetic Resolution
H Ph
Ph
OMe
O
OMe
O
rapid
O
Me
OMe
OMe
(M)
fast reacting
N
O
B
Me
BH3.THF
O
Me
OMe
OMe
61% yield
94% de
(P)
HO
OH
OMe
OMe
OMe
(M)
slow reacting
OH
OH
OH
OH
Mastigophorene B
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.
Kinetic vs. Dynamic Kinetic
Resolution
CHO
I
OMe
OH
OMe
O
O
O
OMe
OMe
OMe
4% yield
17 steps
Me
OMe
OMe
(M)
Kinetic
resolution
O
1% yield
24 steps
OMe
(M)
50% yield
2 steps
62% de
(no recycles)
52% yield
5 steps
84% de
Dynamic
Kinetic
resolution
OH
OH
OH
OH
Mastigoph ore n e B
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.
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 you
Lei Jiang
Bill Lambert
John Campbell
Eric Voight
Greg Hanson
Melissa Feenstra
Joe Martinelli
Susie Martins
Jason Pontrello
John Herbert
Jen Slaughter
Whitney Erwin
Margaret Biddle
Jason Adasiewicz
Belshaw Group
Tolga Gulmen
Lisa Jungbauer