Kinetic Resolutions
Material outline:
For the Scientist in you:
Definitions
Theoretical treatment
General References:
Vedejs, ACIEE, 2005, 3974
Jacobsen, Adv. Syn. Cat. 2001, 5
Kagan, Topics in Stereochemistry,
1988, 18, 249
For the technician in you:
Practical considerations
Useful KR s
Oxidative KR of allylic alcohols
An extreme example
Acylation/deacylation
Hydrogenation
olefins
ketones
Dynamic kinetic resolution
Epoxide ring opening
A very extreme example
Parallel kinetic resolution
Ready; Catalysis
Kinetic Resolution
Some definitions and examples
Resolution: A process leading to the separation of enantiomers, or
derivatives thereof
Simplest examples:
Resolution by making diastereomeric derivatives
O
CO2H
O
O
O
CO2H
OH
(+)-Menthol
+
enantiomers
(identical mp, mobilitiy on silica gel, bp, etc)
+
diastereomers
(different mp, mobility on silica gel, bp, etc)
Resolution via salt formation:
NH2
HO2C
+
NH2
NH2
NH2
CO2H
HO
OH
H2O/HOAc
(0.5 equiv)
NH3+ -O2C
NH3+
OH
+
NH3+ -O2C
(solid)
OH
-OAc2
NH3+
(soluble)
Larrow, Jacobsen, OS, 1998, 75, 1
1
Ready; Catalysis
Kinetic Resolution
Kinetic Resolution: One enantiomer reacts faster than the other:
OAc
+
Bu
kfast
OH
Bu
high ee product
50% yield max
H2O, Lipase
OAc
OAc
kslow
Bu
Bu
high ee unreacted sm
50% yield max
racemic mixture
slow reacting enantiomer
ΔΔG‡(slow - fast) = ΔG‡ (slow) - ΔG‡(fast)
Potential
Energy
fast reacting enantiomer
(S) + (R)- SM
minor product
Ready; Catalysis
krel = s = kfast/kslow = exp(ΔΔG‡/RT)
major product
Kinetic Resolution
Relationships between krel, ee and conversion
(1)
Calculated from eq 1
Important Points
1. KR can give any arbitrarily high ee recovered
sm with any krel >1 if you sacrifice yield
2. KR can give high ee product only if very high
krel (needs to be more selective than normal
asymmetric reaction
(Jacobsen, 2001)
2
Ready; Catalysis
Kinetic Resolution
Some thoughts:
-Sharpless, JACS, 1981, 6237
Ready; Catalysis
Kinetic Resolution
Note that eq 1 may not always hold:
Ln[(1-c)(1-ee)]
krel =
(1)
Ln[(1-c)(1+ee)]
It assumes rxn is first order in substrate, but consider simple enzyme kinetics:
Sub + Cat
Rate(R-sub) =
k1
k-1
Sub-Cat
k2(R)[Reagent][Cat]t[Sub]
KM + [Sub]
Reagent
k2
Product
KM = (k-1 + k2)/k1 ~ dissociation constant
Sub = substrate
For [sub]>>Km, rxn is 0 order in [sub]; equation 1 does not hold
For [sub]<<Km, rxn is 1st order, equation 1 needs modification:
kcat(R)KM(S)
Ln[(1-c)(1-ee)]
(2)
=
Relative rate = E =
kcat(S)KM(R)
Ln[(1-c)(1+ee)]
Eq. 2 is eq 1 normalized to binding affinity
Many (most?) KR s would likely show enzyme kinetics if anyone looked. Therefore they
may start out zero order, then change. Also, one enantiomer could be 1st order, while the
other is 0th order!
Hallmark of trouble is if krel (as calculated by eq 1) changes as a function of conversion
The real question is: what yield of what ee?
3
Ready; Catalysis
Kinetic Resolution
O
OH
OH
DIPT, Ti(OiPr)4
tBuOOH
47% recovered sm
94% ee
O
+M
Drawbacks to KR s
Max 50% yield
Poor atom economy
Viewed by some as inelegant
Ready; Catalysis
Kinetic Resolution
HO
R
R'
KR s may be useful if the following are true:
1.  Very high ee needed
2.  Racemate cheap; optically active hard to make
3.  Resolving agent cheap
4.  Products easily separable
5.  Catalyst cheap and works well
with D-(-)-DET
OH
EtO2C
CO2Et (cat)
(-)-diethyl tartrate (DET)
(unnatural isomer)
Ti(OiPr)4 (cat), 3AMS
OH
t
BuOOH (TBHP)
R
R'
O
OH
R'
R'
Katsuki, Sharpless,
JACS, 1980, 6237
General trend: asymmetric catalytic reaction disclosed; soon after KR disclosed
OH +
OH
c-C6H11 H (recovered,
48% y, 94%ee)
kslow
krel = 104
dr = 2:98
O
OH
c-C6H11 H
Epoxidation is enantiomer-selective and
diastereoselective
dr = 38:62
O
OH
c-C6H11 H
major product
O
O
OH
c-C6H11 H
with L-(+)-DET
Sharpless, JACS, 1981, 6237
improved (addn MS3A): JOC, 1986, 1922
relative rates: JACS, 1988, 2978
c-C6H11 H
kfast
OH
OH
c-C6H11 H
4
Ready; Catalysis
Kinetic Resolution
Ready; Catalysis
Kinetic Resolution
Examples: isolated products shown
(for a large list, see Adv. Syn Cat, 2001, 5, supporting info)
OH
TMS
C5H11 ~40%y,
99%ee
+ OH
47% y,
>98% ee
TMS
O
big trans group helps
40% y, 99% ee
OH
OH
Ph2P
18%y,
98%ee
HO
OH
OH
45% y
?? ee
OH
32% y
99% ee
O
36% y
95% ee
OH
OH
OH
~40 y
30% ee
+O
37% y
O >95% ee
+
Ph2P
H
OPh
OH
C5H11 ~40%y
99% ee
O
H3C
Bu3Sn
O
43% y OH
94% ee
NH
O
Bu +
O
O
Bu
46% y
+
46% y
47%y
NHTs 95% ee
O
(rxn not general for amines)
5
Ready; Catalysis
Kinetic Resolution
OH
2o KR
(+)-DIPT, Ti(OiPr)4, TBHP
0.36
slow
krel*:
0.62
OH
OH
O
O
ent-1
O
O
~0.98
OH
OH
O
O
O
epi-1
~0.98 slow
OH
O
OH
1
~102
OH
2.04
fast
OH
ent-epi-1
krel*: fast ~102
O
100
O
O
O
de = %(1 + ent-1) - %(epi-1 + ent-epi-1)
ee = %1 - % ent-1
predict ee and de will increase with conversion because of a secondary kinetic resolution
predicted
*krel calc using
OH
yield 1 (%)
ee 1 (%)
conversion
50
99
99.9
99.999
48
93 (max)
91
85
Ready; Catalysis
99.4
99.96
99.664
99.99999
c-Hex
Schreiber, JACS, 1987, 1525
Kinetic Resolution
Experimental validation
OH
time
3h
24 h
140 h
OH
BnO
OH
(+)-DIPT, Ti(OiPr)4, TBHP
-25 oC
OBn
ee
84
93
>97
(+)-DIPT, Ti(OiPr)4, TBHP
-25 oC
de
92
99.7
>99.7
O
OH
BnO
OBn
O
time
1h
3h
44 h
ee
93
95
>97
de
>97
>97
>97
6
Ready; Catalysis
Kinetic Resolution
Next-generation epoxidation??
1 mol% 1
TBHP (70% aq)
CH2Cl2
OH
51% conversion
Ph
potential advantages:
aqueous conditions
substrate classes inaccessible with Sharpless:
Ph
N
O
1=
N
O
O
OH
O
V
OH
Ph
93% ee
Ph
95% ee
Ph
O
O
OH
demonstrated with R = H
KR with R not H??
R
OiPr
R'
obvious disadvantage:
hard to beat tartrate
Ph
Ph
Yamamoto, ACIEE, 2005, 4389
Ready; Catalysis
Kinetic Resolution
Enzymatic acylation/deacylation of amines and alcohols
review: Chem Rev. 1992, 1071
NH2
O
+
R
R
NHAc
(rac)-
NH3 + HCN
R
CN
CO2H
H2O
porcine kidney acylase
(R = straight chain)
H2O
acylase from mold
Aspergillus oryzae
(R = branched)
NHAc
R
AA's produced by Degusa on commercial scale
MeO
CO2H
CO2H
CO2H
BnO
NH2
CH3
OMe
Ph
CO2H
BnS
NH2
NH2
NH2
CO2H
CO2H
NH2
F3C
CO2H
NH2
H3C
CO2H
NH2
H3C
CO2H
NH2
7
Ready; Catalysis
Kinetic Resolution
Enzymatic acylation/deacylation of amines and alcohols
review: Chem Rev. 1992, 1071
enzymes can be used to put Ac on or take Ac off. Isopropenyl acetate or vinyl acetate common
acylating agents
Enzyme 'kits' are available for screening purposes from SigmaAldrich and Biocatalytics
Rxns can be performed in water or organic solvents (hexane common); need exclude water from
esterification reactions
General rule: an enzyme will work for almost any substrate!!:
Cl
Some examples from ester hydrolysis (for details, see tables 8 - 12 in review):
OH
HO
Ph
OH
O
H3C
>95% ee
ent ester >95%ee
89% ee
OH
H3CO
N
OTs
OH
S
OEt
Cl
Ph
>97% ee
ent ester >97% ee
90%
OEt
S
>98% ee
OH
Ready; Catalysis
OH
99% ee
ent ester 99%ee
99% ee
ent ester 93% ee
Kinetic Resolution
Some products from acylation:
Note cleavage of ester or acylation of alcohol gives enantiomeric product
CH3
OAc
EtO2C
Ph
48%y, 98% ee
ent alcohol: 49% y, >98%ee
OAc
OAc OTBDPS
38% y, >98% ee
OAc
H3C
36%, >98% ee
ent alcohol 32%, 98%ee
extension to desymmetrization (often with 2o KR)
Ph
46%y, >95% ee
ent alcohol, 43%y, >95% ee
OAc
OBn
HO
OBn
OAc
O
CO2Me
AcO
OBn
70%, >95% ee
OH
98% ee
43% y, 92% ee
35% y, 99.4% ee
8
Ready; Catalysis
chemical methods for KR of alcohols
Kinetic Resolution
Fu, Accts, 2000, 412;
Accts, 2004, 542
NMe2
σ−plane
N
Fe
NMe2
Ph5
'planar chiral' version of DMAP
σ−plane
N
achiral
OAc
N
R
R'
Ac2O
OH
R
R'
N
+
O
Advantage: clever design
Idea extended to other asymmetric reactions
One of most selective small molecule cat s
Disadvantages: $3000/mmol
Fighting lipases and Noyori hydrogenation
Ready; Catalysis
Kinetic Resolution
Kinetic resolution via asymmetric hydrogenation (much more on asymmetric hydrogenation to come)
Ph2
P O
Ru
O
P O
Ph2
(<0.5 mol%)
OH
R
R
R
R
R
+
R
R
R
R
R
R
only useful when complementary to Sharpless
Pretty tough to separate products
Recovered allylic alcohols:
48%, 96% ee
OH
OH
H2
R
OH
O
OH
46%, >99% ee
OH
44%, 82% ee
OH
O
32%, 98% ee
Noyori, JOC, 1988, 708
9
Ready; Catalysis
Kinetic Resolution
1st (best?) example of dynamic kinetic resolution: racemization faster than reaction
O
O
R
RuX2((R)-BINAP)
H2, CH2Cl2
fast
OCH3
R
OH
O
R
OH
OCH3
O
R
R
OCH3
R
really fast
O
O
OH
O
slow
R
OCH3
R
OCH3
R
R
Products:
OH
O
OH
H3 C
OCH3
NHAc
O
P
H3C
P(OH)2
O
Br
98% ee, 9:1 d.r.
d.r. 1:99, 93% ee
Noyori,
JACS, 1989, 9134; 1993, 144; 1995, 2931
Ready; Catalysis
Kinetic Resolution
Jacobsen Hydrolytic kinetic resolution: background
R
R'
R
R
O
OCH3
O
H3C
OCH3
OCH3
O
OCH3
NHAc
d.r. 94:6, 98% ee
d.r. 99:1, 94% ee
O
O
OH
O
H3C
OCH3
NHAc
d.r. 99:1, 98% ee
OH
OH
O
R'
R
O
Mn
Nu-
M
R
proposed TS for asymmetric epoxidation
R
Lewis-acid catalyzed epoxide opening?
Asymmetric ring-opening of meso epoxides
(salen)CrCl
N
N
Cr
t-Bu
O
O
t-Bu
t-Bu
t-Bu
(cat)
TMSN3
R
R
Cl O
N3
N3
N3
N3
N3
OTMS
R
R
N3
O
OTMS
ee(%)
97
OTMS
OTMS
93
82
OTMS
92
Jacobsen, Accts, 2000, 421
OTMS
85
10
Ready; Catalysis
Kinetic Resolution
catalyst activation:
OAc
1/4O2/AcOH
Co
Co
-1/2 H2O
(salen)Co(II)
Aldrich: $93/5g
(salen)Co(III)OAc
hydrolytic kinetic resolution
O
R
OH
O
(R,R)-(salen)Co(OAc) (0.5 - 2 mol%)
H2O
+
+
R
Product diol
(0.45 equiv H2O)
Unreacted epox
(0.55 equiv H2O)
ee
yield
R
CH3
CH2Ph
t-Bu
CH2Cl
CH2OTBS
CO2Me
Ph
C CTBS
46
46
41
43
47
43
44
41
OH
R
>99
>99
>99
>99
>99
>99
>99
>99
yield
ee
krel
45
40
40
40
42
37
42
41
99
95
95
95
98
97
98
99
500
96
79
190
250
130
130
420
Procedure: JACS, 2002, 1307
Mechanism and improved procedure (CoOTs): JACS, 2004, 1360
Ready; Catalysis
Kinetic Resolution
Terminal epoxides undergo simple KR with Phenols; epibromohydrin is a special case:
OH
OH
+
O
Br
O
O
Br
Br
Br
74%, >>99%ee
(1.05 equiv)
(1 equiv)
O
(R,R)-SalenCo(III) (4mol%)
MS3A, LiBr
OH
(R,R)-SalenCo(III)
PhOH
PhO
OH
+
Br
PhO
Br
major
Br-
minor
BrOH
Br
Br
O
PhO
+
PhO
major
dyanmic kinetic resolution
O
minor
slow
fast
secondary
kinetic
resolution
OH
PhO
OPh
JACS, 1999, 6086
11
Ready; Catalysis
Kinetic Resolution
Parallel kinetic resolution: Theory
SMs
fast
P1S
slow
P1R
slow
P2S
fast
P2R
called 'parallel' because SM --> P1 is an (S)-selective
KR, SM --> P2 is an (R)-selective KR
+
SMR
Parallel kinetic resolution: example
Often make great exam questions; rarely make useful synthetic methods
Hoveyda, Tet, 1995, 4383
1 (cat)
EtMgBr
n-C6H13
O
+
O
H
48% y
OH 98% ee
fast
n-C6H13
ZrCl2
slow
1 (cat)
EtMgBr
n-C6H13
Et
fast
H
Et
1
H
n-C6H13
OH
48% y
98% ee
12