Module 9: Enzymes in Functional
G Tf ti
G
roup
T
rans
f
orma
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Lecture23:
Enzymes in
Functional Group
Transformation
1
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Enzymes in Functional Group Transformation: Lipases in Asymmetric Synthesis, Slides of Biochemistry
An in-depth exploration of enzymatic kinetic resolution (ekr) and enantioselective enzymatic desymmetrization (eed) in the context of lipases in asymmetric synthesis. It covers the mechanisms, substrates, and examples of these reactions, as well as the calculation of the enantioselectivity factor. Additionally, it discusses the importance of acyl donors in acylation reactions and their role in achieving high yields.
Typology: Slides
2011/2012
1 / 12
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Module 9: Enzymes in Functional
G
T
f^
ti
Group TransformationLecture23: Enzymes in
Functional Group
Transformation
Lipases in asymmetric synthesis
1. EKR (enzymatic kinetic resolution)
A^
B^
+^
C
racemic
fast reactingenantiomer
slow reactingenantiomer
E
enantiomer
enantiomer
2. EED (enantioseletive enzymatic desymmetrization)
Maximum 50% yield can be obtianed for individual enantiomers
XH XH
XY XH
XH
XH
XY
XH
hi^
l
E^
E
pro-chiralX = O, NH, SH
enantiopure
meso
enantiopure
Maximum 100% yield can be obtained for individual enantiomers
3. Dynamic kinetic resolution (DKR)
A^
(+)-product E^
*A and A' are enantiomers; racemization can be done enzymaticallyor by means of other methods.
A'^
(-)-product X
or by means of other methods.* Maximum 100% yield can be obtained for individual enantiomers
Acyl donors for acylation reactions
CH^3
7
O^
CF^3
O
C H
S
O
O^
N
O^
O
Acyl
donors for acylation reactions
3 7
3
CH^7
15
S^
O
biacetyl monooxime acetate
S-Ethylthiooctanoate
trifluoroethyl butyrate
O
O^
R
O
O^
O
O^
O^
O^
O
O
R = H; Vinyl acetateR^
M^
i^
l
Succinic anhydride
acetic anhydride
diketene
R = Me, isopropenyl acetateR = Oet; 1-ethoxyviyl acetate
* Th
id
l^
l d^
h^
ld b
i^
i
^ The ideal acyl donor should be inexpensive Acylate quickly and irreversibly in the presence of lipase* Completely unreactive in the absence of lipase
Enantioselectivity factor in EKR
* The enantioselectivity named as enantiomeric ratio (E) measures theability of a enzyme to distinguish between enantiomers.* A non selective reaction has an E 1, while resolutions withE's above 20 are useful for synthetic purpose.* To calculate E one measures two of the three variables: enantiomeric purity of product (eep)* To calculate E, one measures two of the three variables: enantiomeric purity of product (eep),enantiomeric purity of substrtae (ees) and extent of conversion (c) and thenfollows any of the following three equations developed by Sih.
E =
ln[1- ees/1 + (ees/eep)]ln[1+ ees/1 + (ees/eep)]
E =
ln [1-c (1+eep)]l^ [
)]
eq 1
eq 3
ln [1-c (1-eep)]
ln [(1-c) (1-ees)]
/(^
+^
)^
E =
ln [(1-c) (1+ees)]
eq 2
c = ees/(ees + eep)
Often enantiomeric purities (ees and eep) are more correctly measuredOften enantiomeric purities (ees and eep) are more correctly measuredthan conversion; in these cases the eq 3 is more accurate
Selected examples of 2-alkanols resolved by CAL-B OH^
OH^
OH
n
OH^
OH
N
OH
OH
OH
E >150, S-ethyl thiooctanoate
E >100, vinylacetate
n = 6, E >100S-methyl thioacetate
R
OH
OH
N
OH
OH OH
OH
OH
OH
R^
E
Bn^
Ph^
1-naphthyl 57
N
N
N^
Br
OH
1 naphthyl 572-naphthyl 66^ Diketene
E >100, S-ethyl thiooctanoate
73-99% ee for diacylated products
N
OH
R^
N
OH
N^
R
OH
X
OH
R
X
R = H, Br, CH
OTBS, CH 2
OTr, Ph 2
E >100; vinyl acetate
R = H, Br, CH
OTBS 2
R = H, E = 1.3R = TMS, E > 100
X = Cl, BrE >
OH
OH
OH
OH
OH
C^ H^6
13
C^ H^6
13
CH^6
13
E > 150, S-ethylthio octanoate
OH
OH
OAc
E = 10, vinyl acetate
E = 13hydrolysis of chloroacetate
FC^3
OH
R^
FC^3
OH
CF^3
OAc
R = H, nBu, n-pent, n-OctE = 50 vinyl acetate
hydrolysis of diacetate; E >
OH
NC
Cl^
Cl
OH
O
OH
O^
R
MeO
E^
50, vinyl acetate
OMe
MeO
R^
R
E >100, isopropenyl acetate
R = Bn, CH
CH 2
Ph 2
E = 8-
R^
E
Ph^
CH
Ph^2
CH
CH 2
Ph^2
(CH
)OPh 22
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OH^
HN OH^
OH
Selected examples of cyclic 2-alkanols resolved by CRL OH^ R
N O MeO
C 2
OH
R = Et, C
H 6 13 , Ph
E >50hydrolysis of acetate
E = 10vinyl acetate
OH^
O OH
S S
OH R
OH OH Ph
hydrolysis of acetate
OBn
S
OH^
OH^
OH^
OH
E = 24vinyl acetate
E = 20-100; R = n-alkyl
CRL, E > 100vinyl acetate
CF^3 n
OH Ph^
Ph^
CH^5
11
SPh SPh
ON^2
OH
E >100, vinyl acetate
E >50vinyl acetate
E >100h d^
l^ i^
f^
t t
E = 11isopropenyl acetate
OAc CCl MeO
y^
hydrolysis of acetate substituents with similar sizes
CCl
3
MeOE > 50hydrolysis of acetate
substituents with similar sizes
OH^
OH H
OH H
OH
Br
OH
Selected exam ples of cyclic secondary alcohols resolved by C R L
H^
H
O
Ph Ph
NH O
R
E = 50, hydrolysisof butyrate
E = 27, hydrolysisof acetate
E = 125vinyl acetate
E = 61-64hydrolysis of butyrateR^
iP^ Ph
OH^
OH
Ar
OH
OtBu N
N^3
OAc
Br
OAc
Br
vinyl acetate
R = iPr, Ph
E^ 10 t
50
E = 50
N^3
Br OAc
Br OAc
OH
O
O
OH
N^
OH
E = 10 to 50transesterification orhydrolysis of acetate
E^
50 Ar = Ph, 4tBuPhtransesterification
E > 100hydrolysis of butyrate
regioselective hydrolysis of diacetate
O^
O N
F
O
N^3
CO^2
Me
R OH
E = 20
E = 39hydrolysis of acetate
CRL
E^
8 24
OH OAc
OH
O Me OTBS
OH
Ph
y^
y
E >50, hydrolysisof formate
CRL, E = 8-24R = OM e, Cl, Br, I, SM ehydrolysis of butanoate
OAc
OAc
O Me
OTBS
O
98% eehydrolysis of diacetate (EED)
ee = 98%hydrolysis of diacetate (EED)
E = 36-76vinyl acetate