Chemistry Reference
In-Depth Information
Lipase from
C. antarctica
B
CO
2
Et
CO
2
H
CO
2
Et
+
Water,
i
-Pr
2
O, 65°C
49% conversion
NH
2
NH
2
NH
2
rac
-
cis
-
44
(1
S
,2
R
)-
45
47% yield
98% ee
(1
R
,2
S
)-
44
E>200
HCl
CO
2
H
NH
3
Cl
(1
R
,2
S
)-
46
46% yield
99% ee
Scheme 6.16.
A further widely applied lipase-catalyzed resolution is the enantioselective hydrolysis
of racemic α-amino acids esters [56]. As a representative example, an effi cient kinetic
resolution of racemic octyl pipecolate has been achieved by Kazlauskas et al. using a
lipase from
Aspergillus niger
[57] . The desired (
S
) - 2 - piperidinecarboxylic acid was
obtained with an enantioselectivity of E > 100. The engineering of the reaction medium
for lipase-catalyzed resolution via ester hydrolysis has been reported jointly by Land-
fester, Gröger, and coworkers. In the presence of porcine pancreas lipase as enzyme,
the hydrolytic resolution of racemic phenylalanine
n
-propyl ester reaction proceeds at
high substrate concentrations of up to 827 g/L of solvent [55]. Furthermore, a dynamic
kinetic resolution, which is based on a hydrolase-catalyzed ester hydrolysis in combina-
tion with amino ester racemization using an aromatic aldehyde, has been developed by
the Beller group. For this type of reaction, a protease was used as hydrolase. For
example, L-tyrosine is formed in 92% yield and with an enantioselectivity of 97% ee
from the corresponding benzyl ester when using alcalase in combination with 3,5-
dichlorosalicylaldehyde [58]. Alternatively, pyridoxal 5-phosphate was successfully used
in combination with α - chymotrypsin and alcalase, respectively [59,60] .
Lipases also turned out to be suitable for the resolution of complex molecules bearing
more than one additional functional group. This is exemplifi ed by the enzymatic hydro-
lysis of
47
, which represents a key building block of epothilones. The Wessjohann and
Bornscheuer group found that in the presence of a lipase from
Burkholderia cepacia
(Amano PS), the acyloin acetate
47
was hydrolyzed highly enantioselectively with an E
value of >300, leading to the corresponding diol (3
S
,10
R
) -
48
in >99% ee (Scheme 6.17)
[61] .
The power of hydrolases to recognize also “remote chiral centers” has been demon-
strated by Liu et al. in the synthesis of Lasofoxifene, a potent and selective estrogen
receptor modulator [62]. The Pfi zer researchers found that, in particular, a cholesterol
esterase from porcine pancreas is capable for this type of resolution. Although in substrate
rac
-
cis
-
49
the functional group for enzymatic hydrolysis (ester group) is separated from
the stereogenic center by an aromatic group, enzymatic resolution proceeds with a high
enantioselectivity as the E value of 60 indicates. The desired product Lasofoxifene (
cis
-
50
)
is obtained at 35% conversion with an enantiomeric excess of 96% ee (Scheme 6.18 ).
