Chemistry Reference
In-Depth Information
is the transformation of racemic hydantoins into enantiomerically pure D- or L-amino
acids. In this process, hydantoinases and carbamoylases are the enzymes of choice for
the hydrolytic steps, whereas racemization is dependent on pH or occurs by addition of
a hydantoin racemase.
6.3.2. Ester Hydrolysis
A “classic” biocatalytic approach toward chiral carboxylic acids is hydrolysis of racemic
or prochiral esters in enzymatic hydrolysis reactions. Lipases, esterases, and proteases
were used as enzyme components. For resolution based on the use of these types of
hydrolases, a broad range of racemic substrates can be used. Alternatively, prochiral
substrates or
meso
-substrates can be used, which give the opportunity for a desymme-
trization reaction with a (theoretically) quantitative yield of the resulting enantiomer.
The fi eld of enzymatic hydrolytic reactions for the synthesis of chiral carboxylic acids
has been comprehensively reviewed [46]. Thus, in the following, the focus is on selected
recent examples, which additionally show a high degree of synthetic effi ciency, for
example, high volumetric productivity, substrate concentration, and selectivity.
A highly effi cient synthesis of an indole ethyl ester (
R
) -
42
as an intermediate for a
prostaglandin D2 receptor antagonist via lipase-catalyzed hydrolysis of the correspond-
ing racemate has been reported by Merck researchers [50,51]. The desired (
R
) - ester
(
R
) -
42
was obtained with an excellent enantiomeric excess of
99% ee as remaining
ester after hydrolysis of
rac
-
42
with a conversion of 50% (Scheme 6.15). As a catalyst,
a lipase from
Pseudomonas fl uorescens
was used. Notably, the reaction runs at a high
substrate concentration of 100 g/L. Furthermore, the process turned out to be technically
feasible and was applied successfully on a 40-kg scale [51].
>
Lipase from
Pseudomonas
fluorescens
rac
+
Buffer/DMF(3:1),
pH 8.0, 28°C
50% conversion
H
H
H
CO
2
Et
CO
2
Et
CO
2
H
(
R
)-
42
>99% ee
(
S
)-
43
rac
-
42
(100 g/L)
Scheme 6.15.
Highly enantioselective hydrolysis of racemic alicyclic
cis
- and
trans
- β - amino esters
rac
-
44
in the presence of lipase from
C. antarctica
B has been reported by the Fülöp
group [52]. Notably, hydrolysis was performed in diisopropylether with only 0.5 equiva-
lents of water. For example, the resulting
cis
- β-amino acids, for example, (1
S
,2
R
) -
45
,
were obtained in high yields of 42-46% and with excellent enantiomeric excess of 96-
99% ee. The opposite enantiomeric forms have been isolated as hydrochloride salts of
the resulting acids (e.g., (1
R
,2
S
) -
46
) after hydrolysis also in high enantiomeric excess.
In Scheme 6.16, a representative example is given. Enzymatic hydrolysis also turned out
to be very suitable for the lipase-catalyzed resolution of a broad range of other types of
β - amino acids [53 - 55] .
