Chemistry Reference
In-Depth Information
1.
The use of a foreign chiral element to form diastereomers followed by fractional crystallization [45-
49] or the formation of a diastereoselective host-guest inclusion complex [50]. The antituberculostatic
drug ethambutol (Fig.
8
), and the cardiovascular drug diltiazem (Fig.
3
) are separated in this way.
These methods of resolution are very widely used industrially.
2.
The direct crystallization of one enantiomer from a racemic mixture, which includes the well-known
“preferential crystallization” of pure enantiomers form conglomerate mixtures [45,51-53]. This
unusual enantiomeric resolution is referred to as “preferential enrichment” [53-55], and the application
of crystallization inhibitors to chiral separation in racemic compound-forming systems has been
reported [56-58]. The anti-typhoid chloramphenicol (Fig.
8
) is separated in this way. This is widely
used in the industry but hardly 20 per cent of racemates appear in this form of mechanical mixture or
“conglomerates”.
OH
OH
H
N
R
S
Cl
H
N
R
HN
OH
O
2
N
Cl
S
OH
O
Chloramphenicol
Ethambutol
Figure
8
: Separation of racemates.
Asymmetric Synthesis
The field of asymmetric synthesis has enjoyed tremendous progress over the last few decades with the advent of
asymmetric reactions and enantioselective catalysts [1,62]. There are two possibilities: (1) Non-enzymatic methods,
and (2) Enzymatic methods.
Non-Enzymatic Methods
Asymmetric Hydrogenation
The asymmetric hydrogenation, the Sharpless epoxidation amongst asymmetric oxidations, and cycloadditions are
the most important non-enzymatic processes. Knowles and co-workers at Monsanto discovered that a cationic
rhodium complex containing DIPAMP, a chelating diphosphine with two chiral phosphorus atoms, catalyzes highly
enantioselective hydrogenations of enamides such as
1
(Fig.
9
). In the key step of the synthesis of L-DOPA,
enamide
1
is hydrogenated in the presence of a catalytic amount of [Rh(
R,R
)-DIPAMP)COD]
+
BF
4
-
affording the
protected aminoacid
2
in quantitative yield and in 95% ee. A simple acid-catalyzed hydrolysis step completes the
synthesis of L-DOPA [63].
[Rh(
R,R
)-DIPAMP)COD]
+
BF
4
-
catalyst
100%
MeO
COOH
MeO
COOH
+ H
2
H
NHAc
NHAc
AcO
AcO
1
2
95% ee
OMe
H
3
O
+
P
P
HO
COOH
MeO
H
NHAc
HO
COD
L-DOPA
(
R,R
)-DIPAMP
Figure
9:
The Monsanto synthesis of L-DOPA using catalytic asymmetric hydrogenation.
The
Monsanto Process
was the first commercialized catalytic asymmetric synthesis employing a chiral transition
metal complex and it has been in operation since 1974. The spectacular success of this L-DOPA synthesis has
significantly contributed to the remarkable growth of research aimed at the development and application of other
catalytic asymmetric reactions in ensuing years.
