Chemistry Reference
In-Depth Information
Ph
Ph
O
O
H
Ph
Ph
Ph
Ph
H
Ph
Ph
Ru
Ru
OC
CO
O
CO
CO
Racemization
catalyst
14
(2 mol %)
Cl
O
Me
OH
O
rac
+
+
Cl
OH
R
Me
R
Me
Me
O
Lipase CAL-B,
toluene
rac
-
12
13
(
R
)-
15
78-92% yield
>99 ee
16
Scheme 6.6.
donor in Scheme 6.6. Commercially available isopropenyl acetate can be used as an
alternative donor but requires the additional use of hydrogen to prevent decreased yields
due to ketone formation.
Modifi ed versions of this chemoenzymatic dynamic kinetic resolution based on the
use of other racemization catalytic systems were reported by the Kim and Park group
[17,18] as well as the Sheldon group [19]. Notably, a large-scale industrial process at
DSM has been developed recently. Therein, a modifi ed Ru - Noyori - type catalyst was
used in combination with immobilized CAL-B [16,20].
Besides methodology development, this dynamic kinetic resolution process has been
applied for the highly enantioselective synthesis of a broad range of compounds bearing
(at least one) alcohol functionality. For example, racemic/
meso
- diols [21 - 23] , allylic
alcohols [24,25] , α - and β - hydroxy esters [26,27] , halohydrins [28] , and hydroxyl phos-
phonates [29] served as substrates. The reactions typically proceed with high conversion
and excellent enantioselectivities, leading to the corresponding desired esters in high
enantiomeric excess. Thus, this type of dynamic kinetic resolution based on the use of
metal racemization catalysts in combination with a lipase for enzymatic resolution in
organic media is already considered a highly effi cient and mature technology for the
highly effi cient preparation of chiral esters with a broad substrate tolerance with respect
to the alcohol moiety.
A very specifi c, recent application of this type of dynamic kinetic resolution is the
use of this technology by DSM researchers for the enantio- and diastereoselective syn-
thesis of chiral polymers [30]. Dimethyl adipate (
18
) was used as acceptor in combination
with a mixture of racemic and
meso
- alcohols of type
17
, leading to the corresponding
chiral polyester
20
in an enantioselective manner. The ruthenium complex
19
was used
as racemization catalyst in combination with lipase CAL-B as biocatalyst for the resolu-
tion (Scheme 6.7 ).
One limitation is the dependency on relatively expensive heavy metal racemization
catalysts. In the search for a cheap source, the Berkessel group developed a highly effi cient
approach based on a cheap and readily available aluminum racemization catalyst
(Scheme 6.8) [31]. The aluminum racemization catalyst was prepared from AlMe
3
and
binaphthol. CAL-B was applied as an enzyme component. The resulting chemoenzymatic
dynamic kinetic resolution gave the desired products in excellent conversion and enanti-
oselectivity. For example, racemic 1 - phenyl - 1 - propanol (
rac
-
21
) was acylated enantiose-
lectively under formation of the resulting ester (
R
) -
22
with 99% yield and 98% ee.
