Chemistry Reference
In-Depth Information
chain. Since statines are blockbuster drugs of high industrial interest, it is not surprising
that this process has gained attention. Notably, access to a highly effi cient recombinant
form of the enzyme that tolerates a high concentration of chloroacetaldehyde has been
achieved by DSM researchers, thus fulfi lling a key criterion for industrial applicability
of this process [155] .
The use of aldolases in diastereoselective aldolization reactions as key steps in ste-
reospecifi c biocatalytic synthesis of novel pancratistatin analogues has been reported by
Fessner and coworkers [156]. Notably, such structures with a high molecular complexity
and several stereogenic centers were prepared without the need for protective group
strategies. As enzymes, a fructose-1,6-bisphosphataldolase and the stereocomplemen-
tary rhamnulose - 1 - phosphataldolase were used.
When using glycine as a donor, corresponding aldol reaction gives enantio- and dia-
stereoselectively
- phenylserine. Suit-
able enzymes for these reactions are in particular threonine aldolases. The Wong group
reported an elegant approach for
α
- amino
β
-hydroxy acids such as threonine and
β
-phenylserine and substituted derivatives thereof,
obtaining the desired products, for example, L-
threo
-
111
, in yields of up to 93% and
with excellent enantioselectivity (for both diastereomers) in general (Scheme 6.43) [157].
Diastereoselectivity, however, turned out to be modest for most of these reactions. It is
noteworthy that the L-threonine aldolase (from
E. coli
) gave
erythro
-
β
-
L-amino acids with aliphatic aldehydes whereas the
threo -
diastereomers were obtained
as preferred (kinetically controlled) products when using aromatic aldehydes as sub-
strates. When using a D-threonine aldolase (from
Xanthomonus oryzae
), however,
threo
-
α
- hydroxy -
β
-D-amino acids were obtained as kinetically controlled products with
aliphatic as well as aromatic aldehydes. Diastereoselectivity, however, in general varies
broadly with threonine aldolases, and dependent on substrate and enzyme, low or
medium to high diastereomeric ratios were obtained [158 - 161] .
α
- hydroxy -
β
NO
2
O
O
NO
2
OH
O
L-threonine aldolase
H
+
OH
OH
PLP,
Water-DMSO(70:30),
pH 7.5, 37°C
NH
2
NH
2
109
110
L-
threo
-
111
93% yield
dr (
threo
/
erythro
) = 58:42
Scheme 6.43.
This reaction also gained interest for the synthesis of a key intermediate of the drug
thiamphenicol. The Griengl group reported the threonine aldolase-catalyzed aldol reac-
tion of glycine (
110
) with 4 - (methylsulfonyl)benzaldehyde (
112
) under the formation of
the corresponding
- hydroxy acid L -
threo
-
113
as thiamphenicol intermediate
with 68% analytical yield, a diastereoselectivity of 53% de, and excellent enantiomeric
excess of
α
- amino
β
99% ee (Scheme 6.44 ) [162] .
Since an excess of glycine is required for suffi cient conversion and because of low
diastereoselectivity but high stereochemical preference for formation of the
>
- stereogenic
center, often the reverse
retro
-aldol reaction is carried out as an alternative. In such
enzymatic resolution processes, diastereomerically pure
threo
- racemates are used as
α
