falcata [856], Mucor javanicus and Pseudomonas sp. [857] are of limited use as
long as they are not commercially available.
The substrate range of commercially available alcohol dehydrogenases has
been mapped including aldehydes, (acyclic, aromatic, and unsaturated) ketones,
diketones and various oxo-esters [858]. The most commonly used dehydrogenases
are shown in Fig. 2.15, with reference to their preferred size of their substrates [859].
Yeast ADH has a very narrow substrate specificity and, in general, only accepts
aldehydes and methyl ketones [860, 861]. Therefore, cyclic ketones and those
bearing carbon chains larger than a methyl group are not accepted as substrates.
Thus, YADH is only of limited use for the preparation of small chiral secondary
alcohols.
Horse liver ADH is a very universal enzyme with a broad substrate specificity and
excellent stereoselectivity. Historically, it is the most widely used dehydrogenase in
biotransformations [862, 863] and its mechanism was elucidated [863] on the basis of
its crystal structure [864]. Although the primary sequence is quite different, the
tertiary structure of HLADH is similar to that of YADH [865]. The most useful
applications of HLADH are found in the reduction of medium-ring monocyclic
ketones (four- to nine-membered ring systems) and bicyclic ketones [866–868]. Sterically demanding molecules which are larger than decalines are not readily accepted
and acyclic ketones are usually reduced with modest enantioselectivities
[869, 870]. HLADH consists of two isoenzymes (HLADH-E and HLADH-S
28
),
which differ in their substrate preference [871].
A considerable number of monocyclic and bicyclic racemic ketones have been
resolved using HLADH with fair to excellent specificities [872–874]. Even sterically demanding cage-shaped polycyclic ketones were readily accepted [875, 876]
(Scheme 2.113). For instance, rac-2-twistanone was reduced to give the exoalcohol and the enantiomeric ketone in 90% and 68% e.e., respectively
[877]. Also O- and S-heterocyclic ketones were shown to be good substrates
(Scheme 2.113) [878–880]. Thus, (Æ)-bicyclo[4.3.0]nonan-3-ones bearing either
an O or S atom in position 8 were resolved with excellent selectivities
O
O
O
R
O
O
O
R
2
R
1
O
H
R
CPADH and TBADH
HLADH
Rhodococcus and Lactobacillus ADH
HSDH
YADH
Fig. 2.15 Preferred substrate size for dehydrogenases. YADH yeast alcohol dehydrogenase,
HLADH horse liver alcohol dehydrogenase, CPADH Candida parapsilosis alcohol dehydrogenase, TBADH Thermoanaerobium brockii alcohol dehydrogenase, HSDH hydroxysteroid
dehydrogenase
28 The prefix ‘S’ stands for steroids, ‘E’ stands for ethanol.
2.2 Reduction Reactions
141
long as they are not commercially available.
The substrate range of commercially available alcohol dehydrogenases has
been mapped including aldehydes, (acyclic, aromatic, and unsaturated) ketones,
diketones and various oxo-esters [858]. The most commonly used dehydrogenases
are shown in Fig. 2.15, with reference to their preferred size of their substrates [859].
Yeast ADH has a very narrow substrate specificity and, in general, only accepts
aldehydes and methyl ketones [860, 861]. Therefore, cyclic ketones and those
bearing carbon chains larger than a methyl group are not accepted as substrates.
Thus, YADH is only of limited use for the preparation of small chiral secondary
alcohols.
Horse liver ADH is a very universal enzyme with a broad substrate specificity and
excellent stereoselectivity. Historically, it is the most widely used dehydrogenase in
biotransformations [862, 863] and its mechanism was elucidated [863] on the basis of
its crystal structure [864]. Although the primary sequence is quite different, the
tertiary structure of HLADH is similar to that of YADH [865]. The most useful
applications of HLADH are found in the reduction of medium-ring monocyclic
ketones (four- to nine-membered ring systems) and bicyclic ketones [866–868]. Sterically demanding molecules which are larger than decalines are not readily accepted
and acyclic ketones are usually reduced with modest enantioselectivities
[869, 870]. HLADH consists of two isoenzymes (HLADH-E and HLADH-S
28
),
which differ in their substrate preference [871].
A considerable number of monocyclic and bicyclic racemic ketones have been
resolved using HLADH with fair to excellent specificities [872–874]. Even sterically demanding cage-shaped polycyclic ketones were readily accepted [875, 876]
(Scheme 2.113). For instance, rac-2-twistanone was reduced to give the exoalcohol and the enantiomeric ketone in 90% and 68% e.e., respectively
[877]. Also O- and S-heterocyclic ketones were shown to be good substrates
(Scheme 2.113) [878–880]. Thus, (Æ)-bicyclo[4.3.0]nonan-3-ones bearing either
an O or S atom in position 8 were resolved with excellent selectivities
O
O
O
R
O
O
O
R
2
R
1
O
H
R
CPADH and TBADH
HLADH
Rhodococcus and Lactobacillus ADH
HSDH
YADH
Fig. 2.15 Preferred substrate size for dehydrogenases. YADH yeast alcohol dehydrogenase,
HLADH horse liver alcohol dehydrogenase, CPADH Candida parapsilosis alcohol dehydrogenase, TBADH Thermoanaerobium brockii alcohol dehydrogenase, HSDH hydroxysteroid
dehydrogenase
28 The prefix ‘S’ stands for steroids, ‘E’ stands for ethanol.
2.2 Reduction Reactions
141