TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2201–2204
Enantiocomplementary preparation of (S)- and
(R)-1-pyridylalkanols via ketone reduction and alkane
hydroxylation using whole cells of Pseudomonas putida UV4
Mark D. Garrett, Robin Scott and Gary N. Sheldrake*
School of Chemistry, David Keir Building, The Queen’s University of Belfast, Belfast BT9 5AG, UK
Received 28 August 2002; accepted 4 October 2002
Abstract—A previously unreported alcohol dehydrogenase enzyme in the mutant soil bacterium Pseudomonas putida UV4
catalyses the reduction of 2-, 3- and 4-acylpyridines to afford the corresponding (S)-1-pyridyl alkanols, with moderate to high e.e.,
whilst under the same conditions 2,6-diacetylpyridine is readily converted to the corresponding enantiopure C2-symmetric
(S,S)-diol in one step. In contrast, the toluene dioxygenase enzyme in the same organism catalyses the hydroxylation of 2- and
3-alkylpyridines to (R)-1-(2-pyridyl) and (R)-1-(3-pyridyl)alkanols. This combination of oxidative and reductive biotransforma-
tions thus provides a method for preparing both enantiomers of chiral 1-pyridyl alkanols using one biocatalyst. © 2002 Elsevier
Science Ltd. All rights reserved.
In the course of these investigations we have discovered
a new alcohol dehydrogenase enzyme (ADH) in P.
putida UV4 which catalyses the asymmetric reduction
of acyl pyridine substrates. The asymmetric reduction
of ketones to chiral secondary alcohols is one of the
cornerstones of biotransformations in synthetic organic
chemistry but the vast majority of alcohol dehydroge-
nases (ADHs) employed to produce synthetically useful
quantities of chiral alcohols are to be found in yeasts
and mammalian systems. While many bacterial ADHs
have been characterised and investigated mechanisti-
cally,9 relatively few have been used in biotransforma-
tions for chemical synthesis. There has been
considerable recent interest in the synthetic applications
of chiral 1-pyridylethanols. Examples include chiral
ligands in the zinc-catalysed asymmetric alkylation of
aldehydes10 and involvement in asymmetric hydrobora-
tion reactions.11 Generally these alcohols are prepared
by enzymatic or non-enzymatic asymmetric reductions
of the corresponding ketones or by lipase-catalysed
kinetic resolution of racemic esters.12 Such enzymatic
reductions, e.g. using bakers’ yeast, generally allow the
preparation of only one enantiomer of the alcohol, and
similarly, many kinetic resolution processes are also
found to be more efficient for the production of one
enantiomer.
In recent years, bacterial dioxygenase enzymes have
been used to produce a wide range of arene cis-
dihydrodiols1,2 many of which have been used as chiral
raw materials for asymmetric synthesis.2–5 More
recently, some of the other oxidative reactions catalysed
by dioxygenase enzymes have been investigated and
exploited synthetically.6–8 These include sulfoxidations,
alkene dihydroxylations, dehydrogenations, N-, O- and
S-dealkylations and benzylic hydroxylations. Part of
our continuing research into dioxygenase-catalysed oxi-
dations has been aimed at understanding the criteria
that influence the oxidation pathway observed in situa-
tions where there is potential competition between reac-
tion sites in the substrate. In one approach towards this
end we investigated the biotransformation of alkyl
pyridines with Pseudomonas putida UV4, a mutant
strain of a soil bacterium containing a toluene dioxyge-
nase (TDO) enzyme but lacking the diol dehydrogenase
enzyme which catalyses the next step in normal bacte-
rial arene degradation. It has already been observed
that carbocyclic arenes are more readily oxidised by
dioxygenase
enzymes
than
nitrogen-containing
heterocycles1 and we anticipated that alkyl pyridines
would be preferentially hydroxylated at the side chain
rather than on the ring.
The starting point for this study was the attempted use
of a heterocyclic ring (pyridine) to disfavour arene
oxidation and promote the hydroxylation of alkyl side
* Corresponding author.
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