Page 34 - Catalysts for Fine Chemical Synthesis Vol 1 - Robert & Poignant

the integration of biotransformations into catalyst 17

1.3 OXIDATIVE TRANSFORMATIONS

In this important area of synthetic chemistry honours are more equally shared
between biocatalysis and other forms of catalysts, the latter being made up,
almost invariably, of man-made organometallic species. Thus biotransforma-
tions are the preferred pathway for the hydroxylation of aliphatic, alicyclic,
aromatic and heterocyclic compounds, particularly at positions remote from
pre-existing functionality [70] . In contrast organometallic species are the cata-
lysts of choice to convert alkenes into epoxides and diols. Both natural and
non-natural catalysts are adept at the conversion of some sulfides into the
corresponding sulfoxides and in performing stereoselective Baeyer±Villiger
oxidations. Some of the details are provided hereunder.
The ability of microorganisms to convert alicyclic compounds into related
alcohols by regio- and stereo-controlled hydroxylation at positions distant
from regio- and stereo-directing functional groups was used extensively in the
modification of steroids [71] . In a classical example the hydroxylation of proges-
terone (17) with Rhizopus sp. or Aspergillus sp. furnished the oxidized product
(18), forming a key step in a highly efficient pathway to the anti-inflammatory
steroids such as Betnovate [72] . Other complex alicyclic natural products and
closely related compounds (e.g. taxanes) [73] have been selectively hydroxylated
using some of the more easily handled organisms such as Mucor sp., Absidia sp.
and Cunninghamella sp.
The selective monohydroxylation of heterocyclic compounds such as piperi-
dine derivatives [74] and the g-lactam (19) [75] have been studied. It is also been
shown that hydroxylation of phenylcyclohexane can be effected using cyto-
chrome P450 and the regioselectivity of hydroxylation can be altered by site-
directed mutagenesis of the enzyme [76] .
While undoubtedly powerful methodology, the major problem concerning
enzyme-catalysed hydroxylation of alicyclic and saturated heterocyclic com-
pounds is the unpredictability of the site of hydroxylation. Not surprisingly a
start has been made to control the regioselectivity of microbial hydroxylation
by using an easily-introduced and easily-removed directing group which, if such
a suitable auxiliary could be found, would very conveniently promote hydro-
xylation at a set distance from the temporary appendage [77] .
The hydroxylation of aromatic compounds using microorganisms is more
predictable and a number of processes have been adapted to large scale, for
example the preparation of 6-hydroxynicotinic acid [78] and (R)-2-(4-hydroxy-
phenoxy)propanoic acid [79] , important intermediates to pesticides and herbi-
cides respectively.
The biotransformation that has caught the imagination of many synthetic
organic chemists involves the conversion of benzene and simple derivatives
(toluene, chlorobenzene, etc.) into cyclohexadienediols (20) using a recombinant
microorganism E. coli JM109. The one step oxidation, via reduction of the