8692
J . Org. Chem. 1996, 61, 8692-8695
Sch em e 1
A Novel Ap p lica tion of Ch lor op er oxid a se:
P r ep a r a tion of gem -Ha lon itr o Com p ou n d s
Aleksey Zaks,* Asha V. Yabannavar, David R. Dodds,
C. Anderson Evans, Pradip R. Das, and
Rodney Malchow
Schering-Plough Research Institute, 2015 Galloping Hill
Road, Kenilworth, New J ersey 07033
substrate also takes place.6 Chloroperoxidase, in addition
to its ability to halogenate a variety of organic substrates,
also catalyzes numerous oxidative reactions including
oxidation of alcohols to aldehydes and acids,7a,f sulfides
to sulfoxides,7b,c epoxidations of olefins,7d-f and benzylic
hydroxylations.7a,f To the best of our knowledge, oximes
have never been identified as substrates for chloro-
peroxidase.
In our attempt to oxidize oximes directly to nitro
compounds, we incubated the oximes of cyclohexanone
(5) and butanone (4) with CPO in the presence of H2O2
in an aqueous buffer pH 5.0 (see Experimental Section).
To our surprise, after 4 h of incubation the oximes were
converted to the corresponding ketones with no traces of
nitro compounds. The nonenzymatic control reaction
yielded less than 2% of the corresponding ketones. Since
no desired nitro product was produced by the enzymatic
reaction, the reaction pathway was altered by introducing
a halide ion into the system. We proposed that the
presence of halide ions would force the CPO-catalyzed
oxidation/halogenation of oximes to proceed through the
formation of halonitroso intermediates which would be
further oxidized to the desired halonitro products. In-
deed, in the presence of KBr the oxidation of oximes 4
and 5 proceeded smoothly leaving no starting material
after 4 h. As anticipated, the reaction proceeded beyond
the intermediate bromonitroso oxidation level and re-
sulted in gem-bromonitro products.
Received J une 27, 1996
Conversion of carbonyl to nitro compounds is usually
carried out in three or four steps via addition of hydroxyl-
amine to ketones to form the corresponding oximes,
oxidation of the oximes to halonitroso intermediates
followed by ozonolysis, and halogen removal by catalytic
hydrogenation (Scheme 1).1
The second step of the transformation, chlorination of
oximes to chloronitroso compounds, is achieved by a
number of reagents including elemental chlorine2a and
bromine,2b,e aqueous hypochlorous acid,2a tert-butyl
hypochlorite,2c and N-bromosuccinimide.2d The resulting
chloronitroso intermediate is then oxidized further to
chloronitro product with nitric,2d trifluoroperoxyacetic,2e
or m-chloroperbenzoic acids,3b ozone,3a aqueous sodium,3c
or n-butylammonium hypochlorite.2c This two-step oxi-
dation method proceeding through the gem-chloronitroso
species is considered superior to the oxidation of oximes
directly to chloronitro compounds. The latter when
performed using trifluoroperacetic, pyridinium dichro-
mate, ozone, or lithium hypochlorite usually yields larger
amounts of byproducts.1a There are reports that some
triazine derivatives convert oximes to gem-halonitro
compounds in good yield;4 however, the reaction takes
up to 48 h to complete and requires approximately 5
equiv of the halogenating reagent.
A variety of oximes were converted in a similar fashion
in the presence of KCl and KBr to the corresponding
halonitro products (Table 1). In all the cases but one
(oxime 9 with KBr) most of the substrate was converted
to a mixture of the corresponding gem-halonitro product
and ketone. No enantioselectivity was observed with
substrates 1, 2, 4, and 7. The ratio of the amount of gem-
halonitro products to that of ketones varies significantly
among the substrates. Moreover, under more acidic
conditions (pH < 3.5) the nonenzymatic hydrolysis of
oximes back to their parent ketones lowers the yield of
gem-halonitro products. The use of tert-butyl hydroper-
oxide as an oxidant, instead of hydrogen peroxide and
lower reaction temperatures (4 °C) have only a minor
effect on the reaction yield and product composition.
Surprisingly, the addition of water miscible cosolvents
(dioxane, acetone) significantly decreases the yield of the
halonitro products and increases the yield of the ketones.
In fact, 5 is nearly quantitatively converted to cyclohex-
We report in this paper that chloroperoxidase from the
fungus Caldaromyces fumago (CPO) is effective in con-
verting oximes to halonitro compounds and ketones in a
single step. The reaction is carried out in aqueous media
in the presence of halide ions and hydrogen peroxide.
Chloroperoxidase C. fumago is a hemoprotein that
catalyzes H2O2-dependent oxidation of inorganic and
organic substrates.5 It is generally believed that halo-
genation proceeds via the enzymatic formation of hypo-
halous acid, which then halogenates substrates in solu-
tion without assistance by the enzyme.5a Nevertheless,
there are indications that direct transfer of a halogen
species from a halogenated enzyme intermediate to the
(1) (a) Boyer, J . H. Chem. Rev. 1980, 495-561. (b) for review of
chemistry of nitro compounds see: The Chemistry of Nitro and Nitroso
Group; Feuer, H., Ed.; Wiley-Interscience: New York, 1969; Part 1.
(2) (a) Archibald, T. G.; Garvier, L. C.; Baum, K.; Cohen, M. C. J .
Org. Chem. 1989, 54, 2869. (b) Marchand, A. P.; Arney, B. E., J r; Dave,
P. R. J . Org. Chem. 1988, 53, 443. (c) Corey, E. J .; Estreicher, H.
Tetrahedron Lett. 1980, 21, 1117-20. (d) Iffland, D. C.; Criner, G. X.
J . Am. Chem. Soc. 1962, 27, 1933. (e) Manchand, A. P.; Suri, S. C. J .
Org. Chem. 1984, 49, 2041.
(3) (a) Barnes, M. W.; Patterson, J . M. J . Org. Chem. 1976, 41, 733.
(b) Ibne-Roza, K. M.; Edwards, J . O. Chem. Ind. (London) 1974, 964.
(c) Baum, K.; Archibald, T. G. J . Org. Chem. 1988, 53, 4645.
(4) Walters, T. R.; Zajac, W. W., J r.; Woods, J . M. J . Org. Chem.
1991, 56, 316-321.
(5) For recent reviews of chloroperoxidases see: (a) Franssen, M.
C. R. Catal. Today 1994, 22, 441-457. (b) Casella, L.; Colonna, S.
Metalloporphyrins Catalyzed Oxidations Montanari, F., Casella, L.
Eds.; Kluwer Academic Publishers: Netherlands, 1994; pp 307-40.
(c) Franssen, M. C. R.; van der Plas, H. C. Adv. Appl. Microbiol. 1992,
37, 41-99. (d) Fransen, M. C. R. Biocatalysis 1994, 10, 87-111.
(6) Libby, R. D.; Rotberg, N. S.; Emerson, J . T.; White, T. C.; Yen,
G. M.; Friedman, S. H.; Sun, N. S.; Goldowski, R. J . Biol. Chem. 1989,
264, 15284-92. (b) Dunford, H. B.; Lambeir, A. M.; Kashem, M. A.;
Pickard, M. Arch. Biochem. Biophys. 1987, 252, 292-302.
(7) (a) Neidelman, S. L.; Geigert, J . Biochem. Soc. Symp. 1981, 48,
39-52. (b) Colonna, S.; Gaggero, N.; Casella, L.; Carrea, G.; Pasta, P.
Tetrahedron: Asymmetry 1992, 3, 95-106. (c) Pasta, P.; Carrea, G.;
Colonna, S.; Gaggero, N. Biochem. Biophys. Acta 1994, 1209, 203-8.
(d) Allain, E. J .; Hager, L. P.; Deng, L.; J acobsen, E. N. J . Am. Chem.
Soc. 1993, 115, 4415-16. (e) Lakner, F. J .; Hager, L. P. J . Org. Chem.
1996, 61, 3923-25. (f) Zaks, A.; Dodds, D. R. J . Am. Chem . Soc. 1995,
117, 10419-24. (g) Miller, V. P.; Tschirret-Guth, R. A.; Ortiz de
Montellano, P. R. Arch. Biochem. Biophys. 1995, 319, 333-40.
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