Flavin-catalyzed Baeyer-Villiger reaction of ketones: Oxidation of cyclobutanones to γ lactones using hydrogen peroxide

Full text of DOI:10.1021/jo951905b

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J . Org. Chem. 1996, 61, 8-9
F la vin -Ca ta lyzed Ba eyer -Villiger Rea ction
of Keton es: Oxid a tion of Cyclobu ta n on es
to γ La cton es Usin g Hyd r ogen P er oxid e
Claudio Mazzini, J acques Lebreton, and
Roland Furstoss*
Groupe de Chimie Organique et Bioorganique, URA CNRS
1320, Faculte´ des Sciences de Luminy, Case 901, 163
Avenue de Luminy, 13288 Marseille Cedex 9, France
Received October 26, 1995
were the cyclobutanones 3 (see Table 1), a choice which
results from our previous experience on such biocatalyzed
BV reactions4 and from our current interest in the use
of chiral γ-lactones as building blocks for the synthesis
of biologically active molecules like, for instance, phero-
mones or flavor compounds.10
The Baeyer-Villiger (BV) oxidation of ketones to
lactones is a well-known reaction in organic synthesis.
This is, in general, carried out using stoichiometric
quantities of various oxidants,1 although catalytic pro-
cesses have also been achieved.2 Only two approaches
allowing enantioselective BV reactions have been de-
scribed up to now, but they lead only to lactones showing
modest ees.2c,d On the other hand, during recent years,
several studies have been devoted to enzymatically
catalyzed BV oxidations.3 Thus, the use of microbial
whole-cell cultures4 as well as of purified enzymes5
proved to be a very efficient way to achieve the synthesis
of various lactones in enantiopure form. It has been well
documented that a flavin moiety must be implied as a
coenzyme during the enzymatic oxidation of various
ketones, sulfites, amines, and other types of organic
molecules.6 In the frame of our work concerning these
biocatalyzed BV transformations, we were interested in
investigating the possible use of isoalloxazine derivatives
as enzyme models for achieving such type of reactions.
Many studies have been performed in this field;7 however,
to our best knowledge, there are no successful examples
relating the use of such catalysts in the BV oxidation of
ketones. Following the pioneering work by Bruice,7a
Shinkai7b and others,7c,d we report here the first example
of the BV-type oxidation of ketones to lactones, achieved
using a flavin entity as a catalyst.
In order to find the proper experimental conditions for
optimum reactivity, several parameters (nature of the
catalyst, catalyst ratio, temperature, proportion of hy-
drogen peroxide) including the use of various solvents
allowing good solubility of the catalyst and of the
substrate were examined. Our first results showed that
the nonalkylated isoalloxazine 1 was inactive, even when
used in stoichiometric amount. The use of 2, however,
led to much more interesting results and catalyzed the
BV oxidation of ketones 3 in various conditions. Running
the oxidation in the presence of benzene, toluene, aceto-
nitrile, tetrahydrofuran, or ethyl ether only led to poor
(if any) yields of lactone 4. Different alcohols, i.e.,
methanol, ethanol, 2-propanol, and 2-methyl-2-propanol
were also tested and led to much better results. In all
cases the system was heterogeneous: indeed, the catalyst
2 was only partially soluble into all the tested solvents.
The best experimental conditions appeared to be the use
of a 5% proportion of catalyst 2, at room temperature,
using 2-methyl-2-propanol as a solvent in the presence
of 2 equiv of hydrogen peroxide added all in one shot.
The use of a smaller proportion of catalyst did afford
unreproducible results. We also noticed that when
molecular oxygen was used as the oxidant (atmospheric
pressure) only small proportions (5-10% by GC) of
lactones were formed and that, contrary to what was
observed previously,11 these reactions were not influenced
by light. Thus, the oxidations performed using these
optimized conditions, resulted in the formation of the
corresponding lactones in 45-90% yields after 3-24 h
reaction, depending on the structure of the substrate.12
No products resulting from either overoxidation or trans-
esterification with the solvent were observed.
As we already mentioned, the use of molecules like 1
or 2 as catalysts has been well documented in the liter-
ature.7 Moreover, as described by Bruice,7a the catalytic
activity of this kind of compound was shown to be
increased by alkylation of the N(5) position. Thus, the
flavin 1 as well as its N(5) alkylated derivative 2 were
tested. Their synthesis was achieved according to the
synthetic schemes described by Shinkai8 and by Mager9
for similar products. The model substrates to be oxidized
(1) Krow, G. R. Org. React. 1993, 43, 251.
(2) (a) Kaneda, K.; Ueno, S.; Imanaka, T.; Nishhiyama, Y.; Ishii, Y.
J . Org. Chem. 1994, 59, 2915. (b) Bolm, C.; Schlingloff, G.; Weickhardt,
K. Tetrahedron Lett. 1993, 3405; (c) Angew. Chem., Int. Ed. Engl. 1994,
33, 1848. (d) Gusso, A.; Baccin, C.; Pinna, F.; Strukul, G. Organome-
tallics 1994, 13, 3442.
(3) Alphand, V.; Furstoss, R. In Enzyme Catalysis in Organic
Synthesis; Drauz, K., Waldmann, H., Eds.; VCH Publishers: New York,
1995; 745-772.
(4) (a) Alphand, V.; Furstoss, R. J . Org. Chem. 1992, 57, 1306. (b)
Petit, F.; Furstoss, R. Tetrahedron Asymmetry 1993, 4, 1341.
(5) Gagnon, R.; Grognan, G.; Groussain, E.; Pedragosa-Moreau, S.;
Richardson, P. F.; Roberts, S. M.; Wan, P. W. H.; Willetts, A.; Alphand,
V.; Lebreton, J .; Furstoss, R. J . Chem. Soc., Perkin Trans. 1 1995, 2527.
(6) Walsh, C. T.; Chen, Y.-C. J . Angew. Chem., Int. Ed. Engl. 1988,
27, 333.
(7) (a) Keum, S.-R.; Gregory, D. H.; Bruice, T. C. J . Am. Chem. Soc.
1990, 112, 2711 and references therein. (b) Shinkai, S.; Nakao, H.;
Kuwahara, I.; Miyamoto, M.; Yamaguchi, T.; Manabe, O. J . Chem. Soc.,
Perkin Trans. 1 1988, 313 and references therein. (c) Ohno, A.;
Kunitomo, J .; Kawamoto, T.; Tomishima, M.; Bessho, K.; Yoneda, F.
Tetrahedron Lett. 1994, 9729 and references therein. (d) Kim, J .-M.;
Hoegy, S. E.; Mariano, P. S. J . Am. Chem. Soc. 1995, 117, 100 and
references therein.
However, in the absence of catalyst, the corresponding
lactone was shown to be also formed, but only in small
proportions. Only in the case of 3c was a noticeable
spontaneous lactone formation observed. Thus, the reac-
tion was run in 2-propanol instead of 2-methyl-2-propanol
(8) Shinkai, S. Enzyme Chemistry; Suckling, C. L., Ed.; Chapman
and Hall, Publishers: London, 1984; 40.
(9) Mager, H. I. X.; Tu, S.-C. Tetrahedron 1994, 50, 5287.
(10) (a) Alphand, V.; Archelas, A.; Furstoss, R. J . Org. Chem. 1990,
55, 347. (b) Lebreton, J .; Alphand, V.; Furstoss, R. Tetrahedron Lett.,
in press.
(11) Shinkai, S.; Yamaguchi, T.; Manabe, O.; Toda, F. J . Chem. Soc.,
Chem. Commun. 1988, 1399.
(12) A typical experiment was as follows: Ketone 3 (5 mmol) and
the catalyst 2 (100 mg, 5 mol %) were dissolved in t-BuOH (10 mL),
and 1 mL of 35% H2O2/water solution (10 mmol) was added via syringe.
The mixture was stirred at room temperature for 3-24 h depending
on the substrate. Evaporation of the solvent in vacuo and filtration on
silica afforded the pure lactones 4 (up to 95% purity as checked by GC
and by NMR).
0022-3263/96/1961-0008$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 1, 1996
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Ta ble 1. Oxid a tion a t Room Tem p er a tu r e of Va r iou s
Cyclobu ta n on es by 2 in th e P r esen ce of H2O2
F igu r e 1. Proposed catalytic cycle for the BV oxidation of
ketones 3.
In light of the previous works of Bruice7a and Shinkai,7b
the mechanism we propose to explain these oxidations
is depicted in Figure 1. As outlined previously, hydrogen
peroxide, in the presence of isoalloxazine 2, presumably
forms the peroxide 5 which has also been postulated to
be the oxidizing species in enzymatic BV transforma-
tions.6 Such an intermediate has also been isolated and
fully characterized previously.15 This peroxide interme-
diate will then react further on with ketones 3, affording
the corresponding lactones 4 and the hydroxyflavin 6
which, over dehydration, leads back to the catalyst 2.
In conclusion, these results describe for the first time
the possibility of using flavin derivatives as enzyme
models for catalyzing the BV oxidation of ketones, a
reaction which can be run in a very simple fashion at
room temperature using hydrogen peroxide as a cheap
oxidant. Moreover, the possibility to introduce some
chiral moieties into such isoalloxazine catalysts opens the
way to the design of chiral catalysts with the aim to
perform enantioselective Baeyer-Villiger oxidations. At-
tempts to improve the range of reactivity of these flavin
models as well as efforts to achieve asymmetric oxida-
tions using some chiral isoalloxazines are underway in
our laboratory.
a
b
Isolated yield in the presence of catalyst 2. Without catalyst,
GC yield. c Reaction performed using i-PrOH as a solvent at -5
°C.
in order to allow the reaction to be run at -5 °C. The
results we have obtained are indicated in Table 1.
Bicyclobutanones 3c-e were the most reactive and led
to high yields of the corresponding lactones 4c-e. In all
cases, the expected regioisomer was formed, contrary to
what we had observed previously in the case of biocata-
lyzed reactions.4 Interestingly, the double bond of sub-
strate 3e was not oxidized, even over long reaction
periods. Unfortunately, under such conditions, cyclohex-
anones, cyclopentanones, and linear ketones were less
reactive and only R-alkoxycyclohexanones,13,14 such as 3f,
gave good results. The lower yield observed in this case
was presumably due to the extreme liability of the lactone
4f during its isolation. The chemical-physical data of
the various lactones 4 were consistent with the ones
described previously.4a,13
Ack n ow led gm en t. This work has been accom-
plished in the frame of the EU Human Capital and
Mobility Scheme on Biooxygenations. A fellowship to
C.M. is greatly acknowledged in this context. We also
would like to thank Dr. V. Alphand for advice concern-
ing the GC separation and identification of the products.
Su p p or tin g In for m a tion Ava ila ble: Procedure and cop-
ies of spectra are included (5 pages).
J O951905B
(13) Hata, E.; Takai, T.; Yamada, T.; Mukaiyama, T. Chem. Lett.
1994, 535.
(14) Chida, N.; Tobe, T.; Ogawa, S. Tetrahedron Lett. 1994, 7249.
(15) Kemal, C.; Bruice, T. C. Proc. Natl. Acad. Sci. U.S.A. 1976, 73,
995.