Mixed peroxides from the chloroperoxidase-catalyzed oxidation of conjugated dienoic esters with a trisubstituted terminal double bond

Article abstract of DOI:10.1016/S0040-4039(02)00819-5

The chloroperoxidase (CPO)-catalyzed oxidations of conjugated dienoic esters with a trisubstituted terminal double bond were studied by using tert-butyl hydroperoxide as the terminal oxidant. Most of the substrates gave disubstituted mixed peroxides as the major products.

Full text of DOI:10.1016/S0040-4039(02)00819-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4511–4514
Mixed peroxides from the chloroperoxidase-catalyzed oxidation
of conjugated dienoic esters with a trisubstituted terminal
double bond†
Despina J. Bougioukou and Ioulia Smonou*
Department of Chemistry, University of Crete, Iraklio 71409, Crete, Greece
Received 7 March 2002; revised 15 April 2002; accepted 25 April 2002
Abstract—The chloroperoxidase (CPO)-catalyzed oxidations of conjugated dienoic esters with a trisubstituted terminal double
bond were studied by using tert-butyl hydroperoxide as the terminal oxidant. Most of the substrates gave disubstituted mixed
peroxides as the major products. © 2002 Elsevier Science Ltd. All rights reserved.
Chloroperoxidase (CPO) from Caldariomyces fumago1,2
has been used extensively over the last few years as a
catalyst in the halide-independent oxidation of alke-
nes.3–18 Recently,19 we showed that in the case of dienes
conjugated to an ester group, 1, the ratio of epoxida-
tion to allylic oxidation depends on the stereochemistry
of the C4ꢀC5 double bond. Our continuing interest in
the substrate structural features that control this ratio,
led us to study the oxidation of conjugated dienoic
esters with a trisubstituted terminal double bond. As
far as we know, CPO does not catalyze the reaction of
trisubstituted alkenes,16 the only reported12 exception
being substrate 2, that leads to the exclusive formation
of the epoxide 3 (Scheme 1).
group, with a trisubstituted terminal double bond, to
give disubstituted mixed peroxides. We also discuss a
possible
mechanism
for
these
interesting
transformations.
All reactions were carried out in the absence of light, in
a phosphate buffer (100 mM, pH 6), by using 0.2 mmol
of substrate, 2000 units of commercially available CPO
and
2
equiv. of 70% tert-butyl hydroperoxide
(tBHP),20,21 which was added in two aliquots to give a
total volume of 5 ml. All the reactions were done under
anaerobic conditions (under a nitrogen flow), except for
the reaction of substrate 12. They were monitored by
gas chromatography and the products were separated
by flash column chromatography (SiO2, 10–30% Et2O
in pentane) and identified with 500 MHz H and 13C
1
5
CO2Me
4
1
NMR and GC–MS. All product yields reported were
calculated after completion of the reactions (2–3 hours).
Substrates 4, 8, 10 and 12 were prepared according to
known methods by using the Brittelli reaction22 as a
key step for their synthesis.† The dienone 17 was com-
mercially available. All the substrates were stable under
the reaction conditions without enzyme.
In this communication, we report the CPO-catalyzed
oxidation of dienes, which are conjugated to an ester
O
CPO
H2O2
The CPO-catalyzed oxidation of methyl (2E)-5-methyl-
2,4-hexadienoate 4 gave the epoxide 5 as the major
product (48%) with low enantioselectivity (5% ee),
accompanied by the E,E-aldehydic ester 6 (28%)
derived from the allylic hydroxylation of the exo methyl
2
3 (81% ee)
Scheme 1.
Keywords: chloroperoxidase; oxidation; dienoic esters; mixed perox-
ides; epoxidation.
* Corresponding author. Tel.: +30-810-393610; fax: +30-810-393601;
e-mail: smonou@chemistry.uoc.gr
† In each case, the appropriate starting aldehyde was reacted with
bromoacetic acid to produce a carboxylic acid, which was then
esterified and the resulting ester was purified by flash column
chromatography.
†
Dedicated to Professor G. J. Karabatsos on the occasion of his 70th
birthday.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00819-5

4512
D. J. Bougioukou, I. Smonou / Tetrahedron Letters 43 (2002) 4511–4514
Scheme 2. CPO-catalyzed oxidation of 4.
usual product of the reaction of a Z double bond with
CPO.
group (86% de), and the disubstituted mixed peroxide 7
(24%) (Scheme 2).
The methyl (2E)-4-methyl-2,4-pentadienoate 12 was
also oxidized under aerobic conditions. In addition to
the mixed peroxides 13 and 14 (13% and 31% relative
yields, respectively) and the epoxide 16 (23%, 80% ee),
the carbon–carbon cleavage product, ketone 15, was
also formed in 33% yield (Scheme 5). Its formation was
not surprising according to our previous related work
on CPO-catalyzed oxidations of conjugated dienoic
esters.19
When the C2 hydrogen in diene 4 was replaced by a
methyl group, producing methyl (2E)-2,5-dimethyl-2,4-
hexadienoate 8, the only isolated product (50% yield)
was compound 9, accompanied by a small amount of
allylic hydroxylation products (under 2%). No epoxide
was observed in this case (Scheme 3).
The above results show that CPO is an efficient
catalyst for the oxidation of conjugated dienoic esters
with a trisubstituted terminal double bond. In all cases,
reactions of 4, 8, 10 and 12 with CPO led to the
formation of mixed peroxides in considerable
amounts.‡ Interestingly, no mixed peroxides were
obtained in the reaction of 17, where the diene is
conjugated to a ketone instead of an ester group
(Scheme 6). Epoxide 18 was the major product (83%)
Scheme 3. CPO-catalyzed oxidation of 8.
The CPO-catalyzed oxidation of methyl (2E,4Z)-4-
methyl-2,4-hexadienoate 10 gave the aldehydic ester 11
as the major product (70%), and a mixture of peroxidic
compounds (30%) which could not be isolated (Scheme
4). Surprisingly, no epoxide was formed, which is the
Scheme 4. CPO-catalyzed oxidation of 10.
Scheme 5. CPO-catalyzed oxidation of 12.
‡ It is interesting to note here that synthesis of analogous mixed peroxides through radical intermediates has appeared recently in the literature.24,25

D. J. Bougioukou, I. Smonou / Tetrahedron Letters 43 (2002) 4511–4514
4513
Acknowledgements
We thank the Greek Secretariat of Research and
Technology (PENED 1999) for financial support and
for a research fellowship to D.J.B. This work was
also supported by the graduate program EPEAEK.
Scheme 6. CPO-catalyzed oxidation of ketone 17.
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