One-pot synthesis of non-symmetric tetraoxanes with the H2O2/MTO/fluorous alcohol system

Article abstract of DOI:10.1016/S0040-4039(03)01472-2

1,2,4,5-Tetraoxanes, potent antimalarial drugs, were selectively synthesized in fluorous alcohols (2,2,2-trifluoroethanol-TFE and 1,1,1,3,3,3-hexafluoro-2-propanol-HFIP). A use of these solvents enabled for the first time a one-pot synthesis of non-symmet

Full text of DOI:10.1016/S0040-4039(03)01472-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6309–6312
One-pot synthesis of non-symmetric tetraoxanes with the
H2O2/MTO/fluorous alcohol systemꢀ
Jernej Iskra,a Danie`le Bonnet-Delponb,* and Jean-Pierre Be´gue´b
aLaboratory of Organic and Bioorganic Chemistry, ‘Jozef Stefan’ Institute, Jamova 39, Slovenia
bBIOCIS UPRES-A 8079, Faculte´ de Pharmacie, Universite´ Paris-Sud, Chatenay-Malabry, France
Received 21 May 2003; revised 13 June 2003; accepted 14 June 2003
Abstract—1,2,4,5-Tetraoxanes, potent antimalarial drugs, were selectively synthesized in fluorous alcohols (2,2,2-trifluoroethanol–
TFE and 1,1,1,3,3,3-hexafluoro-2-propanol–HFIP). A use of these solvents enabled for the first time a one-pot synthesis of
non-symmetric tetraoxanes in good yields from simple ketones and aldehydes with 2 equiv. of 30% hydrogen peroxide and 0.1
mol% of methyltrioxorhenium (MTO).
© 2003 Elsevier Ltd. All rights reserved.
Artemisinin and its semisynthetic derivatives represent
a new class of antimalarials, active against Plasmodium
sentatives of this group of compounds were struc-
turally very limited and good yields of symmetric
falciparum,
a
chloroquine-resistant parasite, which
tetraoxanes
2 could be achieved only in some
causes several million deaths per year worldwide.1,2
They contain an endoperoxide functional group as the
pharmacophore and several types of synthetic
cyclic peroxides were established to have good anti-
malarial activity.3 Among them, dispiro-1,2,4,5-tetra-
cases.6,9,10
Bearing in mind that symmetric tetraoxanes 2 are lim-
ited in number, non-symmetric tetraoxanes would offer
more opportunity for selective incorporation of various
functional groups on the tetraoxane scaffold. Very
recently two methods have been reported for the syn-
thesis of mixed tetraoxanes. They are multi-step proce-
dures with isolation of the explosive dihydroperoxide
intermediate (Scheme 1).11
oxanes
2
(7,8,15,16-tetraoxadispiro[5.2.5.2]-hexa-
decanes) exhibit remarkable antimalarial activity. They
are structurally simple and easily prepared by acid-
catalyzed condensation of substituted cyclohexanones
and hydrogen peroxide.4–8 However, until now repre-
Scheme 1.
ꢀ Supplementary data associated with this article can be found at doi:10.1016/S0040-4039(03)01472-2
* Corresponding author. Tel.: +33-146835739; fax: +33-146835740; e-mail: daniele.bonnet-delpon@cep.u-psud.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01472-2

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J. Iskra et al. / Tetrahedron Letters 44 (2003) 6309–6312
An easy, safe and efficient route to mixed tetraoxanes
would give strong impetus to find candidates with good
activity and determine their structure/activity relation-
ship and their mode of action against malarial para-
sites. A one-pot procedure for synthesis of mixed
tetraoxanes would demand quantitative conversion of
the starting ketone to a gem-dihydroperoxide under
neutral conditions with no excess of hydrogen peroxide,
followed by addition of a second carbonyl compound
and acid to promote cyclization. We envisaged that
H2O2/MTO/fluorous alcohol could be a good system,
since we, among others, have shown that fluorous
absence of an acid catalyst, we could hope to prevent
the cyclization process. Reaction of 1 with 2 equiv. of
30%H2O2/0.1 mol% MTO/TFE was followed by TLC
and after 2 h of stirring only trace amounts of starting
ketone remained. After a work-up procedure, 4-methyl-
1,1-dihydroperoxycyclohexanone 5 was obtained as the
major product and its structure was determined by a
comparison of NMR spectra (Scheme 4).11b
A clean preparation of mixed tetraoxanes using the
H2O2/MTO/TFE oxidative system could be envisaged,
since first, conversion of a carbonyl compound to a
gem-dihydroperoxide could be obtained with no excess
of H2O2, and second, the acid-catalyzed conversion of
the ketone to tetraoxane was selective. We thus pro-
ceeded towards the one-pot synthesis of mixed tetra-
oxanes by first oxidizing the most reactive carbonyl
compound to a gem-dihydroperoxide, followed by the
addition of the less oxidizable carbonyl compound in
the presence of acid.
alcohols, trifluoroethanol (TFE) and hexafluoro-
12
propanol, (HFIP) can activate both H2O2
and
methyltrioxorhenium13 for oxidation and epoxidation
reactions, while nucleophile oxirane ring opening reac-
tions exhibit remarkable selectivity.14
We tested the usefulness of fluorous alcohols in the
synthesis of tetraoxane in the case of 4-methyl cyclo-
hexanone, which is known to provide mainly hexaoxo-
nane instead of the tetraoxane.9After reaction of 1 with
1 equiv. H2O2 30%, 0.1 mol% MTO and 1 equiv. of
acid (HBF4 in ether) in TFE, tetraoxane 2 was the only
product formed as determined by its characteristic sig-
A solution of ketone 1/2 equiv. H2O2 30%/0.1 mol%
MTO in TFE (0.5 M) was stirred for 2 h at room
temperature, then 2 equiv. of 5-nonanone were added,
followed by the addition of 1 equiv. of HBF4. The
reaction mixture was stirred for an additional hour, and
after the usual work-up procedure, mixed tetraoxane 6a
was obtained as the major reaction product, accompa-
nied by a small amount of symmetric tetraoxane 2
(6a:2=15:1). Product 6a was easily separated from the
starting ketones by column chromatography and
purified by crystallization, yielding 64% of mixed tetra-
oxane 6a (Scheme 5). When the more oxidizable 4-tert-
butylcyclohexanone was taken as the second carbonyl
1
nal in H NMR spectra at 3.1 ppm15 and was isolated
in 74% yield (Scheme 2). No formation of the hexaoxo-
nane was observed. Similar reaction in ethanol yielded
complex reaction mixture that contained 20% of
tetraoxane.
Using similar reaction conditions, aliphatic ketones
(e.g. 5-nonanone) did not react. In the same way,
benzaldehyde 3a reacted and tetraoxane 4a was the sole
reaction product, while aliphatic aldehyde 3b yielded a
complex reaction mixture. By replacing TFE by HFIP,
the reaction was successful and the corresponding tetra-
oxane 4b was obtained in 86% yield (Scheme 3). How-
ever, there was no reaction with 5-nonanone even in
HFIP.
In the next step, we were interested in the possible
synthesis of a gem-dihydroperoxide using the same
oxidative system. If the reaction was performed in the
Scheme 4.
Scheme 2.
Scheme 5.
Scheme 3.

J. Iskra et al. / Tetrahedron Letters 44 (2003) 6309–6312
6311
compound, reaction was less selective, since besides the
mixed tetraoxane, both symmetric ones were formed in
small quantities. Nevertheless 6b was obtained in 45%
yield after crystallization. Aliphatic as well as aromatic
aldehydes could also be used for the cyclization, as may
be seen in Scheme 5.
Supporting information. Experimental procedures and
full characterization for compounds 2, 4, 5, 6 and 7.
Acknowledgements
This research was supported by the European Commu-
nity Human Potential Programme Marie Curie Individ-
ual Fellowship (J.I.) under contract number
HPMF-CT-1999-00097 and GDR Parasitology. We are
grateful to Dr. Dusan Zigon and Dr. Bogdan Kralj for
MS measurements and Miche`le Oure´vitch for the help
with NMR spectra.
Having established that the H2O2/MTO/fluorous alco-
hol oxidative system quantitatively converts aldehydes
into symmetrical tetraoxanes with only 1 equiv. of 30%
H2O2 and 0.1 mol% of MTO, we tried to extrapolate to
the synthesis of mixed tetraoxanes with the basic car-
bonyl unit of an aldehyde and the secondary one of an
aliphatic ketone. Reaction was performed with octanal
and 2 equiv. of H2O2 and 0.1 mol% of MTO in HFIP
(rt, 1 h) followed by the addition of 2 equiv. of 5-
nonanone and 1 equiv. of HBF4 (rt, 1 h). Again, mixed
tetroxane 7 was obtained in 51% isolated yield after
column chromatography and crystallization (Scheme
6).
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