Synthesis of benzene-fused 1,7,8-trioxa-spiro[5.6]dodecanes

Article abstract of DOI:10.1016/j.tetlet.2005.08.031

Two novel organic peroxides with one or two benzene rings fused to a 1,7,8-trioxaspiro[5.6]dodecan framework were synthesized, which provided the first examples of employing Kobayashi's methodology in the synthesis of seven-membered peroxy rings. CSA was

Full text of DOI:10.1016/j.tetlet.2005.08.031

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6801–6803
Synthesis of benzene-fused 1,7,8-trioxa-spiro[5.6]dodecanes
Hong-Xia Jin and Yikang Wu*
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 1 June 2005; revised 5 August 2005; accepted 8 August 2005
Available online 19 August 2005
Abstract—Two novel organic peroxides with one or two benzene rings fused to a 1,7,8-trioxaspiro[5.6]dodecan framework were syn-
thesized, which provided the first examples of employing Kobayashiꢀs methodology in the synthesis of seven-membered peroxy
rings. CSA was found to be a potent catalyst for introduction of the hydroperoxyl group, making a useful complement to Koba-
yashiꢀs methodology in constructing spiroperoxides.
Ó 2005 Elsevier Ltd. All rights reserved.
Design and synthesis of novel organic peroxides is a
rapid-developing area in organic chemistry in recent
years, mainly because of the great potential of this type
of compounds in malaria chemotherapy.1 A key issue in
the synthesis of organic peroxides is construction of the
peroxy bond. Although theoretically an organic peroxy
bond could form from two alkoxyl radicals (which has
also been actually demonstrated by Porter et al.2), the
peroxy bonds of essentially all synthetic organic perox-
ides are derived from some species where two oxygen
atoms are already bonded together. Apart from 1O2,
which can be obtained either by the classic photosensiti-
ence of F3BÆOEt2 to give 3. The MOM protecting group
was removed with conc. HCl in MeOH. The resulting 4
was oxidized to yield an intermediate aldehyde-ketone,
which was treated with Ph3P@CHCO2Et to afford the
a,b-unsaturated ester 5 predominantly as E-isomer
(J = 15.7 Hz for the –CH@CHCO2Et).
Removal of the allyl protecting group was attempted
under several sets of conditions, including PdCl2/MeO-
H,10a PdCl2/CuCl/DMF–H2O/air,10b Pd–C/MeOH,10c
and Pd(PPh3)4/p-TsOH/CH2Cl2.10d In all cases, we
obtained a mixture of many components, from which
we managed to isolate and identify three of them, that
is, compounds 6, 7, and 8. Then, we found that all
these compounds could be transformed eventually into
the desired hydroperoxide 9 (J = 15.7 Hz for the
–CH@CHCO2Et) and thus the mixture of the deallyl-
ation products was used directly in the next step without
the painstaking chromatographic separation.
zation3 or disproportion4 of H2O2, ozone5 and H2O2
6
are also among the most frequently employed sources
of O–O bonds. In 2001, Kobayshi and co-workers7
reported a very convenient protocol utilizing UHP
(H2O2–urea complex) as the reagent. The methodology,
however, was only demonstrated on some six-membered
molecules up to now. In this letter, we wish to describe
the synthesis of two seven-membered peroxides with
one or two benzene rings fused to a novel peroxy spiro-
dodecane framework.
The subsequent hydroperoxidation was performed using
Kobayashiꢀs7 protocol, but the expensive catalyst
Sc(OTf)3 and the solvent MeOH were replaced with
p-TsOH (monohydrate) and DME (1,2-dimethoxy-
ethane), respectively, as we have done before in the
synthesis11 of some 1,6,7-trioxa-spiro[4.5]decanes. The
resulting hydroperoxy species was treated with HNEt2
in F3CCH2OH gave the end product12 10.
The synthesis of the first molecule is depicted in Scheme
1. The epoxide 1 reacted with the lithium species 2 (gen-
erated in situ from the bromide8 by reaction with n-BuLi
using the procedure9 of Parhem) at À78 °C in the pres-
The second molecule was synthesized using epichlorohy-
drin as the central fragment (Scheme 2). Concatenation
of the building blocks was realized through two epoxy
ring-opening reactions by the lithium reagents derived
Keywords: Peroxides; Spiroketals; Cyclizations; Hemiketals;
Aromatics.
*
Corresponding author. E-mail: yikangwu@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.031

6802
H.-X. Jin, Y. Wu / Tetrahedron Letters 46 (2005) 6801–6803
HO
HO
OMOM
Li
O
b
c
a
+
Oallyl
OH
Oallyl
OMOM
O
2
6
1
4
3
O
O
O
O
d
+
+
OMe
OH
Oallyl
OH
5
CO2Et
7
CO2Et
8
CO2Et
CO2Et
O
e
f
OOH
CO2Et
CO2Et
10
9
O O
O
Scheme 1. Reagents and conditions: (a) F3BÆOEt2/À78 °C/1 h, 80%; (b) conc. HCl/MeOH/rt/4 d, 93%; (c) (i) (COCl)2/DMSO/Et3N; (ii)
Ph3P@CHCO2Et/rt/12 h, 85% (from 4); (d) PdCl2/MeOH/rt/24 h, then 60 °C/4 h; (e) UHP (ca. 7 equiv)/p-TsOH (0.9 equiv)/DME/rt/22 h, 71%
(from 5); (f) HNEt2/CF3CH2OH/rt/19 h, 59%.
OMOM
O
a
Cl
c
Cl
Li
b
O
OH
OMOM
O
+
OMOM
12
13
11
14
2
O
O
e
f
d
OH
O
OH
OMOM
CHO
16
OH
15
O
HO
O
g
O
+
HO
+
O
CO2Et
O
CO2Et
20
CO2Et
18
17
19
CO2Et
O
O
h
i
O
O
O
22
OH
21
CO2Et
CO2Et
Scheme 2. Reagents and conditions: (a) F3BÆOEt2/À78 °C; (b) NaH/THF, 67% from 2; (c) n-BuLi/BrC6H4CH2OCH2CH@CH2/À78 °C/1 h, then
13/BF3OEt2/À78 °C/1 h, 76%, (d) conc. HCl/MeOH/rt/3 d, 99%; (e) (COCl)2/DMSO/Et3N; (f) Ph3P@CHCO2Et/rt/12 h, 77% from 15; (g) PdCl2/
CuCl/DMF–H2O/air/rt/12 h; (h) UHP (ca. 13 equiv)/CSA (ca. 5 equiv)/DME–EtOH (4:1)/rt/7 d, 33% from 17 (together with ca. 67% of recovered
18 and 20); (i) HNEt2/CF3CH2OH/rt/21 h, 24%.
from protected o-bromophenylmethanol. Thus, in the
presence of F3BÆOEt2 epichlorohydrin reacted with 2
to yield 12. Although this reaction could also give epox-
ide 13 directly, the yield of 13 was significantly higher if
12 was worked up before treating with NaH. The second
epoxy ring-opening was achieved using an allyl-pro-
tected lithium species but still under similar conditions.
The MOM protecting group was then removed by
hydrolysis. The resulting 15 was oxidized and treated di-
rectly with Ph3P@CHCO2Et to afford 17 predominantly
as E-isomer (J = 15.9 Hz for the –CH@CHCO2Et).
The subsequent deallylation was first carried out with
PdCl2/MeOH at 60 °C. The product was very compli-

H.-X. Jin, Y. Wu / Tetrahedron Letters 46 (2005) 6801–6803
6803
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done in the synthesis of 9 led to no peroxy products at
all after one dayꢀs stirring, giving the first sign that the
situation was different in this system. Using PdCl2/
CuCl/DMF–H2O/air/rt10b gave a simpler product mix-
ture, which allowed for separation and identification
of three main components (18, 19, and 20).
3. (a) Griesbeck, A. G.; El-Idreesy, T. T.; Fiege, M.; Brun, R.
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Treatment of 19 with 7 equiv of UHP and 0.9 equiv of p-
TsOH/DME for three days, however, failed to yield any
expected product. Addition13 of 3 equiv of CSA (10-
camphorsulfonic acid) facilitated the reaction signifi-
cantly. After only 12 h at rt, the desired 21 could be
clearly spotted on TLC, along with some 18 and 20
(which were much more resistant to the hydroperoxida-
tion). In preparative runs, the mixture of 18, 19 and 20
was treated with 13 equiv of UHP and 5 equiv of CSA14
to afford 21 (J = 15.9 Hz for the –CH@CHCO2Et) in
33% yield, together with the recovered 18 and 20 (ca.
67% altogether, which could be recycled).
The final ring closure was also realized with HNEt2/
F3CCH2OH. However, with an additional benzene ring
in the substrate, the Michael addition became much
more difficult. The highest yield of 2215 we could
obtain was only 24%, significantly lower16 than that
for 10. The reason for this unexpected outcome was
not clear yet. Perhaps the p–p interactions between
the benzene rings somehow made it more difficult for
the hydroperoxyl group to approach the C–C double
bond.
In summary, to develop potential antimalarial leads we
have designed and synthesized two novel peroxides that
carry one or two benzene rings fused to a 1,7,8-trioxa-
spiro[5.6]dodecan framework (which may be useful
because of the presence of UV chromophore(s) stable
to hydrolysis and the ability to generate benzyl radicals
on cleavage by single-electron reducing species). CSA
was found to be a potent catalyst for introduction
of the hydroperoxyl group, making a useful comple-
ment to Kobayashiꢀs methodology in constructing
spiroperoxides.
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11. Jin, H.-X.; Liu, H.-H.; Zhang, Q.; Wu, Y.-K. Tetrahedron
Lett. 2005, 46, 5767–5769. Noted that Kobayashi also
examined p-TsOH. However, the yields for the non-cyclic
hemiketal substrates were rather low unless 20-fold excess
of UHP was employed.
12. For spectroscopic data of 10 and 22 (used as starting
materials there) see: Wu, Y.-K.; Jin, H.-X.; Liu, H.-H.;
Zhang, Q. J. Org. Chem. 2005, 70, 4240–4247.
13. We have also tried some other acid catalysts (e.g.,
F3BÆOEt2, F3CCO2H, CH3SO3H), but none of them gave
satisfactory results.
Acknowledgements
This work was supported by the National Natural
Science Foundation of China (20025207, 20272071,
20372075, 20321202), the Chinese Academy of Sciences
(ꢁKnowledge Innovationꢀ project, KGCX2-SW-209),
and the Major State Basic Research Development
Program (G2000077502).
14. In order to dissolve the large excess of UHP and CSA
required for (partially) converting 18 and 20 into 21 some
EtOH must be introduced as a co-solvent.
15. Although the diastereomers of monocyclic peroxides
could be separated,7b most of the spiroperoxides we
prepared appeared as one spot on TLC. Besides, the
separated7b diastereomers showed essentially the same
antimalarial potency. Therefore, we did not make exhaus-
tive efforts (e.g., using HPLC) to separate our
diastereomers.
16. We have also examined some other bases (LiOH, Et3N,
etc.) or extending the reaction time, but none of them led
to better yields.
References and notes
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