Synthesis of 1,6,7-trioxa-spiro[4.5]decanes

Article abstract of DOI:10.1016/j.tetlet.2005.06.110

As potential antimalarial agents, four novel spiro-peroxides were designed and synthesized with the peroxy bond introduced employing the Kobayashi's methodology (with modifications). The results showed that by using cyclic hemiketal as substrates the inco

Full text of DOI:10.1016/j.tetlet.2005.06.110

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5767–5769
Synthesis of 1,6,7-trioxa-spiro[4.5]decanes
Hong-Xia Jin, He-Hua Liu, Qi Zhang 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 9 May 2005; revised 30 May 2005; accepted 2 June 2005
Available online 7 July 2005
Abstract—As potential antimalarial agents, four novel spiro-peroxides were designed and synthesized with the peroxy bond intro-
duced employing the KobayashiÕs methodology (with modifications). The results showed that by using cyclic hemiketal as substrates
the incorporation of the hydroperoxyl group could be achieved in high yields without recourse to the expensive Sc(OTf)3 catalyst.
Ó 2005 Elsevier Ltd. All rights reserved.
Although even back in the 19th century organic per-
oxides were already known,1 the value of this class of
compounds was neverfully recognized by the scientific
communities around the world until the late 1980s,
when qinghaosu (artemisinin, an outstanding antimalar-
ial agent discovered2 in China) was made broadly
known to the West. Now, with the great potential of
organic peroxides as a novel class of antimalarial agents
demonstrated through many qinghaosu derivatives and
various simple analogues,3 design and synthesis of new
organic peroxides have gradually grown into an active
area in organic chemistry.
intramolecular4d hemiketals as the precursors is that
the products would carry a new structural feature—a
spiro framework with the peroxy bond and the hemi-
ketal alkoxy bond in different rings. Besides, we were
also interested in examining whether other Michael
acceptors than a,b-unsaturated esters could serve well
in the ring-closure step. All these prompted us to
conduct the work reported below.
We first designed simple targets 1 and 2, which were syn-
thesized using the route shown in Scheme 1. The known5
dithiane 3 was protected as a MOM ether before being
deprotonated and alkylated at the dithiane C-2 position
to yield acetal 4. The masked aldehyde carbonyl group
was then freed by hydrolysis in acetone in the presence
of a catalytic amount of PPTS (pyridinium p-toluene-
sulfonate). The resulting aldehyde was immediately trea-
ted with Ph3P@CHCO2Et orPh 3P@CHCO2Bn in
CH2Cl2 to give 5 or 6, respectively. The sulfur protecting
Recently, Kobayashi and co-workers4a,b reported a
very convenient way to construct six-membered mono-
cyclic peroxides using UHP (H2O2–urea complex, a
commercially available solid reagent) as the peroxy
bond source. In their methodology the hydroperoxyl
group (–OOH) was incorporated into the substrate
6
structure through
a
Sc(OTf)3-catalyzed OH/OOH
group was then removed with I2/NaHCO3 to afford 7
or 8, respectively.
exchange. Hence, the presence of a hemiketal formed
in situ from a ketone and MeOH (solvent) was appar-
ently a pre-requisite for the OOH incorporation. We
reasoned that if the hemiketal formed intramolecularly,
the corresponding hemiketal would be available times
forthe subsequent exchange. The inotrduction of
OOH might be significantly facilitated and the expen-
sive Sc(OTf)3 perhaps could be replaced with a com-
monly utilized acid.4c An additional advantage to use
Introduction of the OOH group was achieved using
KobayashiÕs method at very similar substrate concentra-
tions, but the catalyst Sc(OTf)3 was replaced with
p-TsOH (the commercially available monohydrate).
Kobayashi also examined p-TsOH. However, the yields
for their non-cyclic hemiketal substrates were rather low
unless 20-fold excess of UHP was employed. In our
cases, the reaction appeared to be much easier to occur.
Thus, in the presence of 7.5 equiv of UHP, 9 could
be readily obtained in 82% isolated yield after ca. 20 h
reaction at the ambient temperature. Further treatment
of 9 or 10 with HNEt2 in F3CCH2OH gave the end
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.2005.06.110

5768
H.-X. Jin et al. / Tetrahedron Letters 46 (2005) 5767–5769
OMe
CO2R
OMe
a
c
b
HO
MOMO
MOMO
S
S
S
S
S
S
R = Et
5
4
3
R = Bn 6
9
10
O
3
CO2R
CO2R
6
7
O
e
d
CO2R
O
O
O
OOH
R = Et
1
OH
R = Et
1
9
R = Et
7
R = Bn 2
R = Bn 10
R = Bn 8
Scheme 1. Reagents and conditions: (a) (i) CH2(OMe)2, LiBr, TsOH, rt, 48 h; (ii) BuLi, HMPA, I(CH2)2CH(OMe)2, 0 °C, 48 h, 71% (overtwo
steps); (b) (i) PPTS, acetone, reflux, 12 h; (ii) Ph3P@CHCO2Et orPh 3P@CHCO2Bn, CH2Cl2, rt, 12 h, 86% for 5 or94% for 6 (overtwo steps); (c) (i)
p-TsOH, EtOH, reflux or 2 N HCl, THF, 40–50 °C; (ii) I2, acetone, NaHCO3, 0 °C, 30 min, 75% for 7 or50% for 8 (overtwo steps); (d) UHP,
p-TsOH, MeOH, rt, 82% for 9 or54% for 10 (not optimized); (e) HNEt2, CF3CH2OH, rt, 24 h, 52% for either 1 or 2.
OMe
OMe
O
NO2
a
b
NO2
MOMO
MOMO
S
S
S
S
OH
12
11
4
c
NO2
NO2
O
O
O
O
OOH
13
Scheme 2. Reagents and conditions: (a) (i) PPTS, acetone, reflux, 12 h; (ii) CH3NO2, DBU, rt, 15 h; (iii) MsCl, NEt3, rt, 24 h, 91% (over three steps);
(b) (i) I2, NaHCO3, 0 °C, 30 min; (ii) concd HCl, acetone–H2O, rt, 17 h, 23% (over two steps); (c) UHP, p-TsOH, DME, rt, 10.5 h, 35%.
product4e 1 or 2, respectively (presumably as a mixture4f
of the diastereomers).
Apart from changing the electron-withdrawing group on
the C–C double bond, we also attempted incorporation
of an aromatic ring into the core structures of the targets
because presence of an UV chromophore may facilitate
future studies (i.e., tracing the molecule) and alter the
bioactivity as a consequence of its influence on the radi-
cal-mediated cleavage8 pathways. The synthesis of such a
molecule (19) is shown in Scheme 3. Thus, the known
alcohol 147 was oxidized into the corresponding alde-
hyde and treated with the lithium reagent9 generated in
situ from o-bromophenylmethanol. The intermediate
diol 15 was oxidized into an aldehyde–ketone, which
was directly treated with Ph3P@CHCO2Et to give the
a,b-unsaturated ester 16. The terminal TBS protecting
group was then removed and the resulting alcohol–
ketone 17 was treated with UHP in DME to give the
hydroperoxy species 18 in 86% yield. On further treat-
ment with HNEt2 in F3CCH2OH, the end product 19
was obtained in 54% yield.
As part of our interest in examining the scope and limi-
tation of the KobayashiÕs method, we next tried to use a
–NO2 as the electron-withdrawing group in place of the
–CO2R (Scheme 2). Thus, the acetal 4 was transformed
into 11 by a three-step sequence. First, the acetal was
protected as mentioned above. The intermediate alde-
hyde was then treated with nitromethane in the presence
of DBU to give an intermediate alcohol. The OH group
b to the nitro group was then eliminated after being con-
verted to the corresponding mesylate, yielding the alke-
nyl nitro compound 11. Deprotection of the ketone
carbonyl group and the hydroxyl group was rather com-
plicated, presumably because of the presence of the alken-
yl nitro partial structure. However, as we were mainly
interested whether the final ring-closing could take
place, we went on with 12 despite the low yield.
In the subsequent hydroperoxidation of 12, we modified
the reaction conditions slightly (utilizing DME to
replace MeOH), because from other closely-related
experiments we had already observed that MeOH read-
ily underwent Michael addition to the C–C double bond
if a –NO2 group was present. After such an adjustment,
the hydroperoxidation did occur as wished. However,
due to the presence of the highly reactive –CH@CHNO2
partial structure, the resulting hydroperoxy species
could not be isolated. Instead, it proceeded directly to
yield the end cyclic peroxide 13.
In summary, we have designed and synthesized four
novel spiro-peroxides, extending KobayashiÕs method-
ology to cyclic hemiketals. We also examined the feasibil-
ity of using a nitro group as the electron-withdrawing
group to replace the ester group in the original proce-
dure. The results showed that by using cyclic hemiketals
as substrates the hydroperoxidation could be realized in
high yields without recourse to the expensive catalyst
Sc(OTf)3. DME (1,2-dimethoxyethane) was found to
be a good substitute forMeOH as the solvent in the
hydroperoxidation, which could eliminate the problem

H.-X. Jin et al. / Tetrahedron Letters 46 (2005) 5767–5769
5769
O
OH
OTBS
a
OTBS
b
OTBS
O
HO
OH
CO2Et
16
14
15
O
HOO
O O
CO2Et
OH
CO2Et
e
c
d
O
CO2Et
19
17
18
Scheme 3. Reagents and conditions: (a) (i) (COCl)2, DMSO, NEt3; (ii) BuLi, BrC6H4CH2OH, À78 °C, 1 h, then the aldehyde, À78 °C, 40 min, 61%
(two steps); (b) (i) (COCl)2, DMSO, NEt3; (ii) PhP@CHCO2Et, rt, 3 h, 74% (over two steps); (c) p-TsOH, THF–H2O (4:1), rt, 5 h, 96%; (d) UHP,
CSA, DME, rt, 18 h, 86%; (e) HNEt2, CF3CH2OH, rt, 2 h, 54%.
Dong, Y.; Matile, H.; Chollet, J.; Kaminsky, R.; Wood, J.
K.; Vennerstrom, J. L. J. Med. Chem. 1999, 42, 1477–1480;
(d) Tsuchiya, K.; Hamada, Y.; Masuyama, A.; Nojima, M.;
McCullough, K. J.; Kim, H.-S.; Wataya Tetrahedron Lett.
1999, 40, 4077–4080; (e) Kim, H.-S.; Shibata, Y.; Wataya,
Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M. J. Med.
caused by addition of MeOH to the a,b-unsaturated
moiety in some substrates (with a strong electron-with-
drawing group on the C–C double bond).
Acknowledgements
Chem. 1999, 42, 2604–2609; (f) Solaja, B. A.; Terzic, N.;
Pocsfalvi, G.; Gerena, L.; Tinant, B.; Opsenica, D.;
This work has been supported by the National Natural
Science Foundation of China (20025207, 20272071,
20372075, 20321202), the Chinese Academy of Sciences
(ÔKnowledge InnovationÕ project, KGCX2-SW-209),
and the Major State Basic Research Development Pro-
gram (G2000077502).
Milhous, W. K. J. Med. Chem. 2002, 45, 3331–3336.
4. (a) Murakami, N.; Kawanishi, M.; Itagaki, S.; Horii, T.;
Kobayashi, M. Tetrahedron Lett. 2001, 42, 7281–7285; (b)
Murakami, N.; Kawanishi, M.; Itagaki, S.; Horii, T.;
Kobayashi, M. Bioorg. Med. Chem. Lett. 2002, 12, 69–72;
(c) A higheryield in consturcting a similarmethoxy-
hydroperoxy ketal with O3/MeOH was reported by Dus-
sault and co-workers very recently. See: Xu, C.; Raible, J.
M.; Dussault, P. H. Org. Lett. 2005, 7, 2509–2511, We
thank one of the referees for providing this reference.; (d)
Schreiber, S. L.; Sammakia, T.; Hulin, B.; Schulte, G. J.
Am. Chem. Soc. 1986, 108, 2106–2108, We thank one of the
referees for providing this reference; (e) For spectroscopic
data of these compounds (used as starting materials there)
see Wu, Y.-K.; Jin, H.-X.; Liu, H.-H.; Zhang, Q. J. Org.
Chem. 2005, 70, 4240–4247; (f) Unlike the monocyclic
peroxides reported by Kobayashi, the diastereomers of our
spiro-peroxides in most cases were indistinguishable/insep-
arable on TLC.
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