A synthetic strategy to bridged 2,3,8-trioxabicyclo[3,3,1]nonane endoperoxides

Article abstract of DOI:10.1016/j.tetlet.2012.12.075

As a part of our work in the development of novel antimalarials, we were interested in elaborating an appropriate synthetic strategy for the preparation of endoperoxide-containing bridged bicyclic scaffolds. Through a TMSOTf-promoted dehydrative cyclization strategy we synthesized 2,3,8-trioxabicyclo[3,3,1] nonane endoperoxides. Alkyl substituents at C4 of the bicyclic scaffold could be readily introduced through exposure to Grignard reagents.

Full text of DOI:10.1016/j.tetlet.2012.12.075

Tetrahedron Letters 54 (2013) 1233–1235
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A synthetic strategy to bridged 2,3,8-trioxabicyclo[3,3,1]nonane endoperoxides
Sandra Gemma a,b, Sanil Kunjir a,b, Margherita Brindisi a,b, Ettore Novellino a,c, Giuseppe Campiani a,b,
,
⇑
Stefania Butini a,b
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy
b Centro Interuniversitario di Ricerche sulla Malaria, Università di Torino, Torino, Italy
c Dipartimento di Chimica Farmaceutica e Tossicologica, University of Naples Federico II, via D. Montesano 49, 80131 Naples, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
As a part of our work in the development of novel antimalarials, we were interested in elaborating an
appropriate synthetic strategy for the preparation of endoperoxide-containing bridged bicyclic scaffolds.
Received 3 December 2012
Revised 17 December 2012
Accepted 19 December 2012
Available online 28 December 2012
Through
a TMSOTf-promoted dehydrative cyclization strategy we synthesized 2,3,8-trioxabicyclo
[3,3,1]nonane endoperoxides. Alkyl substituents at C4 of the bicyclic scaffold could be readily introduced
through exposure to Grignard reagents.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Endoperoxide
Lactol
Trimethylsilyl triflate
Introduction
More recently, we disclosed a novel class of bicyclic analogues
of dihydroplakortin having a tetrahydrofuro[2,3-c][1,2]dioxane
Peroxide-based antimalarials such as artemisinin (1, Fig. 1) and
its semisynthetic derivatives are the only highly effective therapy
for the treatment of malaria caused by chloroquine-resistant Plas-
modium falciparum strains. Although highly effective, artemisinins
are also expensive, and this factor limits the wide distribution of
these drugs to malaria endemic countries.1,2 Since the discovery
of artemisinin, research activities have been focused in developing
more affordable endoperoxides characterized by the same highly
effective mechanism of action of artemisinin (linked to the pres-
ence of the endoperoxide moiety) but endowed with simplified
and more synthetically affordable chemical scaffolds.3–9
system (typified by 4).20 For the preparation of these analogues
Several natural compounds have been isolated and are charac-
terized by the presence of the endoperoxide ring system. Among
them, dihydroplakortin (2)10,11 and Yingzhaosu A (3)12 show inter-
esting antimalarial properties, and are characterized by an overall
simpler scaffold with respect to artemisinin. As a part of our work
in the design and synthesis of novel antimalarials,13–18 we recently
focused our research activities on the development of endoperox-
ides based on structural analogues of 9,10-dihydroplakortin, a nat-
ural product isolated from the Caribbean sponge Plakortis simplex.
In particular, we described the total synthesis of dihydroplakortin
and prepared 9,10-dihydroplakortin analogues with a simplified
structure.11,19
⇑
Corresponding author. Tel.: +39 0577 234172; fax: +39 0577 234333.
E-mail address: campiani@unisi.it (G. Campiani).
Figure 1. Reference and title compounds.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.075

1234
S. Gemma et al. / Tetrahedron Letters 54 (2013) 1233–1235
we developed a trimethylsilyl triflate (TMSOTf)-promoted dehyd-
rative cyclization of lactols.
The natural compound Yingzhaosu A (3) presents a 2,3-dioxabi-
cyclo[3,3,1]nonane scaffold that has been exploited for the synthe-
sis of potent analogues (e.g., arteflene and ant its carvone-derived
peroxyacetal analogues).21–24 In order to explore the potential of
our cyclization protocol and to synthesize novel endoperoxide-
containing scaffolds, we decided to prepare the 2,3,8-trioxabicy-
clo[3,3,1]nonane peroxyacetals 5a,b and 6a,b shown in Figure 1.
These derivatives combine the bridged endoperoxide ring of Yingz-
haosu A with the cyclic peroxyacetal moiety of artemisinin. These
endoperoxides could be synthesized exploiting our cyclization
strategy, starting from the lactol intermediate shown in Figure 1.
In particular, TMSOTf simultaneously promotes the deprotection
of the peroxide moiety and the dehydrative cyclization.
The synthesis of C4-dimethyl endoperoxides 5a,b is described
in Scheme 1. Pyranones 7a,b25,26 were prepared as described in
the literature and reacted with isopropenylmagnesium bromide
in the presence of copper(I) bromide to afford olefin intermediates
8a,b.27–29 Regioselective hydroperoxysilylation at the disubstituted
olefin carbon of compounds 8a,b was accomplished under an O2
atmosphere using bis(2,2,6,6-tetramethylheptane-3,5-dienoate)
Co(II) (Co(thd)2) as the catalyst, in the presence of triethylsi-
lane.11,19,30 Subsequently, intermediates 9a,b were subjected to a
DIBAL-promoted reduction of the lactone carbonyl group. Expo-
sure of the resulting lactol derivatives to TMSOTf at À78 °C for
5 min efficiently afforded the target compounds 5a,b.31
In our previous series of bicyclic derivatives, the C3 aliphatic
chain displayed a key role in modulating the antimalarial activity
of the endoperoxides. Accordingly, we explored the possibility of
introducing different alkyl chains at C4 of the bridged endoperox-
ide scaffold (compounds 6a,b). The trisubstituted olefin 12
(Scheme 2) was a key intermediate for the synthesis of 6a. As de-
scribed in Scheme 2, the olefin moiety of 8a was subjected to an
ozonolysis reaction in order to obtain ketone 10. In our original
plan, we hypothesized that this versatile intermediate could be
readily converted into a variety of trisubstituted olefins exploiting
the classical Wittig olefination reaction conditions.
Scheme 2. Attempted syntheses of intermediate 12. Reagents and conditions: (a)
(i) O3, DCM, À78 °C, 40 min, (ii) dimethylsulfide, À78 °C, 25 min; (b) DIBAL, DCM,
À78 °C, 1.5 h; (c) p-TsOH, MeOH, 25 °C, 40 min.
a
b,c
7a
O
O
OMe
d
60%
16
O
17
85%
O
MgBr
R1
R1
O
R1
g
19a-c
O
O
O
60-75%
e,f
50-65%
OMe
OMe
OMe
21a-c
18
20a-c
h
31-70%
H
O
H
R1
Me
Me
Me
R1
However, when ketone 10 was treated with the phosphorous
ylide 11, the expected olefin 12 was not isolated from the reaction
mixture. The same results were obtained when the protected cyclic
acetal 14 was subjected to the same olefination protocol. Interme-
diate 14 was in turn readily obtained from 8a by reduction of the
lactone and protection of the resulting lactol as the corresponding
cyclic acetal 13, followed by ozonolysis of the olefin.
R1
i
O
H
O
H
O
OMe
O
O
O
41-62%
O
TESO
rac-6a,b
22a-c
R1
=
OMe
a
b
c
Scheme 3. Synthesis of bicyclic endoperoxides rac-6a,b. Reagents and conditions:
(a) vinylmagnesium bromide, CuI, THF, À78 °C, 3 h; (b) DIBAL, DCM, À78 °C, 1.5 h;
(c) p-TsOH, MeOH, 25 °C, 40 min; (d) (i) O3, DCM, À78 °C, 40 min, (ii) PPh3, À78 °C,
25 min; (e) 19a–c, THF, reflux, 1 h; (f) Dess–Martin periodinane, DCM, 25 °C,
30 min; (g) PPh3CH3Br, n-BuLi, THF, À40 °C, 1 h, 25 °C, 2 h; (h) Et3SiH, Co(thd)2 (for
21a,b) or Co(acac)2 (for 21c), O2, t-BuOOH, 25 °C, 4 h; (i) TMSOTf, À78 °C, 5 min.
Due to synthetic constraints in obtaining intermediate 12, prob-
ably due to an inherent low reactivity of the cyclohexylemethylene
Wittig reagent, we decided to modify the synthetic route as de-
scribed in Scheme 3. Indeed, exploiting the regiochemistry of the
hydroperoxysilylation reaction, in which the peroxide moiety is
selectively placed at the most substituted olefin carbon, the target
intermediate 22a could also be obtained from gem-disubstituted
olefins as the substrates for the hydroperoxysilylation reaction.
Following the above-described strategy, pyranone 7a was con-
verted into the vinyl derivative 16 by reaction with vinyl magne-
sium bromide in the presence of copper(I) iodide. The lactone
moiety of 16 was then protected as the corresponding cyclic acetal
Scheme 1. Synthesis of bicyclic endoperoxides rac-5a,b. Reagents and conditions:
(a) isopropenylmagnesium bromide, CuI, THF, À78 °C, 3 h; (b) Et3SiH, Co(thd)2, O2,
DCE, t-BuOOH, 25 °C, 4 h; (c) DIBAL, DCM, À78 °C, 1.5 h; (d) TMSOTf, DCM, À78 °C,
5 min.

S. Gemma et al. / Tetrahedron Letters 54 (2013) 1233–1235
1235
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tion of the carbonyl group followed by acetalization in methanol.
Ozonolysis of the terminal olefin furnished aldehyde 18, which
was then reacted with different Grignard reagents 19a–c to furnish
the corresponding secondary alcohols. These latter compounds
were oxidized to the corresponding ketones 20a–c using Dess–
Martin periodinane in DCM. At this point of the synthetic pathway,
olefination of the carbonyl group with methylphosphorane affor-
ded the desired olefins 21a–c, bearing cyclohexylmethyl-, cyclo-
hexyl-, or 4-methoxyphenyl-substituents, respectively.
Compounds 21a–c were smoothly converted into the corre-
sponding hydroperoxysilylated intermediates 22a–c. For com-
pounds 21a,b Co(thd)2 was used as the catalyst. On the contrary,
the higher reactivity of 21c toward the oxidation reaction resulted
into the decomposition of the starting material. Starting from 21c,
the less reactive Co(acac)2 catalyst smoothly furnished intermedi-
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the expected bridged endoperoxides 6a,b32 as inseparable mixture
of diastereoisomers. However, under the same reaction conditions,
extensive decomposition of 21c was observed leading to a complex
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cyclization reaction of silylperoxide-containing lactols for the syn-
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scaffold for developing new antimalarials. Moreover, we developed
a versatile synthetic strategy for introducing different alkyl substit-
uents at the C4 that takes advantage of readily available Grignard
reagents. This synthetic methodology will pave the way to the
exploration of the structure–activity relationships study of a novel
class of bridged peroxyacetals.
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Acknowledgment
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Authors thank NatSynDrugs and MIUR-PRIN for financial
support.
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31. 4,4-Dimethyl-2,3,8-trioxabicyclo[3.3.1]nonane (5a): 1H NMR (300 MHz, CDCl3) d
5.14 (s, 1H), 4.81–4.67 (m, 1H), 3.97–3.84 (m, 1H), 2.31–2.21 (m, 1H), 2.13–
1.90 (m, 2H), 1.80–1.68 (m, 2H), 1.47 (s, 3H), 1.24 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 95.9, 81.5, 64.6, 31.2, 29.0, 27.2, 25.2, 24.4; MS (ESI) m/z 181 (M+Na)+;
HRMS (C8H14NaO3) 181.0835, found: 181.0830. 4,4,5-Trimethyl-2,3,8-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.
075.
trioxabicyclo[3.3.1]nonane (5b): 1H NMR (CDCl3)
d 5.19 (t, J = 2.2 Hz, 1H),
References and notes
4.79–4.64 (m, 1H), 4.00–3.90 (m, 1H), 2.09 (dt, J = 13.0, 3.0 Hz, 1H), 2.04–1.92
(m, 1H), 1.77–7.57 (m, 1H), 1.45 (d, J = 2.1 Hz, 1H), 1.42 (s, 3H), 1.16 (s, 3H),
0.87 (s, 3H); 13C NMR (75 MHz, CDCl3) d 97.3, 85.1, 65.9, 35.6, 35.1, 31.2, 25.3,
21.5, 21.0. MS (ESI) m/z 195 (M+Na)+. HRMS (C9H16NaO3) 195.0992, found:
195.0986.
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32. 4-Cyclohexylmethyl-4-methyl-2,3,8-trioxabicyclo[3.3.1]nonane (6a): 1H NMR
(300 MHz, CDCl3) d 5.16–5.13 (m, 2H), 4.83–4.68 (m, 2H), 3.98–3.86 (m, 2H),
2.35–2.19 (m, 2H), 2.12–1.95 (m, 4H), 1.94–1.56 (m, 16H), 1.99 (s, 3H), 1.33–
1.13 (m, 9H), 1.12–0.79 (m, 8H); 13C NMR (75 MHz, CDCl3) d 96.1, 95.9, 84.1,
83.9, 64.7, 64.6, 45.0, 43.0, 35.5, 35.4, 35.0, 34.5, 34.0, 33.3, 30.7, 29.9, 29.8,
28.9, 27,3, 27.1, 27.6, 26.5, 26.4, 26.3, 22.5, 21.2; MS (ESI) m/z 263 (M+Na)+.
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4.71 (m, 2H), 4.04–3.87 (m, 2H), 2.38 -2.20 (m, 2H), 2.20–1.91 (m, 6H), 1.92–
1.64 (m, 10H), 1.64–1.45 (m, 3H), 1.36 (s, 3H), 1.34–1.04 (m, 10H), 1.05–0.85
(m, 3H); 13C NMR (75 MHz, CDCl3) d 96.0, 95.8, 85.6, 85.0, 65.1, 64.6, 43.3, 40.0,
29.0, 28.5, 28.2, 28.1, 27.3, 27.2, 27.1, 26.9, 26.8, 26.7, 26.6, 26.4, 26.3, 26.1,
17.5, 16.2; MS (ESI) m/z 249 (M+Na)+; HRMS (C13H22NaO3) 249.1461, found:
249.1465.
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