Synthetic studies toward 1,2-dioxanes as precursors of potential endoperoxide-containing antimalarials

Article abstract of DOI:10.1016/j.tetlet.2009.07.137

Introduction in therapy of the naturally occurring trioxane artemisinin opened a new era in malaria treatment and prompted the development of semisynthetic and synthetic derivatives characterized by the presence of the key peroxide bridge. The 1,2-dioxane

Full text of DOI:10.1016/j.tetlet.2009.07.137

Tetrahedron Letters 50 (2009) 5719–5722
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies toward 1,2-dioxanes as precursors of potential
endoperoxide-containing antimalarials
a,c
Sandra Gemma a,b, Francesc Martí a,b, Emanuele Gabellieri a,b, Giuseppe Campiani a,b, , Ettore Novellino
,
*
Stefania Butini a,b
a European Research Centre for Drug Discovery and Development—NatSynDrugs—University of Siena, via Aldo Moro, 53100 Siena, Italy
b Dipartimento Farmaco Chimico Tecnologico, University of Siena, via Aldo Moro, 53100 Siena, Italy
c Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, via D. Montesano 49, 80131 Napoli, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Introduction in therapy of the naturally occurring trioxane artemisinin opened a new era in malaria treat-
ment and prompted the development of semisynthetic and synthetic derivatives characterized by the
presence of the key peroxide bridge. The 1,2-dioxane ring is present in some natural endoperoxides such
as plakortin and dihydroplakortin, which are endowed with interesting antimalarial properties. Here we
describe the development of a versatile stereocontrolled synthetic strategy to 1,2-dioxanes functional-
ized at the critical C3, C4, and C6 positions, potentially useful for the development of innovative
antimalarials.
Received 19 June 2009
Revised 11 July 2009
Accepted 27 July 2009
Available online 6 August 2009
Keywords:
1,2-Endoperoxides
Isayama reaction
Ó 2009 Elsevier Ltd. All rights reserved.
Sharpless epoxidation
Enantioselective synthesis
Malaria is a severe world-wide health problem mainly affecting
developing countries and causing high social and economic costs.1
Due to the lack of a vaccine and to the emergence of parasites resis-
tant to well-established antimalarial therapies, there is an urgent
need for new, effective, and affordable drugs.2 The introduction
in therapy of artemisinin (1, Fig. 1), a naturally occurring endoper-
oxide sesquiterpene lactone, and of its semisynthetic derivatives,
represented a breakthrough in the malaria treatment. To overcome
the problems related to resistance, the World Health Organization
recommends the use of artemisinin-based combination therapies
(ACTs) in all malaria-endemic regions since artemisinins are
among the few molecules active in the treatment of multidrug
resistant Plasmodium falciparum malaria.3,4
Me
H
O
Me
O
O
Me
O
O
O
H
O
H
O
O
Me
Me
2, 1,2,4,5-tetraoxane
1, Artemisinin
H
O
Me
Ph
O
O
O
O
Although still matter of debate,5 considerable evidences suggest
that the peroxide bond of 1 has a key role in antimalarial activity,
being reductively activated by heme iron(II),6–10 and leading to the
formation of carbon-centered free radicals, toxic for the parasite. A
number of synthetic cyclic peroxides are being developed as low
cost alternatives to the expensive artemisinins.11,12 Among the
six-membered cyclic peroxide scaffolds explored, 1,2,4,5-tetraox-
anes and spiro 1,2,4-trioxanes provided highly potent antimalarials
(e.g., 2 and 3),13–17 while the 1,2-dioxane ring, although occurring
in several natural compounds such as peroxyplakoric acids,18,19
Yingzhaosu A (4),20 Yingzhaosu C,21 and plakortin (5),22 was not
Ph
Me
Me
OH
3, 1,2,4-trioxane
Me
Me
Me
R
Me
CO2Me
OH
4, Yingzhaosu A
O
Me
O
5, Plakortin
Me
R1
6a, R = Me, R1 = Et, R2 = Ac
4
3
6b, R = Me, R1 = n-Pr, R2 = Ms
(6S,R)-6c, R = Et, R1 = H, R2 = Ac
(6S,R)-6d, R = n-Pr, R1 = H, R2 = Ac
6
O
O
OR2
OH
* Corresponding author. Tel.: +39 0577 234172; fax: +39 0577 234333.
E-mail address: campiani@unisi.it (G. Campiani).
Figure 1. Examples of natural and synthetic antimalarials (1–5) and target 1,2-
dioxanes (6a–d).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.137

5720
S. Gemma et al. / Tetrahedron Letters 50 (2009) 5719–5722
widely synthetically explored.23 It has been reported that, in gen-
eral, the 1,2-dioxane ring system may provide compounds less ac-
tive than 1,2,4-trioxanes and 1,2,4,5-tetraoxanes.24,25 Moreover,
the 1,2-dioxane derivative arteflene (a synthetic analogue of 4),
has been discontinued during Phase II clinical trials due to high
recrudescence rate.26 However, appropriate decoration of the 1,2-
dioxane system may lead to an increased antimalarial potency.
Consequently, the development of appropriate synthetic strategies
is required to explore the structure–activity relationships (SARs)
for this scaffold. Previously, we reported the structural character-
ization and the antimalarial activity of plakortin,22,27,28 an endo-
peroxide isolated from the Caribbean sponge Plakortis simplex
and characterized by a relatively simpler skeleton with respect to
artemisinins, although less potent. We attempted a semisynthetic
approach to analogues of plakortin, but the reduced availability
of the sponge, together with synthetic constrains linked to the poor
stability of the 1,2-dioxane system during functional group elabo-
ration, led to a limited number of semisynthetic derivatives.
Furthermore, none of the analogues synthesized showed signifi-
cantly higher in vitro activity against different P. falciparum strains
with respect to the natural counterpart. Consequently, to explore
SARs and to identify novel 1,2-endoperoxide antimalarials, we
started some preliminary synthetic studies toward 1,2-dioxanes
6a–d, described here, bearing alkyl moieties at C6 or C4 and a pro-
tected 1,2-diol functionality at C3. The latter is a versatile func-
tional group whose activation to form reactive intermediates can
be potentially exploited for the decoration of the 1,2-dioxane scaf-
fold. Although the simplest route for the construction of the 1,2-
dioxane ring could be the [4+2] cycloaddition of oxygen to 1,3-
dienes,29 this methodology does not provide control of the stereo-
chemistry. Consequently, for the synthesis of compounds 6a–d, we
followed the strategy outlined by Xu et al. for the synthesis of
Yingzhaosu C.21 Accordingly, the peroxide functionality was intro-
duced by using the Isayama peroxidation reaction,30 followed by
cyclization through an intramolecular peroxide-mediated stereo-
selective epoxy ring opening. In the case of derivatives 6c,d, the
Isayama hydroperoxydation reaction furnished epimeric mixtures
at C6. However, due to the hypothesized radical-mediated mecha-
nism of the Isayama reaction, no attempts were made to develop a
stereoselective methodology based on this protocol (e.g., use of
chiral cobalt(II) ligands).31,32
1. (a) NaHDMS,
THF, -78 °C
O
O
H C
(b)
2
Br
Me
Me
Me
OH
-40 °C
Me
Me
N
O
CH2
2. LiAlH4, Et2O
0 °C
75% (for two steps)
Bn
7
8
1. PDC
DCM, 25 °C, 72%
2. (EtO)2P(O)CH2CO2Et
NaH, THF, 0 °C, 89%
DIBAL, DCM
-78 °C
Me
OH
Me
Me
CH2
CH2
95%
10
9
CO2Et
Ti(O-i-Pr)4
MS 4A, t-BuOOH
D(-)DIPT,
60%
DCM, -30 °C
Me
Ac2O, Pyr, DMAP
Me
Me
OH
Me
DCM (for 12a), 98%
O
O
or
CH2
CH2
MsCl, Et3N,
DCM (for 12b), 99%
11
12a, R = Ac
12b, R = Ms
OR
Me
O
Et3SiH, O2
Co(acac)2
1,2-DCE, 25 °C
Me
Me
4
3
OH
O
Amberlyst
DCM, 25 °C
2'
Me
6a, R = Ac, 75%
6b, R = Ms, 45%
Me
Et3SiOO
13a,b
Me
O
OR
Me
Me
OR
O
Me
10%, from 12a
AcO
OH
Scheme 1. Synthesis of 3,4,6-trisubstituted 1,2-dioxanes 6a,b.
epoxide 12a, the above described one-pot three-step procedure
stereoselectively afforded the cyclization product 6a36 in 75% over-
all yield, along with a small amount (ꢁ10%) of a tetrahydrofuran
derivative probably arising from a reduction of the peroxide group
to the corresponding alcohol before intramolecular cyclization. In
order to broaden the possibility of the diol functionalization at
C3, mesylate 6b37 was also synthesized in 45% yield starting from
intermediate 12b, in turn prepared by treatment of alcohol 11 with
mesyl chloride and triethylamine in DCM.
The synthesis of intermediates (6S,R)-6c,d is described in
Scheme 2. Levulinic acid methyl ester 14 was selected as a suitable
starting material for the synthesis of both (6S,R)-6c and (6S,R)-6d.
Accordingly, compound 14 was easily converted into the corre-
sponding olefins 15a and 15b through the standard Wittig proto-
col, using ethyltriphenylphosphonium bromide or n-propyltri-
phenylphosphonium bromide, respectively.
The synthesis of 3,4,6-trisubstituted 1,2-dioxanes 6a,b is
described in Scheme 1. (S)-4-Benzyl-3-butyryloxazolidin-2-one
733 was converted into the corresponding sodium enolate by
treatment with NaHDMS in THF at ꢀ78 °C and the latter was
alkylated with 3-bromo-2-methylpropene. LiAlH4-promoted
reductive cleavage of the chiral auxiliary afforded alcohol 8 in
75% overall yield. The primary alcohol of 8 was oxidized to the cor-
responding aldehyde by using an excess of PDC in dichloromethane
(DCM). The resulting highly volatile aldehyde intermediate was
converted into the corresponding
a,b-unsaturated ester 9 via
Wadsworth–Emmons olefination using triethylphosphonoacetate
and sodium hydride. Reduction of 9 with DIBAL in DCM at
ꢀ78 °C gave access to the allylic alcohol 10, which was in turn sub-
The resulting esters were obtained as 1:1 mixture of E and Z ole-
fins. In the subsequent steps of the synthetic pathway, reduction of
the ester group performed by using DIBAL in DCM at ꢀ78 °C fur-
nished the corresponding aldehydes which were immediately re-
acted with (carbomethoxymethylidene)triphenylphosphorane to
mitted to a Sharpless asymmetric epoxidation using
D
-(ꢀ)-diiso-
propyl tartrate as the chiral auxiliary. (2R,3R)-Epoxy alcohol 11
was converted into the corresponding acetate 12a by treatment
with acetic anhydride in the presence of pyridine and N,N-dimeth-
ylaminopyridine. Following Isayama protocol,34 regioselective
hydroperoxysilylation of 12a was achieved by treatment with co-
balt(II) acetyl acetonate and triethylsilane under an oxygen atmo-
sphere. In an attempt to reduce the number of steps, intermediate
13a was not isolated, but the addition of acidic resin Amberlyst-15
directly to the reaction mixture resulted into deprotection of the
silyl-protected hydroperoxide followed by a nucleophilic attack
of the free hydroperoxy group on the epoxide.35 Starting from
afford the a,b-unsaturated esters 16a,b. In this case, the olefination
reaction resulted into the selective formation of the conjugated E-
olefins (98:2 E/Z ratio). Following the synthetic sequence already
described for the synthesis of 6a, DIBAL promoted reduction of
the esters 16a,b afforded the corresponding allylic alcohols which
were submitted to the Sharpless epoxidation protocol, stereoselec-
tively furnishing the epoxide intermediates 17a,b. Protection of the
primary alcohol of 17a,b as the corresponding acetate ester was
followed by the hydroperoxysilylation reaction, firstly attempted

S. Gemma et al. / Tetrahedron Letters 50 (2009) 5719–5722
5721
PPh3EtBr (for 16a)
or
was converted into the corresponding tosylate with the final aim of
hydrolyzing the ester functionality of 21 affording, under basic
conditions, epoxide 22. However, due to steric constrain, the tosy-
lation reaction occurred in low yield. Consequently, an alternative
synthetic pathway for the construction of the epoxide ring was
pursued. At this purpose, the synthesis of mesylate 6b was under-
taken, and the latter was cyclized under alkaline conditions afford-
ing epoxide 23.40 Finally, epoxide 23 was treated with an excess of
sodium azide in N,N-dimethylformamide to afford azide 24.
In conclusion, we described herein synthetic studies toward 1,2-
dioxane rings functionalized at C3, C4, and C6 positions. Control of
stereochemistry was achieved at both C3 and C4. Chemical derivati-
zation at the C3 has been performed by the synthesis of aldehydes
and epoxides. With the final aim of synthesizing potential antimala-
rials, the versatile aldehyde and epoxide functional groups can be
exploited for the decoration of the 1,2-dioxane scaffold.
R
O
PPh3nPrBr (for 16b)
OEt
OEt
Me
Me
n-BuLi, THF, 0 °C
48-52%
O
O
O
14
15a, R = Me (1:1 E/Z)
15b, R = Et (1:1 E/Z)
1. DIBAL, DCM,
-78 °C
67-61%
R
2.
CO2Et
Ph3P
Me
R
1. DIBAL, DCM
-78 °C
THF, 25 °C
2. Ti(O-i-Pr)4
MS 4A, t-BuOOH
D(-)DIPT,
Me
CO2Et
17a,b
OH
16a,b
DCM, -30 °C
78-82% (two steps)
1. Ac2O, Pyr
DMAP
2. Et3SiH, O2
Co(thd)2
1,2-DCE, 25°C
Me
Me
6
Acknowledgment
Amberlyst
R
DCM, 25 °C
R
6
O
Et3SiOO
O
OH
This investigation received financial support from the EU Com-
mission, Antimal-LSHP-CT-2005-18834.
58-65%
O
(6S,R)-6c, R = Me
(6S,R)-6d, R = Et
(6S,R)-18a,b
OAc
OAc
References and notes
Scheme 2. Synthesis of 3,6-disubstituted 1,2-dioxanes (6S,R)-6c,d.
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case, the trisubstituted olefin had a lower reactivity than the pre-
viously used disubstituted olefin. As reported in the literature,31
the use of cobalt(II) bis[2,2,6,6-tetramethylheptane-3,5-dienoate]
resulted in the formation of the desired intermediates. Following
our developed protocol, cyclization of (6S,R)-18a,b to afford 1,2-
dioxanes (6S,R)-6c,d was performed without preliminary isolation
of the silylated intermediates and resulted in good overall yield.
As shown in Scheme 3, intermediates 6a–d were further elabo-
rated to furnish reactive intermediates potentially useful for the
decoration of the 1,2-dioxane moiety. Intermediates 6a,c,d were
converted into the corresponding diols 19a–c38 by potassium car-
bonate-promoted hydrolysis of the ester group, performed in
methanol at 25 °C. The diol moiety was then converted into alde-
hydes 20a–c39 by treatment with sodium periodate in a 5:1 mix-
ture of acetonitrile and water.
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Me
O
Me
O
R
R1
R
R1
OH
K2CO3, MeOH
25 °C, 100%
NaIO4
6a,c,d
O
O
CHO
10:1 MeCN/H2O
70-83%
OH
19a, R = Me, R1 = Et
20a-c
(6S,R)-19b, R = Et, R1 = H
(6S,R)-19c, R = n-Pr, R1 = H
Me
Me
Me
Me
TsCl, Pyr
O
OTs
OAc
6d
6b
O
O
O
O
DCM, 25 °C
15%
(6S,R)-21
(6S,R)-22
Me
Me
Me
Me
Me
OH
Me
O
NaN3, Pyr
K2CO3
52%
O
O
O
O
DMF, 80 °C
30%
23
24
N3
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Scheme 3. Synthesis of diols 19a–c and further elaboration of the cis-diol moiety.

5722
S. Gemma et al. / Tetrahedron Letters 50 (2009) 5719–5722
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35. A mixture of 12a (0.25 mmol) and Co(acac)2 (11 mg) in 1,2-dichloroethane
(5 mL), was stirred under an oxygen atmosphere. To the resulting pink
2H), 1.53 (m, 1H), 1.23 (s, 3H), 1.20 (m, 2H), 1.14 (s, 3H), 0.84 (t, 3H, J = 7.3 Hz).
MS-ESI (m/z) 269 (M+Na)+.
37. (3S,4R,20S)-6b: 1H NMR (CDCl3) d 4.44 (dd, 1H, J = 3.5, 11.9 Hz, 4.27 (m, 1H),
4.18 (m, 1H), 3.83 (m, 1H), 3.07 (s, 3H), 2.60 (d, 1H, J = 7.6 Hz), 1.85–1.52 (m,
3H), 1.28 (s, 3H), 1.26 (m, 1H), 1.21 (s, 3H), 0.92 (t, 3H, J = 7.2 Hz). MS-ESI (m/z)
305 (M+Na)+.
38. (3S,4R,20R)-19a: 1H NMR (CDCl3) d 3.90 (m, 2H), 3.72 (m, 2H), 2.58 (d, 1H,
J = 8.5 Hz), 2.10 (m, 1H), 1.82–1.73 (m, 2H), 1.55 (m, 1H), 1.29 (s, 3H), 1.27 (m,
2H) 1.21 (s, 3H), 0.91 (t, 3H, J = 7.3 Hz). 13C NMR (CD3OD) d 87.1, 78.8, 72.1,
62.3, 39.2, 33.9, 26.6, 24.4, 22.6, 9.8. MS-ESI (m/z) 227 (M+Na)+.
39. (3S,4R)-20a: 1H NMR (CDCl3) d 9.78 (s, 1H), 4.01 (d, 1H, J = 7.33 Hz), 1.78 (dd,
J = 4.7, 13.2 Hz), 1.72–1.63 (m, 1H), 1.42–1.33 (m, 3H), 1.31 (s, 3H), 1.23 (s, 3H),
0.92 (t, 3H, J = 7.3 Hz). MS-ESI (m/z) 195 (M+Na)+.
solution, triethylsilane (82 lL, 0.52 mmol) was added, followed by a catalytic
amount of t-BuOOH (6 M in nonane). The resulting dark green solution was
stirred at 25 °C until the starting material disappeared. Amberlyst-15 (20 mg)
was subsequently added to the reaction mixture which was stirred at 25 °C for
3 h. The resin was removed by filtration and the solvent was evaporated to
afford a crude product which was purified by flash chromatography (1:2
diethyl ether/petroleum ether) to afford 6a as a colorless oil (75%).
40. (3S,4R,20S)-23: 1H NMR (CDCl3) d 3.31 (dd, 1H, J = 6.2, 9.7 Hz), 2.86–2.83 (m,
1H), 2.73 (m, 1H), 1.84–1.78 (m, 3H), 1.36 (s, 3H), 1.35 (m, 1H), 1.18 (s, 3H),
0.95 (t, 3H, J = 7.4 Hz). MS-ESI (m/z) 209 (M+Na)+.
36. (3S,4R,20S)-6a: 1H NMR (CDCl3) d 4.24 (dd, 1H, J = 2.7, 11.9 Hz), 4.12–4.01 (m,
2H), 3.82 (dd, 1H, J = 3.2, 9.4 Hz), 2.37 (d, 1H, J = 7.0 Hz), 2.04 (s, 3H), 1.75 (m,