Synthesis of disubstituted 1,2-dioxolanes, 1,2-dioxanes, and 1,2-dioxepanes

Article abstract of DOI:10.1016/j.tet.2009.11.026

A route to cyclic peroxides containing 1,2-dioxolane, 1,2-dioxane or 1,2-dioxepane rings is described. These compounds present simpler structures related to the bicyclic core of stolonoxides, metabolites with marked cytotoxicity against several mammalian

Full text of DOI:10.1016/j.tet.2009.11.026

Tetrahedron 66 (2010) 157–163
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Tetrahedron
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Synthesis of disubstituted 1,2-dioxolanes, 1,2-dioxanes, and 1,2-dioxepanes
b
a
a
,
b
b
*
´
´
Francisco M. Guerra , Eva Zubıa , Marıa J. Ortega , F. Javier Moreno-Dorado , Guillermo M. Massanet
a
´
´
´
´
´
Departamento de Qu´ımica Organica, Facultad de Ciencias del Mar y Ambientales, Universidad de Cadiz, Polıgono Rıo San Pedro s/n, 11510 Puerto Real, Cadiz, Spain
Departamento de Qu´ımica Organica, Facultad de Ciencias, Polıgono Rıo San Pedro s/n, 11510 Puerto Real, Cadiz, Spain
b
´
´
´
´
a r t i c l e i n f o
a b s t r a c t
Article history:
A route to cyclic peroxides containing 1,2-dioxolane, 1,2-dioxane or 1,2-dioxepane rings is described.
These compounds present simpler structures related to the bicyclic core of stolonoxides, metabolites
with marked cytotoxicity against several mammalian tumor cell lines, isolated from the marine tunicate
Stolonica socialis. The key synthetic step consists in the intramolecular Michael addition of a secondary
Received 16 September 2009
Received in revised form
30 October 2009
Accepted 4 November 2009
Available online 10 November 2009
hydroperoxide group to an a,b-unsaturated ester.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyclic peroxides
Hydroperoxide cyclization
Bioactivity
Stolonoxides
1. Introduction
stolonoxides on mitochondrial electron transport system of mam-
malian cells, showing that stolonoxides inhibited mitochondrial
respiration. Moreover, the results again suggested that the ring
arrangement seems critical for the biological activity.
In 2000, the chemical studies of the marine ascidian Stolonica
socialis from the southern coast of Spain1,2 and an unidentified
species of the same genus collected off the Maldiva islands3 yielded
the isolation of stolonoxides A–D (e.g., 1) and stolonic acids A and B
(e.g., 2), respectively (Fig. 1). These compounds showed an un-
precedented molecular rearrangement containing a 1,2-dioxane
ring linked through a single C–C bond to a tetrahydrofuran ring
affixed to a long side chain. This new class of natural products
exhibited potent cytotoxic activity against different tumoral cell
lines. Interestingly, stolonoxide-derived compounds lacking the
endoperoxide ring were inactive, suggesting the crucial role of this
group for cytotoxicity.2 In order to elucidate the mode of action,
Fontana and co-workers4 studied the activity of two methyl ester
Because of the biological activity of the stolonoxides and the
synthetic challenges presented by their bicyclic arrangement, we
have embarked on a program aimed at developing synthetic
strategies based on the structural simplification of stolonoxides.
Structural simplification can be considered an efficient strategy to
design analogs that are accessible through shorter synthetic routes
than the natural lead and that can be used to investigate the rele-
vance of the different structural fragments of the natural lead for
the bioactivity.5 Thus, taking into account the crucial role of the
endoperoxide for the cytotoxicity of stolonoxides mentioned above,
we addressed our attention to the synthesis of compound 3, which
exhibits the same carbon framework that the bicyclic core of sto-
lonoxides and the same 1,2-dioxane ring, but an aromatic five-
membered ring. To further explore the biological importance of the
endoperoxide function and the versatility of the synthetic meth-
odology we also envisaged the preparation of the analogs 4 and 5,
containing 1,2-dioxolane and 1,2-dioxepane rings, respectively
(Fig. 2).
H
H
HO2C
HO2C
O
H
H
O O H
1 stolonoxide A
H
H
O
O O H
With these structural frameworks as targets, the major challenge
was the introduction in a straightforward manner of the secondary
hydroperoxide group and the subsequent cyclization to form the
endoperoxide ring. Although several methods for the synthesis of
cyclic peroxides can be found in literature,6 the most appropriate
method to obtain in a single step the 1,2-dioxane, 1,2-dioxolane or
1,2-dioxepane rings of 3–5, together with the side chain at C-3,
2 stolonic acid
Figure 1. Stolonoxide A (1) and stolonic acid A (2).
* Corresponding author. Tel.: þ34 956016020; fax: þ34 956016193.
E-mail address: mariajesus.ortega@uca.es (M.J. Ortega).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.026

158
F.M. Guerra et al. / Tetrahedron 66 (2010) 157–163
MeOOC
also act as the nucleophile to build different size cyclic peroxides
through an intramolecular Michael addition.
3
O
O
O
O
1
3
MeOOC
2. Results and discussion
3
O
O
1
4
The endoperoxide formation through the intramolecular con-
jugated addition of a primary or secondary hydroperoxide onto an
a,b-unsaturated ester was assayed in the synthesis of the model
MeOOC
3
O
O
1
5
O
compounds 6a and 6b. The initial retrosynthesis is outlined in
Scheme 1, showing an endoperoxide disconnection through a Mi-
chael addition on intermediate A, which is previously formed via
a Wittig reaction on hydroperoxide B.
The synthesis of model compounds 6a and 6b (Scheme 2, for the
sake of clarity from now onwards 6) started with the TBDPS ether
derivatives 7,11 which were transformed into 8 by treatment with
molecular iodine. The displacement of the iodine with 2-methoxy-
prop-2-yl hydroperoxide12 in basic medium yielded the perketals 9.
Deprotection of the TBDPS group using TBAF afforded the corres-
ponding alcohols 10.
Figure 2. Compounds 3–5.
consists in the intramolecular addition of a pendant hydroperoxide
group to an -unsaturated ester. The conjugated addition of a hy-
droperoxide to an -unsaturated ester was first described by Bar-
a,b
a,b
lett et al.7 in a step toward the synthesis of polyether-type
tetrahydrofurans. More recently, various 3-methoxy-6-methoxy-
carbonylmethyl-1,2-dioxane,8a–g 3-methoxy-5-methoxycarbonyl-
methyl-1,2-dioxolane8h compounds and spiroperoxides,8i some of
which with antimalarial activity, have been synthesized by
The following step involved the oxidation of 10 with Dess–
Martin periodinane and the in situ Wittig olefination of the
resulting aldehyde with methyl (triphenylphosphoranylidene)
acetate to afford the unsaturated methyl esters 11. The acid
hydrolysis of 11 with AcOH/H2O13 produced quantitatively hy-
droperoxides 12. The cyclization of 12 to give 6 was based on the
procedure described by Kobayashi et al. for the conjugate addition
intramolecular Michael addition of hydroperoxyketals to
saturated esters. Posner et al. also described the intramolecular
attack of a tertiary hydroperoxide group to the -unsaturated
a,b-un-
a,b
carbonyl of carvone,9 a process favored by the spatial proximity
between both groups, a favorable situation not always met. Finally,
Woerpel et al. have recently synthesized 1,2-dioxane systems by
intramolecular palladium-catalyzed addition of hydroperoxides
onto olefins.10 However, this method appears to be specific for ter-
tiary hydroperoxides because less substituted substrates did not
cyclize. Herein we report the synthesis of compounds 3–5, which
demonstrates that a primary or secondary hydroperoxide group can
of hydroperoxyketals to
a,b
-unsaturated esters.8a–d Except for
a single substrate where a high cyclization yield (72%) was ach-
ieved using a catalytic amount of Et2NH and (CF3)2CHOH as sol-
vent,8a the conditions more usually employed by these8b–d and
other authors8e–i consist on the use of Et2NH with CF3CH2OH as
solvent. The yields significantly varied among substrates typically
in the range of 40–60%. However, under these conditions (Et2NH/
(CF3)2CHOH or Et2NH/CF3CH2OH) either transformation of 12 into
the corresponding alcohol or no reaction, respectively, was ob-
served. We tried different conditions either changing the acidity
of the reaction medium with different Lewis acids as CeCl3,
Sc(OTf)3, and BF3$Et2O, or using other bases as CsOH and LiOH, but
none of them led to the expected dioxanes. Finally, exposure of
hydroperoxyenoate 12 to catalytic amounts of CsOH in
(CF3)2CHOH/MeOH (7:3) led to the cyclization product 6, with
yield similar to those previously reported for the cyclization of
hydroperoxyketals. It is interesting to note that the cyclization
process involved in the formation of the 3,6-disubstituted
endoperoxide 6b, furnished the trans stereoisomer. This stereo-
chemical outcome could be explained considering in the corre-
sponding precursor 12b a chair-like conformation with the methyl
Conjugate addition
MeOOC
O
O
R
MeOOC
R
OOH
A
6a R = H
6b R = Me
Wittig rxn
O
R
R
HO
H
X
OOH
C
B
Scheme 1. Retrosynthetic analysis of compounds 6a and 6b.
R
I2, imidazole
R
TBDPSO
R
HOO OMe
Ph3P
TBDPSO
TBDPSO
OO
OCH3
I
OH
CsOH
DMF
CH2Cl2
7a R = H
7b R = Me
8a 93%
8b 98%
9a 70%
9b 35%
O
Dess-Martin periodinane,
then Ph3P=CHCO2Me
R
R
TBAF
THF
HO
CH3O
OO
OCH3
OO
OCH3
CH2Cl2
10a 59 %
10b 58 %
11a 80 %
11b 78 %
O
CsOH
(CF3)2CHOH:MeOH (7:3)
R
R
HOAc
H2O
CH3O
MeO
O O
OOH
O
12a 99 %
12b 99 %
6a R = H 35%
6b R = Me 41 %
Scheme 2. Synthesis of compounds 6a–6b.

F.M. Guerra et al. / Tetrahedron 66 (2010) 157–163
159
and the
a
,
b
-unsaturated ester substituents in equatorial orienta-
a sequence consisting in Dess–Martin oxidation and in situ Wittig
olefination with methyl (triphenylphosphoranylidene) acetate led
to ester 20. Removal of the protecting group in 20 was also difficult
as the acid conditions previously employed with compound 11
failed when applied to compound 20. The instability of the furan
ring to acid conditions led under the deprotection conditions to
a molecular rearrangement transforming the furan ring into a pyr-
anone. Different mixtures of AcOH/H2O and other acid conditions
were assayed but none of them provided the desired hydroper-
oxide. However, when compound 20 was subjected to the same
conditions used to fashion the hydroperoxide group, namely,
treatment with hydrogen peroxide and p-TsOH, hydroperoxide 21
was cleanly and quantitatively obtained.
tion during the reaction (Scheme 3).
H
H
H
Me
Me
O
O
O
O
O
O
Me
Me
H
12b
H
O
O
6b (trans-diasteromer)
Scheme 3. Proposed mechanism for the cyclization of compound 12b.
Once the base-promoted cyclization was tested, we turned our
attention to the development of a synthetic route to compounds 3–
5 (Scheme 4). Although the retrosynthetic analysis is closely related
to that already established for the model compounds 6, it was
necessary to introduce some modifications. The synthesis com-
menced with the coupling of 2-methylfuran with suitable alde-
hydes 15a–15c (from now onwards 15),14 prepared from the diol 13
by monoprotection with TBDPSCl.11 The resulting hydroxyl group in
16 is then displaced by a hydroperoxide group, a maneuver made
possible by the presence of the furan ring.15 As we were cognizant
of the lability of the hydroperoxide group under different reaction
conditions we decided its protection as a perketal. Thus, compound
17 was treated with 2-methoxypropene under acid catalysis
yielding the peroxide 18.16 Removal of the TBDPS protecting group
was troublesome. When compound 18 was treated with TBAF un-
der different solvents and reaction temperatures, an intractable
mixture of compounds was obtained. After some experimentation,
we found that exchanging TBAF with NH4F in MeOH at 0 ꢀC17
allowed the formation of alcohol 19 in moderate yields.18 Next,
It is worth noting that we tested if the synthesis from 16 to 21
could be improved through an alternative sequence consisting in the
introduction in the late stage of the synthesis of the hydroperoxide
group, after building the a,b-unsaturated ester (Scheme 5). How-
ever, attempts to protect the hydroxyl group in 16a and 16b yielded
complex mixtures with low yields of the desired compound. Even
worse results werelaterobtained in the deprotectionof the hydroxyl
group adjacent to the furan ring, due to the transformation of the
furan ring into a pyranone 26 under the acid reaction conditions.
Nonetheless, the alternative sequence was taken until the final steps
and also different conditions were tried for the hydroperoxidation.
However, the major compound was again the pyranone derivative
26 and only trace amounts of the desired hydroperoxide compound
21 were obtained. Therefore, this alternative route was disregarded.
The intramolecular Michael addition that would lead to the
endoperoxide compounds was expected to proceed by treatment of
TBDPSCl
DIPEA
PCC
ms 4A
TBDPSO
HO
OH
O
TBDPSO
OH
n
n
n
CH2Cl2
4h
DMF
5h
15a 62%
13a n = 1
13b n = 2
13c n = 3
14a 37%
15b 87%
15c 85%
7a 62%
14c 50%
OMe
H2O2
p-TsOH
O
n-BuLi
TBDPSO
TBDPSO
PPTS
O
O
n
n
O
CH2Cl2
20 min
OH
16a 90%
16b 88%
16c 88%
THF
DME
16h
HO
0º to r.t.
45 min
90%
17a 59%
17b 93%
17c 80%
TBDPSO
MeO
HO
MeO
O
n
O
O
Dess-Martin periodinane,
then Ph3P=CHCO2Me
n
NH4F
O
MeO2C
MeO
n
O
O
O
O
MeOH
16h
O
CH2Cl2
18a 80%
18b 88%
18c 87%
19a 15%
19b 45%
19c 60%
20a 53%
20b 65%
20c 40%
Et2NH
H2O2
p-TsOH
CF3CH2OH/MeOH (7:3)
series a and b
MeO2C
O
n
MeO2C
n
O
O
O
O
HO
CsOH
DME
1h
59%
4 n=1 (cis) 17% + 28 23%
21a 97%
21b 99%
21c 99%
CF3CH2OH/MeOH (7:3)
series c
3 n=2 (trans) 35% + 27 29%
5 n=3 (cis+trans, 1:1) 15% + 29 23%
O
MeO2C
O
MeO2C
O
O
MeO2C
O
OH
29
O
OH
OH
27
28
Scheme 4. Synthesis of endoperoxides 3–5.

160
F.M. Guerra et al. / Tetrahedron 66 (2010) 157–163
Specifically, the synthesis of 3 led to the trans-diastereomer while
TBDPSO
TBDPSO
O
the synthesis of 4 led to the cis-diastereomer. However, the cycli-
zation of 21c was almost absent of diastereoselectivity leading to an
equimolar mixture of cis- and trans-1,2-dioxepane diastereomers
5.21
The final compounds 3–5, together with the corresponding
acyclic precursors 20a–20c and 21a–21c were submitted to cyto-
toxicity assays against the tumor cell lines MDA-MB-231, A-549,
and HT29. All the compounds were inactive at the higher concen-
O
n
OH
n
OR
16
22 R=different protecting groups
HO
O
n
O
n
MeO2C
n
OR
OR
23
24
O
+
O
MeO2C
MeO2C
O
OH
n
tration tested (10
were moderately active. In particular, compound 20b exhibited
growth inhibitory activity of A-549 cells with GI50¼25.6 M and
20c was active against the three cell lines with GI50 values of
15.3 M (MDA-MB-231), 14.1 M (A-549), and 27.6 M (HT29).
mg/mL) excepting compounds 20b and 20c, which
OH
25 minor compound
26 major compound
m
21 trace amounts + 26 (major compound)
Scheme 5. Alternative synthetic sequence for compound 21.
m
m
m
3. Conclusions
In summary, we have prepared several cyclic peroxides with
structures that are related to the bicyclic core of the cytotoxic stolon-
oxides. The synthesis demonstrates that not only tertiary, but primary
and secondary hydroperoxide groups as well can act as nucleophiles in
compound 21 with CsOH in a 7:3 mixture of (CF3)2CHOH/MeOH, as
defined in the synthesis of model 6. However, under these condi-
tions, the only compound obtained was the pyranone derivative 26.
To minimize this transformation we tested either less acid solvents,
change the base or both. Finally, using Et2NH in CF3CH2OH/MeOH
(7:3) the desired 1,2-dioxane 3 and 1,2-dioxolane 4 were obtained,
while synthesis of 1,2-dioxepane 5 required the use of catalytic
amounts of CsOH in the same solvent system.
Several synthesis of 1,2-dioxane rings by cyclization of hydro-
peroxyketals in Et2NH/CF3CH2OH have provided better yields than
this obtained for compound 3, which was accompanied by the cor-
responding intramolecular Weitz–Scheffer oxidation product 27.19
The presence of the acid-sensitive furan ring in 21 imposed the use of
less acid solvent in which the conjugate addition of the hydroper-
oxide is efficiently produced, but the evolution of the endoperoxide
toward the epoxy derivative is not completely avoided.
an intramolecular Michael reaction on an a,b-unsaturatedesterandthe
feasibility of this cyclization procedure to produce a 1,2-dioxolane,
a 1,2-dioxane or a 1,2-dioxepane ring. Given the scarcity of methods to
prepare these interesting motifs, especially the 1,2-dioxepanes, this
methodology constitutes an alternative to consider for their synthesis.
More studies toward the synthesis of stolonoxide analogs with in-
creased bioactivity are currently in progress.
4. Experimental section
4.1. General
1H and 13C NMR spectra were recorded at 400 or 600 MHz and
100 or 150 MHz, respectively, on a Varian INOVA 400 or Varian
INOVA 600 spectrometers using CDCl3 as solvent. Proton chemical
1,2-Dioxolane 4 and 1,2-dioxepane 5 were obtained in low yields
together with the products 28 and 29, respectively, which are
formed by the base catalyzed decomposition of dialkyl peroxides
(Scheme 6).20 It is to be noted that these results again indicate that
the conjugate addition is successful, but the intermediate cyclic
peroxides are not stable under the reaction conditions.
shifts were referenced to the residual CHCl3 signal at
NMR spectra were referenced to the central peak of CDCl3 at
d
7.26. 13C
77.0.
d
1H–1H-COSY, HMQC, and HMBC were performed using standard
VARIAN pulse sequences. Low resolution mass spectra were
recorded on a Finnigan Voyager GC8000top spectrometer. High
resolution mass spectra were recorded on a VG Autospec spec-
trometer. All reagents were obtained from commercial suppliers
and used without further purification. THF solvent was dried over
sodium-benzophenone or purified by filtration through a column
of activated alumina under an argon atmosphere.
MeO2C
n
H
MeO2C
n
O
O
O
H
B-
O
O
OH
4 n=1
5 n=3
28 n=1
29 n=3
Scheme 6. Base catalyzed decomposition of dialkyl peroxides.
4.2. General procedures for the synthesis of compounds
16–21 and 3–5
Other recently described procedures such as the palladium-
catalyzed cyclization of unsaturated hydroperoxides have failed to
prepare 1,2-dioxolane derivatives.10 On the other hand, it has been
reported that the intramolecular Michael addition of the hydro-
peroxide group to close a seven-membered ring is impossible if all
Compound 16. To a 0.34 M solution of 2-methylfuran in THF at
ꢁ78 ꢀC was added 2.45 mL of a BuLi solution (2 M in cyclohexane).
The solutionwasstirred for 45 min andthena solution of aldehyde 15
(7.0 mmol) in THF (30 mL) was added dropwise at ꢁ40 ꢀC and the
reaction was stirred for 2 h at rt. The reaction mixture was quenched
by addition of saturated aqueous NH4Cl (40 mL) and diluted with
EtOAc (40 mL). The aqueous layer was extracted with EtOAc
(2ꢂ40 mL). The organic layers were combined and dried over anhy-
drous MgSO4 and the solution taken to dryness on a rotary evapo-
rator. Purification of the mixture (20% EtOAc/hexanes) afforded pure
16 aspaleorangeoils(90%for16a, 88%for16b, and88%for16c yields).
the bonds involved in the process are
s-bonds without any re-
striction to their rotation.8i Thus, the only achieved cyclizations
were in substrates in which the hydroperoxide-containing chain
and the a,b-unsaturated ester moiety were linked to a benzene ring
in ortho positions. The preparation of 1,2-dioxolane 4 and 1,2-
dioxepane 5 show that the conjugated addition of hydroperoxide
groups to close five- and seven-membered endoperoxides is pos-
sible and furthermore, it seems likely that substrates, which had
greater acid stability would give better yields both in the 1,2-
dioxolane and in the 1,2-dioxepane series.
4.2.1. Compound 16a. 1H NMR (400 MHz, CDCl3)
d: 1.09 (s, 9H),
2.09 (m, 1H), 2.29 (br s, 3H), 2.15 (m, 1H), 3.85 (ddd, J¼10.5, 6.8,
4.0 Hz, 1H), 3.93 (ddd, J¼10.5, 6.2, 4.4 Hz, 1H), 4.99 (dd, J¼8.2,
4.1 Hz, 1H), 5.92 (br dq, J¼3.1, 1.0 Hz, 1H), 6.14 (d, J¼3.1 Hz, 1H), 7.41
It is noteworthy to mention that in the synthesis of the 1,2-di-
oxane 3 and 1,2-dioxolane 4 only one diastereomer is formed.

F.M. Guerra et al. / Tetrahedron 66 (2010) 157–163
161
(m, 6H), 7.77 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3)
d: 13.5, 19.0,
anhydrous MgSO4 and the solvent evaporated to give the pure
26.8, 37.1, 62.2, 66.8, 105.9, 106.5, 127.7, 129.8, 133.0, 135.5, 151.5,
154.7 ppm. HRMS (CI) calcd for C24H29O3Si [MꢁH]þ 393.1886;
found: 393.1903.
compound 18 (80% for 18a, 88% for 18b, and 87% for 18c yields).
4.2.7. Compound 18a. 1H NMR (400 MHz, CDCl3)
d: 1.08 (s, 9H),
1.32 (s, 3H),1.34 (s, 3H), 2.09 (dddd, J¼12.3, 6.6, 6.6, 5.4 Hz,1H), 2.30
(br s, 3H), 2.33 (dddd, J¼12.6, 6.9, 6.9, 5.4 Hz, 1H), 3.24 (s, 3H), 3.68
(ddd, J¼10.3, 6.9, 5.4 Hz,1H), 3.85 (ddd, J¼10.3, 6.4, 5.6 Hz,1H), 5.24
(t, J¼7.2 Hz,1H), 5.94 (br dq, J¼3.1, 1.0 Hz,1H), 6.22 (d, J¼3.1 Hz,1H),
4.2.2. Compound 16b. 1H NMR (400 MHz, CDCl3)
d: 1.08 (s, 9H),
1.70 (m, 2H), 1.96 (m, 2H), 2.29 (br s, 3H), 3.73 (t, J¼6.15 Hz, 2H),
4.66 (dd, J¼7.4, 6.2 Hz, 1H), 5.91 (br dq, J¼3.1, 1.0 Hz, 1H), 6.10 (d,
J¼3.1 Hz, 1H), 7.41 (m, 6H), 7.77 (m, 4H) ppm. 13C NMR (100 MHz,
7.41 (m, 6H), 7.67 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3)
d: 13.6,
CDCl3)
d
: 13.5, 19.1, 26.8, 28.6, 32.3, 63.8, 67.6, 105.9, 106.6, 127.6,
19.1, 22.5, 22.8, 26.8, 34.0, 49.0, 60.3, 75.7, 104.6, 106.1, 109.8, 127.6,
129.5, 133.7, 135.5, 151.4, 151.9 ppm. HRMS (CI) calcd for C24H29O3Si
[MꢁC4H9O2]þ 393.1886; found: 393.1884; calcd for C24H29O2Si
[MꢁC4H9O3]þ 377.1937; found: 377.1948.
129.6, 133.7, 135.5, 151.5, 154.9 ppm. HRMS (CI) calcd for C25H32O3Si
[M]þ 408.2121; found: 408.2110.
4.2.3. Compound 16c. 1H NMR (400 MHz, CDCl3)
d: 1.04 (s, 9H),1.42
(m, 1H), 1.54 (m, 1H), 1.61 (m, 2H), 1.82 (m, 2H), 2.28 (br s, 3H), 3.67
(t, J¼6.4 Hz, 2H), 4.58 (t, J¼6.7 Hz,1H), 5.89 (br dq, J¼3.1, 1.0 Hz,1H),
6.08 (d, J¼3.1 Hz, 1H), 7.38 (m, 6H), 7.66 (m, 4H) ppm. 13C NMR
4.2.8. Compound 18b. 1H NMR (400 MHz, CDCl3)
d: 1.05 (s, 9H),1.31
(s, 3H), 1.32 (s, 3H), 1.56 (m, 1H), 1.68 (m, 1H), 1.96 (m, 1H), 2.07 (m,
1H), 2.28 (br s, 3H), 3.23 (s, 3H), 3.68 (td, J¼6.4, 3.1 Hz, 2H), 4.87 (t,
J¼7.3 Hz, 1H), 5.92 (br dq, J¼3.1, 1.0 Hz, 1H), 6.19 (d, J¼3.1 Hz, 1H),
(100 MHz, CDCl3) d: 13.5,19.2, 22.0, 26.9, 32.2, 35.2, 63.7, 67.8,105.9,
106.7, 127.6, 129.6, 134.0, 135.6, 151.6, 154.9 ppm. HRMS (CI) calcd
7.40 (m, 6H), 7.66 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3)
d: 13.6,
for C26H33O3Si [MꢁH]þ 421.2199; found: 421.2198.
19.2, 22.6, 22.8, 26.8, 27.6, 28.8, 49.1, 63.5, 78.8, 104.7, 106.0, 109.5,
127.6, 129.5, 133.9, 135.5, 151.5, 151.8 ppm. HRMS (CI) calcd for
C25H31O3Si [M-C4H9O2]þ 407.2042; found: 407.2026; calcd for
C25H31O2Si [MꢁC4H9O3]þ 391.2093; found: 391.2096.
Compound 17. 1 mmol of compound 16 was dissolved in 1,2-
dimethoxyethane (11 mL) and treated with 2 equiv of 33% H2O2
and 0.12 equiv of p-TsOH at room temperature. The reaction was
monitored by TLC until it was deemed complete. Then, the mix-
ture was diluted with Et2O and the organic phase washed with
brine and dried over magnesium sulfate. After removing the sol-
vent the crude product was used without further purification in
the next reaction (59% for 17a, 93% for 17b, and 80% for 17c
yields).
4.2.9. Compound 18c. 1H NMR (400 MHz, CDCl3)
d: 1.08 (s, 9H),1.34
(s, 3H), 1.36 (s, 3H), 1.44 (m, 1H), 1.57 (m, 1H), 1.63 (m, 2H), 1.86 (m,
1H), 2.02 (m, 1H), 2.30 (br s, 3H), 3.27 (s, 3H), 3.70 (t, J¼6.3 Hz, 2H),
4.88 (t, J¼7.3 Hz, 1H), 5.94 (br dq, J¼3.1, 1.0 Hz, 1H), 6.23 (d,
J¼3.1 Hz, 1H), 7.38 (m, 4H), 7.43 (m, 2H), 7.69 (dd, J¼7.6, 1.6 Hz, 4H)
ppm. 13C NMR (100 MHz, CDCl3)
d: 13.6, 19.1, 22.2, 22.5, 22.8, 26.8,
30.9, 32.3, 49.0, 63.6, 78.9, 104.6, 106.0, 109.4, 127.5, 129.5, 134.0,
135.5,151.7 (2C) ppm. HRMS (CI) calcd for C26H33O3Si [MꢁC4H9O2]þ
421.2199; found: 421.2214; calcd for C26H33O2Si [MꢁC4H9O3]þ
405.2250; found: 405.2237.
4.2.4. Compound 17a. 1H NMR (400 MHz, CDCl3)
d: 1.01 (s, 9H),
2.09 (m, 1H), 2.25 (br s, 3H), 2.28 (m, 1H), 3.73 (ddd, J¼10.5, 7.2,
4.5 Hz,1H), 3.86 (ddd, J¼10.6, 6.8, 4.5 Hz,1H), 5.15 (dd, J¼7.7, 6.2 Hz,
1H), 5.94 (br dq, J¼3.3, 1.0 Hz, 1H), 6.25 (d, J¼3.1 Hz, 1H), 7.41 (m,
6H), 7.66 (m, 4H), 8.37 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3)
d:
Compound 19. To a 0.1 M solution of compound 18 in MeOH was
added 7 equiv of NH4F and the reaction mixture was stirred over-
night at rt. The solution was poured onto a saturated aqueous
NaHCO3 solution and it was extracted with EtOAc (2ꢂ50 mL). The
solvent was removed and the crude residue was purified by silica
gel chromatography (20% and 30% EtOAc/hexanes) (15% for 19a,
45% for 19b, and 60% for 19c yields).
13.6, 19.1, 26.8, 33.4, 60.5, 78.1, 106.2, 110.2, 127.7, 129.7, 133.3, 135.6,
150.6, 152.5 ppm. HRMS (CI) calcd for C24H29O3Si [MꢁH]þ
393.1886; found: 393.1896; calcd for C24H29O2Si [MꢁOH]þ
377.1937; found: 377.1925.
4.2.5. Compound 17b. 1H NMR (400 MHz, CDCl3)
d: 1.05 (s, 9H),
1.68 (m, 2H), 1.97 (m, 1H), 2.06 (m, 1H), 2.29 (br s, 3H), 3.70 (t,
J¼6.3 Hz, 2H), 4.86 (t, J¼7.2 Hz, 1H), 5.95 (br dq, J¼3.1, 1.0 Hz, 1H),
6.25 (d, J¼3.2 Hz,1H), 7.40 (m, 6H), 7.66 (m, 4H), 7.93 (br s,1H) ppm.
4.2.10. Compound 19a. 1H NMR (400 MHz, CDCl3)
d: 1.29 (s, 3H),
1.34 (s, 3H), 2.03 (m, 1H), 2.20 (m, 1H), 2.26 (br s, 3H), 3.25 (s, 3H),
3.70 (m, 1H), 3.82 (m, 1H), 5.05 (dd J¼9.1, 5.5 Hz, 1H), 5.90 (br dq,
J¼3.1, 1.0 Hz, 1H), 6.21 (d, J¼3.1 Hz, 1H) ppm. 13C NMR (100 MHz,
13C NMR (100 MHz, CDCl3)
d: 13.6, 19.2, 26.8, 26.9, 28.5, 63.4, 80.8,
106.2, 110.3, 127.6, 129.6, 133.8, 135.5, 150.7, 152.5 ppm. HRMS (CI)
calcd for C25H32O3Si [MꢁO]þ 408.2121; found: 408.2082;
C25H31O3Si [MꢁOH]þ 407.2042; found: 408.2047.
CDCl3) d: 13.6, 22.0, 22.7, 34.3, 59.6, 76.8, 78.6, 105.2, 106.1, 109.4,
151.3, 152.1 ppm. HRMS (FAB) calcd for C12H20O5Na [MþNa]þ
267.1208; found: 267.1222.
4.2.6. Compound 17c. 1H NMR (400 MHz, CDCl3)
d: 1.03 (s, 9H),1.42
4.2.11. Compound 19b. 1H NMR (400 MHz, CDCl3)
d: 1.30 (s, 3H),
(m,1H),1.48 (m,1H),1.58 (m, 2H),1.80 (m,1H),1.94 (m,1H), 2.29 (br
s, 3H), 3.65 (t, J¼6.2 Hz, 2H), 4.82 (t, J¼7.2 Hz, 1H), 5.94 (br dq, J¼3.1,
1.0 Hz, 1H), 6.25 (d, J¼3.1 Hz, 1H), 7.38 (m, 4H), 7.41 (m, 2H), 7.65
(dd, J¼7.6, 1.6 Hz, 4H), 7.81 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3)
1.31 (s, 3H), 1.63 (m, 1H), 1.68 (m, 1H), 1.91 (m, 1H), 2.05 (m, 1H),
2.27 (br s, 3H), 3.23 (s, 3H), 3.67 (t, J¼6.5 Hz, 2H), 4.88 (t, J¼7.3 Hz,
1H), 5.91 (br dq, J¼3.1, 1.0 Hz, 1H), 6.21 (d, J¼3.2 Hz, 1H) ppm. 13C
d: 13.6, 19.2, 22.0, 26.8, 30.3, 32.2, 63.6, 81.0, 106.2, 110.3, 127.6,
NMR (100 MHz, CDCl3) d: 13.6, 22.5, 22.9, 27.7, 29.1, 49.1, 62.6, 78.7,
129.5, 134.0, 135.6, 150.0, 152.5 ppm. HRMS (CI) calcd for
C26H33O3Si [MꢁOH]þ 421.2199; found: 421.2204; calcd for
C26H33O2Si [MꢁOOH]þ 405.2250; found: 405.2250.
104.8, 106.1, 109.6, 151.5, 151.9 ppm. HRMS (CI) calcd for C9H13O3
[MꢁC4H9O3]þ 169.0865; found: 169.0862; calcd for C9H13O2
[MꢁC4H9O2]þ 153.0916; found: 153.0914.
4.2.12. Compound 19c. 1H NMR (400 MHz, CDCl3)
d: 1.30 (s, 3H),1.31
Compound 18. To a solution of compound 17 (1 mmol) in 15 mL
of dichloromethane was added 1 equiv of 2-methoxypropene and
0.10 equiv of PPTS and stirred for 1 h. The reaction mixture was
quenched with water and extracted with dichloromethane
(3ꢂ50 mL). The combined organic layers were dried over
(s, 3H), 1.38 (m, 1H), 1.49 (m, 1H), 1.60 (quint, J¼7.1 Hz, 2H), 1.84 (m,
1H), 2.01 (m, 1H), 2.28 (br s, 3H), 3.23 (s, 3H), 3.64 (t, J¼6.5 Hz, 2H),
4.84 (t, J¼7.2 Hz,1H), 5.91 (br dq, J¼3.1,1.0 Hz,1H), 6.20 (d, J¼3.1 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3)
d: 13.6, 22.0, 22.5, 22.9, 30.9,

162
F.M. Guerra et al. / Tetrahedron 66 (2010) 157–163
32.4, 49.1, 62.7, 78.8, 104.8, 106.1, 109.5, 151.6, 151.9 ppm. HRMS (CI)
calcd for C10H15O3 [MꢁC4H9O2]þ 183.1021; found: 183.1014; calcd
for C10H15O2 [MꢁC4H9O3]þ 167.1072; found: 167.1066.
121.4, 148.2, 150.1, 152.6, 167.1 ppm. HRMS (FAB) calcd for
C
12H16O5Na [MþNa]þ 263.0895; found: 263.0893.
4.2.18. Compound 21c. 1H NMR (400 MHz, CDCl3)
d: 1.49 (m, 1H),
1.60 (m,1H),1.83 (m,1H),1.98 (m,1H), 2.23 (br q, J¼7.2 Hz, 2H), 2.28
(br s, 3H), 3.71 (s, 3H), 4.82 (t, J¼7.2 Hz, 1H), 5.81 (dt, J¼15.7, 1.5 Hz,
1H), 5.94 (br dq, J¼3.1, 1.0 Hz, 1H), 6.25 (d, J¼3.1 Hz, 1H), 6.93 (dt,
Compound 20. A solution of compound 19 (0.59 mmol) and
Dess–Martin periodinane (0.71 mmol) in 15 mL of CH2Cl2 was
stirred for 15 min at 0 ꢀC and then allowed to warm to rt. After
completion of the reaction (TLC, 1 h), 0.7 mmol of methyl triphe-
nylphosphoranylidene acetate was added in one portion and stirred
overnight. The reaction mixture was quenched by addition of
aqueous saturated sodium thiosulfate and sodium bicarbonate so-
lutions. The mixture was stirred for 20 min and extracted with
CH2Cl2 (2ꢂ50 mL), dried over anhydrous MgSO4 and evaporated to
dryness. The crude residue was purified on silica gel using 30%
Et2O/hexanes as eluent (53% for 20a, 65% for 20b, and 40% for 20c
yields).
J¼15.5, 6.9 Hz, 1H), 8.14 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3)
d:
13.6, 24.1, 30.0, 31.7, 51.4, 80.5, 106.2, 110.3,121.6, 148.8, 150.5, 152.6,
167.1 ppm. HRMS (FAB) calcd for C13H18O5Na [MþNa]þ 277.1052;
found: 277.1060.
4.2.19. Compound 3. Hydroperoxide 21b (0.56 mmol) was dis-
solved in CF3CH2OH/CH3OH (7:3, 35 mL). The solution was cooled
to 0 ꢀC and diethyl amine (22
mL, 0.21 mmol) was added dropwise
for 45 min, after which the reaction mixture was stirred at rt for 1 h.
The solvent was removed in vacuo and the residue purified by
column chromatography (silica, 25% EtOAc/hexanes) to afford the
1,2-dioxane compound 3 (35% yield) and methyl 2,3-epoxy-5-hy-
droxy-5(5-methylfuran-2-yl)-pentanoate (27) (29% yield). 1,2-di-
4.2.13. Compound 20a. 1H NMR (400 MHz, CDCl3)
d: 1.30 (s, 6H),
2.25 (br s, 3H), 2.76 (dddd, J¼14.6, 7.2, 7.2, 1.5 Hz, 1H), 2.91 (dddd,
J¼14.6, 7.2, 7.2, 1.5 Hz, 1H), 3.21 (s, 3H), 3.68 (s, 3H), 4.95 (t,
J¼7.1 Hz, 1H), 5.88 (dt, J¼15.6, 1.5 Hz, 1H), 5.89 (br dq, J¼3.1,
1.0 Hz, 1H), 6.21 (d, J¼3.1 Hz, 1H), 6.89 (dt, J¼15.6, 7.2 Hz, 1H)
oxane 3: 1H NMR (400 MHz, CDCl3)
d
: 1.65 (m, 1H), 1.95 (dq, J¼9.2,
2.3 Hz, 1H), 2.01 (dq, J¼9.2, 2.3 Hz, 1H), 2.17 (m, 1H), 2.27 (s, 3H),
2.37 (dd, J¼15.6, 5.9 Hz, 1H), 2.49 (dd, J¼15.6, 7.2 Hz, 1H), 3.70 (s,
3H), 4.58 (dddd, J¼11.0, 7.2, 5.9, 2.1 Hz, 1H), 5.03 (dd, J¼11.8, 2.3 Hz,
1H), 5.88 (br dq, J¼3.1, 1.0 Hz, 1H), 6.28 (d, J¼3.3 Hz, 1H) ppm. 13C
ppm. 13C NMR (100 MHz, CDCl3)
d: 13.5, 22.5, 22.7, 33.9, 49.1,
51.4, 77.2, 104.9, 106.3, 110.4, 123.2, 144.0, 149.7, 152.4, 166.6 ppm.
HRMS (FAB) calcd for C15H22O6Na [MþNa]þ 321.1314; found:
321.1320.
NMR (100 MHz, CDCl3) d: 13.5, 26.6, 29.3, 38.3, 51.9, 76.4, 77.5,
106.4, 110.7, 148.8, 153.1, 170.3 ppm. HRMS (FAB) calcd for
C12H16O5Na [MþNa]þ 263.0895; found: 263.0885.
4.2.14. Compound 20b. 1H NMR (400 MHz, CDCl3)
d: 1.27 (s, 3H),
1.28 (s, 3H),1.95 (m,1H), 2.15 (m,1H), 2.25 (s, 3H), 2.28 (m, 2H), 3.20
(s, 3H), 3.70 (s, 3H), 4.82 (t, J¼7.2 Hz, 1H), 5.81 (dt, J¼15.8, 1.2 Hz,
1H), 5.89 (br dq, J¼2.9, 1.2 Hz, 1H), 6.18 (d, J¼2.9 Hz, 1H), 6.94 (dt,
4.2.20. Compound 4. Hydroperoxide 21a (0.29 mmol) was dis-
solved in CF3CH2OH/CH3OH (7:3,18 mL). The solution was cooled to
0 ꢀC and diethyl amine (11
mL, 0.11 mmol) was added dropwise,
after which the reaction was stirred at rt for 3 h. The solvent was
removed in vacuo and the residue purified by column chromatog-
raphy (silica, 30% Et2O/hexanes) to afford the 1,2-dioxolane 4 (17%
yield) and methyl 3-hydroxy-5(5-methylfuran-2-yl)-5-oxopenta-
noate (28) (23% yield). 1,2-dioxolane 4: 1H NMR (400 MHz, CDCl3)
J¼15.8, 6.7 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3)
d: 13.5, 22.4,
22.8, 28.3, 29.4, 49.0, 51.3, 77.8, 104.7, 106.1, 109.8, 121.4, 148.1, 150.7,
152.0, 166.9 ppm. HRMS (CI) calcd for C16H25O6 [MþH]þ 313.1651;
found: 313.1667.
4.2.15. Compound 20c. 1H NMR (400 MHz, CDCl3)
d: 1.28 (s, 3H),
d
: 2.26 (br s, 3H), 2.57 (m,1H), 2.68 (dd, J¼16.2, 6.7 Hz,1H), 2.92 (dd,
1.30 (s, 3H),1.48 (m,1H),1.58 (m,1H),1.82 (m,1H),1.98 (m,1H), 2.22
(qd, J¼7.2, 1.5 Hz, 2H), 2.26 (br s, 3H), 3.21 (s, 3H), 3.70 (s, 3H), 4.82
(t, J¼7.2 Hz, 1H), 5.80 (dt, J¼15.6, 1.5 Hz, 1H), 5.90 (br dq, J¼3.1,
1.0 Hz, 1H), 6.18 (d, J¼3.1 Hz, 1H), 6.93 (dt, J¼15.6, 6.9 Hz, 1H) ppm.
J¼16.2, 6.9 Hz, 1H), 3.04 (m, 1H), 3.69 (s, 3H), 4.82 (dddd, J¼7.5, 6.5,
6.4, 4.7 Hz, 1H), 5.18 (dd, J¼8.1, 7.3 Hz, 1H), 5.94 (br dq, J¼3.1, 1.0 Hz,
1H), 6.31 (d, J¼3.1 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3)
d: 13.6,
38.8, 43.3, 51.9, 75.8, 77.7, 106.6,111.6,147.1,153.6, 170.9 ppm. HRMS
13C NMR (100 MHz, CDCl3)
d: 13.6, 22.5, 22.8, 24.2, 30.6, 31.8, 49.1,
(FAB) calcd for C11H14O5Na [MþNa]þ 249.0739; found: 249.0733.
51.3, 78.5, 104.7, 106.1, 109.6, 121.2, 148.9, 151.3, 151.9, 167.0 ppm.
HRMS (FAB) calcd for C17H26O6Na [MþNa]þ 349.1627; found:
349.1616.
4.2.21. Compound 5. Hydroperoxide 21c (0.47 mmol) was dis-
solved in CF3CH2OH/CH3OH (1:1, 23 mL). The solution was treated
with CsOH (0.184 mmol in 75 mL MeOH) dropwise, after which the
Compound 21. A solution of compound 20 in DME was treated
under the same experimental conditions described above for the
synthesis of compound 17, furnishing quantitatively 21 (97% for
21a, 99% for 21b, and 99% for 21c yields).
reaction mixture was stirred at rt overnight. The solvent was re-
moved in vacuo and the residue purified by HPLC (silica, 15% EtOAc/
hexanes) to afford compound cis-1,2-dioxepane 5 (7% yield),
trans-1,2-dioxepane 5 (8% yield), and methyl 7-(5-methylfuran-
2-yl)-7-oxoheptanoate (29) (23% yield).
4.2.16. Compound 21a. 1H NMR (400 MHz, CDCl3)
d: 2.27 (br s, 3H),
4.2.21.1. cis-1,2-Dioxepane 5. 1H NMR (600 MHz, CDCl3)
d: 1.32
2.76 (dddd, J¼14.9, 7.2, 7.2, 1.5 Hz, 1H), 2.91 (dddd, J¼14.9, 7.2, 7.2,
1.5 Hz, 1H), 3.70 (s, 3H), 4.94 (t, J¼7.0 Hz, 1H), 5.91 (dt, J¼15.9,
1.5 Hz, 1H), 5.93 (br dq, J¼3.1, 1.0 Hz, 1H), 6.27 (d, J¼3.1 Hz, 1H), 6.91
(dt, J¼15.9, 7.2 Hz, 1H), 7.99 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3)
(ddd, J¼11.1, 11.1, 4.2 Hz, 1H), 1.62 (m, 1H), 1.72 (br d, J¼15.2 Hz, 1H),
1.76 (ddd, J¼12.7, 12.7, 3.7 Hz, 1H), 1.81 (br d, J¼12.9, 1H), 1.95 (br tt,
J¼13.2, 2.9, 1H), 2.27 (s, 3H), 2.44 (dd, J¼15.5, 7.0 Hz, 1H), 2.69 (dd,
J¼15.5, 6.3 Hz, 1H), 3.67 (s, 3H), 3.93 (dddd, J¼11.3, 6.7, 6.7, 2.1 Hz,
1H), 4.39 (dd, J¼10.8, 2.8 Hz, 1H), 5.88 (br dq, J¼3.1, 1.0 Hz, 1H), 6.12
d
: 13.5, 33.5, 51.6, 78.9, 106.4, 110.9, 123.4, 143.9, 149.3, 152.9,
166.9 ppm. HRMS (FAB) calcd for C11H14O5Na [MþNa]þ 249.0739;
(d, J¼3.1 Hz, 1H) ppm. 13C NMR (150 MHz, CDCl3)
d: 14.0, 23.3, 29.0,
found: 249.0737.
30.8, 41.3, 51.6, 73.5, 74.6, 106.0, 107.3, 152.0, 153.2, 171.3 ppm.
HRMS (FAB) calcd for C13H18O5Na [MþNa]þ 277.1052; found:
277.1043.
4.2.17. Compound 21b. 1H NMR (400 MHz, CDCl3)
d: 1.97 (m, 1H),
2.15 (m, 1H), 2.29 (s, 3H), 2.31 (m, 2H), 3.72 (s, 3H), 4.84 (t, J¼7.0 Hz,
1H), 5.84 (dt, J¼15.8, 1.5 Hz, 1H), 5.95 (br dq, J¼2.9, 1.2 Hz, 1H), 6.18
(d, J¼3.2 Hz, 1H), 6.94 (dt, J¼15.8, 6.7 Hz, 1H), 8.02 (br s, 1H) ppm.
4.2.21.2. trans-1,2-Dioxepane 5. 1H NMR (600 MHz, CDCl3)
(m, 1H), 1.72 (m, 1H), 1.74 (m, 1H), 1.79 (m, 1H), 1.88 (m, 1H), 2.0 (m,
d: 1.40
13C NMR (100 MHz, CDCl3)
d: 13.5, 28.2, 28.6, 51.5, 79.7, 106.2, 110.5,

F.M. Guerra et al. / Tetrahedron 66 (2010) 157–163
163
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1H), 2.28 (s, 3H), 2.43 (dd, J¼14.9, 5.7 Hz, 1H), 2.62 (dd, J¼14.9,
8.0 Hz, 1H), 3.69 (s, 3H), 4.10 (dddd, J¼13.5, 8.3, 5.7, 3.1 Hz, 1H), 4.91
(br t, J¼4.4 Hz, 1H), 5.92(br dq, J¼3.0, 1.1 Hz, 1H), 6.18 (d, J¼3.0 Hz,
´
´
´
2003, 9, 282–290; (c) Pinacho Crisostomo, F. R.; Carrillo, R.; Leon, L. G.; Martın,
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1H) ppm. 13C NMR (150 MHz, CDCl3)
d: 13.6, 19.2, 26.8, 30.4, 40.4,
6. (a) Zmitek, K.; Zupan, M.; Iskra, J. Org. Biomol. Chem. 2007, 5, 3895–3908; (b)
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51.6, 68.3, 68.8, 106.0, 108.4, 151.5, 152.2, 171.7 ppm. HRMS (FAB)
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Compounds 3–5, 20a–20c, 21a–21c were tested against the
human tumor cell lines MDA-MB-231 (breast adenocarcinoma),
A-549 (lung carcinoma), and HT29 (colon adenocarcinoma). A
colorimetric assay using sulforhodamine B (SRB) reaction was
adapted for quantitative measurement of cell growth and viability
as described in the literature.22
Acknowledgements
10. Harris, J. R.; Waetzig, S. R.; Woerpel, K. A. Org. Lett. 2009, 11, 3290–3293.
11. Yu, C.; Liu, B.; Hu, L. Tetrahedron Lett. 2000, 41, 4281–4285.
This research was supported by grants from Ministerio de
12. The reagent 2-methoxyprop-2-yl hydroperoxide is easily generated through
ozonolysis of 2,3-dimethylbut-2-ene in either MeOH or MeOH/CH2Cl2. Re-
moval of the solvent in vacuo and replacement with the desired reaction
solvent affords easily handled solution of the reagent. See: (a) Dussault, P.;
Sahli, A. J. Org. Chem. 1992, 57, 1009–1012; (b) Dussault, P. H.; Zope, U. R.;
Westermeyer, T. A. J. Org. Chem. 1994, 59, 8267–8268.
´
Educacion y Ciencia (Spain)-FEDER (research project CTQ2004-
´
02361) and from Junta de Andalucıa (FQM-285 and FQM-169).
Cytotoxicity assays were performed through a cooperation agree-
ment with PharmaMar.
13. Dussault, P. Synlett 1995, 997–1003.
´
14. For 15a: Ferrie, L.; Boulard, L.; Pradaux, F.; Bouzbouz, S.; Reymond, S.;
Supplementary data
Capdevielle, P.; Cossy, J. J. Org. Chem. 2008, 73, 1864–1880; For 15b: Nonaka,
H.; Maeda, N.; Kobayashi, Y. Tetrahedron Lett. 2007, 48, 5601–5604; For 15c:
Experimental details and spectroscopic data for compounds 6
and 8–12. Stereochemical analysis for compounds 6b and 3–5. 1H
NMR and 13C NMR spectra for compounds 6a and 6b and 3–5.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.11.026.
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Ferrie, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2006, 8,
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15. The acid-catalysed oxidation of alcohols with hydrogen peroxide by alkyl-
oxygen heterolysis has been described by treatment of the corresponding al-
cohol with 90% H2O2 in sulfuric acid: Davies, A. G.; Feld, R. J. Chem. Soc. 1956,
665–670; However, the lability of the furan ring to these conditions led us to
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18. Different silyl ether based protective groups were also tried but they were not
robust enough to resist the hydroperoxide formation step.
19. Adam, W.; Rao, P. B.; Degen, H.-G.; Saha-Moeller, C. R. J. Am. Chem. Soc. 2000,
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