Synthesis of antimalarial G-factors endoperoxides: relevant evidence of the formation of a biradical during the autoxidation step

Article abstract of DOI:10.1016/j.tet.2008.07.047

In the search for new antimalarial endoperoxides related to G-factors series, using a methodology based on autoxidation of a dienol sytem, unexpected cyclic ether alcohols and hydroperoxides were obtained confirming the structure of the previously postula

Full text of DOI:10.1016/j.tet.2008.07.047

Tetrahedron 64 (2008) 9216–9224
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Synthesis of antimalarial G-factors endoperoxides: relevant evidence of the
formation of a biradical during the autoxidation step
a
a,
a
b
c
*
´
`
Virginie Bernat , Christiane Andre-Barres , Michel Baltas , Nathalie Saffon , Henri Vial
a Laboratoire de Synthe`se et de Physicochimie de Mole´cules d’Inte´rˆet Biologique, UMR CNRS 5068, Universite´ Paul-Sabatier, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France
b Structure Fe´de´rative Toulousaine en Chimie Mole´culaire, FR 2599, Universite´ Paul-Sabatier, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France
c
´
´
Dynamique Moleculaire des Interactions Membranaires, UMR CNRS 5539, Universite Montpellier 2, cc107, Place E. Bataillon, F-34095 Montpellier Cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2008
Received in revised form 11 July 2008
Accepted 14 July 2008
Available online 18 July 2008
In the search for new antimalarial endoperoxides related to G-factors series, using a methodology based
on autoxidation of a dienol sytem, unexpected cyclic ether alcohols and hydroperoxides were obtained
confirming the structure of the previously postulated biradical intermediate implicated in oxygen up-
take. Antimalarial activities of PMB-endoperoxides are greatly enhanced when the peroxyhemiketal
function is methylated for the G3 endoperoxide.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
shown that the alkylating properties of the C-centred radical rely on
a good balance between stability and reactivity and could be corre-
Newantimalarial agentsarestill thesubjectofintensiveresearch.1
Since the isolation and discovery of the activity of artemisinin, the
search for a new generation of artemisinin based therapeutics is be-
ing pursued by several research groups.2 Recently synthetic perox-
ides including 1,2,4-trioxanes,3 1,2,4-trioxolanes,4 tetraoxanes,5
cyclic peroxyketals6 and endoperoxides7,8 were discovered. The an-
timalarial activity of all these compounds arises from ferrous iron-
mediated bioactivation within the parasite food vacuole. Currently
we have worked on modified endoperoxides belonging to the
G-factors series in order to understand and possibly to improve their
antiplasmodial activities. G-factors are natural endoperoxides first
extracted from leaves of Eucalyptus grandis.9 They are considered as
phytohormones and growth regulators probably controlling the
electron transport properties of membranes.10 Some of the pre-
viously synthesized derivatives present moderate to good antima-
larial activity. Several parameters were found to be important for
their antimalarial potency: lipophilicity, redox potential involving
one electron exchanged during O–O reduction,11,12 and alkylation of
the peroxyhemiketalic function.13 In this latter case benzyl ether
analogues (G3Bn) exhibited the highest activities (IC50¼300–100 nM
on chloroquine sensitive and resistant strains, respectively) in the
same value of magnitude between the two enantiomers and three-
fold better than the methylated ether (G3Me).14 Concerning Fe(II)-
reduction of the O–O bond, our mechanistic studies revealed two
different pathways for the initially formed C-centred radical
depending on the alkylation or not of the peroxyhemiketal function
andon the substitutionpattern of theperoxycycle.15 Our studies have
lated to the antimalarial activities of the G-factors analogues studied.
Moreover, aminoendoperoxides were found to be inactive thus
questioning previous biological hypothesis suggesting that these
functions could generally improve bioavailability by an accumula-
tive effect in the parasite food vacuole.16
Our ongoing research program presents dual objectives (i)
a mechanistic insight on the comprehension of the G-factors ana-
logues formation, (ii) biological activity in relation to their struc-
ture. In that respect, we wish to report our efforts on exploration of
the endoperoxide formation leading to new rearrangements and on
the evaluation of the antimalarial activities.
This work relates our efforts on the functionalization of the
lateral chain from the primary alcohol in the aim of attaching
a second active molecule (Fig. 1).
2. Results and dicussion
Commercially available
a-methyl-g-butyrolactone may be con-
sidered as the starting compound for preparing the aldehydic
OH
OR
O
O
O
O
O
O
R1
R2
OH
O
O
R1
Et
R2
G1
G2
G3
Me
Me Et
Me Me
* Corresponding author. Tel.: þ33 5 61 55 68 09; fax: þ33 5 61 55 82 55.
´
`
Figure 1. G-factors and functionalized endoperoxides.
E-mail address: candre@chimie.ups-tlse.fr (C. Andre-Barres).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.047

V. Bernat et al. / Tetrahedron 64 (2008) 9216–9224
9217
partner of syncarpic acid in the Knoevenagel-type reaction. Our
O
OH
CH2Cl2
95%
efforts to operate without protecting groups proved to be un-
successful (Scheme 1). In fact the thermodynamically favoured
five-membered ring was in each case formed. Reduction of the
lactone 1 in presence of DIBAL-H afforded lactol 2 in good yield.
Lactol 2 was subjected to react under our reported sequence, pi-
peridine and then syncarpic acid. No Mannich base was observed
but bicyclic compound 5 was obtained in good yield as a di-
astereoisomeric mixture issued from hemiaminal 3.
9
4
+
+
N
N
H
O
O
MeO
11
OH
O
DIBAL-H
H
HO
O
O
CH2Cl2, -78 °C
O
O
H+
O
OMe
11
1
2
O
O
12
Scheme 3. Mannich base and ene-one synthesis.
N
H
H
O
HO
HO
N
CH2Cl2
N
O
cyclization into lactone 1. It must be compatible with the following
steps: acidic conditions, basic and reductive ones. It has to be
cleaved selectively with respect to the peroxide bond, which ex-
cludes catalytic hydrogenation. The para-methoxybenzyl group
(PMB) was chosen as it fulfils the required conditions. It was in-
troduced via a mild protection method for hydroxyl functions using
the para-methoxybenzyl trichloroacetimidate reagent (7), which
was easily prepared from para-methoxybenzyl alcohol and tri-
chloroacetonitrile in the presence of sodium hydride (10 mol %).18
Weinreb amide 6 is then treated with the trichloroacetimidate
derivative 7, in the presence of camphorsulfonic acid (0.2 equiv)19
and after 20 h the expected PMB protected product 8 was obtained
in good yield (81%). The DIBAL-H reduction of the amide 8, by the
method reported by Hollenberg20 provides the aldehyde 9 in good
yield (80%) as well as compound 10 (10%) issued from the reductive
amination of the desired aldehyde 9 with methoxymethylamine.
The modified Knoevenagel reaction between syncarpic acid and
the iminium intermediate formed by aldehyde 9 and piperidine in
equimolar quantities afforded the expected Mannich base in
quantitative yield (Scheme 3). In aqueous acid, elimination of pi-
peridine occurred affording the corresponding ene-one 12. 1H NMR
spectrum showed no tendency to enolization. This methodology
avoids production of bisadducts.21
3
O
60%
X
O
4
O
O
O
O
O
O
H
O
O
OH
O
5
O
N
O
Scheme 1. Formation of bicycle
5 without use of protective group on primary
hydroxyl.
We then decided to open the lactone via the formation of the
Weinreb amide17 (Scheme 2). Treatment of
-methyl- -butyro-
lactone with the aluminium salt of methoxymethylamine afforded
the Weinreb amide 6 in good yield (75%). The protective group has
to be introduced in neutral or acidic conditions in order to avoid
a
g
Ene-one 12 was then subjected to different oxygen uptake
conditions. First, as in previous experiments the solution of ene-
one 12 was left under air at room temperature. The reaction was
O
O
N
AlMe3
CH2Cl2
NH, HCl
O
O
+
HO
O
75%
1
6
8
7
OH
OH
HO
O
9
O
6
3
1
2
HO
5
4
MeO
Cl
MeO
O2
Cl
NaH
Et2O
NH
Cl
13
14
+
+
12
C
N
12
11
OH
EtOAc
O
10
Cl
Cl
16
Cl
O
O
O
O
17
96%
15
7
18
20
19
MeO
MeO
O
N
(+/-) 13
(+/-) 14
CSA
6
7
+
(19%)
(17%)
O
CH2Cl2
O
MeO
81%
8
11
OH
12
21
22
OMe
OH
20
19
O
O
O
O
10
7
3O 16
9
1 2
O
+
O
N
21
20
6
4
O
OPMB
DIBAL-H
CH2Cl2
8
5
13
18
17
H
+
MeO
8
14
O
O
15
O
O
O
MeO
(+/-) 15 (anti)
(+/-) 16 (syn)
(6%)
10 (10%)
9 (80%)
(5%)
Scheme 2. Synthesis of aldehyde 9 via Weinreb amide.
Scheme 4. Procedure 1 for oxygen uptake.

9218
V. Bernat et al. / Tetrahedron 64 (2008) 9216–9224
OH
O
O
O
OH
OH
O
OH
O
O
MeO
MeO
13
14
Figure 2. Molecular view of alcohols 13 and 14 in the solid state (thermal ellipsoids at 50% probability; hydrogen atoms are omitted for clarity).
followed by 1H NMR until disappearance of the vinyl proton signal
of ene-one 12. After 13 days the reaction was complete. Surprisingly
analyses of formed compounds show that oxygen uptake didn’t
proceed as usual. After column chromatography on silica gel, the
major compounds isolated were diastereoisomeric cyclic ethers
containing a tertiary hydroxyl group: 13 and 14 (19% and 17%, re-
spectively) as well as just 11% of endoperoxides (Scheme 4).
Structures of these unexpected compounds were confirmed by
X-ray diffraction of crystals22 and relative configurations could be
established (Fig. 2).
OH
OH
O
O
O-O°
O
O-O°
O
O
O
MeO
MeO
In an attempt to understand this peculiar rearrangement it was
necessary to consider a precedent report concerning an EPR/spin
trapping study of the spontaneous addition of dioxygen on the
precursor of G3-factor.26 During this study the use of nitroso and
nitrone spin traps allowed the detection of two radical centres,
providing the evidence that addition of dioxygen follows a radical
pathway. Structures of biradical intermediates have been postu-
lated and are presented in Figure 3.
type I biradical
PMB oxidation
(-e°; -H+)
O-O° reduction
OH
OH
Pursuing this hypothesis, a mechanism can be proposed in
which biradical species participate but in this special case can
evolve differently from the sole formation of endoperoxides as
described in previous reports. The proposal of the mechanism of
formation of these cyclic ethers 13 and 14 is based on the postu-
lated biradical species of type I as intermediates (Scheme 5): oxi-
dation of PMB and inter or intra-molecular reduction of the
peroxide could lead to 13 and 14. This autoxidation is quite slow (13
days) and the determining step is probably enolization.
OH
O
O
OH
O
O
13 + 14
O
H
C
H
C
O
MeO
MeO
Photoenolization in dichloromethane under argon is then car-
ried out on ene-one 12 using Rayonet apparatus equipped with
350 nm low-pressure mercury lamps (Scheme 6).
Scheme 5. Mechanism proposal for cyclic ethers 13 and 14 formation.
Enolization was followed by 1H NMR. After irradiation for 2 h,
90% of the enol form 120 was obtained. Afterwards the solution was
kept under air and aliquot was analyzed by 1H NMR. Autoxidation
was then quite fast since precursor 120 disappeared after 24 h. Be-
sides endoperoxides and cyclic ethers, a new compound was
formed, which proved to be hydroperoxide 17 (Scheme 7). Only one
O
O
O
OH
350 nm
OPMB
OPMB
O
O
12
12'
Scheme 6. Photoenolization at 350 nm.
OH
O O
OH
O
O
O
O
O O
type I
O
O
O OH
O
O
O
O
O
3O2/ EtOAc
and/ or
12'
14
15
16
13
+
+
+
+
OH
OH
O O
OH
O O
(9%) (7%)
(21%) (6%)
type II
MeO
17
(24%)
Figure 3. Proposal for structure of biradical species during autoxidation step.26
Scheme 7. Procedure 2 for oxygen uptake.

V. Bernat et al. / Tetrahedron 64 (2008) 9216–9224
9219
O
O
O
O
O-OCH3
O-OH
OH
OH
O
O
MeO
MeO
17
22
Figure 4. Molecular view of hydroperoxide 17 and peroxide 22 in the solid state (thermal ellipsoids at 50% probability; hydrogen atoms are omitted for clarity).
diastereoisomer could be isolated and its structure was confirmed
by X-ray diffraction of crystals22 (Fig. 4). This hydroperoxide was
stable once isolated and purified but was reduced leading to 14
when left as a crude mixture after autoxidation. We suppose this is
the reason why it was not isolated in procedure 1, as reaction time
was quite long. Even if we haven’t explained, we can notice that
diastereoisomeric ratio for endoperoxides 15 and 16 was almost
1:1, which is significantly different from ratio obtained previously16
with derivatives featuring O-SitBu(Ph)2 instead of O-PMB.
Finally photoenolisation in the presence of singlet oxygen fol-
lowing the Snider procedure for oxidation of dienol system27 (Rose
Bengal as sensitizer in dichloromethane/methanol) was attempted.
The dienol precursor 120 was quickly oxidized furnishing endo-
peroxides 15/16 as major compounds (34%) as well as cyclic ether
alcohols 13/14 (27%) and hydroperoxide 17 (13%) (Table 1). Com-
petition between reactivity of dienol 120 towards triplet and singlet
oxygen occurred. The reactivity of the postulated biradical in-
termediate formed during autoxidation cannot be completely
bypassed and so cyclic ether alcohols and hydroperoxide were also
formed. Others examples of oxygen uptake on similar systems can
be found in the literature: for instance, Frimer28 depicted photo-
sensitized oxygenation of tetrasubstituted cyclopropenes included
in large rings and Schobert29 compared photooxygenation and
radical autoxidation of 3-alkylidene dihydrofuran-2,4-diones
leading to hydroperoxides and/or endoperoxides lactones.
and 15-Me for endoperoxide 18 while, for endoperoxide 19, NOE
effect was observed between OMe and CH2. Likewise endoperox-
ides, hydroperoxide 17 was also methylated in the same basic
conditions (BuLi/TfOMe) and methyl peroxide 22 was isolated in
the aim to evaluate its antimalarial properties (Scheme 8). X-ray
diffusion of crystals of 22 allowed us to determine its relative
configuration (Fig. 4).22
Deprotection of the para-methoxybenzyl group was easily per-
formed under oxidative conditions: dichlorodicyanobenzoquinone/
water,30 for each endoperoxide. Endoperoxides 20 and 21 were
thus obtained in quantitative yield. Surprisingly, 21 was unstable
under acidic conditions. Even on silica gel, this endoperoxide
rearranged via 1,2-dioxetane in aldehyde and ketone. This sensi-
tivity to acidic medium has also been observed previously in a syn
series of silylated endoperoxides.16
3. Antimalarial activity
Compounds 15, 16, 18, 19 and 22 were tested in vitro against the
Nigerian strain of Plasmodium falciparum (Table 2). The activity was
determined by Desjardins et al.31 using [3H] hypoxanthine in-
corporation to assess parasite growth. Parasitic viability was
expressed as IC50, the drug concentration causing 50% parasite
growth inhibition. Remarkably, antimalarial activity of the peroxy-
ketal compounds 18 and 19 increased 20-fold when compared to
the peroxyhemiketals 15, 16, which emphasize the crucial role of
this methylation, and led us to believe that these compounds be-
have under Fe(II)-induced reduction in the same manner as G3 and
G3Me.14 When TBDPS instead of PMB was used as protective group,
Endoperoxides 15 and 16 obtained pure after silica gel chro-
matography were separately methylated on the peroxyketal posi-
tion to furnish methylated endoperoxides 18 and 19, respectively
(Scheme 8). Endoperoxides 18 (anti: defined by OMe and
CH2CH2OPMB on the opposite side of the heterocycle) and 19 (syn)
were characterized and differentiated by HMBC (Heteronuclear
Multiple Bond Correlation), HSQC (Homonuclear Single Quantum
Correlation), and NOESY (Nuclear Overhauser Effect Spectroscopy)
for the stereochemistry. NOE effect was observed between OMe
the biological activity was in the same range, around 1 mM, both for
the hydroxylated and for the methylated endoperoxides,16 which
was significant of other radical mechanism pathways for the re-
duction of the O–O bridge. Only one deprotected diastereoisomer,
20, could be tested as the other one, 21, was unstable in acidic
Table 1
Yield of isolated products following the chosen procedure
Procedures Conditions
Precursor 12 (%) 13 (%) 14 (%) Alcohols 13þ14 (%) 15 (%) 16 (%) Endoperoxides 15þ16 (%) Hydroperoxide 17 (%)
1
2
Air 13 days; CH2Cl2
Photoenolisation (350 nm) and then
air (24 h); CH2Cl2
0
19
17
36
11a
16
0
0
21
6
27
9
7
25
3
Photoenolisation (350 nm) and then 20
1O2; CH2Cl2/MeOH
13
14
27
20
14
34
13
a
Isolated together.

9220
V. Bernat et al. / Tetrahedron 64 (2008) 9216–9224
LRMS data were obtained by DCI/NH3 on a TSQ 7000 Thermo-
NOE
OMe
O
OH
electron, or by ESI on API 365 Perkin Elmer Sciex or Q-TRAP Applied
Biosystems. HRMS were recorded by ESI on GC TOF Waters. IR
spectra were recorded on a Perkin Elmer 1760-X. Products desig-
nation has been defined using ChemDraw Ultra 8.0 (Cambridge
Soft/ Chem. Office 2004) software, which determines IUPAC no-
menclature. Structures’ numbering used for NMR spectra de-
scription doesn’t follow IUPAC rules.
O
O
BuLi
O
O
O
O
TfOMe
-78 °C
OPMB
OPMB
OPMB
O
O
O
O
15 (anti)
18 (anti)
NOE
OH
O
OMe
O
O
BuLi
O
O
TfOMe
OPMB
-78 °C
5.2. Tetrahydro-3-methylfuran-2-ol (2)
16 (syn)
19 (syn)
a
-Methyl-g-butyrolactone (2 g, 20 mmol) was solubilized in
anhydrous dichloromethane (40 mL) under argon. DIBAL-H 1 M in
dichloromethane (30 mL, 30 mmol) was added slowly at ꢀ78 ꢁC
and the solution was stirred at ꢀ78 ꢁC for 4 h. Methanol (5 mL) and
then silica gel/water (70 mL/5 mL) were added. Crude mixture was
stirred for 2 h at room temperature, then filtered and evaporated in
vacuo (P¼40 mmHg, T¼30 ꢁC) to give lactol 2 as an uncoloured oil
(1.53 g, 15 mmol) in 75% yield.
OMe
O
O
O
DDQ
18 (anti)
19 (syn)
OH
O
20 (anti)
21 (syn)
5.3. 4-(Tetrahydro-3-methylfuran-2-yl)-5-hydroxy-2,2,6,6-
tetramethylcyclohex-4-ene-1,3-dione (5)
O
O
O
O
O OH
O OMe
BuLi
Lactol 2 (0.102 mg, 0.999 mmol) was solubilized in anhydrous
dichloromethane (4 mL) at room temperature under argon. Piper-
OH
OH
O
O
TfOMe
-78 °C
idine (99
mL, 0.999 mmol) was added. Fifteen minutes later, syn-
MeO
MeO
carpic acid (0.182 mg, 0.999 mmol) and then H2SO4 (53
m
L,
17
22
0.999 mmol) were added. The mixture was stirred for 48 h and then
saturated NaHCO3 solution was poured. After extraction with
dichloromethane, the organic phase was washed with water, dried
over MgSO4, filtered and concentrated in vacuo. Compound 5 was
Scheme 8.
obtained as
a mixture of two diastereoisomers (0.157 mg,
Table 2
IC50 values of several peroxides on Nigerian strains of Plasmodium falciparum
0.589 mmol, 59%) and analyzed without any treatment.
5.3.1. Diastereoisomer 1
15
10.5
16
9.9
18
0.67
19
0.47
20
21
22
3.7
3
1H NMR (300 MHz, CDCl3)
d
0.76 (d, 3H, CH3CH, JHH¼7.2 Hz),
IC50
(
m
M)
73a
ndb
a
1.30 (s, 6H, 2CH3),1.42 (s, 6H, 2CH3),1.74 (m, part of ABX system,1H,
CH2–CH2O), 2.27 (m, part of ABX system, 1H, CH2–CH2O), 2.75 (m,
1H, CH3CH), 3.92–4.08 (m, ABX system, 2H, CH2O), 4.96 (d,1H, CHO,
cf. Ref 16.
b
Not determined (unstable in acidic medium).
3JHH¼5.2 Hz); 13C NMR (75.47 MHz, CDCl3)
d 11.88 (CH3CH), 24.50
medium. However, 20 lost antimalarial activity. Finally, methyl
peroxide 22 possessing different structural frames showed a weak
activity.
(2CH3), 25.41 (2CH3), 32.89 (CH2CH2O), 35.62 (CHCH3), 50.20 (Cq),
54.79 (Cq), 66.48 (CH2O), 83.48 (CHO), 106.62 (C]COH), 176.36
(C]COH), 197.24 (C]O), 213.16 (C]O); MS (DCI/NH3, DCM) m/z:
301 [MN2H7]þ, 284 [MNH4]þ, 267 [MH]þ.
4. Conclusion
5.3.2. Diastereoisomer 2
3
1H NMR (300 MHz, CDCl3)
d
1.08 (d, 3H, CH3CH, JHH¼6.6 Hz),
The autoxidation approach in order to synthesize functionalized
endoperoxides related to the G-factors series did not lead to en-
couraging results in terms of synthetic methodology. Nevertheless
from a fundamental point of view, the formation of new cyclic ether
alcohols or hydroperoxides allowed us to pursue the comprehen-
sion of the reaction mechanism of this intriguing oxygen uptake.
The previous proposal of a biradical intermediate26 is reinforced.
Moreover, antimalarial activity of methylated endoperoxides 18
and 19 are below the micromolar level and in the same range as
1.31 (s, 6H, 2CH3), 1.41 (s, 6H, 2CH3),1.71 (m, part of ABX system,1H,
CH2–CH2O), 2.09 (m, 1H, CH3CH), 2.19 (m, part of ABX system, 1H,
CH2–CH2O), 3.92–4.08 (m, ABX system, 2H, CH2O), 4.75 (d, 1H, CHO,
3JHH¼7.9 Hz); 13C NMR (75.47 MHz, CDCl3)
d 16.87 (CH3CH), 24.09
(2CH3), 24.87 (2CH3), 34.06 (CH2CH2O), 41.29 (CHCH3), 50.20 (Cq),
54.79 (Cq), 67.26 (CH2O), 84.26 (CHO), 108.71 (C]COH), 175.60
(C]COH), 197.24 (C]O), 212.94 (C]O); MS (DCI/NH3, DCM) m/z:
301 [MN2H7]þ, 284 [MNH4]þ, 267 [MH]þ.
methylated G3 (0.22 mM), which led us to think that the function-
alized chain introduced does not bring steric hindrance either in
5.4. 4-Hydroxy-N-methoxy-N,2-dimethylbutanamide (6)
the syn or in the anti series.
Trimethylaluminium (5 mL, 10 mmol) was added at 0 ꢁC to N,O-
5. Experimental section
5.1. General
dimethylhydroxylamine (976 mg, 10 mmol) in dichloromethane
(35 mL). After 30 min at room temperature,
a-methyl-g-butyro-
lactone (100 mg, 4 mmol) in dichloromethane (10 mL) was added
to the mixture. After 24 h silica gel was added and then filtered.
Melting points were measured on a Bu¨chi and were un-
corrected. The NMR spectra were recorded on a Brucker Avance 300
FT-NMR or Brucker Avance 400 or Brucker Avance 500 FT-NMR.
Weinreb amide 6 (485 mg, 3.009 mmol) was obtained in 75% yield.
3
1H NMR (300 MHz, CDCl3)
d
1.16 (d, 3H, CH3–CH, JHH¼7.0 Hz),
1.80 (m, ABX system, 2H, CH2), 3.10 (m, 1H, CH–CH3), 3.20 (s, 3H,

V. Bernat et al. / Tetrahedron 64 (2008) 9216–9224
9221
3
N–CH3), 3.64 (m, 2H, CH2OH), 3.72 (s, 3H, NO–CH3); 13C NMR
(75.47 MHz, CDCl3) 17.42 (CH3–CH), 32.26 (NCH3), 32.98 (CH–
CH3), 36.07 (CH2), 60.55 (CH2–OH), 61.57 (NO–CH3), 178.48 (C]O);
MS: (DCI/NH3) m/z: 162 [MH]þ, 179 [MNH4]þ.
Ph), 6.87 (d, 2H, CH aromatic, JHH¼8.7 Hz), 7.23 (d, 2H, CH aro-
3 3
d
matic, JHH¼8.7 Hz), 9.63 (d, 1H, CHO, JHH¼1.7 Hz); 13C NMR
(75.47 MHz, CDCl3) d 13.28 (CH3–CH), 30.87 (CH2–CH2O), 43.80
(CH–CH3), 55.30 (CH3OPh), 67.09 (CH2–CH2O), 72.53 (Ph–CH2O),
113.80 (2CH, aromatic), 129.22 (2CH, aromatic), 130.31 (C, aro-
5.5. p-Methoxybenzyl trichloroacetimidate (7)
matic),159.22 (C, COCH3), 204.79 (C]O); IR (thin film) n 2952–2835
(CH aliphatic), 2711 and 1725 (CH and HC]O), 1612, 1586 and 1513
(C]C aromatic), 1248 and 1173 (C–O) cmꢀ1; MS (DCI/NH3) m/z: 240
[MNH4]þ; HRMS (IS, MeOH): calculated for C13H18O3Na 245.1154,
found 245.1140.
Sodium hydride (60% in oil, 40.2 mg, 1.01 mmol) was added
under argon to p-methoxybenzyl alcohol (556 mg, 4.024 mmol),
which was previously solubilized in anhydrous ether (1.5 mL). The
mixture was stirred for 30 min at room temperature and then
cooled at 0 ꢁC. Trichloroacetonitrile (403
mL, 4.024 mmol) was then
5.7.2. 4-(4-Methoxybenzyloxy)-N-methoxy-N,2-dimethylbutan-1-
amine (10)
added. When room temperature was reached, the mixture was
stirred for 2 h, then neutralized with saturated NaHCO3 solution
and extracted with diethyl ether. Organic layer was dried over
MgSO4 and concentrated to obtain the trichloroacetimidate
(1.090 g, 3.858 mmol, 96%) as oil. Rf (petroleum ether/AcOEt: 1:1)
Rf (petroleum ether/AcOEt: 7:3) 0.60; 1H NMR (300 MHz, CDCl3)
d
0.95 (d, 3H, CH3–CH, 3JHH¼6.6 Hz), 1.41 and 1.81 (m, ABX system,
1H, CH2, CH2–CH2O), 1.88 (m, 1H, CH–CH3), 2.43 (m, 2H,
CH2NOCH3), 2.54 (s, 3H, NCH3), 3.50 (s, 3H, NOCH3), 3.51 (m,
2H, CH2–CH2O), 3.80 (s, 3H, PhOCH3), 4.44 (s, 2H, OCH2–Ph), 6.87 (d,
0.78; 1H NMR (300 MHz, CDCl3)
d 3.71 (s, 3H, CH3O), 5.18 (s, 2H,
3
3
3
CH2O), 6.81 (d, 2H, 2CH aromatics, JHH¼8.7 Hz), 7.27 (d, 2H, 2CH
2H, CH aromatic, JHH¼8.7 Hz), 7.26 (d, 2H, CH aromatic, JHH
¼
aromatic).
8.7 Hz); 13C NMR (75.47 MHz, CDCl3)
d
18.46 (CH3–CH), 28.38 (CH–
CH3), 34.95 (CH2–CH2O), 45.48 (NCH3), 55.22 (CH3OPh), 59.73
(NOCH3), 67.86 (CH2N), 68.24 (CH2–CH2O), 72.46 (Ph–CH2O), 113.69
(2CH, aromatic), 129.13 (2CH, aromatic), 130.75 (C, aromatic),
159.03 (COCH3); MS (DCI/NH3) m/z: 268 [MH]þ.
5.6. 4-(4-Methoxybenzyloxy)-N-methoxy-N,2-
dimethylbutanamide (8)
p-Methoxybenzyl trichloroacetimidate (7) (987
and then camphorsulfonic acid (69 mg, 0.297 mmol) were added to
Weinreb amide (479 mg, 2.971 mmol) in dichloromethane
mL, 4.754 mmol)
5.8. 6-(4-(4-Methoxybenzyloxy)-2-methylbutylidene)-2,2,4,4-
tetramethylcyclohexane-1,3,5-trione (12)
6
(30 mL). After 20 h, the mixture was diluted with diethyl ether and
then treated with NaHCO3. After extraction with diethyl ether, or-
ganic phases were dried over MgSO4, filtered and then concen-
trated. Crude product was purified on silica gel (petroleum ether/
AcOEt: 7:3 then 1:1) to furnish the pure compound 8 (673 mg,
2.392 mmol, 81%) as yellow oil. Rf (petroleum ether/AcOEt: 7:3)
5.8.1. Mannich base 11 synthesis
Aldehyde 9 (0.405 g, 1.822 mmol) in dichloromethane (10 mL)
was added to piperidine (180
temperature. Syncarpic acid (0.332 g, 1.822 mmol) and piperidine
(90 L, 0.911 mmol) were solubilized in dichloromethane (10 mL).
mL, 1.822 mmol) under argon at room
m
0.19; 1H NMR (300 MHz, CDCl3)
d
1.12 (d, 3H, CH3–CH, 3JHH¼6.9 Hz),
Then, half an hour later, the two solutions were mixed together
under argon and stirred for 24 h. After concentration in vacuo,
Mannich base 11 was obtained as yellow solid.
1.67 (m, ABX system,1H, CH2–CH2O), 2.01 (m, ABX system,1H, CH2–
CH2O), 3.15 (m, 1H, CH–CH3), 3.17 (s, 3H, N–CH3), 3.45 (m, 2H, CH2–
CH2O), 3.65 (s, 3H, NO–CH3), 3.80 (s, 3H, PhOCH3), 4.40 (s, 2H,
3
OCH2–Ph), 6.86 (d, 2H, CH aromatic, JHH¼8.7 Hz), 7.83 (d, 2H, CH
5.8.2. Precursor 12 synthesis
aromatic, 3JHH¼8.7 Hz); 13C NMR (75.47 MHz, CDCl3)
d
17.64 (CH3–
Mannich base 11 (221 mg, 0.469 mmol) in dichloromethane
(10 mL) was treated by saturated NH4Cl in 1 M HCl solution (10 mL).
After 30 min, the aqueous phase was extracted with dichloro-
methane. Organic phase was washed, dried over MgSO4, filtered
and evaporated to give the ene-one 12 as yellow oil (166 mg,
0.430 mmol) in 92% yield, which was immediately engaged in the
CH), 32.05(NCH3), 32.05 (CH–CH3), 33.56 (CH2–CH2O), 55.29
(CH3OPh), 61.45 (NO–CH3), 67.95 (CH2–CH2O), 72.53 (Ph–CH2O),
113.73 (2CH, aromatic), 129.27 (2CH, aromatic), 130.64 (C, aro-
matic), 159.13 (C, COCH3), 177.66 (C]O); IR (thin film) n 2966–2868
(CH2 and CH3), 2839 (OCH3), 1659 (C]O, amide), 1613, 1586 and
1513 (C]C aromatic), 1248 and 1117 (C–O) cmꢀ1; MS (DCI/NH3)
m/z: 282 [MH]þ, 299 [MNH4]þ; HRMS (IS, MeOH): calculated for
next step.
1H NMR (300 MHz, CDCl3)
d
1.12 (d, 3H, CH3–CH, JHH¼6.7 Hz),
3
C
15H24NO4 282.1705, found 282.1724; calculated for C15H23NO4Na
1.25 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.31 (s, 3H, CH3),
1.77 (m, 2H, CH2–CH2–O), 3.49 (m, 3H, CH–CH3 and CH2–CH2–O),
3.79 (s, 3H, OCH3), 4.36 (d, 2H, PhCH2O), 6.84 (d, 2CH aromatic),
7.20 (d, 2H, 2CH aromatic), 7.30 (d, 1H, C]CH, 3JHH¼10.7 Hz).
304.1525, found 304.1496.
5.7. Reduction of Weinreb amide (8)
DIBAL-H 1 M in toluene (6.9 mL, 6.824 mmol) was added at
ꢀ78 ꢁC to Weinreb amide 8 (480 mg, 1.706 mmol) in dichloro-
methane (35 mL). After 75 min, the mixture was treated with
methanol, water and then HCl (1 N) then extracted with dichloro-
methane. The organic phase is washed with water, then dried over
MgSO4, filtered and concentrated. Column chromatography on
silica gel (petroleum ether/AcOEt: 17:3) allowed to separate
aldehyde 9 and N-methoxy-amine 10 (45 mg, 0.171 mmol, 10%).
Aldehyde (303 mg, 1.365 mmol, 80%) was obtained as yellow oil.
5.9. Oxygen uptake
5.9.1. Procedure 1
Ene-one 12 (125 mg, 0.323 mmol) solubilized in dichloro-
methane was kept under air for 13 days. The mixture was con-
centrated and then purified. Hydroxy-pyranes 13 (24 mg,
0.060 mmol, 19%) and 14 (22 mg, 0.055 mmol, 17%) and endoper-
oxides 15/16 (15 mg, 0.035 mmol, 11%, 1:1) were separated on silica
gel column chromatography (petroleum ether/Et2O: 3:1 then 1:1).
5.7.1. 4-(4-Methoxybenzyloxy)-2-methylbutanal (9)
5.9.2. Procedure 2
Rf (petroleum ether/AcOEt: 7:3) 0.55; 1H NMR (300 MHz, CDCl3)
Ene-one precursor 12 (230 mg, 0.595 mmol) was solubilized in
dichloromethane/methanol 19:1 (80 mL) and then irradiated at
350 nm (Rayonnet) for 2 h 15 min. After evaporation dienol pre-
cursor 120 was kept under air atmosphere at room temperature for
d
1.10 (d, 3H, CH3–CH, 3JHH¼7.1 Hz), 1.69 (m, ABX system, 1H, CH2–
CH2O), 2.02 (m, ABX system, 1H, CH2–CH2O), 2.54 (m, 1H, CH–CH3),
3.50 (m, 2H, CH2–CH2O), 3.80 (s, 3H, PhOCH3), 4.41 (s, 2H, OCH2–

9222
V. Bernat et al. / Tetrahedron 64 (2008) 9216–9224
24 h. After removal of the solvents, the crude mixture was purified
by column chromatography on silica gel (petroleum ether/AcOEt:
8:2). Hydroxy-pyranes 13 (50 mg, 0.124 mmol, 21%) and 14 (14 mg,
0.035 mmol, 6%) and endoperoxides 15 (22 mg, 0.053 mmol, 9%)
and 16 (17 mg, 0.041 mmol, 7%) and hydroperoxide 17 (61 mg,
0.146 mmol, 25%) were separated.
2.02 (m, 2H, CH2CH2O, ABX system), 3.30 (s, 3H, PhOCH3), 3.37 (m,
3
2H, CH2CH2O), 4.19 (2d, 2H, OCH2Ph, JHH¼11.4 Hz), 6.83 (d, 2H,
3
2CH-21, JHH¼8.7 Hz), 7.15 (s, 1H, C]CH), 7.19 (d, 2H, 2CH-20,
3JHH¼8.7 Hz); 13C NMR (125.76 MHz, C6D6)
d 15.69 (CH3, C-11 or
12), 20.96 (CH3, C-11 or 12), 21.27 (CH3, C-15), 24.46 (CH3, C-13 or
14), 26.77 (CH3, C-13 or 14), 37.30 (CH2, C-16), 51.93 (C, C-10), 54.79
(OCH3), 55.01 (C, C-8), 65.52 (CH2, C-17), 72.98 (CH2, C-18), 80.72 (C,
C-4), 97.79 (C, C-1), 114.17 (2CH, C-21), 129.61 (2CH, C-20), 130.63
(C, C-19), 131.99 (C, C-6), 142.46 (CH, C-5), 159.86 (C, C-22), 197.79
5.9.3. Procedure 3
Ene-one 12 (95 mg, 0.245 mmol) solubilized in dichloro-
methane/methanol 19:1 (25 mL) was irradiated at 350 nm under
argon (Rayonnet) for 1 h 15 min. Rose Bengal (12 mg, 10% weight)
was added. The solution was then irradiated in the visible region
(Schott Lamp 150 W) under air for 1 h 30 min. The mixture was
then concentrated and purified by column chromatography on
silica gel (petroleum ether/AcOEt: 8:2). Two diastereoisomers were
obtained as uncoloured oil in 34% yield. The anti diastereoisomer 15
(20 mg, 0.047 mmol) was obtained in 19% yield and the syn di-
astereoisomer 16 (14 mg, 0.033 mmol) in 14% yield, hydroxy-pyr-
anes 13/14 in 27%(1:1) yield and hydroperoxide 17 in 13% yield.
(C]O, C-7), 209.87 (C]O, C-9), IR (thin film)
2872 (CH2 and CH3), 1725 (C]O), 1692 (C]O
n
3440 (OH), 2979–
-unsaturated),
a,b
1638 (C]C ethylenic),1608,1514 (C]C aromatics), 1302 to 1170 (C–
O), 1100 (C–O peroxide), 1068 (C–O alcohol) cmꢀ1; MS (IS) m/z: 441
[MNa]þ; HRMS (IS, MeOH): calculated for C23H30O7Na 441.1889,
found 441.1859.
5.9.7. (3R
*
,8aR )-3-(2-(4-Methoxybenzyloxy)ethyl)-8,8a-dihydro-
*
8a-hydroxy-3,6,6,8,8-pentamethylbenzo[c][1,2]dioxine-5,7(3H,6H)-
dione (16)
Rf (petroleum ether/AcOEt: 7:3)¼0.42; 1H NMR (500 MHz, C6D6)
*
,3R
*
,4R
*
)-Tetrahydro-4-hydroxy-2-(4-methoxy-
´
d 0.81 (s, 3H, CH3-11 or 12), 1.15 (s, 3H, CH3-15), 1.43 (s, 3H, CH3-13
5.9.4. 4-((2R
phenyl)-4-methyl-2H-pyran-3-yl)-5-hydroxy-2,2,6,6-
tetramethylcyclohex-4-ene-1,3-dione (13)
or 14), 1.44 (m, 2H, CH2-16), 1.47 (s, 3H, CH3-13 or 14), 1.55 (s, 3H,
CH3-11 or 12), 3.11 (m, 2H, CH2CH2O), 3.25 (s, 3H, PhOCH3), 4.07 (2d,
2H, OCH2Ph, 3JHH¼11.7 Hz), 6.75 (d, 2H, H-21, 3JHH¼8.7 Hz), 7.03 (s,
1H, C]CH), 7.09 (d, 2H, H-20, 3JHH¼8.5 Hz); 13C NMR (125.76 MHz,
Rf (petroleum ether/AcOEt: 7:3)¼0.08; 1H NMR (300 MHz,
CDCl3) d 0.60 (s, 3H, CH3-9 or 10), 1.17 (s, 3H, CH3-7 or 8), 1.19 (s, 3H,
CH3-9 or 10), 1.28 (s, 3H, CH3-21), 1.35 (s, 3H, CH3-7 or 8), 1.63 and
1.14 (2m, ABX system, 2H, CH2-13), 3.69 (d, 1H, CH-11,
3JHH¼11.1 Hz), 3.70 (s, 3H, OCH3), 4.94 (d, 1H, CH-16, 3JHH¼11.1 Hz),
C6D6) d 15.66 (CH3, C-11 or 12), 20.49 (CH3, C-11 or 12), 23.53 (CH3,
C-15), 23.90 (CH3, C-13 or 14), 26.76 (CH3, C-13 or 14), 36.92 (CH2,
C-16), 51.37 (C, C-10), 54.73 (OCH3), 55.07 (C, C-8), 65.42 (CH2, C-
17), 72.73 (CH2, C-18), 80.69 (C, C-4), 97.54 (C, C-1), 114.21 (2CH, C-
21), 129.47 (C, C-19), 129.58 (2CH, C-20), 133.35 (C, C-6), 140.46 (CH,
3
4.01 (m, 2H, CH2-14), 6.72 (d, 2H, CH-19, JHH¼8.7 Hz), 7.17 (d, 2H,
CH-18, 3JHH¼8.7 Hz); 13C NMR (75.47 MHz, CDCl3)
d 23.85 (CH3, C-9
or 10), 24.24 (CH3, C-7 or 8), 24.63 (CH3, C-9 or 10), 25.41 (CH3, C-7
or 8), 28.35 (CH3, C-21), 40.27 (CH2, C-13), 47.18 (CH, C-11), 48.47 (C,
C-6), 54.27 (C, C-4), 55.32 (OCH3) 63.92 (CH2, C-14), 74.91 (CH, C-
12), 76.63 (CH, C-16), 109.51 (C, C-2), 113.38 (2CH, C-19), 128.43
(2CH, C-18),132.30 (C, C-17),159.60 (C, C-20),174.43 (C, C-1), 198.29
C-5),160.00 (C, C-22),197.49 (C, C-7), 209.86 (C, C-9); IR (thin film)
n
3440 (OH), 2979–2872 (CH2 and CH3), 1724 (C]O),1692 (C]O, a,b-
unsaturated), 1638 (C]C, ethylenic), 1612, 1587, 1514 (C]C, aro-
matic), 1302–1172 (C–O), 1099 (C–O, peroxide), 1070 (C–O, alco-
hol) cmꢀ1; MS: (IS) m/z 441 [MNa]þ; HRMS (IS, MeOH): calculated
for C23H30O7Na 441.1889, found 441.1897.
(C, C-3), 213.55 (C, C-5); IR (diamond compression system)
n 3338
(OH), 2974–2876 (CH aliphatic), 1713 (C]O), 1610, 1518, 1458 (C]C
aromatic), 1255 (C–O alcohol), 1064 and 1034 (C–O ether); MS (DCI/
NH3) m/z: 403 [MH]þ, 420 [MNH4]þ.
5.9.8. 4-((2R
*
,3S
*
,4R )-Tetrahydro-4-hydroperoxy-2-(4-
*
methoxyphenyl)-4-methyl-2H-pyran-3-yl)-5-hydroxy-2,2,6,6-
tetramethylcyclohex-4-ene-1,3-dione (17)
5.9.5. 4-((2R
*
,3S
*
,4R
*
)-Tetrahydro-4-hydroxy-2-(4-methoxy-
Rf (petroleum ether/AcOEt: 7:3)¼0.38; 1H NMR (300 MHz,
phenyl)-4-methyl-2H-pyran-3-yl)-5-hydroxy-2,2,6,6-
tetramethylcyclohex-4-ene-1,3-dione (14)
CDCl3) d 0.91 (s, 3H, CH3-9 or 10), 1.04 (s, 3H, CH3-7 or 8), 1.21 (s, 3H,
CH3-21), 1.23 (s, 3H, CH3-9 or 10), 1.33 (s, 3H, CH3-7 or 8), 1.98 (m,
2H, CH2-13), 3.72 (s, 3H, OCH3), 4.22 (m, 2H, CH2-14), 4.39 (d, 1H,
Rf (petroleum ether/AcOEt: 7:3)¼0.19; 1H NMR (300 MHz,
3
3
CDCl3)
d
0.92 (s, 3H, CH3-9 or 10), 1.04 (s, 3H, CH3-7 or 8), 1.21 (s, 3H,
CH-11, JHH¼3.8 Hz), 5.32 (d, 1H, CH-16, JHH¼3.8 Hz), 6.76 (d, 2H,
3
3
CH3-21), 1.24 (s, 3H, CH3-9 or 10), 1.32 (s, 3H, CH3-7 or 8), 1.61 and
1.91 (m, ABX system, 2H, CH2-13), 3.72 (s, 3H, OCH3), 3.80 (m, 1H,
CH-11), 4.30 (m, 2H, CH2-14), 5.47 (d, 1H, CH-16, 3JHH¼3.4 Hz), 6.76
CH-19, JHH¼8.9 Hz), 7.15 (d, 2H, CH-18, JHH¼8.9 Hz). 13C NMR
(75.47 MHz, CDCl3) d 22.36 (CH3, C-21), 22.58 (CH3, C-9 or 10), 24.45
(CH3, C-7 or 8), 25.41 (CH3, C-7 or 8), 26.33 (CH3, C-9 or 10), 31.65
(CH2, C-13), 40.76 (CH, C-11), 48.72 (C, C-6), 54.97 (C, C-4), 55.26
(OCH3), 65.30 (CH2, C-14), 76.48 (CH, C-16), 82.33 (C, C-12), 108.26
(C, C-2), 113.33 (2CH, C-19), 125.18 (2CH, C-18), 130.87 (C, C-17),
158.74 (C, C-20), 175.16 (C, C-1), 199.36 (C, C-3), 212.84 (C, C-5); MS
(DCI/NH3) m/z 419 [MH]þ, 420 [MNH4]þ.
3
3
(d, 2H, CH-19, JHH¼8.9 Hz), 7.15 (d, 2H, CH-18, JHH¼8.9 Hz); 13C
NMR (75.47 MHz, CDCl3) d 22.75 (CH3, C-9 or 10), 24.47 (CH3, C-7 or
8), 25.55 (CH3, C-7 or 8), 26.41 (CH3, C-9 or 10), 28.77 (CH3, C-21),
35.65 (CH2, C-13), 47.04 (C, C-11), 48.76 (C, C-6), 54.99 (C, C-4),
55.21 (OCH3), 65.52 (CH2, C-14), 70.90 (C, C-12), 76.48 (CH, C-16),
108.94 (C, C-2), 113.24 (2CH, C-19), 125.27 (2CH, C-18), 131.08 (C, C-
17), 158.59 (C, C-20), 174.28 (C, C-1), 199.42 (C, C-3), 212.96 (C, C-5);
IR (diamond compression system)
matic), 2978 to 2867 (CH aliphatic), 1711 (C]O), 1613, 1516, 1459
(C]C aromatic),1253 (C-O alcohol),1053 and 1036 (C–O ether) cmꢀ1
MS (DCI/NH3) m/z: 403 [MH]þ, 420 [MNH4]þ.
n
3396 (OH), 3073 (]C–H aro-
5.10. Methylation of peroxyhemiketal (15) or (16)
;
Compound anti (15) or syn (16) endoperoxide (35 mg,
0.084 mmol) was solubilized in tetrahydrofurane (6 mL) under ar-
gon. At ꢀ78 ꢁC, butyllithium (1.3 M in hexane) (64
mL, 0.084 mmol)
5.9.6. (3S
*
,8aR
*
)-3-(2-(4-Methoxybenzyloxy)ethyl)-8,8a-dihydro-
was added and the mixture was stirred for 15 min. Then, methyl
8a-hydroxy-3,6,6,8,8-pentamethylbenzo[c][1,2]dioxine-5,7(3H,6H)-
dione (15)
triflate (9.5
m
L, 0.084 mmol) was introduced. After 4 h at ꢀ78 ꢁC,
saturated NH4Cl solution was added. Aqueous phase was extracted
with dichloromethane. After washing with water, the organic phase
was filtered and dried (MgSO4). Methylated endoperoxide was
obtained after purification on silica gel column chromatography
Rf (petroleum ether/AcOEt: 7:3)¼0.32; 1H NMR (500 MHz, C6D6)
d
0.77 (s, 3H, CH3-11 or 12), 0.99 (s, 3H, CH3-15), 1.42 (s, 3H, CH3-13
or 14), 1.44 (s, 3H, CH3-13 or 14), 1.48 (s, 3H, CH3-11 or 12), 1.92 and

V. Bernat et al. / Tetrahedron 64 (2008) 9216–9224
9223
(petroleum ether/AcOEt: 9:1) as uncoloured oil (19 mg,
0.046 mmol) in 52% yield.
or 14), 37.67 (CH2), 53.29 (C-10), 54.33 (OCH3), 54.66 (C-8), 64.89
(CH2OH), 80.24 (C-4), 101.01 (C-1), 128.38 (C-6), 145.69 (CH-5),
198.08 (C-7), 209.48 (C-9); IR (neat)
n
3450 (OH), 2924–2854 (CH2
5.10.1. (3S
*
,8aR
*
)-3-(2-(4-Methoxybenzyloxy)ethyl)-8,8a-dihydro-
and CH3), 1723 (C]O), 1691 (C]O, a,b-unsaturated), 1631 (C]C),
8a-methoxy-3,6,6,8,8-pentamethylbenzo[c][1,2]dioxine-5,7(3H,6H)-
dione (18)
1260 (C–O), 1100 (C–O–O–C) cmꢀ1; MS (IS, MeOH) m/z: 335
[MNa]þ; HRMS (IS, MeOH): calculated for C16H24O6Na 335.1471,
found 335.1467.
Rf (petroleum ether/EtOAc: 7:3)¼0.57; 1H NMR (400 MHz,
CDCl3) d 1.00 (s, 3H, CH3-11 or 12), 1.29 (s, 6H, 2CH3-11 or 12 and 13
or 14), 1.32 (s, 3H, CH3-13 or 14), 1.35 (s, 3H, CH3-15), 2.08 (m, 2H,
CH2-16), 3.45 (s, 3H, OMe), 3.61 (m, 2H, CH2O-17), 3.80 (s, 3H,
5.12. 4-((2R
*
,3S
*
,4R )-Tetrahydro-4-hydroperoxy-2-(4-
*
methoxyphenyl)-4-methyl-2H-pyran-3-yl)-5-hydroxy-2,2,6,6-
tetramethylcyclohex-4-ene-1,3-dione (22)
3
PhOMe), 4.43 (s, 2H, OCH2Ph), 6.87 (d, 2H, 2CH-21, JHH¼8.8 Hz),
3
7.24 (d, 2H, 2CH-20, JHH¼8.8 Hz), 7.40 (s, 1H, CH-5); 13C NMR
(100.61 MHz, CDCl3)
d 15.66 (CH3-11 or 12), 21.23 (CH3-15), 21.75
Hydroperoxide 17 (66 mg, 0.157 mmol) was solubilized in an-
hydrous THF (15 mL) under argon. At ꢀ78 ꢁC, BuLi (1.3 M/hexane)
(CH3-11 or 12), 24.81 (CH3-13 or 14), 25.91 (CH3-13 or 14), 36.63
(CH2-16), 53.18 (C-10), 54.47 (C-8), 54.73 (OMe), 55.28 (PhOMe),
65.36 (CH2O-17), 72.86 (OCH2Ph), 80.22 (C-4), 100.38 (C-1), 113.84
(2CH-21), 128.06 (C-6), 129.30 (2CH-20), 130.06 (C-19), 145.44 (CH-
(121 mL, 0.157 mmol) was added dropwise and the solution
was stirred for 15 min. Then, methyl triflate (18 mL, 0.157 mmol)
was added and the solution stirred for 4 h at ꢀ78 ꢁC. Reaction was
quenched with saturated NH4Cl solution. Extraction was performed
with dichloromethane. Organic phase was washed with water,
dried over MgSO4, filtered and evaporated. Crude mixture was
purified on silica gel column chromatography (petroleum ether/
EtOAc: 9:1) to furnish methyl peroxide 22 as a white solid (27 mg,
0.062 mmol, 40%).
5), 159.26 (C-22), 198.85 (C-7), 210.47 (C-9); IR (thin film)
n 2978–
2873 (CH2 and CH3), 2838 (CH, OMe), 1724 (C]O), 1692 (C]O,
a,b-
unsaturated), 1636, 1613, 1514 (C]C aromatic), 1298–1173 (C–O),
1101 (C–O peroxide) cmꢀ1; MS (IS, MeOH) m/z: 455 [MNa]þ; HRMS
(IS, MeOH): calculated for C24H32O7Na 455.2046, found 455.2039.
5.10.2. (3R
*
,8aR )-3-(2-(4-Methoxybenzyloxy)ethyl)-8,8a-dihydro-
*
Rf (petroleum ether/EtOAc: 7:3)¼0.58; 1H NMR (300 MHz,
8a-methoxy-3,6,6,8,8-pentamethylbenzo[c][1,2]dioxine-5,7(3H,6H)-
dione (19)
CDCl3) d 0.91 (s, 3H, CH3-9 or 10), 1.03 (s, 3H, CH3-7 or 8), 1.19 (s, 3H,
CH3-21), 1.23 (s, 3H, CH3-9 or 10), 1.32 (s, 3H, CH3-7 or 8), 1.90 (m,
2H, CH2-13), 3.72 (s, 3H, PhOMe), 3.91 (s, 3H, OOCH3), 4.20 (m, 2H,
Rf (petroleum ether/EtOAc: 7:3)¼0.57; 1H NMR (400 MHz,
CDCl3)
d
1.05 (s, 3H, CH3-11 or 12), 1,29 (s, 3H, CH3-13 or 14), 1.30 (s,
3
CH2-14), 4.35 (d, 1H, CH-11, JHH¼3.8 Hz), 5.31 (d, 1H, CH-16,
3H, CH3-11 or 12), 1.34 (s, 3H, CH3-13 or 14), 1.46 (s, 3H, CH3-15),
2.01 (t, 2H, CH2-16), 3.39 (s, 3H, OMe), 3,53 (t, 2H, CH2O-17), 3.80 (s,
3H, PhOMe), 4.40 (s, 2H, CH2Ph), 6.87 (d, 2H, 2CH-21, 3JHH¼8.7 Hz),
3
3JHH¼3.8 Hz), 6.75 (d, 2H, CH-19, JHH¼8.9 Hz), 7.15 (d, 2H, CH-18,
3JHH¼8.9 Hz); 13C NMR (75.47 MHz, CDCl3)
d 22.66 (CH3, C-9 or 10),
22.77 (CH3, C-21), 24.41 (CH3, C-7 or 8), 25.41 (CH3, C-7 or 8), 26.21
(CH3, C-9 or 10), 32.10 (CH2, C-13), 40.97 (CH, C-11), 48.68 (C, C-6),
54.96 (C, C-4), 55.25 (PhOCH3), 63.34 (OOCH3), 65.31 (CH2, C-14),
76.55 (CH, C-16), 81.83 (C, C-12), 108.19 (C, C-2), 113.29 (2CH, C-19),
125.20 (2CH, C-18), 130.98 (C, C-17), 158.64 (C, C-20), 175.52 (C, C-
1), 198.82 (C, C-3), 213.12 (C, C-5); IR (diamond compression sys-
3
7.24 (d, 2H, 2CH-20, JHH¼8.7 Hz), 7.53 (s, 1H, CH-5); 13C NMR
(100.61 MHz, CDCl3)
d 15.66 (CH3-11 or 12), 21.73 (CH3-11 or 12),
22.52 (CH3-15), 24.80 (CH3-13 or 14), 25.93 (CH3-13 or 14), 37.51
(CH2-16), 53.29 (C-10), 54.47 (OMe), 54.73 (C-8), 55.28 (PhOMe),
64.76 (CH2O-17), 72.91 (OCH2Ph), 80.30 (C-4), 100.52 (C-1), 113.85
(2CH-21), 128.06 (C-6), 129.35 (2CH-20), 129.88 (C-19), 145.67 (CH-
tem)
1639 (C]O,
n 2996 (CH3 peroxide), 2977–2891 (CH aliphatic), 1713 (C]O),
5), 159.29 (C-22), 198.60 (C-7), 210.48 (C-9); IR (thin film)
n 2977–
a,b-unsaturated), 1597, 1515, 1460 (C]C, aromatic),
2866 (CH2 and CH3), 2836 (CH, OMe), 1725 (C]O), 1691 (C]O,
a,b-
1249, 1085 and 1048 (C–O ether) cmꢀ1; MS: (DCI/NH3) m/z:
433[MHþ]; HRMS (IS, MeOH): calculated for C24H33O7 433.2226,
found 433.2245.
unsaturated), 1636, 1613, 1514 (C]C aromatics), 1302–1173 (C–O),
1101 (C–O peroxide) cmꢀ1; MS (IS, MeOH) m/z: 455 [MNa]þ; HRMS
(IS, MeOH): calculated for C24H32O7Na 455.2046, found 455.2035.
Acknowledgements
5.11. Deprotection of PMB
`
We thank Ministere de l’Education Nationale for a grant to V.B.
Methylated endoperoxide (19 mg, 0.044 mmol) was dissolved in
dichloromethane (4.5 mL). Water (0.25 mL) was added and then
dichlorodicyanobenzoquinone (12 mg, 0.053 mmol) at room tem-
perature. After 5 h, saturated NaHCO3 solution was poured on crude
mixture, which was extracted by ethyl acetate. Organic phase was
washed with water and then brine. After drying on magnesium
sulfate, filtering and concentrating, hydroxyl-endoperoxide was
obtained as uncoloured oil in quantitative yield.
and Marjorie Maynadier for antimalarial tests.
References and notes
1. Renslo, A. R.; McKerrow, J. H. Nat. Chem. Biol. 2006, 2, 701–710.
2. O’Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945–2964 and references
cited herein.
3. Singh, C.; Malik, H.; Puri, S. K. J. Med. Chem. 2006, 49, 2794–2803.
4. Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C. K.;
Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padma-
nilayam, M.; SantoTomas, J.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.;
Wittlin, S.; Charman, W. N. Nature 2004, 430, 900–904.
5. Vennerstrom, J. L. J. Med. Chem. 2000, 43, 2753–2758.
6. Posner, G. H.; Dowd, H. O.; Ploypradith, P.; Cumming, J. N.; Xie, S.; Shapiro, T.
J. Med. Chem. 1998, 41, 2164–2167.
7. Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.; Ploypradith, P.; Xie, S.;
Shapiro, T.; Posner, G. J. Med. Chem. 2003, 46, 2516–2533.
8. O’Neill, P. M.; Stocks, P. A.; Pugh, M. D.; Araujo, N. C.; Korshin, E. E.; Bickley, J. F.;
Ward, S. A.; Bray, P. G.; Pasini, E.; Davies, J.; Verissimo, E.; Bachi, M. D. Angew.
Chem., Int. Ed. 2004, 43, 4193–4197.
5.11.1. (3R
*
,8aS )-8,8a-Dihydro-3-(2-hydroxyethyl)-8a-methoxy-
*
3,6,6,8,8-pentamethylbenzo[c][1,2]dioxine-5,7(3H,6H)-dione (20)
See Ref. 16.
5.11.2. (3R
*
,8aR )-8,8a-Dihydro-3-(2-hydroxyethyl)-8a-methoxy-
*
3,6,6,8,8-pentamethylbenzo[c][1,2]dioxine-5,7(3H,6H)-dione (21)
Rf (petroleum ether/EtOAc: 7:3)¼0.17; 1H NMR (500 MHz, C6D6)
d
0.79 (s, 3H, CH3-11 or 12), 1.15 (s, 3H, CH3-15), 1.38 (s, 3H, CH3-13
´
9. Najjar, F.; Baltas, M.; Gorrichon, L.; Moreno, Y.; Tzedakis, T.; Vial, H.; Andre-
Barre`s, C. Eur. J. Org. Chem. 2003, 17, 3335–3343.
10. Ghisaberti, E. Phytochemistry 1996, 41, 7–22.
or 14), 1.42 (s, 3H, CH3-13 or 14), 1.55 (s, 3H, CH3-11 or 12), 1.68 (m,
2H, CH2), 3.20 (m, 2H, CH2–OH), 3.24 (s, 3H, OCH3), 7.50 (s, 1H,
C]CH); 13C NMR (125.77 MHz, C6D6)
d
16.16 (CH3-11 or 12), 21.67
´
`
11. Najjar, F.; Andre-Barres, C.; Baltas, M.; Lacaze-Dufaure, C.; Magri, D. C.; Work-
(CH3-11 or 12), 22.49 (CH3-15), 26.04 (CH3-13 or 14), 26.22 (CH3-13
entin, M. S.; Tzedakis, T. Chem.dEur. J. 2007, 13, 1174–1179.

9224
V. Bernat et al. / Tetrahedron 64 (2008) 9216–9224
12. Najjar, F.; Fre´ville, F.; Desmoulin, F.; Gorrichon, L.; Baltas, M.; Gornitzka, H.;
0594(10) Å, b¼10.0918(11) Å, c¼11.9515(13) Å,
a
¼82.985(2)ꢁ,
b
¼86.242(2)ꢁ,
Tzedakis, T.; Andre-Barres, C. Tetrahedron Lett. 2004, 45, 6919–6922.
13. Najjar, F.; Gorrichon, L.; Baltas, M.; Vial, H.; Tzedakis, T.; Andre´-Barre`s, C. Bioorg.
Med. Chem. Lett. 2004, 14, 1433–1436.
g
¼85.038(2)ꢁ, V¼1078.8(2) Å3, Z¼2, crystal size 0.30ꢂ0.30ꢂ0.20 mm3, 8527
´
`
reflections collected (4294 independent, Rint¼0.0320), 374 parameters,
R1[I>2
s
(I)]¼0.0495, wR2 [all data]¼0.1376, largest diff. peak and hole: 0.297
14. Najjar, F.; Gorrichon, L.; Baltas, M.; Andre´-Barre`s, C.; Vial, H. Org. Biomol. Chem.
and ꢀ0.156 e Åꢀ3. Crystal data for 22: C24H32O6, M¼432.57, orthorhombic,
space group Fdd2, a¼16.6546(5) Å, b¼65.3587(17) Å, c¼8.1613(2) Å, V¼8883.
8(4) Å3, Z¼16, crystal size 0.40ꢂ0.20ꢂ0.10 mm3, 20,376 reflections collected
2005, 3, 1612–1614.
´
`
15. Andre-Barres, C.; Najjar, F.; Bottalla, A.-L.; Massou, S.; Zedde, C.; Baltas, M.;
Gorrichon, L. J. Org. Chem. 2005, 70, 6921–6924.
(3627 independent, Rint¼0.0666), 310 parameters, R1 [I>2 (I)]¼0.0436, wR2 [all
s
16. Givelet, C.; Bernat, V.; Danel, M.; Andre-Barres, C.; Vial, H. Eur.J. Org. Chem.
2007, 19, 3095–3101.
data]¼0.0917, largest diff. peak and hole: 0.175 and ꢀ0.156 e Åꢀ3. Data for all
´
`
structures were collected at 173(2) K using an oil-coated shock-cooled crystal
17. (a) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989–993; (b)
Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000, 342, 340–346 and
references cited herein.
18. Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139–
4142.
19. Rodeschini, V.; Boiteau, J.-G.; Van de Weghe, P.; Tarnus, C.; Eustache, J. J. Org.
Chem. 2004, 69, 357–373.
20. Toy, P. H.; Dhanabalasingam, B.; Newcomb, M.; Hanna, I. H.; Hollenberg, P. F. J.
on a Bruker-AXS APEX II diffractometer (
l
¼0.71073 Å). Semi-empirical ab-
sorption corrections were employed for 13, 14, 17 and 22.23 The structures were
solved by direct methods (SHELXS-97),24 and refined using the least-squares
method on F2.25 Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC-689774 (13), CCDC-689775 (14), CCDC-689776 (17) and
CCDC-689777 (22). These data can be obtained free of charge via www.ccdc.
cam.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: þ44 1223 336 033; or deposit@ccdc.cam.ac.uk).
23. SADABS, Program for Data Correction; Bruker-AXS.
Org. Chem. 1997, 62, 9114–9122.
21. Gavrilan, M.; Andre´-Barre`s, C.; Baltas, M.; Tzedakis, T.; Gorrichon, L. Tetrahedron
Lett. 2001, 42, 2465–2468.
24. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467–473.
22. Crystal data for 13: C23H30O6, M¼402.47, orthorhombic, space group P212121,
a¼9.4105(8) Å, b¼12.4752(10) Å, c¼18.3094(15) Å, V¼2149.5(3) Å3, Z¼4, crystal
size 0.30ꢂ0.20ꢂ0.15 mm3, 13,140 reflections collected (3052 independent,
25. Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refinement; University
of Go¨ttingen: Go¨ttingen, 1997.
´
`
26. Najjar, F.; Andre-Barres, C.; Lauricella, R.; Gorrichon, L.; Tuccio, B. Tetrahedron
Rint¼0.0586), 270 parameters, R1 [I>2 (I)]¼0.0347, wR2 [all data]¼0.0747,
s
Lett. 2005, 46, 2117–2119.
largest diff. peak and hole: 0.148 and ꢀ0.128 e Åꢀ3
.
27. Snider, B. B.; Shi, Z. J. Am. Chem. Soc. 1992, 114, 1790–1800.
28. Frimer, A. A.; Afri, M.; Baumel, S. D.; Gilinsky-Sharon, P.; Rosenthal, Z.; Gottlieb,
H. E. J. Org. Chem. 2000, 65, 1807–1817.
29. Schobert, R.; Stehle, R.; Milius, W. J. Org. Chem. 2003, 68, 9827–9830.
30. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885–888.
31. Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chulay, J. D. Antimicrob. Agents
Chemother. 1979, 16, 710–718.
Crystal data for 14: C23H30O6, M¼402.47, monoclinic, space group C2/c, a¼27.
226(2) Å, b¼17.7789(14) Å, c¼9.4816(8) Å,
b
¼107.9940(10)ꢁ, V¼4365.1(6) Å3,
Z¼8, crystal size 0.20ꢂ0.15ꢂ0.10 mm3, 13,086 reflections collected (3092 in-
dependent, Rint¼0.0602), 270 parameters, R1 [I>2 (I)]¼0.0477, wR2 [all da-
s
ta]¼0.1142, largest diff. peak and hole: 0.250 and ꢀ0.164 e Åꢀ3
.
Crystal data for 17:
C23H30O7, M¼418.47, triclinic, space group P1, a¼9.