Design, synthesis and evaluation of new tricyclic endoperoxides as potential antiplasmodial agents

Article abstract of DOI:10.1039/c4ob00787e

Diastereoselective autoxidation allowed preparation of new tricyclic endoperoxides. These compounds and their methylated analogs were evaluated against the in vitro growth of Plasmodium falciparum, the malaria-causing parasite, showing moderate activities. However, hybrid molecules composed of the tricyclic peroxide moiety and 7-chloro-4-aminoquinoline were synthesized and displayed a marked increase in antiplasmodial activity.

Full text of DOI:10.1039/c4ob00787e

Organic &
Biomolecular Chemistry
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PAPER
Design, synthesis and evaluation of new tricyclic
endoperoxides as potential antiplasmodial agents†
Cite this: Org. Biomol. Chem., 2014,
12, 5212
Jérémy Ruiz,a Sonia Mallet-Ladeira,b Marjorie Maynadier,c Henri Vialc and
Christiane André-Barrès*a
Diastereoselective autoxidation allowed preparation of new tricyclic endoperoxides. These compounds
and their methylated analogs were evaluated against the in vitro growth of Plasmodium falciparum, the
malaria-causing parasite, showing moderate activities. However, hybrid molecules composed of the
tricyclic peroxide moiety and 7-chloro-4-aminoquinoline were synthesized and displayed a marked
increase in antiplasmodial activity.
Received 15th April 2014,
Accepted 21st May 2014
DOI: 10.1039/c4ob00787e
www.rsc.org/obc
of a tertiary C-centered radical which cyclizes in a 5-exo-trig
manner in all cases. Only in the case of the G3Me, competition
Introduction
The emergence of artemisinin-resistant Plasmodium falciparum between 5-exo-trig cyclisation and disproportionation of
in Southeast Asia has exacerbated the need and stimulated the the radical does occur, favoring disproportionation, which
search for new synthetic molecules that possess antimalarial becomes the prevalent mechanism (disproportionation–cycli-
activity. Consequently, we continue our efforts to design and zation: 70/30). So, this tertiary C-centered radical can indeed
synthesize new G-factor analog endoperoxides. The new com- interact with vital biomolecules of the parasite, for instance
pounds will act as artemisinin or artemisinin-like compounds. alkylating the heme, explaining the effect observed on anti-
They will have to form, after Fe(II) induced reduction, C-cen- malarial activity. In contrast, in the case of G3 or G3F, the radical
tered radicals potentially able to alkylate heme or to react is more reactive and leads to self-quenching via cyclization in a
with vital biomolecules.1 The formation of primary and/or 5-exo-trig manner, finally giving rise to Fe(II) and a neutral
secondary C-centered radicals has been described after Fe(II) molecule.
induced reduction of artemisinin or its derivatives,2 trioxanes,3
trioxolanes,4 tetraoxanes5 or arteflene6 (Scheme 1).
So, in order to obtain secondary radicals as described for
known antimalarial peroxides acting like artemisinin, we
Previous studies have shown that endoperoxides belonging designed tricyclic endoperoxide analogs of known G-factor
to the G-factor family, natural compounds extracted from derivatives. Fe(II)-induced reduction could indeed afford sec-
leaves of Eucalyptus grandis,7 possess interesting antimalarial ondary C-centered radicals. In this case, the 5-exo-trig cyclisa-
properties after methylation of the hydroxyl group of the peroxy- tion could be preferentially replaced by an intermolecular
hemiketal moiety. The concentration of the methylated endo- addition on heme or parasite vital biomolecules (Scheme 2).
peroxide to inhibit by 50% the growth of chloroquine sensitive
and resistant P. falciparum strains (IC50) was in the range of
Results and discussion
200–300 nM, i.e. 100-fold better than the hydroxylated one, the
fluorinated one being inactive.8,9 A study of the Fe(II)-induced
The aim of this work was to synthesize and evaluate antimalar-
reduction of these three compounds10 has shown the presence
ial properties of these new tricyclic endoperoxides. Synthesis
is based on an autoxidation step on dienol intermediates as
previously described for the G-factors and analogs.11 These
aLaboratoire de Synthèse et de Physicochimie de Molécules d’Intérêt Biologique, UMR
precursors were obtained following a modified Knoevenagel-
CNRS 5068, Université Paul-Sabatier, 118 route de Narbonne, F-31062 Toulouse
type procedure in two steps from bicyclic dienone.
cedex 4, France. E-mail: candre@chimie.ups-tlse.fr
bInstitut de Chimie de Toulouse, FR2599, Université Paul-Sabatier, 118 route de
Narbonne, F-31062 Toulouse cedex 9, France
Furthermore,
a patent from Syngenta described the
synthesis of bicyclic diones used as precursors in herbicide
synthesis.12
cDynamique des Interactions Membranaires Normales et Pathologiques, UMR CNRS
5235, Université Montpellier 2, Place E. Bataillon, F-34095 Montpellier cedex 5,
France
I. Synthesis of bicyclo[3.2.1]oct-6-ene-2,4-diones 6 and 7
†Electronic supplementary information (ESI) available. CCDC 997078 and
997079. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4ob00787e
Synthesis of bicyclo[3.2.1]oct-6-ene-2,4-dione 6 was optimized
following the patent description.12
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Scheme 1 Fe(II)-induced primary or secondary C-centered radical formation.
a water–dioxane mixture. The C–Cl bond of the product 5 was
reduced by Zn(0) in acetic acid–dioxane 4/6 to afford dione 6
in 30% yield in a three-step reaction (Scheme 3).
The patent also describes the bicyclo[3.2.1]octane-2,4-dione
7 in 59% yield by hydrogenation and reduction of the product
5 in the presence of acetic acid and a catalytic amount of Pd/C
(0.1 eq.) at 55 °C in dioxane under 1 bar H2.
Following these conditions, the product 8 was obtained in
58% yield after 6 hours of hydrogenation. If the reaction is left
longer (17 hours) the alcohol 9 was isolated in lower yield
(34%). Finally the dione 7 was obtained in good yield from the
unsaturated dione 6 after one hour of catalytic hydrogenation
at room temperature in the dioxane–ethyl acetate mixture.
II. Syntheses of tricyclic peroxides
Scheme 2 Hypothesis of Fe(II)-induced reduction.
Tricyclic peroxides were synthesized following a previously
described procedure11 with autoxidation as
a key step.
Mannich bases were prepared by reaction of the bicyclooctane-
diones 6 or 7 with the iminium obtained from isobutyr-
aldehyde and piperidine. After treatment with saturated NH4Cl
in HCl (1 M), precursors 10 and 13 were obtained in 89% and
98% yields respectively (Scheme 4).
The first step was a [4 + 2] cycloaddition reaction between
cyclopentadiene and perchloropropene 2 previously obtained
in situ after HCl elimination from pentachlorocyclopropane 1.
The Diels–Alder adduct 3 rearranged itself into tetrachlori-
nated product 4.13 The product 5 was then obtained after
chloride substitution by hydroxide, using sodium hydroxide in
Autoxidation reactions on precursors 10 and 13 were
then optimized by varying different conditions: solvent
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Scheme 3 Synthesis of diones 6 and 7: (a) KOH, dioxane, RT, 1 h then cyclopentadiene, 85 °C, 2 h, 81%; (b) NaOH–H2O, 90 °C, 18 h, 59%; (c) Zn,
3 eq., RT, dioxane–AcOH 6/4, 20 h, 62%; (d) Pd/C H2 dioxane–EtOAc, 1 h; (e) Pd/C, H2, 55 °C dioxane–EtOAc.
Scheme 4 Synthesis of endoperoxides 11 and 14.
(ethyl acetate or benzene), O2 pressure (air, 1 and 5 bars), UV
irradiation (300 nm or 350 nm).
Concerning precursor 13, 1H NMR did not indicate the
presence of the dienol form 13b. As autoxidation proceeds in
The precursor 10 is in equilibrium between its dienone this form, oxygen uptake proved to be very slow in this case as
form 10a and dienol 10b as shown by the 1H NMR spectro- it took several days (50% after 30 days in ethyl acetate). O2
scopy analysis of the precursor 10.
pressure did not accelerate the overall kinetics.
Autoxidation under O2 (1 bar) in ethyl acetate was quite
As previously described, photoenolization was then
slow and led to the formation of endoperoxide 11 in 60% yield attempted using ethyl acetate or benzene as a solvent. At
along with epoxide 12 in 7% yield after 4 days. The reaction 350 nm, dienol 13b in mixture with the enone form 13a along
was accelerated in benzene as endoperoxide was observed with its deconjugated form was detected by 1H NMR. Then
alone in around 50% yield after one day under O2 pressure of autoxidation occurred quickly in competition with displace-
1 bar or after only 4 hours under O2 pressure of 5 bars.
ment of the equilibrium towards the enone form. So, several
Photoenolization of 10 using a Rayonet apparatus equipped cycles consisting of irradiation for 15 min followed by aut-
with 350 nm low pressure mercury lamps under O2 (1 bar) in oxidation under O2 (1 bar) for 45 min allowed endoperoxide
deuterated benzene allowed the formation of dienol 10b in a formation with roughly 45% yield after 8 cycles. Whatever the
1/1 mixture with enone 10a after 15 minutes of irradiation as solvent, yield and reaction time were similar. In this case, eno-
indicated by 1H NMR spectroscopy. After 3 hours, the peroxide lization seems to be the rate-limiting step of the global
11 was then obtained with 48% yield.
kinetics.
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the 6-membered cycle adopts a boat conformation. We have
previously shown that kinetics of autoxidation is considerably
lower in the case of 2-alkylidene cycloheptane dione. So
it seems that both 11cis and 14cis obtained are kinetic
products.19
Previous studies have shown the crucial role of the methyl-
ation of the peroxyhemiketal position,9,11 so methylation of
11 and 14 was planned (Scheme 5).
First attempts with K2CO3, Li2CO3 in DMF using MeI or
(MeO)2SO2 as a methylating agent at room temperature did
not work, and only the starting material was totally recovered.
When Cs2CO3 was used as a base, whatever the methylating
agent used (MeI or (MeO)2SO2), degradation occurred. Finally,
butyl lithium (1 eq.) at −78 °C, in THF, followed by addition of
TfOMe afforded endoperoxides 15 and 16 in about 50% yield,
and 50% of the starting material was recovered. Increasing
equivalents of BuLi (2 eq.) due to the presence of another
acidic proton in the α-position of the carbonyl did not increase
the yield of methylated endoperoxides and starting material
recovery decreased too.
Fig. 1 ORTEP molecular view of endoperoxides 11 and 14 in the solid
state (thermal ellipsoids at 50% probability; hydrogen atoms are omitted
for clarity).
III. Hybrid molecules
Both endoperoxides 11 and 14 were obtained as single dia-
stereoisomers. Both compounds could be crystallized and crys-
tals were analyzed by X-ray diffraction.14
Our recent work concerning the synthesis of hybrid molecules
containing an endoperoxide moiety belonging to the G-factor
family linked to a second pharmacophore, e.g. a streptocyanine
or a 7-chloro-4-aminoquinoline, has shown that this approach
can increase antiplasmodial activity.20 So we decided to
prepare hybrid molecules with a dual mode of action contain-
ing the tricyclic endoperoxide and a 7-chloro-4-aminoquino-
line mimicking chloroquine. We designed and synthesized a
functionalized aldehyde which could easily lead to the enone
precursor of autoxidation. A piperidine linker was chosen to
avoid the formation of diastereoisomers after autoxidation.
Starting from 4,7-dichloroquinoline, alcohol 17 was first
obtained after substitution of the chloride by 4-piperidinyl-
methanol. Oxidation of 17 by 2-iodoxybenzoic acid (IBX) in
refluxing acetone led to aldehyde 18 quantitatively (Scheme 6).
Then this aldehyde 18 was added to diones 6 and 7 follow-
ing the previous Knoevenagel modified procedure: formation
of the iminium by condensation of one equivalent of piper-
idine on the aldehyde, addition of this iminium to diones 6
and 7 furnishing the Mannich bases, and then aqueous acidic
treatment allowing the formation of precursors 19 and 20 in
99% and 67% yields respectively in the three-step reaction.
1H NMR spectra of these precursors indicated in both cases
that they were present only in the enone form. As previously
observed, autoxidation occurred very slowly on both structures
and endoperoxides 21 and 22 were obtained in respectively
19% and 34% yield, after 33 and 15 days in ethyl acetate under
O2 (1 bar). An increase of the O2 pressure to 10 bars did not
enhance the rate of oxygen uptake. So, photoenolization was
attempted at 350 nm, 300 nm and 254 nm but no dienol form
appeared as shown by 1H NMR spectroscopy. Incidentally we
realize that deposing the precursor 20 on silica gel allowed its
enolization. The dienol was then trapped by O2, helping to
shift the equilibrium in favor of the dienol, thus allowing for-
Endoperoxide 11 crystallizes in a triclinic structure (a =
6.47 Å b = 8.74 Å, c = 10.93 Å, α = 110.2°, β = 95.6°, γ =
101.3°).15 Using the numbering indicated in Fig. 1 and used in
X-ray diffraction analysis, its configuration is 1S,4R,5R or
1R,4S,5S.
Endoperoxide 14 crystallizes in a monoclinic structure (a =
6.50 Å, b = 20.28 Å, c = 8.37 Å, α = 90°, β = 99.7°, γ = 90°).16 Its
configuration is also 1S,4R,5R or 1R,4S,5S.
The hydroxyl and the methylene C8 groups are on the same
side for both endoperoxides, so the diastereoisomers are
called 11cis and 14cis respectively.
To compare the energy levels of the two diastereoisomers
11cis and 11trans, on the one hand, and 14cis and 14trans, on
the other hand, the four structures were fully optimized using
density functional theory (DFT) and the GAUSSIAN 09 software
package.17 We chose the B3LYP hybrid functional.18 The com-
putations were done with the B3LYP/6-311+G(d,p) scheme and
the stationary points were characterized as minima by a
vibrational analysis. Geometries and enthalpies of the four
compounds are presented in Fig. 2. The gaps between the two
enthalpy levels of 11cis and 11trans on the one hand and 14cis
and 14trans on the other hand are 0.8 kcal mol−1 and 0.3 kcal
mol−1 respectively. Those values are too low to explain the
selectivity observed. Probably a higher transition state must be
reached in both cases during the reaction path leading to
11trans (14trans) than 11cis (14cis).
Geometries of both diastereoisomers were compared with
the geometry of the endoperoxides 6-Endo and 7-Endo (Fig. 2)
obtained after autoxidation of 2-alkylidene cyclohexane dione
and 2-alkylidene cycloheptane dione. The geometry obtained
for 11cis (14cis) is similar to that of 6-Endo with a chair confor-
mation for the 6-membered cycle while for 11trans (14trans),
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Fig. 2 Optimized geometries and enthalpies of 6-Endo, 7-Endo, 11cis and 11trans, 14cis and 14trans at the B3LYP 6-311+G(d,p) level of theory.
mation of endoperoxide 22 with a great increase of the global
rate: 3 hours over 2 weeks. The same procedure was tried for
the precursor 19 without success, the starting material being
entirely recovered in the enone form. As previously, a single
diastereoisomer was obtained in both cases. NMR spectro-
scopy analysis allowed concluding that the hydroxyl and the
methylene are on the same side, as their 1H NMR spectra
present the same pattern as those for 11 and 14 (Scheme 7).
Methylation in this series was particularly risky and delicate
as several positions could be methylated. After several trials,
Scheme 5 Methylation of endoperoxides 11 and 14.
Scheme 6 Preparation of aldehyde 18.
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Scheme 7 Synthesis of hybrid endoperoxides +/− 21 and +/− 22.
than 16, with an IC50 below 1 µM, both on 3D7 and W2 para-
site strains.
Conclusion
Endoperoxides were prepared following an autoxidation step
in moderate to good yields. Oxygen uptake proved to be dia-
stereoselective leading to peroxides 11 and 14, with the same
configuration (+/−)-cis. Unfortunately, those compounds pre-
sented very low activity whether methylated or not. The same
methodology was followed for the preparation of hybrid mole-
cules 21 and 22 combining the 7-chloro-4-aminoquinoline
with the tricyclic endoperoxide moiety. The same diastereo-
selectivity during the autoxidation step was observed. After
methylation of the peroxyhemiketal function, the hybrid com-
pound 23 displayed a marked increase in its antiplasmodial
activity, with an IC50 between 100 and 250 nM against both the
chloroquine-susceptible and/or -resistant strains of Plasmo-
dium falciparum. It seems that the 7-chloro-4-aminoquinoline
moiety can interact with heme by π–π interaction, leading to
the localization of the compound near its target, the heme.
The heme provides iron(II) for reduction of the peroxide;
the production of C-centered radicals in the vicinity of heme
renders alkylation feasible.
Scheme 8 Methylation of endoperoxide 21: BuLi–THF, −78 °C, then
TfOMe, 16%.
and several conditions, only endoperoxide 21 was methylated
using BuLi–TfOMe (1 eq./1 eq.) at low temperature in THF,
affording 23 in a low yield after purification by silica gel
chromatography (16%) (Scheme 8).
IV. Antimalarial activity
Endoperoxides 11, 14, 21 and 22 and their methylated analogs
15, 16 and 23 were tested in vitro against the chloroquine-
sensitive 3D7 strain and the chloroquine-resistant W2 strain of
Plasmodium falciparum (Table 1). The activities were deter-
mined according to the method of Desjardins et al. using [3H]
hypoxanthine incorporation to assess parasite growth. Para-
sitic viability was expressed as IC50, the drug concentration
causing 50% parasite growth inhibition.21
In contrast to previous results,9,11 methylation of 11 and 14
allowed only a slight increase in activity (respectively 4-fold
and 2-fold for the methylated endoperoxides 15 and 16).
However, as previously, methylation of 21 provided endoperox-
Experimental part
2,3,4,4-Tetrachlorobicyclo[3.2.1]octa-2,6-diene (4)
ide 23 which was 28–32 fold more potent. The introduction of KOH pellets (369 mg, 5.60 mmol, 4.00 eq.) were powdered
7-chloro-4-aminoquinoline improved the activity. Indeed the in 20 mL of dry toluene. Pentachlorocyclopropane 1 (0.7 mL,
hybrid endoperoxide 23 was 16-fold to 25-fold more potent 4.9 mmol, 1.0 eq.) was added at room temperature under an
Table 1 IC50 values of several endoperoxides, artemisinin (ART) and chloroquine on chloroquine-susceptible (3D7) and chloroquine-resistant (W2)
strains of Plasmodium falciparum
11
14
15
16
21
22
23
G3
G3Me
ART
Chloroquine
IC50 (µM) (3D7)
IC50 (µM) (W2)
31.5
—
10.55
8.45
7.75
6.35
3.85
4.55
6.75
6.05
2.45
1.40
0.24
0.185
62
38
0.40
0.23
0.019
0.019
0.019
0.42
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inert atmosphere. The suspension was stirred at room temp- (1H, d, CO–CH2–CO), 6.19–6.23 (2H, m, CHvCH); 13C NMR
erature for 1 h. Freshly distilled cyclopentadiene was added (75.47 MHz, CDCl3) δ 37.0 (CH2, CH–CH2–CH), 50.4 (CH2, CO–
dropwise. The reaction was heated at 85 °C for 2 h. The CH2–CO), 55.3 (CH, CH–CH2–CH), 134.9 (CH, CHvCH), 201.6
mixture was filtered through celite. The filtrate was concen- (C, CO–CH2–CO); IR (KBr blades) ν: 3512, 1708, 1638, 1587,
+
trated to give 965 mg of a yellowish crystal (81%). mp = 91 °C; 1244, 1223 cm−1; HR-MS (DCI/CH4): calculated for C8H9O2 ,
1
Rf = 0.65 (petroleum ether); H NMR (300 MHz, CDCl3) δ 2.23 137.0603, found 137.0607.
(1H, td, CH–CH2–CH), 2.49 (1H, d, CH–CH2–CH), 3.17–3.20
(1H, m, CClvCCl–CH), 3.76–3.79 (1H, m, CCl2–CH), 6.19 (1H,
Bicyclo[3.2.1]octane-2,4-dione (7a) and its enol isomer 7b
dd, CCl–CH–CHvCH), 6.67 (1H, dd, CHvCH–CH–CCl2); Bicyclo[3.2.1]oct-6-ene-2,4-dione (6) (331 mg, 1.94 mmol,
13C NMR (75.47 MHz, CDCl3) δ 42.2 (CH2, CH–CH2–CH), 49.1 1.0 eq.) was dissolved with 16 mL of 1,4-dioxane. The mixture
(CH, CCl–CH–CH2), 58.4 (CH, CCl2–CH–CH2) 88.9 (C, CCl2), was degassed with Ar for 20 min. Pd/C (10%, 104 mg,
127.7 (C, CCl2–CClvCCl), 132.7 (CH, CCl–CH–CHvCH), 140.6 0.10 mmol, 0.05 eq.) was added and then the mixture was
(C, CH–CClvCCl), 141.8 (CH, CCl2–CH–CHvCH).
bubbled with H2 for 5 min. The reaction was stirred under H2
at atmospheric pressure at room temperature (23 °C) for 1 h.
The reaction was filtered through a pad of celite. The residue
was washed with EtOAc. The filtrate was concentrated to give a
3-Chlorobicyclo[3.2.1]oct-6-ene-2,4-dione (5a) and its enol
isomer 5b
2,3,4,4-Tetrachlorobicyclo[3.2.1]octa-2,6-diene (4) (72 mg, white solid of the expected product (99%).
0.3 mmol, 1.0 eq.) was dissolved in 2 mL of dioxane. Then
mp = 122–123 °C; Rf = 0.1 (petroleum ether–EtOAc; 50/50);
1.5 mL of NaOH solution (2 M) (3.0 mmol, 30 eq.) was added. 1H NMR (300 MHz, CDCl3) (7a major product) δ 1.87–1.98
The reaction was stirred at 90 °C for 18 h. The reaction was (4H, m, CH–CH2–CH2–CH), 2.11–2.16 (2H, m, CH–CH2–CH),
extracted with 10 mL of EtOAc. The aqueous layer was adjusted 3.01–3.05 (2H, m, CH–CH2–CH), 3.15 (1H, dd, CO–CH2–CO),
to pH 1 with HCl (6 M) aqueous solution and extracted with 3.31 (1H, d, CO–CH2–CO); 1H NMR (300 MHz, CD3OD) (7b
3 × 10 mL of EtOAc. Combined organic layers were washed major product) δ 1.58–170 (3H, m, CH–CH2–CH, CH–CH2–
with 15 mL of brine, dried over MgSO4 and concentrated to CH2–CH), 2.00 (1H, d, J = 11.5 Hz, CH–CH2–CH), 2.06–2.18
give 30 mg of a crude brownish solid (59% yield).
(2H, m, CH–CH2–CH2–CH), 2.79–2.83 (2H, m, CH–CH2–CH),
mp = 137 °C; Rf = 0.1 (petroleum ether–AcOEt; 50/50); 4.90 (1H, s, CO–CHvCOH); 13C NMR (75.47 MHz, CDCl3)
1H NMR (300 MHz, CDCl3) (5a and 5b mixture) δ 2.33–2.50 (7a and 7b mixture) δ 26.1 (CH2, A, CH–CH2–CH2–CH), 27.9
(2H, m, CH–CH2–CH), 2.59–2.76 (2H, m, CH–CH2–CH), 3.53 (CH2, B, CH–CH2–CH2–CH), 31.3 (CH2, A, CH–CH2–CH), 38.7
(2H, t, CO–CH), 3.71–3.73 (1H, m, CO–CH), 3.82 (1H, dd, CO– (CH2, B, CH–CH2–CH), 45.6 (CH, B, CH–CH2–CH), 49.6 (CH, A,
CH), 5.22 (1H, d, COH–CH–CHvCH), 5.55 (1H, d, COH–CH– CH–CH2–CH), 51.4 (CH2, A, CO–CH2–CO), 99.7 (CH, B, CO–
CHvCH), 6.19 (1H, d, CO–CH–CHvCH), 6.41–6.42 (1H, m, CHvCOH), 197.8 (C, B, CO–CHvCO), 207.2 (C, A, CO–CH2–
CO–CH–CHvCH), 6.52 (1H, s, CHCl); 1H NMR (300 MHz, CO); 13C NMR (75.47 MHz, CD3OD) (7b major product) δ 28.8
MeOD) (5b major product) δ 2.38–2.44 (1H, m, AA′MX system, (CH2, CH–CH2–CH2–CH), 39.5 (CH2, CH–CH2–CH), 46.9 (CH,
CH–CH2–CH), 2.55–2.57 (1H, m, AA′MX system, CH–CH2–CH), CH–CH2–CH), 100.1 (CH, CO–CHvCOH), 198.3 (C, CO–
3.43–3.45 (2H, m, AMXX′ systems, CH–CH2–CH), 6.54 (2H, s, CHvCOH); IR (KBr pellet) ν: 1637, br. 1568 cm−1; HR-MS
+
CH–CHvCH–CH); 13C NMR (75.47 MHz, MeOD) (5b major (DCI/CH4): calculated for C8H11O2 , 139.0759, found 139.0763.
product) δ 50.9 (CH2, CH–CH2–CH), 53.2 (CH, CH–CH2–CH),
101.0 (C, CCl), 138.5 (CH, CHvCH), 187.3 (C, CO–CClvCOH).
3-Chloro-4-hydroxybicyclo[3.2.1]oct-3-en-2-one (8)
3-Chlorobicyclo[3.2.1]oct-6-ene-2,4-dione (7) (50 mg, 0.3 mmol,
1.0 eq.) was dissolved in 3.5 mL of dioxane. 2.5 mL of water
Bicyclo[3.2.1]oct-6-ene-2,4-dione (6)
3-Chlorobicyclo[3.2.1]oct-6-ene-2,4-dione
(5)
(1.47
g, and acetic acid were added. The mixture was degassed with Ar
8.60 mmol, 1.0 eq.) was dissolved in 35 mL of dioxane. 23 mL for 10 min. Pd/C 10% (3.2 mg, 0.03 mmol, 0.1 eq.) was added.
of acetic acid was added, followed by zinc powder (1.64 g, The mixture was degassed with H2. The reaction was heated to
25.9 mmol, 3.0 eq.). The reaction was stirred at room tempera- 55 °C under H2 at atmospheric pressure for 6 h. The reaction
ture (20 °C) for 21 h. The reaction was filtered through a pad was filtered through a pad of celite. The residue was washed
of celite. The residue was washed with water and EtOAc. Layers with EtOAc and water. The aqueous layer was separated, acidi-
were acidified with HCl (6 M) to pH 2 and separated. The fied to pH 1 with HCl (6 M) and extracted with 3 × 15 mL of
aqueous layer was extracted with 3 × 60 mL of EtOAc. Com- EtOAc. The combined organic layers were washed with 15 mL
bined organic layers were washed with 2 × 20 mL of brine, of brine, dried over MgSO4 and concentrated. The crude was
dried over MgSO4 and concentrated to give a brown oil. The purified by flash chromatography on silica gel (DCM, 0% to
crude was dry loaded to be purified by flash chromatography 3% of MeOH) to give 29 mg (58% yield). Rf = 0.1 (DCM–MeOH;
over silica gel (petroleum ether–AcOEt; 80/20 then 50/50) to 90/10); 1H NMR (300 MHz, CDCl3) δ 1.60 (1H, td, CH–CH2–
give 729 mg of a yellow oil (62% yield). Rf = 0.3–0.4 (petroleum CH), 1.73–1.80 (2H, m, CH–CH2–CH2–CH), 2.08–2.12 (3H, m,
ether–AcOEt; 80/20); 1H NMR (300 MHz, CDCl3) δ 2.44–2.48 CH–CH2–CH2–CH, CH–CH2–CH), 3.11–3.15 (2H, m, CH–CH2–
(1H, m, CH–CH2–CH), 2.52–2.60 (1H, m, CH–CH2–CH), 3.20 CH); 13C NMR (75.47 MHz, CDCl3) δ 27.5 (CH2, CH–CH2–CH2–
(1H, d, CO–CH2–CO), 3.48–3.50 (2H, m, CH–CH2–CH), 3.51 CH), 38.0 (CH2, CH–CH2–CH), 45.8 (CH, CH–CH2–CH), 106.1
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(C, CCl), 186.5 (C, CO–CClvCOH); IR (KBr pellet) ν: 1638, CH2–CH2), 2.45 (1H, d, J = 12.6 Hz, CH–CH2–CH), 2.43–2.58
1567 cm−1; HR-MS (DCI/CH4): calculated for C8H11O2Cl+, (1H, m, COH–CH), 2.82–2.86 (1H, m, CO–CH), 6.46 (1H, s,
173.0369, found 173.0368.
CvCH–C): 13C NMR (75.47 MHz, CDCl3) δ 23.1 (CH2, CH2–
CH2), 23.5 (CH3, C–CH3), 24.5 (CH3, C–CH3), 28.6 (CH2, CH2–
CH2), 31.8 (CH2, C–CH2–C), 42.0 (CH, COH–CH), 50.2 (CH,
4-Hydroxybicyclo[3.2.1]octan-2-one (9)
Rf = 0.5 (DCM–MeOH; 90/10); 1H NMR (300 MHz, CDCl3) CO–CH), 78.9 (C, (CH3)2C–O), 100.2 (C, CH–COH), 135.3
δ 1.60 (1H, d, CHOH–CH–CH2–CH2), 1.64–1.73 (1H, m, CO– (C, CvCH–C), 140.1 (CH, CvCH–C), 201.9 (C, CH–CO–C); IR
CH–CH2–CH2), 1.76 (1H, t, CH–CH2–CH), 1.78–1.98 (2H, m, (KBr pellet) ν: 3337 (br.), 1690, 1642, 1277, 1128, 1088,
CH–CH2–CH2–CH), 2.04–2.13 (1H, m, CH–CH2–CH), 2.25 (1H, 1036 cm−1; MS (DCI/NH3 ): 207 (100, [MH − H2O]+), 224 (41,
+
dd, CO–CH2–CHOH), 2.41–2.46 (1H, m, CHOH–CH), 2.58 (1H, [M]+), 242 (34, [MNH4]+); HR-MS (DCI/CH4): calculated for
+
dd, CO–CH2–CHOH), 2.66 (1H, t, CO–CH), 2.81 (1H, br. s, C12H17O4 , 225.1127, found 225.1122.
CHOH), 4.04 (1H, ddd, CHOH); 13C NMR (75.47 MHz, CDCl3) δ
(+/−)-3a-Hydroxy-2,2-dimethylhexahydro-4,7-methanocyclo-
21.8 (CH2, CH–CH2–CH), 27.9 (CH2, CO–CH–CH2–CH2), 32.9 hepta[b]oxireno[2,3-c]furan-8(3aH)-one (12). White solid, mp =
(CH2, CHOH–CH–CH2–CH2), 41.7 (CH, CHOH–CH), 44.4 (CH2, decomposition; Rf = 0.2 (petroleum ether–EtOAc, 80/20);
CHOH–CH2–CO), 49.3 (CH, CO–CH), 71.8 (CH, CHOH), 211.9 1H NMR (300 MHz, CDCl3) δ 1.38 (3H, s, C–CH3), 1.42 (3H, s,
(C, CO); IR (KBr blades) ν: 3424 (br.), 1712, 1065 cm−1; HR-MS C–CH3), 1.66–1.78 (1H, m, CO–CH–CH2–CH2), 1.82–1.88 (1H,
+
(DCI/CH4): calculated for C8H12O2 , 140.0837, found 140.0834.
m, COH–CH–CH2–CH2), 1.93 (1H, td, CH–CH2–CH), 2.05–2.21
(2H, m, CH–CH2–CH2–CH), 2.38 (1H, d, CH–CH2–CH), 2.62
(1H, dd, COH–CH–CH2), 3.00 (1H, dd, CO–CH–CH2), 3.79 (1H,
General procedure for cyclic peroxide preparation
The aldehyde (1.20 eq.) (isobutyraldehyde or aldehyde 18) was s, CH–O–C); 13C NMR (125.77 MHz, CDCl3) δ 24.4 (CH2, CH–
diluted in anhydrous DCM (0.12 M). Piperidine (1.20 eq.) was CH2–CH2–CH), 25.0 (CH3, C–CH3), 25.5 (CH3, C–CH3), 26.7
added dropwise and the mixture was stirred at room tempera- (CH2, CH–CH2–CH2–CH), 34.2 (CH2, CH–CH2–CH), 44.8 (CH,
ture for 10 min. A solution of diketone (1 eq.) (6 or 7) and CH–COH), 49.9 (CH, CH–CO), 70.3 (C, CO–C–COH), 74.9 (CH,
piperidine (1.10 eq.) in anhydrous DCM (0.1 M) was added C(CH3)2–CH–O–C), 81.2 (C, O–C(CH3)2–CHO), 106.9 (C, COH),
dropwise to the iminium solution. The reaction was stirred at 203.3 (C, CO); IR (KBr pellet) ν: 3433, 1722, 1295, 1126, 1116,
room temperature for 30 min and then was concentrated. The 1089, 1062, 1023 cm−1
; LR-MS (DCI/NH3): 207.0 (100,
excess of piperidine was removed under vacuum to give the [M − OH]+), 224.0 (30, [M]+), 242.0 (2%, [MNH4]+); HR-MS
+
Mannich base as a solid. The Mannich base was dissolved (DCI/CH4): calculated for C12H17O4
,
225.1127, found
with DCM (0.1 M). The solution was stirred for 10 minutes 225.1132.
with a saturated solution of NH4Cl in 1 N HCl as a (1 : 1)
mixture with DCM. Then the mixture was immediately 5H-6,9-methanocyclohepta[c][1,2]dioxin-5-one
(+/−)-(6S,9R,9aS)-9a-Hydroxy-3,3-dimethyl-3,6,9,9a-tetrahydro-
(14). See:
extracted 3 times with EtOAc or DCM. The combined organic general procedure for cyclic peroxide preparation (36 days,
layers were washed with water, until pH 5–6 was reached, and 49% yield); white crystal; mpvdecomposition; Rf = 0.2 (pet-
1
brined, dried over MgSO4 and concentrated to give the autoxi- roleum ether–EtOAc, 80/20); H NMR (300 MHz, CDCl3) δ 1.29
dation precursor (10, 13, 19, 20). The precursor was solubilized (3H, s, C–CH3), 1.35 (3H, s, C–CH3), 2.40 (1H, dt, J = 12 Hz, J =
in benzene (0.1 M) and the reaction was stirred at room temp- 5 Hz, CH–CH2–CH), 2.66 (1H, d, J = 12 Hz, CH–CH2–CH), 3.01
erature under O2 (1 bar). The reaction was followed by 1H NMR (1H, dd, J = 5 Hz, J = 3 Hz, COH–CH), 3.21 (1H, dd, J = 5 Hz, J =
spectroscopy analysis until consumption of the enol and 3 Hz, CO–CH), 6.10 (1H, dd, J = 5.7 Hz, J = 3 Hz, CH–CHvCH–
enone forms of the precursor. The reaction was concentrated CH) 6.16 (1H, dd, J = 5.7 Hz, J = 3 Hz, CH–CHvCH–CH), 6.43
and purified by flash chromatography over silica gel.
(1H, s, CvCH–C); 13C NMR (75.47 MHz, CDCl3) δ 23.6 (CH3,
Use of the Rayonet for photoenolization: the apparatus was C–CH3), 24.2 (CH3, C–CH3), 37.7 (CH2, CH–CH2–CH), 46.6
equipped with 350 nm low pressure mercury lamps. Precursors (CH, COH–CH), 55.0 (CH, CO–CH), 79.5 (C, (CH3)2C–O), 98.9
(10, 13, 19, 20) were solubilized in ethyl acetate or benzene (C, CH–COH), 135.5 (CH, CH–CHvCH–CH), 136.2 (CH, CH–
(0.1 M). The solution was irradiated for 15 minutes and then CHvCH–CH), 136.3 (C, CvCH–C), 140.5 (CH, CvCH–C),
analyzed by 1H NMR. The peroxide 11 was obtained after 197.1 (C, CH–CO–C); IR (KBr pellet) ν: 3363 (br.), 1694, 1639,
15 minutes of irradiation and then 3 h under an O2 atmos- 1263, 1110, 1085, 1052 cm−1; HR-MS (DCI/CH4): calculated for
+
phere. The peroxide 13 was obtained after 8 cycles of C12H15O4 , 223.0970, found 223.0979.
irradiation (15 minutes) followed by 45 minutes under an O2
atmosphere.
General procedure for methylation
(+/−)-(6R,9S,9aS)-9a-Hydroxy-3,3-dimethyl-3,6,7,8,9,9a-hexa- To a solution of the peroxy-alcohol (1.0 eq.) in anhydrous THF
hydro-5H-6,9-methanocyclohepta[c][1,2]dioxin-5-one (11). See: (0.025 M) at −78 °C, BuLi (1.6 M, 1.0 eq.) was added dropwise
general procedure for cyclic peroxide preparation (1 day, 48% under Ar. After 10 min, methyl-triflate (1.2 eq.) was added
yield); white crystal; mp = decomposition; Rf = 0.45 (petroleum dropwise. The reaction was quenched with an aqueous satu-
1
ether–EtOAc, 80/20); H NMR (300 MHz, CDCl3) δ 1.37 (3H, s, rated solution of NH4Cl. The reaction was diluted with water
C–CH3), 1.45 (3H, s, C–CH3), 1.55–1.64 (1H, m, CH2–CH2), and phases were separated. The aqueous layer was extracted
1.70–1.80 (3H, m, CH2–CH2, CH–CH2–CH), 1.83–1.95 (1H, m, with EtOAc. The combined organic layers were washed with
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brine, dried over MgSO4 and concentrated. The crude was puri-
fied by flash chromatography over silica gel.
(+/−)-1-(7-Chloroquinolin-4-yl)-9a′-hydroxy-9′,9a′-dihydrospiro-
[piperidine-4,3′-[6,9]methanocyclohepta[c][1,2]dioxin]-5′(6′H)-
(+/−)-(6R,9S,9aS)-9a-Methoxy-3,3-dimethyl-3,6,7,8,9,9a-hexa- one (21). See: general procedure for cyclic peroxide prepa-
hydro-5H-6,9-methanocyclohepta[c][1,2]dioxin-5-one
(15). ration (DCM, 33 days, 19% yield); colorless oil; Rf = 0.11
(−70 °C, 4 h, 48% yield); colorless oil; Rf = 0.45 (petroleum (DCM–EtOAc, 80/20); 1H NMR (300 MHz, CDCl3) δ 1.84–2.00
1
ether–EtOAc, 85/15); H NMR (300 MHz, CDCl3) δ 1.29 (3H, s, (2H, m, C–CH2–CH2–N), 2.11–2.21 (2H, m, C–CH2–CH2–N),
C–CH3), 1.43 (3H, s, C–CH3), 1.58–1.73 (3H, m, CH2–CH2, CH– 2.42–2.49 (1H, m, CH–CH2–CH), 2.71 (1H, d, CH–CH2–CH),
CH2–CH), 1.78–1.95 (2H, m, CH2–CH2), 2.29 (1H, d, CH–CH2– 3.04–3.07 (1H, m, CH–CH2–CH), 3.13 (1H, dt, C–CH2–CH2–N),
CH), 2.70 (1H, t, COH–CH), 2.85 (1H, t, CO–CH), 3.38 (3H, s, 3.23–3.28 (2H, m, CH–CH2–CH, C–CH2–CH2–N), 3.30–3.38 (2H,
OCH3), 6.51 (1H, s, CvCH–C); 13C NMR (75.47 MHz, CDCl3) m, C–CH2–CH2–N), 6.12–6.19 (2H, m, CHvCH), 6.48 (1H, s,
δ 23.4 (CH3, C–CH3), 23.5 (CH2, C–CH2–C), 24.8 (CH3, C–CH3), CvCH–CO), 6.85 (1H, d, N–CHvCH–C), 7.42 (1H, dd,
29.1 (CH2, CH2–CH2), 31.4 (CH2, CH2–CH2), 38.7 (CH, COCH3– C–CHvCH–CCl), 7.86 (1H, d, C–CHvCH–CCl), 8.06 (1H, d,
CH), 50.3 (CH, CO–CH), 50.4 (CH3, OCH3), 78.2 (C, (CH3)2C– C–CHvCCl), 8.71 (1H, d, N–CHvCH–C); 13C NMR
O), 102.9 (C, CH–COH), 133.5 (C, CvCH–C), 140.6 (CH, (75.47 MHz, CDCl3) δ 31.4 (CH2, C(CH2)2), 33.1 (CH2, C(CH2)2),
CvCH–C), 201.6 (C, CH–CO–C); IR (KBr blades) ν: 1701, 1649, 37.8 (CH2, CH–CH2–CH), 46.8 (CH, CH–CH2–CH), 47.5 (CH2,
1270, 1126, 1091, 1074, 1003 cm−1; HR-MS (DCI/CH4): calcu- N(CH2)2), 48.0 (CH2, N(CH2)2), 55.1 (CH, CH–CH2–CH), 78.4
+
lated for C13H19O4 , 239.1283, found 239.1287.
(C, CH–C–(CH2)2), 99.4 (C, COH), 109.3 (CH, CvCH–CHvN),
(+/−)-(6S,9R,9aS)-9a-Methoxy-3,3-dimethyl-3,6,9,9a-tetrahydro- 122.0 (C, CHvC–C–CH), 125.0 (CH, C–CHvCH–CCl), 126.5
5H-6,9-methanocyclohepta[c][1,2]dioxin-5-one (16). (−70 °C, (CH, C–CHvCH–CCl), 128.9 (CH, C–CHvCCl), 135.2 (C, CCl),
2.5 h, 50% yield); colorless oil; Rf = 0.4 (petroleum ether– 135.5 (CH, CHvCH), 136.2 (CH, CHvCH), 138.0 (C, COH–
EtOAc, 90/10); 1H NMR (300 MHz, CDCl3) δ 1.26 (3H, s, CvCH), 138.4 (CH, COH–CvCH), 150.0 (C, N–C–CH), 151.9
C–CH3), 1.32 (3H, s, C–CH3), 2.30–2.37 (1H, m, AA′MX system, (CH, CvCH–CHvN), 157.3 (C, CHvC–C–CH), 196.6 (C, CO);
CH–CH2–CH), 2.49 (1H, d, CH–CH2–CH), 3.15–3.20 (2H, m, 2 × IR (ATR) ν: 3060, 1700, 1572 cm−1
; MS (CI/NH3): 424
CH–CH2–CH), 3.42 (3H, s, O–CH3), 6.07–6.12 (2H, m, ABX (5, [MH]+), 382 (5), 260 (100), 217 (21), 190 (23), 155 (30%);
systems, CH–CHvCH–CH), 6.43 (1H, s, CvCH–C); 13C NMR HR-MS (DCI/CH4): calculated for C23H22N2O4Cl+, 425.1268,
(75.47 MHz, CDCl3) δ 23.4 (CH3, C–CH3), 24.6 (CH3, C–CH3), found 425.1253.
37.1 (CH2, CH–CH2–CH), 43.4 (CH, COH–CH), 50.5 (CH3,
(+/−)-1-(7-Chloroquinolin-4-yl)-9a′-hydroxy-7′,8′,9′,9a′-tetra-
OCH3), 55.0 (CH, CO–CH), 78.9 (C, (CH3)2C–O), 101.5 (C, CH– hydrospiro[piperidine-4,3′-[6,9]methanocyclohepta[c][1,2]-
COH), 133.9 (C, CvCH–C), 135.8 (CH, CH–CHvCH–CH), dioxin]-5′(6′H)-one (22). See: general procedure for cyclic per-
136.2 (CH, CH–CHvCH–CH), 141.1 (CH, CvCH–C), 197.0 (C, oxide preparation (DCM, 15 days, 34% yield); white solid; mp =
CH–CO–C); IR (KBr blades) ν: 1704, 1648, 1258, 1106, 1085, 138 °C followed by decomposition at 140 °C; Rf = 0.28 (DCM–
+
1
1057 cm−1
; HRMS (DCI/CH4): calculated for C13H17O4 , MeOH, 97/3); H NMR (300 MHz, CDCl3) δ 1.62–1.71 (1H, m,
237.1127, found 237.1126.
CH–CH2–CH2–CH), 1.74–1.88 (3H, m, CH–CH2–CH, CH–CH2–
1-(7-Chloroquinolin-4-yl)piperidine-4-carbaldehyde
(18). CH2–CH), 1.89–2.29 (5H, m, C–CH2–CH2–N, CH–CH2–CH2–
Alcohol 17 (200 mg, 0.72 mmol, 1.0 eq.) and IBX (407 mg, CH), 2.54 (1H, d, CH–CH2–CH), 2.61–2.65 (1H, m, CH–CH2–
1.45 mmol, 2.0 eq.) in 5 mL of acetone were heated at 60 °C for CH), 2.90–2.94 (1H, m, CH–CH2–CH), 3.27–3.43 (3H, m,
5 h. Then the reaction was filtered. The white precipitate was C–CH2–CH2–N), 6.52 (1H, s, CvCH–CO), 6.85 (1H, d,
washed with DCM. The filtrate was concentrated to give N–CHvCH–C), 7.41 (1H, dd, C–CHvCH–CCl), 7.86 (1H, d,
237 mg (99% yield) of a yellow oil of aldehyde. Rf = 0.44 (DCM– C–CHvCH–CCl), 8.07 (1H, s, C–CHvCCl), 8.70 (1H, br. s,
EtOAc, 50/50); 1H NMR (300 MHz, CDCl3) δ 1.90–2.03 (2H, N–CHvCH–C); 13C NMR (75.47 MHz, CDCl3) δ 23.3 (CH2,
m, CH2–CH2–CH–CH2–CH2), 2.10–2.19 (2H, m, CH2–CH2–CH– CH2–CH2), 28.6 (CH2, CH–CH2), 31.7 (CH2, C(CH2)2), 32.0
CH2–CH2), 2.48–2.52 (1H, m, CH2–CH2–CH–CH2–CH2), (CH2, CH–CH2–CH), 33.0 (CH2, C(CH2)2), 42.3 (CH, CH–CH2–
2.91–2.99 (2H, m, CH2–CH2–CH–CH2–CH2), 3.50 (2H, td, CH2– CH), 47.6 (CH2, N(CH2)2), 48.0 (CH2, N(CH2)2), 50.3 (CH, CH–
CH2–CH–CH2–CH2), 6.81 (1H, d, NvCH–CH), 7.41 (1H, dd, CH2–CH), 77.7 (C, CH–C–(CH2)2), 100.8 (C, COH), 109.3 (CH,
CClvCH–CH), 7.87 (1H, CClvCH–CH), 8.02 (1H, d, CH–CCl), CvCH–CHvN), 122.0 (C, CHvC–C–CH), 125.0 (CH,
8.68 (1H, d, NvCH–CH), 9.76 (1H, d, CHO); 13C NMR C–CHvCH–CCl), 126.5 (CH, C–CHvCH–CCl), 128.7 (CH,
(75.47 MHz, CDCl3) δ 25.4 (CH2, CH2–CH2–CH–CH2–CH2), C–CHvCCl), 135.3 (C, CCl), 137.2 (C, COH–CvCH), 137.9
25.5 (CH2, CH2–CH2–CH–CH2–CH2), 47.6 (CH, CH2–CH2–CH– (CH, COH–CvCH), 149.8 (C, N–C–CH), 151.8 (CH, CvCH–
CH2–CH2), 51.7 (CH2, CH2–CH2–CH–CH2–CH2), 109.1 (CH, CHvN), 157.4 (C, CHvC–C–CH), 201.4 (C, CO); IR (ATR) ν: br.
NvCH–CHvC), 122.0 (C, C–CvCH), 125.0 (CH, CClvCH– 3360, 1697, 1574, 1200, 1102, 1088 cm−1; MS (CI/NH3): 427 (5,
CH), 126.3 (CH, CClvCH–CH), 128.7 (CH, CCl–CHvC), 134.9 [MH]+), 429 (1, [MH + 2]+), 261 (100, C14H14ClN2O+), 263 (32%,
(C, CCl), 150.0 (C, CCl–CHvC), 151.8 (CH, NvCH–CH–C), [C14H14ClN2O
+
2]+); HR-MS (DCI/CH4): calculated for
157.3 (C, NvCH–CH–C), 202.9 (CH, CHO); IR (ATR) ν: 3062, C23H24N2O4Cl+, 427.1425, found 427.1416.
2945, 2920, 2816, 1724, 1607, 1574, 1425 and 869 cm−1; LR-MS
(+/−)-1-(7-Chloroquinolin-4-yl)-9a′-methoxy-9′,9a′-dihydro-
(DCI/NH3): 275 (100, [MH]+), 277 (34%, [MH + 2]+); HR-MS spiro[piperidine-4,3′-[6,9]methanocyclohepta[c][1,2]dioxin]-5′-
(ESI): calculated for C15H16N2OCl+, 275.0951, found 275.0953.
(6′H)-one (23). See: general procedure for methylation (−70 °C
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1
to −65 °C, 2.5 h, 16%); H NMR (300 MHz, CDCl3) δ 1.92–1.99 10 C. André-Barrès, F. Najjar, A.-L. Bottalla, S. Massou,
(2H, m, C–(CH2–CH2)2–N), 2.07–2.21 (2H, m, C–CH2–CH2–N),
C. Zedde, M. Baltas and L. Gorrichon, J. Org. Chem., 2005,
2.35–2.43 (1H, m, CH–CH2–CH), 2.54 (1H, d, CH–CH2–CH),
70, 6921–6924.
3.10–3.18 (1H, m, C–(CH2–CH2)2–N), 3.19–3.28 (3H, m, CH– 11 F. Najjar, M. Baltas, L. Gorrichon, Y. Moreno, T. Tzedakis,
CH2–CH, C–(CH2–CH2)2–N), 3.31–3.38 (2H, m, C–(CH2–CH2)2–
N), 3.48 (3H, s, OCH3), 6.11–6.13 (2H, m, CHvCH), 6.48 (1H,
H. Vial and C. André-Barrès, Eur. J. Org. Chem., 2003, 3335–
3343.
s, CvCH–CO), 6.86 (1H, d, N–CHvCH–C), 7.43 (1H, dd, J = 2.1 12 R. Beaudegnies, C. Lüthy, A. Edmunds, J. Schaetzer and
Hz, C–CHvCH–CCl), 7.88 (1H, d, C–CHvCH–CCl), 8.05 (1H,
d, C–CHvCCl), 8.71 (1H, d, N–CHvCH–C); 13C NMR
S. Wenderborn, World Intellectual Property Organisation,
WO 2005/123667 A1, 2005.
(75.47 MHz, CDCl3) δ 31.7 (CH2, C(CH2)2), 32.9 (CH2, C(CH2)2), 13 D. C. Law and S. W. Tobey, J. Am. Chem. Soc., 1968, 90,
37.2 (CH2, CH–CH2–CH), 43.3 (CH, CH–CH2–CH), 47.7 (CH2, 2376–2386.
N(CH2)2), 48.1 (CH2, N(CH2)2), 50.5 (CH3, OCH3), 55.1 (CH, 14 G. M. Sheldrick, Acta Crystallogr., Sect. A: Fundam. Crystal-
CH–CH2–CH), 77.7 (C, CH–C–(CH2)2), 102.0 (C, COMe), 109.3 logr., 2008, 64, 112–122.
(CH, CvCH–CHvN), 122.0 (C, CHvC–C–CH), 125.0 (CH, C– 15 Crystal data for 11: C12H16O4, M = 224.25, triclinic, a =
CHvCH–CCl), 126.5 (CH, C–CHvCH–CCl), 128.9 (CH, C–
CHvCCl), 135.2 (C, CCl), 135.8 (C, COH–CvCH), 136.1 (CH,
CHvCH), 136.2 (CH, CHvCH), 139.0 (CH, COH–CvCH),
150.0 (C, N–C–CH), 151.9 (CH, CvCH–CHvN), 157.4 (C,
CHvC–C–CH), 196.7 (C, CO); IR (ATR) ν: 3064, 1703,
1574 cm−1; LR-MS (CI/NH3): 438 (42, [MH]+), 372 (46), 260
(100), 217 (52), 191 (66), 155 (66%); HR-MS (DCI/CH4): calcu-
lated for C24H24N2O4Cl+, 439.1425, found 439.1419.
6.4719(5), b = 8.7411(6), c = 10.9321(8) Å, V = 559.87(7) Å3,
ˉ
T = 193 K, space group P1, Z = 2, 10 737 reflections col-
lected, 2765 unique (Rint = 0.0203), R1[I > 2σ(I)] = 0.0379.
The final wR(F2) was 0.1055 (all data). Crystallographic
data have been deposited at the Cambridge Crystallo-
graphic Data Centre and have been assigned the deposition
number CCDC 997078.
16 Crystal data for 14: C12H14O4, M = 222.23, monoclinic, a =
6.5048(5), b = 20.2812(16), c = 8.3695(6) Å, V = 1088.27(14)
Å3, T = 193 K, space group P21/c, Z = 4, 17567 reflections
collected, 2338 unique (Rint = 0.0371), R1[I > 2σ(I)] = 0.0372.
The final wR(F2) was 0.0908 (all data). Crystallographic
data have been deposited at the Cambridge Crystallo-
graphic Data Centre and have been assigned the deposition
number CCDC 997079.
Acknowledgements
We acknowledge the “Ministère de l’Education Nationale” for a
grant to J. Ruiz.
17 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven, J. A. Montgomery Jr., J. E. Peralta,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox,
GAUSSIAN 09 (Revision A.1), Gaussian, Inc., Wallingford CT,
2009.
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