A straightforward enantioselective synthesis of F17807

Article abstract of DOI:10.1016/j.tet.2015.10.065

An efficient approach for the enantioselective synthesis of the 1,4-benzodioxane F17807 drug is reported. The developed route relied on two key steps, namely S_NAr and Mitsunobu reactions, which permitted a straightforward access to the title co

Full text of DOI:10.1016/j.tet.2015.10.065

Accepted Manuscript
A straightforward enantioselective synthesis of F17807
Julien Alliot, Edmond Gravel, David-Alexandre Buisson, Laurent Larquetoux, Marc
Nicolas, Eric Doris
PII:
S0040-4020(15)30165-4
10.1016/j.tet.2015.10.065
TET 27237
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 October 2015
Revised Date: 22 October 2015
Accepted Date: 23 October 2015
Please cite this article as: Alliot J, Gravel E, Buisson D-A, Larquetoux L, Nicolas M, Doris E,
A straightforward enantioselective synthesis of F17807, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.10.065.
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A straightforward enantioselective synthesis of F17807
a
a
a
b
b
Julien Alliot , Edmond Gravel , David-Alexandre Buisson , Laurent Larquetoux , Marc Nicolas , and Eric
a,
Doris *
a
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, 91191 Gif-sur-Yvette, France.
eric.doris@cea.fr
b
Les Laboratoires Pierre Fabre, Centre de Développement de Chimie Industrielle, 16 rue Jean Rostand, 81600
Gaillac, France

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A straightforward enantioselective synthesis of F17807
a
a
a
b
b
Julien Alliot , Edmond Gravel , David-Alexandre Buisson , Laurent Larquetoux , Marc Nicolas , and Eric
Doris *
a,
a
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, 91191 Gif-sur-Yvette, France. eric.doris@cea.fr
Les Laboratoires Pierre Fabre, Centre de Développement de Chimie Industrielle, 16 rue Jean Rostand, 81600 Gaillac, France
b
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient approach for the enantioselective synthesis of the 1,4-benzodioxane F17807 drug is
reported. The developed route relied on two key steps, namely S Ar and Mitsunobu reactions,
N
Received in revised form
Accepted
which permitted a straightforward access to the title compound with full preservation of the
enantiomeric excess throughout the synthetic sequence.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
benzodioxane
S Ar
N
Mitsunobu
Enantioselective synthesis
1
. Introduction
The first synthesis (in its racemic form) of a 1,4-benzodioxane
derivative was reported by Moureu in 1899 when studying the
thermal degradation of 2-(2,2-diethoxypropoxy)phenol. More
The 1,4-benzodioxane motif is routinely found not only in
naturally occurring compounds such as silybin A (1) which is
1
6
extracted from Silybum marianum, but also in synthetic drugs as
2
3
generally, substituted racemic benzodioxanes can be prepared by
WB4101 (2) and doxazosin (3) (treatment of hypertension), or
4
7–
fluparoxan (4) (antidepressant) (Figure 1). Also, Pierre Fabre
condensation of catechol derivatives with various electrophiles,
11
laboratories have recently developed
a
series of 1,4-
or by organometallic tandem ring opening/coupling of epoxides
In addition, access to optically
14
active 1,4-benzodioxanes can be achieved by chemical and
enzymatic kinetic resolution of the racemate or by condensing
optically active glycidyl tosylate with catechols. Other
approaches involve, for example, chiral palladium-complexes to
12,13
using α-halogenophenols.
benzodioxane derivatives that are currently evaluated for the5
treatment of neuropsychiatric disorders such as schizophrenia.
15
One of the lead compounds among the series is F17807 (5).
16
17
catalyze C-O bond formation, and Sharpless asymmetric
18
epoxidation. Although efficient, the above routes are not fully
satisfactory as kinetic resolution leads to the loss of at least half
of the material, and erosion of enantiomeric purity is sometimes
observed in the other cases. With these features in mind and as
part of our ongoing interest in the synthesis of bioactive
19
compounds, we sought to investigate an efficient and original
route for the enantioselective synthesis of F17807 (5).
2
. Results and discussion
The structure of F17807 is composed of two blocks, i.e. a
“
west” 1,4-benzodioxane fragment bearing the chiral centre, and
an “east” piperidine fragment. Our strategy for the construction
of the key 1,4-benzodioxane core in its optically active form
relies on both the use of intramolecular S Ar and Mitsunobu
N
reactions. Two approaches were investigated, one starting from
glycidol as chiral source (Scheme 1, Path A) and the other from
isopropylidene glycerol (Scheme 1, Path B). In Path A, the
Figure 1. Example of 1,4-benzodioxane derivatives.

2
Tetrahedron
benzodioxane ring is planned to be constructe
A
d i
C
n t
C
he
E
fi
P
na
T
l s
E
ta
D
ge MAha
NU
nd
s,
S
w
C
e
R
n
I
e
P
xt looked at the key S Ar reaction for the
N
T
of the synthesis by an intramolecular S Ar reaction on 6. The
latter intermediate could originate from Mitsunobu coupling of
benzodioxane ring-closing step. Compound 6 was thus reacted
with tBuOK in DMF at room temperature, but surprisingly a 1:1
mixture of isomers was obtained and the products could not be
separated by chromatography (Scheme 3). Changing the solvent
N
(R)-glycidol with phenol derivative 7, followed by ring opening
of the epoxide with the piperidine unit.
(
e.g. DMSO, THF, CH CN), base (e.g. DBU, NaH, KHMDS),
3
and temperature (room temperature to reflux) conditions did not
improve the selectivity of the reaction. Although the expected
compound F17807 (5) was produced in the course of the
transformation, ca. 50% of the cyclized benzodioxane product
corresponded to a rearranged derivative to which we tentatively
assigned the structure of compound 15.
The formation of the latter compound can be rationalized by
initial deprotonation of the secondary alcohol of 6 to afford
alcoholate 6’ (Scheme 4). While the S Ar reaction of the
N
alcoholate on the fluorine-bearing C3’ leads to the formation
F17807, its addition to the more activated C4’-position (para to
the CN group) induces the formation of a rearranged compound
6
’’ with the concomitant release of a primary alcoholate. The
ensuing addition of the newly released alcoholate on C3’,
followed by fluorine elimination finally leads to the formation of
isomer 15. Although absolute configurations of the two products
(namely 5 and 15) could not be unambiguously established after
the key cyclization step (products could not be separated by
chromatography), the proposed mechanism suggests that the
stereogenic center borne by compound 6 remains unaffected
Scheme 1. Possible synthetic pathways to F17807.
throughout the S Ar process.
N
In path B on the other hand, the piperidine unit is connected to
an already formed benzodioxane ring 8 that could originate from
sequential S Ar coupling between 9 and (S)-isopropylidene
N
glycerol, removal of the isopropylidene protecting group,
selective activation of the primary alcohol, and Mitsunobu
coupling.
We first explored the route described in Path A (Scheme 1).
Our synthesis commenced with the three-step synthesis of the
piperidine “eastern” fragment from commercially available N-
Boc-4-piperidine ethanol 10 (Scheme 2). The primary alcohol
was activated as the corresponding mesylate 11 before
nucleophilic substitution by 2-oxazolidinone under alkaline
conditions. The Boc-protecting group was finally removed using
HCl in iPrOH to afford, after neutralization with NaOH, the
expected piperidine 13 in 71% overall yield.
Scheme 3. Realization of path A synthesis.
Scheme 2. Synthesis of the piperidine “east” fragment 13.
In parallel to the synthesis of the piperidine fragment, the
condensation of 3-fluoro-4-hydroxybenzonitrile 7 with (R)-
glycidol under Mitsunobu conditions (PPh /DIAD) led to epoxy-
3
ether 14 in which the stereogenic centre is set (Scheme 3). The
epoxide unit was subsequently ring-opened with the above
prepared piperidine fragment 13. The substitution reaction
proceeded regioselectively at the less hindered position of the
epoxide to afford 6 as a single regioisomer. With compound 6 in
Scheme 4. Proposed mechanism for the formation of rearranged
compound 15.

3
1
S
13
As our initial scheme did not work out as a
of the preferential nucleophilic addition of the alcoholate to the
A
nti
C
cip
C
at
E
ed
P
b
T
ec
E
au
D
se MAF2
N
54
U
).
H
I
CRan PTC NMR spectra were recorded on a Bruker
d
Avance DPX 400 spectrometer at 400 and 100 MHz,
respectively. Chemical shifts (δ) are given in ppm and coupling
constants (J) in hertz. IR spectra were recorded on a Perkin-
Elmer 2000 FT-IR System. Optical rotations were determined
using the sodium D line (589 nm) on a Perkin Elmer 341
polarimeter.
C4’-position, we conceived that the S Ar reaction could be more
N
efficiently
promoted
starting
from
4-fluoro-3-
hydroxybenzonitrile 9 in which the leaving fluorine atom is
properly positioned para to the cyano group. Thus, 4-fluoro-3-
hydroxybenzonitrile 9 was first reacted under basic conditions
(
tBuOK) with the more robust glycidol-equivalent (S)-
4
.2. N-Boc-4-(2-((methylsulfonyl)oxy)ethyl)piperidine (11).
isopropylidene glycerol (98% ee) (Scheme 5). Although the
reaction proceeded at 150 °C, it cleanly gave access to the key
intermediate 16, after deprotection of the 1,2-diol. It is to be
noted that, contrary to previous reports, the above S Ar reaction
did not require protection of the phenol group, thus allowing a
more direct route to the target compound. The primary alcohol of
At room temp. under N , mesyl chloride (0.52 mL, 2 equiv.)
2
was added dropwise to a solution of N-Boc piperidine ethanol 10
(840 mg, 3.7 mmol, 1.0 equiv.) and triethylamine (1.0 mL, 2
equiv.) in 20 mL anhydrous toluene. The solution was stirred for
20
N
4
h and was quenched with 20 mL 1 M HCl. The aqueous phase
1
1
6 was then selectively brominated by PPh /CBr (compound
3 4
was extracted with EtOAc (3 × 20 mL), the combined organic
layers were washed with brine (20 mL), dried over Na SO ,
7). This step permitted to differentiate secondary from primary
2
4
alcohols prior to the intramolecular coupling with the phenol
unit. The remaining optically active secondary alcohol was then
activated under Mitsunobu’s conditions and underwent smooth
coupling with the neighboring phenol to give access to optically
active 1,4-benzodioxane 8 where the stereogenic centre is
filtered and concentrated under vacuum. The residual oil was
crystallized from heptane (40 mL) to afford 11 (1.05 g, 93%). H-
1
NMR (CDCl ): δ 4.30 (t, J = 6.4 Hz, 2H), 3.04 (s, 3H), 2.71 (t, J
3
=
12.5 Hz, 2H), 1.75−1.60 (m, 7H), 1.47 (s, 9H), 1.21−1.15 (m,
13
2
H). C-NMR (CDCl ): δ 154.8, 79.4, 77.4, 67.4, 37.5, 35.6,
3
−1
irreversibly set. Of note, the S 2 reaction proceeded with
N
32.4, 31.7, 28.5. IR (neat): 2925, 1775, 1682 cm . ESI-MS
+ +
inversion of configuration of the alcohol-bearing centre. The
synthesis of F17807 (5) was finally completed by the coupling of
(ES ): 308 [M+H] .
8
with piperidine 13 at 110 °C in methyl isobutyl ketone. F17807
(
5) was obtained in seven steps, with a satisfactory overall yield
4
.3. N-Boc-4-(2-(2-oxooxazolidin-3-yl)ethyl)piperidine (12).
of 21% but more importantly with a retained enantiomeric excess
of 98%.
Under N , 2-oxazolidinone (321 mg, 1.2 equiv.) and K CO
3
2
2
(511 mg, 1.2 equiv.) were added to a solution of 11 (950 mg, 3.1
mmol, 1.0 equiv.) in 10 mL anhydrous toluene. The suspension
was heated at 100 °C for 17 h. H O (20 mL) was then added and
2
the the aqueous layer was extracted with EtOAc (3 × 20 mL).
The combined organic layers were washed with brine (20 mL),
dried over Na SO , filtered, and concentrated under vacuum. The
2
4
crude was purified by flash chromatography (Et O/MeOH, 100:0
2
1
to 95:5) to afford 12 (860 mg, 93%). H-NMR (CDCl ): δ 4.35 (t,
3
J = 7.9 Hz, 2H), 3.56 (t, J = 8.1 Hz, 2H), 3.35 (t, J = 6.9 Hz, 2H),
2
1
7
2
.71 (t, J = 11.7 Hz, 2H), 1.75−1.68 (m, 2H), 1.54−1.41 (m,
13
4H), 1.22−1.09 (m, 2H). C-NMR (CDCl ): δ 158.4, 154.8,
3
9.3, 77.3, 61.7, 44.4, 41.8, 33.9, 33.5, 31.9, 28.5. IR (neat):
−1
+
+
925, 1751, 1687 cm . ESI-MS (ES ): 299 [M+H] .
4
.4. 3-(2-(piperidin-4-yl)ethyl)oxazolidin-2-one (13).
Scheme 5. Realization of path B synthesis.
A solution of 12 (820 mg, 2.7 mmol) in 10 mL 2.2 M
HCl/isopropanol was stirred overnight at room temp. The
reaction was quenched by the addition of 20 mL 5% NaOH.
Brine (20 mL) was added and the aqueous phase was extracted
with EtOAc (4 × 40 mL). The combined organic layers were
washed with brine (20 mL), dried over Na SO , filtered, and
3
. Conclusions
We reported here an efficient enantioselective synthesis of
F17807 from 4-fluoro-3-hydroxybenzonitrile and (S)-
isopropylidene glycerol. Our approach is based on two key
coupling steps, namely S Ar and Mitsunobu reactions. The
enantiomeric excess of the starting isopropylidene glycerol was
preserved throughout the synthetic pathway, thus permitting
efficient access to 1,4-benzodioxane F17807 with 98% ee.
2
4
concentrated under vacuum. The residual oil which crystallized
N
spontaneously was then used without further purification (443
1
mg, 82%). H-NMR (CDCl ): δ 4.35 (t, J = 7.9 Hz, 2H), 3.57 (t, J
3
=
7.9 Hz, 2H), 3.35 (t, J = 7.3 Hz, 2H), 3.11−3.06 (m, 2H), 2.71
(
7
td, J = 12.1 Hz, J = 2.2 Hz, 2H), 1.73 (br. s., 3H), 1.52 (q, J =
.1 Hz, 2H), 1.45−1.37 (m, 1H), 1.22−1.09 (m, 2H). C-NMR
1
3
(
CDCl ): δ 158.4, 77.3, 61.6, 44.4, 41.8, 34.5, 33.7, 33.2. IR
3
−1 + +
4
. Experimental
(neat): 3429, 2922, 1741 cm . ESI-MS (ES ): 199 [M+H] .
4
.1. General
Reactions were carried out under nitrogen using dry solvents,
4.5. 3-fluoro-4-(oxiran-2-ylmethoxy)benzonitrile (14).
At 0 °C and under N , PPh (684 mg, 1.2 equiv.), (R)-glycidol
unless otherwise stated. THF was distilled from
sodium/benzophenone before use. Flash chromatography was
carried out on Kieselgel 60 (230–240 mesh, Merck) and
analytical TLC was performed on Merck precoated silica gel (60
2
3
(174 µL, 1.2 equiv.) and DIAD (510 µL, 1.2 equiv.) were added
to a solution of 3-fluoro-4-hydroxybenzonitrile 7 (300 mg, 2.18

4
Tetrahedron
mmol, 1.0 equiv.) in 10 mL anhydrous THF.
A
T
C
he
C
so
E
lu
P
tio
T
n
E
w
as MA4.
D
N
8.
U
(S)
S
-4
C
-(
R
3-bromo-2-hydroxypropoxy)-3-hydroxybenzonitrile
IPT
warmed to room temp and stirred for 2 h. The reaction was then
quenched with H O (10 mL) and extracted with Et O (3 × 10
mL). The combined organic layers were washed with brine (20
mL), dried over Na SO , filtered, and concentrated under
vacuum. The crude mixture was purified by flash
chromatography (CH Cl ) to afford compound 14 (413 mg,
(17).
2
2
Under N , PPh (626 mg, 2.5 equiv.) and CBr (785 mg, 2.5
equiv.) were added to a solution of 16 (200 mg, 0.95 mmol, 1.0
equiv.) in 5 mL CH Cl . The solution was stirred at room temp
for 2 h. The reaction was then quenched with 5 mL 1 M HCl and
the aqueous phase was extracted with CH Cl (3 × 10 mL). The
2
3
4
2
4
2
2
2
2
1
2
2
9
7
8%). H-NMR (CDCl ): δ 7.44 (dd, J = 8.6 Hz, J = 1.7 Hz, 1H),
.40 (dd, JH-F = 10.4 Hz, J = 1.7 Hz, 1H), 7.09 (t, J = 8.6 Hz, JH-F
3
combined organic layers were washed with brine (5 mL), dried
over Na SO , filtered, and concentrated under vacuum. The crude
was purified by flash chromatography (EtOAc/cyclohex, 1:9 to
2
4
=
=
8.6 Hz, 1H), 4.45 (dd, J = 11.4 Hz, J = 2.7 Hz, 1H), 4.08 (dd, J
11.4 Hz, J = 5.9 Hz, 1H), 3.43−3.39 (m, 1H), 2.97 (t, J = 4.5
1
13
1:1) to afford compound 17 (230 mg, 89%). H-NMR (CDCl ): δ
3
Hz, 1H), 2.81 (dd, J = 4.5 Hz, J = 2.7 Hz, 1H). C-NMR
7
4
.53 (br. s, 1H), 7.22−7.18 (m, 2H), 6.92 (d, J = 8.9 Hz, 1H),
.44−4.31 (m, 1H), 4.29−4.19 (m, 2H), 3.67−3.57 (m, 2H). C-
(CDCl ): δ 153.1 (d, J = 250 Hz), 150.6 (d, JC-F = 9.2 Hz),
3 C-F
13
1
29.7 (d, JC-F = 3.1 Hz), 120.0 (d, JC-F = 21.5 Hz), 117.8, 115.2
NMR (CDCl ): δ 149.5, 146.4, 125.4, 119.0, 118.9, 112.7, 105.4,
70.6, 69.5, 33.6. IR (neat): 3455, 3246, 2937, 2245, 1521 cm .
3
(
d, JC-F = 3.1 Hz), 104.7 (d, J = 9.2 Hz), 70.2, 49.7, 44.4. IR
C-F
−1 + +
−1
(neat): 3059, 2233 cm . ESI-MS (ES ): 194 [M+H] .
+
+
[
α] +0.8 (c 0.54, CH Cl ). ESI-MS (ES ): 272.0-274.0 [M+H] .
D 2 2
4
.6. (S)-3-fluoro-4-(2-hydroxy-3-(4-(2-(2-oxooxazolidin-3-
4
.9. (R)-3-(bromomethyl)-2,3-dihydrobenzo[1,4]dioxine-6-
yl)ethyl)piperidin-1-yl)propoxy)benzonitrile (6).
carbonitrile (8).
At room temp and under N , piperidine 13 (40 mg, 1.0 equiv.)
2
PPh (86 mg, 1.2 equiv.) and DIAD (65 µL, 1.2 equiv.) were
3
was added to compound 14 (39 mg, 0.2 mmol, 1.0 equiv.) in 1
mL anhydrous THF. The reaction mixture was heated to 50 °C
overnight. Solvents were evaporated under vacuum and the crude
was purified by flash chromatography (CH Cl /MeOH, 99:1 to
added dropwise at 0 °C to a solution of 17 (75 mg, 0.27 mmol, 1
equiv.) in 2.7 mL anhydrous THF. The solution was stirred for 2
h at room temp. Solvents were evaporated under vacuum and the
crude was purified by flash chromatography (CH Cl ).
2
2
1
2
2
9
0:10) to afford compound 6 as a white solid (62 mg, 81%). H-
1
Compound 8 was isolated as a white solid (59 mg, 80%). H-
NMR (CDCl ): δ 7.43 (dd, J = 8.6 Hz, J = 1.7 Hz, 1H), 7.40 (dd,
3
NMR (CDCl ): δ 7.25−7.16 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H),
3
JH-F = 10.4 Hz, J = 1.7 Hz, 1H), 7.09 (t, J = 8.6 Hz, JH-F = 8.6 Hz,
4
(
.49−4.42 (m, 2H), 4.25 (dd, J = 11.9 Hz, J = 6.8 Hz, 1H), 3.60
1
H), 4.35 (t, J = 8.2 Hz, 2H), 4.15−4.10 (m, 3H), 3.57 (t, J = 8.2
Hz, 2H), 3.34 (t, J = 7.3 Hz, 2H), 3.01 (d, J = 11.3 Hz, 1H), 2.85
d, J = 11.3 Hz, 1H), 2.56−2.49 (m, 2H), 2.33 (td, J = 9.7 Hz, J =
dd, J = 10.9 Hz, J = 4.9 Hz, 1H), 3.51 (dd, J = 10.9 Hz, J = 7.1
1
3
Hz, 1H). C-NMR (CDCl ): δ 147.0, 142.7, 126.4, 121.3, 118.6,
3
(
1
9
−1
1
18.2, 105.2, 71.9, 66.1, 28.1. IR (neat): 2935, 2217 cm . [α]
D
.6 Hz, 1H), 2.02 (td, J = 9.7 Hz, J = 2.2 Hz, 1H), 1.78 (d, J =
13
+8.5 (c 0.52, CH Cl ).
2
2
.7 Hz, 2H), 1.52 (q, J = 7.0 Hz, 2H), 1.37−1.25 (m, 3H). C-
NMR (CDCl ): δ 158.4, 152.0 (d, J = 251 Hz), 151.2 (d, JC-F
=
3
C-F
1
1
4
0.7 Hz), 129.6 (d, JC-F = 4.6 Hz), 119.8 (d, JC-F = 21.4 Hz),
17.8 (d, JC-F = 3.7 Hz), 115.1, 104.3, 77.3, 71.8, 65.2, 61.6, 60.2,
5
4
.10. F17807 (5).
−1
4.4, 41.9, 33.8, 33.1, 32.4. IR (neat): 3421, 2229, 1746 cm .
Under N , K CO (21 mg, 1.5 equiv.) was added to a solution
+
+
2
2
3
ESI-MS (ES ): 392 [M+H] . Chiral HPLC: (Chiralpak AD 150 ×
4
at 220 nm) tmajor = 11.7 min, tminor = 13.7 min, 98% ee.
of 8 (26 mg, 0.104 mmol, 1 equiv.) and piperidine 13 (23 mg, 1.1
equiv.) in 1 mL methyl isobutyl ketone. The reaction mixture was
heated at 110 °C for 5 h. The reaction was then quenched with 5
-
1
.6 mm, hexane/ethanol 40/60, flow rate: 1 mL min , detection
mL 1 M HCl and extracted with 5 mL Et O. The aqueous layer
2
was basified with NaOH 20% and extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (5
mL), dried over Na SO , filtered, and concentrated under
4
.7. (R)-4-(2,3-dihydroxypropoxy)-3-hydroxybenzonitrile (16).
2
4
Under N , (S)-isopropylidene glycerol (330 µL, 1.2 equiv.)
2
vacuum. The crude was purified by flash chromatography
CH Cl /MeOH, 99:1 to 90:10) to afford F17807 5 as a solid (26
and tBuOK (560 mg, 2.3 equiv.) were added to a solution of 4-
fluoro-3-hydroxybenzonitrile 9 (300 mg, 2.15 mmol, 1.0 equiv.)
in 1 mL anhydrous DMF. The suspension was heated at 150 °C
for 3 h. After cooling to 70 °C, 4 mL 5 M HCl were added and
the reaction was cooled down to room temp. The mixture was
diluted with 5 mL H O and extracted with EtOAc (3 × 20 mL).
The combined organic layers were washed with brine (10 mL),
dried over Na SO , filtered, and concentrated under vacuum. The
(
2
2
1
mg, 58%). H-NMR (CDCl ): δ 7.18 (d, J = 1.6 Hz, 1H), 7.14
3
(
4
(
dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H),
.40−4.28 (m, 4H), 4.03 (dd, J = 11.4 Hz, J = 7.3 Hz, 1H), 3.57
t, J = 8.2 Hz, 2H), 3.32 (t, J = 7.3 Hz, 2H), 2.97 (d, J = 9.2 Hz,
2
1
1
1
H), 2.89 (d, J = 9.2 Hz, 1H), 2.67 (dd, J = 13.3 Hz, J = 5.7 Hz,
H), 2.55 (dd, J = 13.3 Hz, J = 6.3 Hz, 1H), 2.19−2.06 (m, 2H),
2
4
.74 (d, J = 8.3 Hz, 2H), 1.51 (q, J = 7.0 Hz, 2H), 1.37−1.25 (m,
crude was purified by flash chromatography (CH Cl /MeOH,
9
2
2
13
1
3H). C-NMR (CDCl ): δ 158.4, 147.5, 143.4, 125.8, 121.3,
3
9:1 to 90:10) to afford compound 16 (323 mg, 72%). H-NMR
1
3
18.9, 115.0, 104.5, 71.5, 67.3, 61.7, 58.6, 54.2, 44.4, 41.9, 33.8,
(DMSO-d ): δ 7.25 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.15 (d, J =
6
−1
2.9, 32.2. IR (neat): 2923, 2224, 1748 cm . [α] +28.3 (c 0.50,
D
2
4
3
.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 5.4 Hz, 1H),
.70 (d, J = 5.4 Hz, 1H), 4.09 (dd, J = 9.9 Hz, J = 3.8 Hz, 1H),
+
+
CH Cl ). ESI-MS (ES ): 372 [M+H] . Chiral HPLC: (Chiralpak
AD 150 × 4.6 mm, hexane/ethanol 40:60, flow rate: 1 mL min ,
2
2
−1
13
.92 (dd, J = 9.9 Hz, J = 6.2 Hz, 1H), 3.85−3.81 (m, 1H). C-
detection at 220 nm) tmajor = 11.4 min, tminor = 13.5 min, 98% ee.
NMR (DMSO-d ): δ 151.6, 147.5, 152.2, 119.7, 118.4, 113.8,
1
6
−1
03.2, 70.9, 70.2, 62.8. IR (neat): 3432, 3341, 2941, 2230 cm .
+ +
D
[
α] +28.3 (c 0.57, EtOH). ESI-MS (ES ): 210 [M+H] .

5
1
5. Rouf, A.; Gupta, P.; Aga, M. A.; Kumar, B.; Chaubey, A.;
Acknowledgments
ACCEPTED MANUSCRIPT
Parshad, R.; Taneja, S. C. Tetrahedron: Asymmetry 2012, 23,
615.
1
J.A. thanks the CEA and “Les Laboratoires Pierre Fabre” for a
CTCI PhD grant. The “Service de Chimie Bioorganique et de
Marquage” belongs to the Laboratory of Excellence in Research
on Medication and Innovative Therapeutics (ANR-10-LABX-
1
6. Lo Monte, F.; Kramer, T.; Gu, J.; Anumala, U. R.; Marinelli, L.;
La Pietra, V.; Novellino, E.; Franco, B.; Demedts, D.; Van
Leuven, F.; Fuertes, A.; Dominguez, J. M.; Plotkin, B.; Eldar-
Finkelman, H.; Schmidt, B. J. Med. Chem. 2012, 55, 4407.
7. Massacret, M.; Lakhmiri, R.; Lhoste, P.; Nguefack, C.; Ben
1
0
033-LERMIT).
Abdelouahab, F. B.; Fadel, R.; Sinou, D. Tetrahedron: Asymmetry
000, 11, 3561.
18. Clark, R.; Kurz, L. Heterocycles 1985, 23, 2005.
2
References and notes
1
9. (a) Hardouin, C.; Doris, E.; Rousseau, B.; Mioskowski, C.;
Nierlich, M. Acta Crystallogr. Sect. C 2000, 56, 225. (b)
Hardouin, C.; Doris, E.; Rousseau, B.; Mioskowski, C. Org. Lett.
1
2
.
.
Lee, D. Y. W.; Liu, Y. J. Nat. Prod. 2003, 66, 1171.
Pallavicini, M.; Budriesi, R.; Fumagalli, L.; Ioan, P.; Chiarini, A.;
Bolchi, C.; Ugenti, M. P.; Colleoni, S.; Gobbi M.; Valoti, E. J.
Med. Chem. 2006, 49, 7140.
(a) Campbell, S. F.; Davey, M. J.; Hardstone, J. D.; Lewis B. N.;
Palmer, M. J. J. Med. Chem. 1987, 30, 49. (b) Rouf, A.; Aga, M.
A.; Kumar, B.; Taneja, S. C. Tetrahedron Lett. 2013, 54, 6420.
Halliday, C. A.; Jones, B. J.; Skingle, M.; Walsh, D. M.; Wise,
H.; Tyers, M. B. Br. J. Pharmacol. 1991, 102, 887.
Sokoloff, P.; Maillos, P.; Cuisiat, F.; Vidaluc, J. L.; Imbert, T.
WO patent 106660 (2014).
2
002, 4, 1151. (c) Hardouin, C.; Doris, E.; Rousseau, B.;
Mioskowski, C. J. Org. Chem. 2002, 67, 6571. (d) Hardouin, C.;
Burgaud, L.; Valleix, A.; Doris, E. Tetrahedron Lett. 2003, 44,
4
Crystallogr. Sect. C 2004, 60, o792. (f) Moisan, L.; Thuéry, P.;
Nicolas, M.; Doris, E.; Rousseau, B. Angew. Chem. Int. Ed. 2006,
4
Leroux, S.; Larquetoux, L.; Nicolas, M.; Doris, E. Org. Lett. 2011,
13, 3549. (i) Giovanelli, E.; Leroux, S.; Moisan, L.; Carreyre, H.;
Thuéry, P.; Buisson, D. A.; Meddour, A.; Coustard, J. M.;
Thibaudeau, S.; Rousseau, B.; Nicolas, M.; Hellier, P.; Doris, E.
Org. Lett. 2011, 13, 4116. (j) Alliot, J.; Gravel, E.; Pillon, F.;
Buisson, D. A.; Nicolas, M.; Doris. E. Chem. Commun. 2012, 48,
3
.
35. (e) Moisan, L.; Doris, E.; Rousseau, B.; Thuéry, P. Acta
4
5
6
7
8
.
.
.
.
.
.
5, 5334. (g) Doris, E. Angew. Chem. Int. Ed. 2009, 48, 7480. (h)
Moureu, C. Bull. Soc. Chim. Paris, Mémoires 1899, SER3, T21,
2
91.
Koo, J.; Avakian, S.; Martin, J. G. J. Am. Chem. Soc. 1955, 77,
373.
Martin, A. R.; Mallick, S. K.; Caputo, J. F. J. Org. Chem. 1974,
9, 1808.
Krapcho J.; Lott, W. A. US patent 2979511 (1961).
5
8
111. (k) Giovanelli, E.; Moisan, L.; Leroux, S.; Comesse, S.;
Rousseau, B.; Hellier, P.; Nicolas, M.; Doris, E. Chem. Eur. J.
013, 19, 1170. (l) Giovanelli, E.; Moisan, L.; Comesse, S.;
3
2
9
1
Leroux, S.; Rousseau, B.; Hellier, P.; Nicolas, M.; Doris, E. Org.
Biomol. Chem. 2013, 11, 5885. (m) Alliot, J.; Gravel, E.;
Larquetoux, L.; Nicolas, M.; Doris, E. J. Nat. Prod. 2013, 76,
0. Ilić, M.; Dunkel, P.; Ilaš, J.; Chabielska, E.; Zakrzeska, A.;
Mátyus P.; Kikelj, D. Eur. J. Med. Chem. 2013, 62, 329.
1. Willard, A. K.; Smith, R. L.; Cragoe, E. J. J. Org. Chem. 1981, 46,
1
2
346. (n) Doris, E. Angew. Chem. Int. Ed. 2014, 53, 4041.
3
846.
2
0. Bollini, M.; Domaoal, R. A.; Thakur, V. V.; Gallardo-Macias, R.;
1
1
2. Bao, W.; Liu, Y.; Lv X.; Quian, W. Org. Lett. 2008, 10, 3899.
3. Kuwabe, S.; Torraca K. E.; Buchwald, S. L. J. Am. Chem. Soc.
Spasov, K. A.; Anderson, K. S.; Jorgensen, W. L. J. Med. Chem.
2
011, 54, 8582.
2
001, 123, 12202.
1
4. Bolchi, C.; Fumagalli, L.; Moroni, B.; Pallavicini M.; Valoti, E.
Tetrahedron: Asymmetry 2003, 14, 3779.