Diastereoconvergent Synthesis of (–)-Paroxetine

Article abstract of DOI:10.1002/ejoc.201700658

A diastereoconvergent approach to (–)-paroxetine from diastereomeric 3,4-epoxy-2-piperidones is reported. For this synthesis, a regioselective and stereodivergent Cu^I-catalyzed epoxide-ring-opening reaction of epoxyamide precursors to give the 4-(4-fluorophenyl)-2-piperidone skeleton with the correct absolute configuration is crucial. Using CuBr·SMe₂ as a catalyst, the epoxide-ring-opening reaction takes place with inversion of configuration; the configuration is retained when CuI is used.

Full text of DOI:10.1002/ejoc.201700658

A Journal of
Accepted Article
Title: Diastereoconvergent Synthesis of (-)-Paroxetine
Authors: Delfino Chamorro-Arenas, Lilia Fuentes, Leticia Quintero,
Silvano Cruz-Gregorio, Herbert Höpfl, and Fernando Sartillo-
Piscil
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700658
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700658
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10.1002/ejoc.201700658
European Journal of Organic Chemistry
FULL PAPER
Diastereoconvergent Synthesis of (-)-Paroxetine
Delfino Chamorro-Arenas, [a]‡ Lilia Fuentes, [a]‡ Leticia Quintero, [a] Silvano Cruz-Gregorio, [a] Herbert
Höpfl, [b] and Fernando Sartillo-Piscil * [a]
Abstract: A diastereoconvergent approach to (-)-paroxetine from
diastereomeric 3,4-epoxy-2-piperidones is reported. For this
synthesis, the regioselective and stereodivergent Cu(I)-catalyzed
epoxide ring-opening of the epoxyamide precursors to give the 4-
fluorophenyl-2-piperidone skeleton with the correct absolute
configuration, is crucial. Using CuBr·SMe2 as catalyst, the epoxide
ring-opening reaction is achieved with inversion of the configuration,
whilst the configuration is retained when CuI is employed.
synthesis community has been focused on developing a number
of efficient approaches for its total synthesis.[3] The use of chiral
pools,[4] chiral auxiliaries,[5-7] asymmetrization of a prochiral
dicarbonyl intermediate,[8] enzymatic resolution methodologies[9]
and asymmetric catalysis[10,11] are the most common strategies
for the stereo- and enantioselective synthesis of this trans-3,4-
disubstituted piperidine. Because of the location and orientation
of the p-fluorophenyl group within the piperidine ring is
responsible for the biological activity,[12] many synthesis of the (-
)-paroxetine are based on the development of efficient methods
for the introduction of this function. Although the selected
chemical operation for attaching the p-fluorophenyl group is the
conjugated addition reaction of the corresponding 4-fluorophenyl
metal reagent onto an ,- unsaturated substrate (e.g., A,
Scheme 1),[4,5,10b,i] addition of lithium cuprates towards
pyridinium salts,[7a] addition of Grignard reagents onto 4-
piperidones[9g], Heck reaction,[13] and Co-catalyzed arylation[14]
are further synthetic methodologies employed for this purpose.
Herein, as part of our studies on the use of sodium chlorite as
oxidant agent in the synthesis of 2,3-epoxyamides from
allylamines and its application in the synthesis of alkaloids
biologically actives,[15] a new strategy to achieve the trans-4-(4-
fluorophenyl)-3-piperidinemethanol skeleton (B) is described.
This method is based on an epoxide ring opening reaction of a
chiral 3,4-epoxy-2-piperidone (e.g., C) as starting material.
Glycidic amide C is easily obtained in multigram quantities from
simple substrates and using environmentally friendly reagents
(Scheme 1).
Introduction
Many 4-arylpiperidines belong to a selected group of synthetic
alkaloids pharmacologically actives (e.g., haloperidol, femoxetin,
and (-)-paroxetine; see Figure 1) that can modulate the
physiological
and
pathophysiological
actions
of
neurotransmitters such as serotonin and dopamine.[1a] In
particular, (-)-paroxetine hydrochloride, also known by the trade
[1b,c]
names Paxil® and Seroxat®,
is a trans-3,4-disubstituted
piperidine derivative that acts as a selective serotonine reuptake
inhibitor (SSRI). Therefore, is a drug used worldwide not only as
antidepressant, but also in the treatment of several other
disorders (i.e., obsessive compulsive disorder, panic disorder
and, post-traumatic stress disorder).[2]
Scheme 1. Common (A) and current strategy (C) for the preparation of the
trans-4-(4-fluorophenyl)-3-piperidinemethanol skeleton (B) of (-)-paroxetine
Figure 1. Selected 4-arylpiperidines pharmacologically actives
Results and Discussion
Since the (-)-paroxetine is one of the most important non-natural
alkaloid commercially available for use in humans, the organic
For this approach, the regio- and stereoselective ring-opening of
epoxyamide 1a with the corresponding Grignard reagent via a
SN2 displacement by means of a Cu(I)-catalyzed reaction is
crucial. Deoxygenation of the tertiary hydroxyl group in 2
(Barton-McCombie reaction) is a second key step, especially
because the trans-configuration of the substituents at C3 and C4
must be created at this stage (3). Incorporation of the sesamol
group (5-benzodioxolol) to 3, reduction of the carbonyl group
and removal of the chiral auxiliary of 4 would finally provide the
target product (Scheme 2).
[a]
Centro de Investigación de la Facultad de Ciencias Químicas,
BUAP. 14 Sur Esq. San Claudio, San Manuel. 72570, Puebla, México.
E-mail: fernando.sartillo@correo.buap.mx
[b]
Centro de Investigaciones Químicas, Instituto de Ciencias Básicas y
Aplicadas, Universidad Autónoma del Estado de Morelos, Av. Universidad
1001. 62209. Cuernavaca, México.
‡These authors contributed equally.
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10.1002/ejoc.201700658
European Journal of Organic Chemistry
FULL PAPER
and 1b) proceeds in high yields and in a multigram scale, but
only poor stereoselectivity has been achieved so far.[15]
Consequently, starting from 2 and 6, which both have the
required absolute configuration at the C4 atom, the synthesis of
(-)-paroxetine can be achieved by
approach.
a diastereoconvergent
Attempts for the deoxygenation of the tertiary alcohols 2 and 6
under classical Barton-McCombie[19] conditions failed, because
the respective xanthates (not shown) either decompose or
hydrolyze to the respective alcohol precursors. Therefore, the
deoxygenation was performed via cyclic thiocarbonates.[20] For
this purpose, compounds 2 and 6 were desilylated with tetra-n-
butylammonium fluoride (TBAF) to diols 7 and 8, respectively.
Fortunately, both compounds gave crystalline materials suitable
for single-crystal X-ray diffraction analysis (see Supporting
Information), which allowed to confirm the Cu(I)-induced
stereodivergence in the epoxide-ring opening.
Scheme 2. General synthetic strategy for the preparation of enantiomerically
pure (-)-paroxetine starting from the easily accessible glycidic amide 1a
In order to test this proposal, the starting epoxyamide 1a was
prepared along with the diastereomeric congener 1b in
multigram scale from the corresponding allyl amine D, which
was prepared in four steps with only two column-
chromatographic steps from commercially available (S)-
methylbenzylamine (MBA) (Scheme 3, eq. 1).[15a,b] Epoxyamide
1a was treated with p-F-C6H4MgBr in THF under catalyst-free
conditions; however, only a complex mixture of byproducts was
observed (Scheme 3, eq. 2). Interestingly, when using CuI as
catalyst,[16] not only a regioselective epoxide ring-opening
occurred, but also complete retention of the configuration was
achieved (5) (Scheme 3, eq. 3). Moreover, when epoxyamide 1a
was tested with CuBr•SMe2 as catalyst under the same
reactions conditions, the expected intermediate 2 was obtained
in good yield following the usual SN2 mechanism (Scheme 3, eq.
4). Intrigued by this apparent stereodivergence in the epoxide
ring-opening reaction of epoxyamide 1a mediated by Cu(I),
epoxyamide 1b was tested with CuI and the epoxide ring-
opening reaction occurred in high yield and complete retention
of the configuration (6). This unexpected retention in the
configuration at C4 can be explained by a premature SN2
epoxide ring-opening mediated by CuI to give, in the first
instance, the respective trans-halohydrin E,[17] which by the
subsequent SN2 substitution with the aryl cuprate provides the
piperidonemethanol
6 in good yield (Scheme 3, eq. 5).
Additionally, the regio- and steredivergent ring-opening reaction
of 1a can also be explained by considering the chelation
complexes F and G as the key intermediates for both: inversion
and retention of the configuration in the epoxide ring-opening
reaction. Aryl group in F is prone for SN2 attack to give directly
compound 2. On the other hand, and the iodine atom in G is
attached temporally (E), and by another subsequent SN2
reaction, mediated by aryl cuprate, compound 6 is formed
(Scheme 3, eq. 6). The presence of an C−H•••O intramolecular
hydrogen interaction between the benzylic hydrogen atom and
the oxygen atom from carbonyl group18,15b might exert a
stabilization effect on the key intermediates F and G.
This diastereodivergent epoxide ring-opening of epoxyamides
1a and 1b mediated by arylcuprates provides an expedient
opportunity for developing
preparation of (-)-paroxetine from either 1a or 1b. The selective
double oxidation of allylamines to 2,3-epoxyamides (i.e., A → 1a
a convergent strategy for the
Scheme 3. Synthesis of 2,3-epoxyamides 1a and 1b from (S)-MBA (eq. 1).
Diastereodivergent epoxide ring-opening of the epoxyamide precursors 1a and
1b with p-F-C6H4MgBr catalyzed with Cu(I) (eqs. 2-5). Key intermediates F
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10.1002/ejoc.201700658
European Journal of Organic Chemistry
FULL PAPER
and G that showcase the regio-and stereoselective epoxide ring-opening of 1a
and 1b (eq. 6).
Having in hands
the trans-4-(4-fluorophenyl)-3-piperidinemethanol (trans-12),
completion of the (-)-paroxetine was achieved following two
different pathways. The first one followed the final steps of
Amat’s paroxetine synthesis,[5] consisting in the simultaneous
debenzylation/protection protocol to obtain 13, which was then
with methanesulfonyl chloride (MsCl) transformed into the
corresponding mesylate 14 followed by a substitution reaction
with sesamol in the presence of NaH. Removal of the Boc
protecting group from 15 yielded (-)-paroxetine quantitatively.
The second route to (-)-paroxetine partially followed a modified
version of Liu’s approach.[6] In the first instance, sesamol was
incorporated via mesylate formation (12 → 16 → 17), giving
after debenzylation of 17 the target product (Scheme 5).
Scheme 4. Diastereoconvergent synthesis of 11 starting from 2 and 6
Diols 7 ann 8 were then transformed quantitatively with 1,1’-
thiocarbonyldiimidazole (TCDI) in the presence of 4-
dimethylaminopyridine (DMAP) tot he corresponding cyclic
thiocarbonates 9 and 10. Without further purification, the
thiocarbonates 9 and 10 were treated with nBu3SnH and ACCN
in refluxing toluene to give, in both cases, a cis/trans mixture of
4-(4-fluorophenyl)-3-piperidonemethanol 11 in good yield with an
approximate 4/1 ratio. Thermodynamic equilibration of cis/trans-
11 mixture to exclusively the trans-diaThe regioselectivity of the
deoxygenation reaction in stereoisomer 11 was achieved with a
methanolic solution of KOH at reflux temperature (Scheme 4).
Conclusions
By taking advantage from a diastereodivergent copper-catalyzed
regioselective ring-opening of diastereomeric 2,3-epoxyamides
with
a Grignard reagent, an efficient protocol could be
established for the synthesis of (-)-paroxetine. The principles of
the current strategy provide valuable elements for further
applications to the synthesis of other biologically important 3,4-
disubustituted piperidines.
Acknowledgements
We gratefully acknowledge financial support from CONACyT
and the Marcos Moshinsky foundations. D. C. A. Acknowledges
CONACyT for graduate scholarship (grant number: 3279).
Access to the X-ray facilities of the Chemical Research Center
at Morelos State University (LANEM) is gratefully acknowledged.
We also thank Mr. Vladimir Carranza-Tellez for technical
assistance in mass spectroscopy, and Dr. Alejandro Cordero-
Vargas for valuable comments on the manuscript.
Scheme 5. Completion of the synthesis of the target product starting from
trans-12
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10.1002/ejoc.201700658
European Journal of Organic Chemistry
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(104.74 mg, 0.55 mmol) and p-fluorophenylmagnesium bromide
(0.27 mL, 0.55 mmol, 2M) was stirred at room temperature for 2
h. Then, a solution of epoxyamide 1b (200.0 mg, 0.55 mmol) in
THF (1 mL) was added dropwise into the reaction mixture during
0.5 h. The resulting reaction mixture was stirred for 6.5 h. at
room temperature. The reaction was quenched with a saturated
solution of ammonium chloride (3 mL) and the aqueous phase
was extracted with EtOAc (4 x 10 mL). The combined organic
layer was dried over Na2SO4 and the solvent was removed
under reduced pressure. The residue was purified by column
chromatography on silica gel (hexane/EtOAc 10:1) to yield 0.097
Experimental Section
General Considerations NMR spectra were obtained in a 500
MHz Bruker spectrometer (500 MHz for 1H and 125 MHz for
13C). All samples were analyzed in CDCl3 with TMS as internal
reference using a relative scale in parts per millon (ppm) for the
chemical shift (δ) and Hz for coupling constants (J). Splitting
patterns are designated as follow: s, singlet; d, doublet; q,
quartet; m, multiplet; dd, doublet doublet; br, broad; and their
combinations. Optical rotation of the compounds was measured
on a Perkin-Elmer model 241 polarimeter on the D-line of
sodium (589 nm) and expressed in degrees; the measurements
were performed at a temperature of 20 °C and the concentration
of the sample was expressed in g/100 mL. The FAB+ and EI
mass spectra were recorded on a JOEL JMS AX505HA
spectrometer. The melting points were determined with a
Fischer-Scientific fusiometer in capillary tube.
20
g (36%) of E as a yellow oil. [α]D = -67.59 (c = 1.03, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 0.11 (s, 3H), 0.12 (s, 3H), 0.90 (s, 9H),
1.55 (d, J = 7.0 Hz, 3H), 2.34 (m, 1H), 2.81 (m, 1H), 2.88 (m,
1H), 3.21 (m, 1H), 3.66 (s, 1H), 4.02 (dd, J = 9.7, 1.2 Hz, 1H),
4.13 (d, J = 10.0 Hz, 1H), 4.53 (dd, J = 12.3, 3.7 Hz, 1H), 5.98 (q,
J = 7.0 Hz, 1H), 7.31 (m, 5H). 13C NMR (125 MHz, CDCl3) δ -5.4,
-5.4, 15.3, 18.3, 26.0, 30.6, 31.9, 42.1, 51.6, 72.3, 74.0, 127.4,
127.5, 128.5, 139.1, 168.0. HRMS-FAB (m/z): [M + H]+ calcd for
C20H33NO3SiI, 490.1274; found 490.1291.
(3S,4S)-3-[((tert-Butyldimethylsilyl)oxy)methyl]-4-(p-
(3R,4S)-3-[((tert-Butyldimethylsilyl)oxy)methyl]-4-(p-
fluorophenyl)-3-hydroxy-1-[(S)-1-phenylethyl]piperidin-2-
one (6). A mixture of CuI (0.52 g, 2.76 mmol) and p-
fluorophenylmagnesium bromide (5.53 mL, 11.06 mmol, 2M)
was stirred at room temperature for 2 h. Then, a solution of
epoxyamide 1b15 (1.0 g, 2.76 mmol) in THF (2.8 mL) was added
dropwise into the reaction mixture during 1.5 h. The resulting
reaction mixture was stirred for 3.5 h at room temperature. The
reaction mixture was quenched with a saturated solution of
ammonium chloride (5 mL) and the aqueous phase was
extracted with EtOAc (4 x 10 mL). The combined organic phases
were dried over Na2SO4 and the solvent was removed under
reduced pressure. The residue was purified by column
chromatography on silica gel (hexane/EtOAc 9:1) to give 1.14 g
fluorophenyl)-3-hydroxy-1-[(S)-1-phenylethyl]piperidin-2-
one (2). A mixture of CuBr•SMe2 (0.22 g, 1.10 mmol) and p-
fluorophenylmagnesium bromide (2.21 mL, 4.42 mmol, 2M) was
stirred at room temperature for 2 h. Then, a solution of
epoxyamide 1a (0.40 g, 1.10 mmol) in THF (1.5 mL) was added
dropwise into the reaction mixture. The resulting reaction
mixture was stirred for 7 h. at room temperature. The reaction
was quenched with a saturated solution of ammonium chloride
(3 mL) and the aqueous phase was extracted with EtOAc (4 x 10
mL). The combined organic phases were dried over Na2SO4 and
the solvent was removed under reduced pressure. The residue
was purified by column chromatography on silica gel
(hexane/EtOAc 14:1) to yield 0.33 g of 2 (66%) as a colorless
20
(90%) of 6 as a colorless syrup. [α]D -14.8 (c = 2.5, CHCl3). 1H
20
syrup. [α]D = -46.25 (c = 1.0, CHCl3). 1H NMR (500 MHz,
NMR (500 MHz, CDCl3) δ: 0.11 (s, 6H), 0.95 (s, 9H), 1.57 (d, J =
7.0 Hz, 3H), 1.83 (dq, J = 13.0, 3.5 Hz, 1H), 2.25 (dddd, J = 13.0,
11.5, 11.5, 4.5 Hz, 1H), 2.72 (d, J = 1.5 Hz, 1H), 2.78 (ddd, J =
12.5, 11.0, 4.0 Hz, 1H), 3.08 (ddd, J = 12.5, 4.5, 3.5 Hz, 1H),
3.29 (d, J = 9.0 Hz, 1H), 3.40 (dd, J = 12.5, 3.5 Hz, 1H), 3.95 (d,
J = 9.0 Hz, 1H), 5.97 (q, J = 7.0 Hz, 1H), 6.99 (m, 2H), 7.24 (m,
2H), 7.32 (m, 5H). 13C NMR (125 MHz, CDCl3) δ: -5.5, -5.3, 14.7,
18.3, 25.8, 25.9, 41.5, 42.6, 51.5, 66.1, 75.2, 114.7 (d, J = 21.1
Hz), 127.4, 127.6, 128.4, 130.7 (d, J = 7.6 Hz), 135.3 (d, J = 3.2
Hz), 139.3, 161.8 (d, J = 243.5 Hz), 171.9. HRMS-FAB (m/z): [M
+ H]+ calcd for C26H37FNO3Si, 458.2527; found 458.2541.
CDCl3) δ: 0.02 (d, J = 1.5 Hz, 6H), 0.92 (s, 9H), 1.57 (d, J = 7.0
Hz, 3H), 1.78 (m, 1H), 2.86 (td, J = 12.0, 5.0 Hz, 1H), 3.01 (dddd,
J = 12.5, 11.5, 11.5, 5.5 Hz, 1H), 3.14 (dd, J = 13.5, 2.5 Hz, 1H),
3.27 (m, 2H), 3.54 (m, 2H), 6.15 (q, J = 7.0 Hz, 1H), 7.00 (m,
2H), 7.34 (m, 7H); 13C NMR (125 MHz, CDCl3) δ -5.8, -5.7, 15.4,
18.1, 23.9, 25.8, 41.0, 46.3, 51.0, 67.2, 74.3, 114.7 (d, J = 20.9
Hz), 127.5, 127.6, 128.5, 130.1(d, J = 7.6 Hz), 135.2 (d, J = 3.4
Hz), 139.5, 161.9 (d, J = 243.6 Hz), 172.9. HRMS-FAB (m/z): [M
+ H]+ calcd for C26H37FNO3Si, 458.2527; found 458.2536.
(3S,4S)-4-(p-Fluorophenyl)-3-hydroxy-3-(hydroxymethyl)-1-
[(S)-1-phenylethyl]piperidin-2-one (8). To a solution of 6
(0.315 g, 0.69 mmol) in THF (8 mL) at room temperature was
added TBAF (1.37 mL, 1.37 mmol, 1M). The reaction mixture
was stirred for 3 h. Then, H2O (4 mL) was added and the
aqueous phase was extracted with EtOAc (4 x 10 mL). The
combined organic phases were dried over Na2SO4. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (hexane/EtOAc,
1:1) to afford 0.227 g of 8 (96%) as a colorless crystal. Mp =
(3R,4R)-3-[((tert-Butyldimethylsilyl)oxy)methyl]-4-(p-
fluorophenyl)-3-hydroxy-1-[(S)-1-phenylethyl]piperidin-2-
one (5). Starting from epoxyamide 1a and by using the same
procedure as for 6, compound 5 was obtained in 80% yield, as a
20
1
colorless syrup. [α]D = -145.26 (c = 1.0, CHCl3). H NMR (500
MHz, CDCl3) δ: 0.08 (s, 3H), 0.11 (s, 3H), 0.94 (s, 9H), 1.55 (d, J
= 7.5 Hz, 3H), 1.79 (dq, J = 13.5, 3.5 Hz, 1H), 2.12 (dddd, J =
13.0, 11.5, 11.5, 4.5 Hz, 1H), 2.72 (d, J = 1.0 Hz, 1H), 2.99 (ddd,
J = 12.5, 4.5, 3.5 Hz, 1H), 3.27 (td, J = 11.5, 3.5 Hz, 1H), 3.31 (d,
J = 12.5 Hz, 1H), 3.48 (dd, J = 13.0, 3.0 Hz, 1H), 3.91 (d, J = 8.5
Hz, 1H), 6.08 (q, J = 7.5 Hz, 1H), 6.97 (t, J = 8.5 Hz, 2H), 7.21
(m, 2H), 7.35 (m, 5H). 13C NMR (125 MHz, CDCl3) δ -5.5, -5.4,
15.8, 18.1, 25.8, 25.8, 41.2, 42.8, 50.8, 65.9, 75.3, 114.8 (d, J =
20.9 Hz), 127.1, 127.4, 128.5, 130.7 (d, J = 7.8 Hz), 135.3 (d, J
= 3.3 Hz), 140.1, 161.8 (d, J = 243.4 Hz), 172.3. HRMS-FAB
(m/z): [M + H]+ calcd for C26H37FNO3Si, 458.2527; found
458.2544.
20
134-136 °C. [α]D = -31.17 (c = 1.01, CHCl3). 1H NMR (500 MHz,
CDCl3) δ: 1.57 (d, J = 7.0 Hz, 3H), 1.86 (ddt, J = 13.5, 5.0, 4.0
Hz, 1H), 2.37 (dddd, J = 13.5, 11.5, 10.0, 5.5 Hz, 1H), 2.78 (ddd,
J = 12.5, 10.0, 5.0 Hz, 1H), 2.97 (dd, J = 11.5, 3.3 Hz, 1H), 3.20
(ddd, J = 12.5, 5.5, 4.0 Hz, 1H), 3.50 (dd, J = 11.5, 10.0 Hz, 1H),
3.62 (s, 1H), 3.69 (dd, J = 11.3, 3.3 Hz, 1H), 3.86 (dd, J = 10.0,
3.0 Hz, 1H), 6.01 (q, J = 7.0 Hz, 1H), 6.98 (m, 2H), 7.22 (m, 2H),
7.30 (m, 3H), 7.37 (m, 2H). 13C NMR (125 MHz, CDCl3) δ: 14.9,
25.6, 40.5, 43.6, 50.9, 66.8, 73.2, 114.9 (d, J = 20.9 Hz), 127.5,
127.7, 128.6, 130.7 (d, J = 7.8 Hz), 134.9 (d, J = 3.2 Hz), 139.2,
(3S,4S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-3-hydroxy-4-
iodo-1-((S) phenylethyl)piperidin-2-one (E). A mixture of CuI
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10.1002/ejoc.201700658
European Journal of Organic Chemistry
FULL PAPER
161.9 (d, J = 244.0 Hz), 172.8. HRMS-EI (m/z) [M]+ calcd. for
C20H22FNO3, 343.1584; found 343.1573.
128.6, 138.5 (d, J = 3.2 Hz), 139.5, 161.7 (d, J = 244.1 Hz),
172.1. HRMS-FAB (m/z) [M + H ]+ calcd for C20H23FNO2;
328.1713 found 328.1707.
(3R,4S)-4-(p-Fluorophenyl)-3-hydroxy-3-(hydroxymethyl)-1-
[(S)-1-phenylethyl]piperidin-2-one
(7).
Starting
from
Procedure for epimerization of cis-11 to trans-11.
compound 2 and by using the same procedure as for 8, 0.226 g
of compound 7 was obtained (96%) as a colorless crystal. Mp =
A solution of cis/trans-11 mixture (0.10 g, 0.30 mmol) in MeOH
(4 mL) was added an aqueous solution of KOH (0.30 mL, 0.30
mmol, 1 M) and heated to reflux temperature for 40 min. The
solvent was removed under reduced pressure, and H2O (2 mL)
was added. The aqueous phase was extracted with EtOAc (5 x
5 mL). The combined organic phases were dried over Na2SO4
and filtered. The solvent was evaporated under reduced
pressure. The residue was purified by column chromatography
on silica gel (hexane/ EtOAc, 3:1) to obtain 0.079 g (78%) of
compound trans-11.
20
1
155-157 °C. [α]D = -103.77 (c = 1.02, CHCl3). H NMR (500
MHz, CDCl3) δ: 1.59 (d, J = 7.5 Hz, 3H), 2.14 (m, 1H), 2.22 (m,
1H), 2.92 (ddd, J = 12.5, 9.0, 5.5 Hz, 1H), 3.00 (br, 1H), 3.20 (d,
J = 10.5, 5.0 Hz, 1H), 3.25 (m, 1H), 3.29 (d, J = 11.5 Hz, 1H),
3.71 (d, J = 11.0 Hz, 1H), 4.10 (s, 1H), 6.08 (q, J = 7.5 Hz, 1H),
7.00 (t, J =8.5 Hz, 2H), 7.21 (m, 2H), 7.35 (m, 5H). 13C NMR
(125 MHz, CDCl3) δ 15.4, 24.8, 40.0, 45.9, 50.8, 66.0, 73.5,
115.13 (d, J = 21.0 Hz), 127.4, 127.7, 128.7, 130.0 (d, J = 7.8
Hz), 134.2 (d, J = 3.4 Hz), 139.2, 161.9 (d, J = 244.4 Hz), 173.0.
HRMS-FAB (m/z) [M + H ]+ calcd for C20H23FNO3 344.1662;
found 344.1661.
((3S,4R)-4-(p-Fluorophenyl)-3-(hydroxymethyl)-1-(1-(S)-
phenylethyl))piperidin (trans-12). A mixture of trans-11 (0.083
g, 0.25 mmol) and LiAlH4 (0.043 g, 1.13 mmol) in THF (3 mL)
was heated to reflux temperature for 1 h. After this time, the
mixture was cooled to 0 °C and H2O (2 mL) was added dropwise
until a salt formation was observed. Then, the resulting solids
were washes with EtOAc (5 x 5 mL) and the organic phase was
dried over Na2SO4. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography
on silica gel (hexanes/EtOAc, 3:1) to obtain 0.075 g of trans-12
(3,4-cis/trans)-(4R)-4-(p-Fluorophenyl)-3-(hydroxymethyl)-1-
[(S)-1-phenylethyl]piperidin-2-one (cis/trans-11). To
a
solution of diol 8 (0.48 g, 1.40 mmol) and DMAP (0.40 g, 3.34
mmol) in CHCl3 (50 mL) at room temperature was stirred for 10
min. Next, a solution of 1,1´-thiocarbonyldiimidazole (0.29 g,
1.67 mmol) in CHCl3 (50 mL) was added via cannula. The
reaction mixture was stirred for 5 h. The solvent was evaporated
under reduced pressure and H2O (10 mL) was added to the
residue. The aqueous phase was extracted with EtOAc (5 x
15mL). The combined organic phases were dried over Na2SO4
and filtered, and the solvent was removed under reduced
pressure. The crude reaction was submitted to the next reaction
without further purification. A solution of the reaction crude and
ACCN (0.47 g, 1.95 mmol) in toluene (245 mL) was heated to
reflux before to add Bu3SnH (0.60 mL, 2.23 mmol). The reaction
mixture was refluxed for 40 min. The reaction mixture was
cooled to ambient temperature, the solvent was evaporated
under reduced pressure and the residue was purified by column
chromatography on silica gel (hexane/EtOAc, 2:1) to give 0.44 g
of the diastereoisomeric mixture cis/trans-11 (94%) in
approximate 5:1 ratio.
20
(94%) as a withe solid. Mp = 129-131 °C. [α]D = -14.23 (c =
20
1
1.06, CHCl3), lit.5b [α]D = -17.4 (c = 1.0, CHCl3). H NMR (500
MHz, CDCl3) δ: 1.44 (d, J = 6.5 Hz, 3H), 1.72 (m, 2H), 1.92 (m,
2H), 2.02 (m, 1H), 2.25 (td, J = 11.0, 5.0 Hz, 1H), 2.91 (m, 1H),
3.23 (dd, J =10.5, 6.5 Hz, 1H), 3.36 (ddd, J = 10.5, 3.5, 2.0 Hz,
1H), 3.40 (dd, J =10.5, 3.5 Hz, 1H), 3.51 (q, J = 6.5 Hz, 1H),
6.96 (t, J = 8.5 Hz, 2H), 7.15 (m, 2H), 7.26 (m, 1H), 7.33 (m, 4H).
13C NMR (125 MHz, CDCl3) δ 19.5, 34.6, 44.4, 44.5, 50.8, 54.5,
64.2, 65.0, 115.3 (d, J = 20.8 Hz), 126.9, 127.8, 128.1, 128.8 (d,
J = 7.7 Hz), 140.2 (d, J = 3.2 Hz), 143.1, 161.4 (d, J = 242.7 Hz).
HRMS-FAB (m/z) [M + H ]+ calcd for C20H25FNO, 314.1920;
found 314.1910.
(3S,4R)-1-(tert-Butoxycarbonyl)-4-(p-fluorophenyl)-3-
Following the same procedure starting from diol 7, 0.34 g of the
diastereoisomeric mixture cis/trans-11 (75%) in approximate 3:1
ratio, was isolated.
(hydroxymethyl)piperidine (13). To a solution of trans-12
(0.032 g, 0.10 mmol), Boc anhydride (0.040 g, 0.18 mmol) and
Pd(OH)2 (0.013 g, at 20 wt. %) in EtOAc (1.5 mL) was stirred
under 100 psi of H2 for 11 h. After this time, the reaction mixture
was filtered over celite and rinsed with EtOAc. The solvent was
removed under reduced pressure. The residue was purified by
flash chromatography on silica gel (hexanes/EtOAc, 3:1) to
(3R,4R)-4-(p-Fluorophenyl)-3-(hydroxymethyl)-1-[(S)-1-
phenylethyl]piperidin-2-one (cis-11). White solid. Mp = 133-
20
1
135 °C. [α]D = -40.97 (c = 1.03, CHCl3). H NMR (500 MHz,
CDCl3) δ: 1.56 (d, J = 7.0 Hz, 3H), 1.87 (m, 1H), 2.08 (ddt, J =
13.0, 8.0, 5.0 Hz, 1H), 2.82 (ddd, J = 13.0 6.2, 5.0 Hz, 1H), 2.91
(ddd, J = 9.0, 6.5, 4.5 Hz, 1H), 3.09 (ddd, J = 13.0 8.5, 5.0 Hz,
1H), 3.35 (m, 2H), 3.82 (t, J = 10.0, 1H), 3.99 (d, J = 8.0 Hz, 1H),
6.17 (q, J = 7.0 Hz, 1H), 6.99 (t, J = 8.5 Hz, 2H), 7.09 (m, 2H),
7.33 (m, 5H). 13C NMR (125 MHz, CDCl3) δ: 14.9, 29.2, 38.3,
39.6, 46.8, 49.9, 62.2, 115.3 (d, J = 21.1 Hz), 127.1, 127.4,
128.4, 129.0 (d, J = 7.8 Hz), 136.0 (d, J = 3.3 Hz), 139.7, 161.5
(d, J = 244.1 Hz) 172.5. HRMS-FAB (m/z) [M + H ]+ calcd for
C20H23FNO2, 328.1713; found 328.1705.
20
afford 0.030 g (96%) as a colorless viscous liquid. [α]D = -5.01
20
(c = 1.87, MeOH), lit.[5b] [α]D = -6.8 (c = 1.75, MeOH)). 1H NMR
(500 MHz, CDCl3) δ: 1.25 (s, 9H), 1.64 (m, 1H), 1.78 (m, 2H),
2.54 (m, 1H), 2.70 (t, J = 12.0 Hz, 1H), 2.77 (br, 1H), 3.25 (dd, J
= 11.0, 6.5 Hz, 1H), 3.43 (dd, J = 11.0, 3.0 Hz, 1H), 4.20 (br, 1H),
4.36 (br, 1H), 6.99 (m, 2H), 7.15 (m, 2H). 13C NMR (125 MHz,
CDCl3) δ 28.4, 34.0, 43.8, 44.0, 63.0, 79.7, 128.7 (d, J = 20.9
Hz), 128.7 (d, J = 7.9 Hz), 139.4 (d, J = 3.2 Hz), 154.9, 161.5 (d,
J = 243.1 Hz).
(3S,4R)-4-(p-Fluorophenyl)-3-(hydroxyl
(3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-1-(tert-
methyl)-1-[(S)-1-phenylethyl]piperidin-2-one (trans-11). Mp =
Butoxycarbonyl)-4-(p-fluorophenyl)piperidine (15). To
a
20
148-150 °C. [α]D = -79.06 (c = 1.02, CHCl3). 1H NMR (500 MHz, solution of 13 (0.047 g, 0.15 mmol) and MsCl (13 μ, 0.17 mmol)
CDCl3) δ 1.56 (d, J = 7.0 Hz, 3H), 1.92 (m, 2H), 2.63-2.73 (m,
2H), 2.80 (ddd, J = 12.5, 8.5, 7.0 Hz, 1H), 3.18 (dt, J =12.5, 4.0
in CH2Cl2 (3.0 mL) at room temperature was added Et3N (21 μ,
0.15 mmol). The reaction mixture was stirred for 1.5 h, next, H2O
Hz, 1H), 3.60 (ddd, J = 11.0, 7.0, 3.2 Hz, 1H), 3.68 (ddd, J =11.0, (1.5 mL) was added and the organic phase was extracted with
9.0, 3.5 Hz, 1H), 4.13 (dd, J = 7.5, 3.5 Hz, 1H), 6.15 (q, J = 7.0
CH2Cl2 (4 x 5 mL). The combined organic phases were dried
over Na2SO4. The solvent was removed under reduced pressure,
and the reaction crude of 14 was submitted to the next reaction
without further purification. A solution of NaH (15 mg, 0.37 mmol,
Hz, 1H), 7.01 (t, J = 8.5 Hz, 2H), 7.14 (m, 2H), 7.34 (m, 5H); 13
C
NMR (125 MHz, CDCl3) δ: 15.2, 30.9, 40.3, 40.9, 49.9, 50.1,
62.4, 115.7 (d, J = 21.2 Hz), 127.4, 127.5, 128.5 (d, J = 7.8 Hz),
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10.1002/ejoc.201700658
European Journal of Organic Chemistry
FULL PAPER
20
60% dispersion in mineral oil) and sesamol (33 mg, 0.24 mmol)
in THF (1.5 mL) was stirred for 1 h. at room temperature. Next,
the reaction crude of 14 in THF (1.5 mL) was added into the
reaction mixture. Finally, the resulting mixture was heated to
reflux temperature for 6 h. After cooling to ambient temperature,
H2O (3 mL) was added and extracted with EtOAc (5 x 8 mL).
The combined organic extracts were dried over Na2SO4 and the
residue was purified by column chromatography on silica gel
(hexane/EtOAc, 10:1) to obtain 42.4 mg (65%) of 15 as colorless
crystals. Mp = 121-123°C, lit.[6] = 123-124°C. [α]D = -84.0 (c =
20
0.27, MeOH), lit.[6] [α]D
= -88.0 (c = 1.0, MeOH). NMR
spectroscopy match perfectly with those reported in the literature.
Supporting information for this article (Experimental procedures
and characterization data, NMR spectra, crystallographic data in
CIF format (CCDC 1541564-1541565), selected crystallographic
data and perspective views of the molecular structures for 7 and
8) is available on the WWW under:
oil. [α]D = -23.46 (c = 0.47, MeOH), lit.[5b] [α]D = -25.1 (c = 1.0,
MeOH). 1H NMR (500 MHz, CDCl3) δ: 1.50 (s, 9H), 1.70 (m, 1H),
1.80 (m, 1H), 2.02 (m, 1H), 2.67 (td, J = 12.5, 3.7 Hz, 1H), 2.81
(m, 2H), 3.44 (dd, J = 9.5. 6.5 Hz, 1H), 3.60 (dd, J = 9.5, 3.0 Hz,
1H), 4.24 (br, 1H), 4.44 (br, 1H), 5.89 (s, 2H), 6.13 (dd, J = 8.5,
2.5 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H),
6.98 (m, 2H), 7.14 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 28.5,
33.9, 41.9, 44.0, 68.7, 79.7, 98.0, 101.1, 105.5, 107.8, 115.5 (d,
J = 21.0 Hz), 128.7 (d, J = 7.8 Hz), 139.1 (d, J = 3.3 Hz), 141.6,
148.1, 154.2, 154.8, 161.6 (d, J = 243.1 Hz).
20
20
Keywords: 2,3-Epoxyamides
Stereodivergence • Alkaloids
•
Convergent synthesis
•
[1]
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a) D. W. Robertson, J. H. Krushinski, R. W. Fuller, J. D. Leander, J.
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fluorophenyl)-1-(1-(S)-phenylethyl)piperidine (17). To
a
solution of trans-12 (0.068 g, 0.22 mmol) and MsCl (18 μ, 0.24
mmol) in CH2Cl2 (4 mL) at room temperature was added Et3N
(28 μ, 0.21 mmol). The reaction mixture was stirred for 3 h
before to add H2O. The organic phase was extracted with EtOAc
(4 x 5 mL), the combined organic layer was dried over Na2SO4
and filtered; the solvent was removed under reduced pressure.
The residue (16) was submitted to the next reaction without
further purification. To the reaction crude of 16 was added a
mixture of xylene/2-butanol (3 mL/1.5 mL), and a solution of
sesamol (0.041g, 0.30 mmol) and NaOH (0.037 g, 0.97 mmol) in
H2O (1 mL). The reaction mixture was heated to reflux
temperature for 18 h. The resulting reaction mixture was cooled
to ambient temperature, extracted with EtOAc (5 x 5 mL) and the
combined organic layer was dried over Na2SO4 and concentrate
under reduced pressure. The residue was purified by column
chromatography on silica gel (hexane/EtOAc, 10:1) to obtain
[3]
[4]
For a review see: C. De Risi, G. Fanton, G. P. Pollini, C. Trapella, F.
Valente and V. Zanirato, Tetrahedron: Asymmetry 2008, 19, 131–155,
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a) M. Amat, J. Hidalgo, J. Bosch, Tetrahedron: Asymmetry 1996, 7,
1591-1594; b) M. Amat, J. Bosch, J. Hidalgo, M. Cantó, M. Pérez, N.
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[6]
[7]
L. T. Liu, P.-C. Hong, H.-L. Huang, S.-F. Chen, C.-L. J. Wang, Y.-S.
Wen, Tetrahedron: Asymmetry 2001, 12, 419-426.
20
0.063 g (67%) of 17 as a colorless oil. [α]D = -67.61 (c = 1.0,
1
a) S. Yamada, I. Jahan, Tetrahedron Lett. 2005, 46, 8673-8676; b) S.
Somaiah, S. Sashikanth, V. Raju, K. V. Reddy, Tetrahedron:
Asymmetry 2011, 22, 1–3.
CHCl3), H NMR (500 MHz, CDCl3) δ 1.44 (d, J = 7.0 Hz, 3H),
1.74 (m, 2H), 1.93 (td, J = 11.0, 3.5, 1H), 2.02 (t, J = 11.0, 1H),
2.22 (m, 1H), 2.38 (td, J = 11.0, 5.0 Hz, 1H), 2.92 (m, 1H), 3.42
(m, 2H), 3.51 (q, J = 7.0 Hz, 1H), 3.57 (dd, J = 9.5, 3.0 Hz, 1H),
5.87 (s, 2H), 6.12 (dd, J = 8.5, 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz,
1H), 6.62 (d, J = 8.5 Hz, 1H), 6.95 (t, J = 8.5 Hz, 2H), 7.14 (m, 2
H), 7.26 (m, 1H), 7.33 (m, 4H). 13C NMR (125 MHz, CDCl3) δ
19.6, 34.6, 42.4, 44.3, 50.9, 54.8, 64.9, 69.7, 97.9, 101.0, 105.5,
107.8, 115.3 (d, J = 21.0 Hz), 126.8, 127.7, 128.1, 128.8 (d, J =
7.7 Hz), 139.9 (d, J = 3.1 Hz), 141.4, 143.4, 148.1, 154.4, 161.4
(d, J = 242.5 Hz). HRMS-FAB (m/z) [M + H ]+ calcd for
C27H29FNO3, 434.2131; found 434.2102.
[8]
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a) D. A. Greenhalgh, N. S. Simpkins, Synlett 2002, 2074-2076; b) C. D.
Gill, D. A. Greenhalgh, N. S. Simpkins, Tetrahedron 2003, 59, 9213-
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23, 1206–1212
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Yamaoka, Y. Kawada, Y. Tagami, M. Otsuki, T. Ohshima, Chem.
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(-)-Paroxetine
To a solution of 15 (37 mg, 0.09 mmol) in CH2Cl2 (0.5 mL) was
added dropwise 0.5 mL of CF3CO2H (6.38 mmol). The resulting
reaction mixture was stirred for 20 min at room temperature.
Then, a saturated aqueous solution of NaHCO3 was added and
the aqueous phase was extracted with CH2Cl2 (4 x 5 mL). The
combined organic phases were dried over Na2SO4. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel (EtOAc:MeOH,
1:1) to afford 21 mg (75%) of (-)-paroxetine as a colorless oil;
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1004-1005; b) T. Senda, M. Ogasawara, T. Hayashi, J. Org. Chem.
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20
20
[α]D = -79.7 (c = 1.0, MeOH) lit.[5b] (-)-paroxetine [α]D = -80.8
(c = 1.25, MeOH). (-)-Paroxetine was dissolved in MeOH (0.5
mL) and a solution of HCl (0.01 mL, 10%) was added. The
solvent was removed under reduced pressure and purification
was accomplished by recrystallization from methanol, ethyl ether
and hexanes to afford paroxetine hydrochloride as colorless
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10.1002/ejoc.201700658
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FULL PAPER
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10.1002/ejoc.201700658
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
By featuring a diastereodivergent
copper-catalyzed regioselective ring-
opening of diastereomeric 2,3-
epoxyamides, a diastereoconvergent
synthesis of (-)-paroxetine is
presented.
Delfino Chamorro-Arenas, Lilia Fuentes,
Leticia Quintero, Silvano Cruz-Gregorio,
Herbert Höpfl, Fernando Sartillo-Piscil*
Page No. – Page No.
Diastereoconvergent Synthesis of (-)-
Paroxetine
* De Novo Synthesis of (-)-Paroxetine
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