Total Asymmetric Synthesis of (+)-Paroxetine and (+)-Femoxetine

Article abstract of DOI:10.1002/ejoc.201901389

Total, asymmetric synthesis of (+)-Paroxetine and (+)-Femoxetine, selective serotonin reuptake inhibitors, used for the treatment of depression, anxiety, and panic disorders is reported. The key step is organocatalytic Michael addition of aldehydes to trans-nitroalkenes realized in bath or continues flow. High efficiency and selectivity in the Michael addition was achieved by application of Wang resin-supported Hayashi–J?rgensen catalyst.

Full text of DOI:10.1002/ejoc.201901389

DOI: 10.1002/ejoc.201901389
Full Paper
Total Synthesis
Total Asymmetric Synthesis of (+)-Paroxetine and (+)-Femoxetine
Piotr Szcześniak,*[a] Szymon Buda,[b] Laura Lefevre,[b] Olga Staszewska-Krajewska,[a] and
Jacek Mlynarski[a]
Abstract: Total, asymmetric synthesis of (+)-Paroxetine and (+)- hydes to trans-nitroalkenes realized in bath or continues flow.
Femoxetine, selective serotonin reuptake inhibitors, used for High efficiency and selectivity in the Michael addition was
the treatment of depression, anxiety, and panic disorders is re- achieved by application of Wang resin-supported Hayashi–
ported. The key step is organocatalytic Michael addition of alde- Jørgensen catalyst.
Introduction
oxetine was ranked 94th on the list of bestselling drugs, with
over $1 billion in sales.
Depression is a common debilitating mental disorder, that
produces negative consequences in the lives of more than
300 million people all over the world, and additional hundreds
of thousands people of all ages are diagnosed with depression
every year. Depression is ranked as the single largest contribu-
tor to global disability, as well as a leading cause of suicide
deaths, which number close to 800 000 per year.[1] Depression
and its treatment has an enormous effect on the economy. It is
estimated to cost the U.S. about $210 billion a year in produc-
tivity loss and health care needs. Global revenue for anti-
depressants was about $14.5 billion in 2014 and is projected to
grow to nearly $17 billion by 2020.[2]
(+)-Femoxetine is related selective serotonin reuptake inhibi-
tor, which was developed as a potent antidepressant by Danish
pharmaceutical company Ferrosan in 1975. However, its devel-
opment was halted to focus attention on paroxetine instead,
given femoxetine′s inability to be administered as a daily pill.[6]
(–)-Paroxetine hydrochloride is an active ingredient of Paxil®,
Seroxat®, which is approved by FDA for treatment of depression
resistant to other antidepressants, depression complicated by
anxiety, panic disorder, social and general anxiety disorder, ob-
sessive-compulsive disorder, premenstrual dysphoric disorder,
premature ejaculation, and hot flashes of menopause in women
with breast cancer.[3] The mechanism of paroxetine action re-
sults from selective inhibition of the reuptake of serotonin by
blocking the serotonin transporter. The other property par-
oxetine has is its ability to block muscarinic receptors, which
causes the drug to have anticholinergic effects. The importance
for this in clinical practice is that central anticholinergic effects
can trigger cognitive impairment in the elder.[4] Although it was
approved for medical treatment in the U.S. in 1992 worldwide
net sales strongly increase year by year.[5] In 2006, paroxetine
was the fifth-most prescribed antidepressant in the U.S. retail
market, with more than 19.7 million prescriptions. In 2007 par-
Because of the medicinal importance of paroxetine and fem-
oxetine, the synthesis of this trans-3,4-disubstituted piperidines
derivative has attracted many researchers at academia as well
as in industry. The most commonly used strategies for the
stereo- and enantioselective synthesis of paroxetine and femox-
etine are based on enzymatic asymmetric desymmetrization,[7]
chiral auxiliary,[8] asymmetric catalysis,[9] chiral pool[10] and chi-
ral base.[11] These methods have proven effective, however their
main drawback results from relatively long and complicated
synthetic sequence. Wherefore, it is still necessary to find an
alternative and improved process for paroxetine and fem-
oxetine manufacturing that would be more competitive and
cost-efficient.
Very recently, we demonstrated that functionalized, optically
active cyclic nitrones or pyrrolidines can be obtained in a simple
and highly efficient manner via organocatalytic Michael addi-
tion of aldehydes to trans-nitroalkenes and subsequent reduc-
tive cyclization.[12–14] This methodology was successfully ap-
plied, as a key step in the asymmetric total synthesis of meth-
dilazine, BZN molecule, and asenapine.
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
https://www.icho.edu.pl
E-mail: pszczesniak@icho.edu.pl
[b] Faculty of Chemistry, Jagiellonian University,
Gronostajowa 2, 30-387 Krakow, Poland
Considering the chemical structure of paroxetine and femox-
etine as a trans-3,4-disubstituted piperidine ring systems. con-
ceptually, we visualized that they can be built form correspond-
https://chemia.uj.edu.pl/pl
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901389.
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Scheme 1. Retrosynthetic analysis of (+)-paroxetine 1a and (+)-femoxetine 10b.
ing δ-nitroaldehyde 2a/b via reductive cyclization reaction.
δ-nitroaldehyde 2a/b can be obtained from γ-nitroaldehyde
3a/b via one-carbon elongation reaction. In turn, synthon
3a/b could be obtained via organocatalytic Michael addition of
aldehydes 4a/b to trans-nitroalkene 5a/b (Scheme 1).
On the basis of the above analysis, the proposed synthetic
strategy seems to be short and simple with high atom econ-
omy. Moreover, the undoubted advantage is that both stereo-
genic center at C3 and C4 are installed in one step. The applica-
tion of the (S)-α,α-diphenylprolinol trimethylsilyl ether (Haya-
shi–Jørgensen catalyst cat. 1) as a catalyst for Michael addition
reaction should lead to (+)-paroxetine 1a and (+)-femoxetine
10b. Successful execution of this strategy will naturally allow
one to synthesize (–)-paroxetine and (–)-femoxetine by simply
switching of the catalyst.
Results and Discussion
Scheme 2. Reagents and conditions: a) bromoacetaldehyde diethyl acetal
(1.1 equiv.), K2CO3 (1.1 equiv.), DMF, 140° C, overnight, 6a 95 %, 6b 97 %; b)
TsOH (10 mol-%), acetone/H2O (10:1), 90 min; c) i. MeNO2 (10 equiv.), N,N,N,N-
tetramethylguanidine (10 mol-%), toluene, 0[°] C, 90 min; ii. MsCl (1.5 equiv.),
Et3N (1.5 equiv.), 0[°] C, 40 min, 5a 62 % (4 steps, starting from sesamol) 5b
48 % (4 steps, starting from 4-methoxyphenol); d) Dess–Martin periodinate
(1.2 equiv.), CH2Cl2, r.t., 30 min, 4a 98 %, 4b 94 %.
The study started with the preparation of nitroalkene 5a and
aldehyde 4a – acceptor and donor in Michael addition reaction
(Scheme 2). The first step in the synthesis of 5a consists of
transformation of commercially available sesamol to acetal 6a.
The reaction proceeds in 95 % yield in the presence of sodium
hydride and bromoacetaldehyde diethyl acetal in boiling 1,4-
dioxane. Subsequent hydrolysis of acetal 6a promoted by p-
toluenesulfonic acid (10 mol-%) in a mixture of acetone and
water (9:1) provided to aldehyde 7a. Then aldehyde 7a was
submitted to Henry reaction with nitromethane and catalytic
amount of N,N,N,N-tetramethylguanidine in toluene. Subse-
quent addition of methanesulfonyl chloride and triethylamine
to the intermediate nitro alcohol effected elimination to give
the desired nitro olefin 5a in good overall yield 62 %. In turn,
aldehyde 4a was obtained in 98 % yield from commercially
available 2-(4-fluorophenyl)ethanol via Dess–Martin oxidation.
The same reaction sequence was used for the preparation of
nitroalkane 5b, and aldehyde 4b. 5b was obtained in overall
yield 48 % started from commercially available 4-methoxy-
phenol, and the aldehyde 4b was obtained in 94 % started from
2-phenylethan-1-ol (Scheme 2).
experience, the reaction between nitro olefin 5a and aldehyde
4b was performed in chloroform in the presence of 10 mol-%
of the Hayashi–Jørgensen catalyst cat. 1. and benzoic acid
(20 mol-%) as an additive, at ambient temperature. The reaction
was complete within 1 h, and the corresponding γ-nitroalde-
hyde 3a was isolated in an excellent yield of 93 %, with high
stereoselectivity (ee 87 %, syn isomer), as an inseparable mix-
ture of diastereoisomers in syn/anti ratio 1.3:1. A comparable
result was obtained in an analogous Michael addition between
5b and 4b. The reaction was complete within 30 min, provided
to γ-nitroaldehyde 3b in an excellent 90 % yield, high stereo-
selectivity (ee 90 %, syn isomer), and low diastereoselectivity
(syn/anti ratio 1.2:1). Based on our previous experience, we rea-
soned that the low diastereselectivity observed in Michael addi-
tion catalyzed by Hayashi–Jørgensen catalyst cat. 1 might result
With the desired Michaele acceptor 5a/b and donor 4a/b in from epimerization of α-substituted γ-nitroaldehydes. The isom-
hand, we initiated the study of the organocatalytic Michaele erization process occurs when the products remain in contact
addition reaction leading to γ-nitroaldehyde 3a/b. Based on our with the catalyst for an extended period of time, after turnover
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is completed. The γ-nitroaldehydes with high syn/anti ratio re- flow was recognized at the end of 2000 by Lectka and co-
act with the catalyst, a low steady-state concentration of the workers[17,18] examples regarding the use of enantioselective
enamine is rapidly established, and the equilibration between organocatalyzed reactions in continuous flow are still scarce,[19]
syn and anti continues until thermodynamic ratio is reached and the field of continuous-flow asymmetric organocatalyzed
(Scheme 3). This effect, intensively studied and explained by reactions is still in its infancy. For the best of our knowledge
Blackmond,[15] has been confirmed by our group.[12–14]
there are only two literature precedents for the organocatalytic
Michael addition of aldehydes to nitroolefins in continuous-
flow. In both examples solid-supported peptides have been ap-
plied as catalysts.[20,21]
In our studies we proposed application of heterogeneous
catalytic system based on an insoluble Wang resin as a solid
support for the Hayashi–Jørgensen catalyst cat. 2. Only recently
we demonstrated that this catalytic system is highly efficient in
stereoselective Michael addition reaction leading to γ-nitroalde-
hydes with high yield, enantio- and diastereoselectivity.[13]
Moreover, the catalyst could be easily recovered and reused in
the next catalytic cycle without significant loss of catalytic activ-
ities and stereoselectivities.
Scheme 3. Reversible enamine formation between cat. 1, 3-syn, and 3-anti.
We began our investigation into organocatalytic Michael ad-
dition in continuous flow with examination of the catalytic effi-
ciency of the immobilized Hayashi–Jørgensen catalyst cat. 2. in
standard bath operation. For this purpose, the Michael addition
between 4a and 5a was performed in deuterated chloroform
in the presence of 15 mol-% of cat. 2 and 20 mol-% of benzoic
acid as an additive, at ambient temperature. After 4 h we ob-
served complete conversion to the desired product 3a with syn/
anti ratio 4.6:1, and ee 93 % (syn isomer). In turn, the reaction
between 4b and 5b under the same reaction condition pro-
vides to corresponding γ-nitroaldehyde 3b with syn/anti ratio
3.6:1, and ee 89 % (syn isomer) (Scheme 4). In both cases, after
simple filtration, catalyst cat. 2 was recovered in 100 % yield,
and crude γ-nitroaldehydes 3a and 3b with perfect purities as
judged by NMR spectroscopy were carried out the subsequent
elongation reaction.
In order to verify this hypothesis we conducted a 1H-NMR
experiment in which we expected to observe the diastereo-
meric ratio decreasing in time during Michael addition reaction.
The reaction between 4a and 5a was performed in deuterated
chloroform in the presence of 10 mol-% of the Hayashi–Jørgen-
sen catalyst cat. 1 and benzoic acid (20 mol-%) as an additive,
at ambient temperature. After 40 min, we observed 95 % con-
version to the desired γ-nitroaldehyde 3a with syn/anti ratio 3:1.
After complete conversion of starting aldehyde 4a, we began
to observe decrease in the syn/anti ratio to 2:1, and the equili-
bration between syn and anti continued until the syn/anti ratio
reached equilibrium at 1.3:1, and didn't change in extra time
(see supporting information, Scheme 1). Moreover, we found
that the isomerization progresses not only after turnover is
completed, but also during purification by column chromatog-
raphy. When crude γ-nitroaldehyde 3a with syn/anti ratio 3:1
was purified on silica gel column chromatography, the syn/anti
ratio of the obtained product decreased to 1.3:1.
Analogue isomerization effect was observed in the Michael
addition between 4b and 5b catalyzed by 10 mol-% of the
Hayashi–Jørgensen catalyst cat. 1. At the moment of complete
conversion the syn/anti ratio of γ-nitroaldehyde 3b, was estab-
lished at 3.5:1 and it decreased during 24 h to equilibrium
reached at 1.2:1 (see supporting information, Scheme 2).
Bearing in mind that in order to maintain the high diastereo-
meric ratio, the catalyst has to be removed from the reaction
mixture immediately after complete conversion of substrates,
and the product should be used for the next step without puri-
fication, we reasoned that this drawback could be mitigated
by replacing batch operation with a continuous flow process
involving a suitable immobilized catalyst. This approach should
ensure minimal contact time between product and catalyst,
moreover continuous flow technologies have recently attracted
attention in modern synthetic chemistry as they offer several
advantages over conventional batch procedures, including im-
proved heat and mass transfer, efficient mixing of substrates
and shorter reaction times.[16] Although the potential of carry-
ing out asymmetric organocatalytic reactions in continuous
Scheme 4. Reagents and conditions: 4a/b (1.5 equiv.), 5a/b (1.0 equiv.), cata-
lyst cat. 2 (15 mol-%)(catalyst loading 1.0 mmol/g), CDCl3, r.t.; 3a, 100 %
conversion(a) after 4 h, syn/anti* 4.6:1, ee(b) 93 % (syn isomer); 3b, 100 % con-
version* after 5 h, syn/anti*3.6:1, ee(b) 89 % (syn isomer); (a)determined by
1H-NMR; (b) determined by HPLC.
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Encouraged by the results, in the next step we investigated 4b and 5b was performed in optimal reaction condition (flow
the behavior of catalyst cat.2 in the flow Michael addition be- rate 0.005 mL min–1) to achieve complete conversion to desired
tween 4a/b and 5a/b. For this purpose, a simple homemade product 3b with syn/anti ratio approximately 3.0:1 (Table 1, en-
flow setup had been constructed consisting of feeding stream try 17–20).
connected to a syringe pump and column packed with immobi-
lized Hayashi–Jørgensen catalyst cat. 2. The column outcome
was connected to the fraction collector (Scheme 5).
Table 1. Optimization of the Michael addition reaction between aldehydes
4a/b and nitroolefins 5a/b catalyzed by Wang resin solid support Hayashi–
Jørgensen catalyst cat. 2 in continues flow.
Entry
Reagent and
condition
Reaction
time [h]
Conversion
[%][a]
syn/anti[a]
1
2
3
4
5
6
7
8
A
A
A
A
A
B
B
B
B
B
C
C
C
C
C
C
D
D
D
D
4
6
9
11
15
3
5
7
9
11
4
6
8
10
12
14
7
9
11
15
100
100
100
100
98
100
100
100
89
73
56
53
51
49
47
45
100
100
100
100
2.9:1
3.0:1
3.2:1
3.3:1
3.3:1
3.3:1
3.7:1
3.8:1
4.0:1
4.2:1
6.5:1
6.5:1
6.6:1
6.6:1
6.7:1
6.7:1
2.7:1
2.9:1
3.0:1
3.2:1
9
10
11
12
13
14
15
16
17
18
19
20
Scheme 5. Continues flow system for the organocatalytic Michael addition
reaction catalyzed by Wang resin solid support Hayashi–Jørgensen catalyst
cat. 2.
The study started with an adjustment of the optimal flow
rate means fine-tuning of the residence time on the catalyst
bed; complete conversion without isomerization. The best re-
sults were obtained in the Michael addition between 4a and
5a with a flow rate 0.005 mL min–1. A complete conversion to
the desired product 3a with syn/anti ratio approximately 3.2:1
was achieved during total operation time, however more than
16 h were required to pump 5 mL of the starting material
through the system (Table 1, entry 1–5). In contrast, when a
flow rate of 0.5 mL min–1 was used, 1 h 40 min were sufficient
for a single run, high syn/anti ratio 4.5:1 was observed, but the
conversion dropped to 17 %. As a compromise, the flow rate
was set to 0.01 mL min–1 to achieve a conversion not exceeding
50 % and syn/anti ratio 3.8:1. Next, the catalytic robustness was
investigated. For this purpose, the reaction was performed with
a double amount of substrates, under optimal flow rate
[a] Reagent and Condition: A: 5a (20 mg, 1.0 equiv.), 4a (25 mg, 2.0 equiv.),
PhCO2H (2.2 mg, 20 mol-%), cat. 2 (13.4 mg, 15 mol-%)(catalyst loading
1.0 mmol/g), CHCl3 (5 mL), r.t., total operation time (16 h 40 min.), flow rate
0.005 mL min–1; B: 5a (40 mg, 1.0 equiv.), 4a (50 mg, 2.0 equiv.), PhCO2H
(4.4 mg, 20 mol-%), cat. 2 (13.4 mg, 7.5 mol-%)(catalyst loading 1.0 mmol/g),
CHCl3 (5 mL), r.t., total operation time (16 h 40 min.), flow rate 0.005 mL min–1
;
C: 5a (40 mg, 1.0 equiv.), 4a (50 mg, 2.0 equiv.), PhCO2H (4.4 mg, 20 mol-%),
cat. 2 (13.4 mg, 7.5 mol-%)(catalyst loading 1.0 mmol/g), CHCl3 (5 mL), 0° C,
total operation time (16 h 40 min.), flow rate 0.005 mL min–1; D: 5b (20 mg,
1.0 equiv.), 4b (23 mg, 2.0 equiv.), PhCO2H (2.2 mg, 20 mol-%), cat. 2
(14.3 mg, 15 mol-%)(catalyst loading 1.0 mmol/g), CHCl3 (5 mL), r.t., total
operation time (16 h 40 min.), flow rate 0.005 mL min–1; [a] determined by
1H-NMR.
It is worth emphasizing that, ee ratio remains constant in
investigated flow condition, and does not differ from that ob-
tained in bath procedure.
Having established the suitable conditions in the organocat-
0.005 mL min–1. To our delight, catalyst cat. 2 remained active alytic Michael addition catalyzed by a solid supported Hayashi–
for most of the reaction time leading to obtaining the desired Jørgensen catalyst cat. 2, we were ready to examine transfor-
product 3a with complete conversion and syn/anti ratio approx- mation of γ-nitroaldehyde 3a into the desired (+)-paroxetine
imately 4.0:1. However, after 9 h the catalytic activity slightly 1a-trans. For this purpose, the requisite one-carbon elongation
decreased (Table 1, entry 6–10). For further optimization, the was achieved by using a Wittig olefination of the crude mixture
temperature impact was investigated. A significant increase in of γ-nitroaldehyde 3a with methoxymethyltriphenylphospho-
syn/anti ratio of approximately 6.6:1 was observed when the niumchloride in the presence of LiHMDS. After short column
reaction between 4a and 5a was performed at 0° C with a flow chromatography corresponding product 8a was obtained in
rate 0.005 mL min–1, however the conversion range was from overall yield 68 % after two steps as a mixture of E/Z and
56 to 45 % (Table 1 entry 11–16). Finally, the reaction between syn/anti isomers. Subsequent hydrolysis of olefin 8a promoted
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Scheme 6. Reagents and conditions: a) (methoxymethyl)-triphenylphosphonium chloride (5.0 equiv.), LiHMDS (1.0
(after two steps); b) 5
(after two steps); d) Et3N (1.0 equiv.), benzyl chloroformate (1.0 equiv.), CH2Cl2, 0[°] C to r.t., 24 h, 9a-trans (71 %, ee 80 %), 9a-cis (71 %, ee 53 %).
M
in THF)(4.8 equiv.), THF, 0[°] C, 1 h, 68 %
M
aq. HCl, THF, bp, 1 h; c) Zn powder (25.0 equiv.), MeOH:AcOH (1:1), 0[°] C to r.t., 24 h, 1a-trans 52 % (after two steps), 1a-cis 12 %
Scheme 7. Reagents and conditions: a) (methoxymethyl)-triphenylphosphonium chloride (5.0 equiv.), LiHMDS (1.0
M in THF)(4.8 equiv.), THF, 0[°] C, 1 h, 62 %
(after two steps); b) 5 aq. HCl, THF, bp, 1 h; c) Zn powder (25.0 equiv.), MeOH:AcOH (1:1), 0[°] C to r.t., 24 h, 1b-trans 45 % (after two steps), 1b-cis 14 %
M
(after two steps); d) NaCNBH3 (3.0 equiv.), formaldehyde (37 %) (1.5 equiv.), AcOH (one drop), MeOH, 0[°] C to r.t., overnight, 10b-trans (96 %), 10b-cis (95 %);
e) Et3N (1.0 equiv.), benzyl chloroformate (1.0 equiv.), CH2Cl2, 0[°] C to r.t., 24 h, 9b-trans (72 %, ee 75.4 %), 9b-cis (73 %, ee 51.8 %).
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by hydrochloric acid in boiling THF was provided to aldehyde Experimental Section
2a as an inseparable mixture of syn/anti isomer. Aldehyde 2a
The synthesis of Hayashi–Jørgensen Catalyst (cat. 1)
turned out to be unstable, and it decomposed during purifica-
tion on column chromatography. 2a was not purified, but after
aqueous workup it was subjected directly to the final reductive
cyclization step. The reductive cyclization reaction was per-
formed with Zn powder (25 equiv.) in a mixture of acetic acid
and methanol (1:1) at 0° C to room temperature over 24 h. After
workup, the obtained mixtures of diastereomeric paroxetine
were separated to single isomers by column chromatography
to afford (+)-paroxetine 1a-trans in overall yield 52 %, and 4-
epi-(+)-Paroxetine 1a-cis in overall yield 12 % after two steps.
The relative configuration of both 1a-trans and 1a-cis isomers
was confirmed on the basis of the analysis of NOE experiments.
The optical purity of 1a-trans and 1a-cis was established after
transformation to corresponding Cbz derivatives 9a-trans and
9a-cis, and it was found to be 80 % for 9a-trans, and 53 % for
9a-cis (Scheme 6).
The same reaction sequence as shown in Scheme 7 was used
for the preparation of (+)-femoxetine 10b. The crude mixture
of γ-nitroaldehyde 3b (syn/anti 3:1) was submitted Wittig olefin-
ation leading to mixture of E/Z and syn/anti 8b in overall yield
62 % after two steps. Then, hydrolysis of olefin 8b with hydro-
chloric acid yielded δ-nitroaldehyde 2b, which was used directly
for the next step without purification. Based on the previous
experiment, the treatment of δ-nitroaldehyde 2b with zinc
powder (25.0 equiv.) in a mixture of acetic acid and methanol
gave the mixture of diastereomeric piperidines which were sep-
arated to single isomers by column chromatography to afford
1b-trans in overall yield 45 %, and 1b-cis in overall yield 14 %
after two steps. The relative configuration of the isomer 1b-
trans and 1b-cis was confirmed on the basis of the analysis of
NOE experiments, in turn optical purity was establish for Cbz
derivatives 9b-trans (ee 75 %) and 9b-cis (ee 52 %). In the final
methylation step, piperidine 1b-trans was treated with form-
aldehyde followed by NaCNBH3 in the presence of a catalytic
amount of acetic acid in methanol to furnish (+)-femoxetine
10b in 96 % yield. The analogues transformation for 1b-cis lead
to 4-epi-(+)-femoxetine 10b-cis in yield 95 %.
The Hayashi-Jorgensen Catalyst cat. 1 was obtained according to
the literature procedure.[12]
The synthesis of Wang Resin-Supported Hayashi–Jørgensen
Catalyst (cat. 2)
The Wang resin-supported Hayashi-Jorgensen Catalyst cat. 2 was
obtained according to the literature procedure.[13]
Synthesis of Nitroolefins 5a and 5b. General Procedure.
To a solution of sesamol or 4-methoxyphenol (14.48 mmol), in dry
DMF (15 mL), potassium carbonate (2.2 g, 15.93 mmol, 1.1 equiv.)
and bromoacetaldehyde diethyl acetal (2.4 mL, 15.93 mmol,
1.1 equiv.) were added under argon. The reaction mixture was
heated to reflux and stirred overnight. After complete conversion of
the starting alcohol (TLC control, 1:3 AcOEt/hexanes), the reaction
mixture was diluted with AcOEt (20 mL) and washed with H2O
(20 mL). After phase separation, the aqueous layer was washed with
AcOEt (3 × 10 mL). The combined organic layers were washed with
H2O (30 mL) and brine (30 mL), dried with Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure to give the crude
product 6a (3.498 g, 95 %) or 6b (3.375 g, 97 %), which was used
to the next step without purification.
5-(2,2-Diethoxyethoxy)benzo[d][1,3]dioxole (6a); brown oil; Rf =
0.52 (1:3 AcOEt/hexanes); 1H NMR (600 MHz, CDCl3) δ = 6.69 (d, J =
8.5 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.34 (dd, J = 8.5, 2.5 Hz, 1H),
5.91 (s, 2H), 4.80 (t, J = 5.2 Hz, 1H), 3.93 (d, J 5.2 Hz, 2H), 3.75 (dq,
J = 9.3, 7.1 Hz, 2H), 3.63 (dq, J = 9.3, 7.0 Hz, 2H), 1.24 (t, J = 7.1 Hz,
6H); 13C NMR (151 MHz, CDCl3) δ = 154.2, 148.2, 141.9, 107.9, 105.9,
101.2, 100.5, 98.4, 69.5, 62.5, 15.3; HRMS (ESI-TOF) m/z calcd. for
C13H18NaO2 [M + Na+] 277.1052, found 277.1047.
1-(2,2-Diethoxyethoxy)-4-methoxybenzene (6b); brown oil; Rf =
1
0.53 (1:3 AcOEt/hexanes); H NMR (600 MHz, CDCl3) δ = 6.88–6.85
(m, 2H), 6.84–6.80 (m, 2H), 4.81 (t, J = 5.2 Hz, 1H), 3.96 (d, J = 5.2 Hz,
2H), 3.80–3.73 (m, 5H), 3.63 (dq, J = 9.4, 7.0 Hz, 2H), 1.25 (t, J =
7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ = 154.0, 152.8, 115.7,
114.6, 100.6, 69.3, 62.5, 55.7, 15.3; HRMS (ESI-TOF) m/z calcd. for
C
13H20NaO4 [M + Na+] 263.1259, found 263.1254.
To a solution of 6a or 6b (14.0 mmol), in acetone/H2O (10:1, 15 mL),
p-toluenesulfonic acid (241 mg, 1.4 mmol, 10 mol-%) was added.
The reaction mixture was heated to 65° C, and stirred until complete
conversion of substrate 6a or 6b (TLC control, 1:3 AcOEt/hexanes).
After that, the mixture was cooled to room temperature, diluted
with Et2O (20 mL) and H2O (20 mL). After phase separation, the
aqueous layer was washed with Et2O (3 × 10 mL). The combined
organic layers were washed brine (30 mL), dried with Na2SO4, and
filtered. The filtrate was concentrated under reduced pressure to
give the crude aldehyde 7a or 7b, which was used directly to the
next step without purification.
Conclusions
In summary, asymmetric total synthesis of (+)-paroxetine and
(+)-femoxetine involving organocatalytic Michael addition reac-
tion as the key step has been reported. As it has been demon-
strated, high efficiency, selectivity, and robustness in asymmet-
ric Michael reactions catalyzed by immobilized Hayashi–Jørgen-
sen catalyst was achieved in batch as well as in continues flow.
The target molecules were obtained with an overall yield of
35 % (4 steps started from Michael addition) and 80 % ee for
(+)-paroxetine, and 27 % (5 steps started from Michael addition)
and 75 % ee for (+)-femoxetine. An equally important advan-
2-(Benzo[d][1,3]dioxol-5-yloxy)acetaldehyde (7a); brown oil; Rf =
1
0.13 (1:3 AcOEt/hexanes); H NMR (600 MHz, CDCl3) δ = 9.83 (t, J =
1.0 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.28 (dd,
J = 8.5, 2.5 Hz, 1H), 5.94 (s, 2H), 4.50 (d, J 1.0 Hz, 2H); 13C NMR
(151 MHz, CDCl3) δ = 199.4, 153.1, 148.6, 142.7, 108.0, 105.6, 101.4,
98.4, 73.7; HRMS (ESI-TOF) m/z calcd. for C10H12NaO5 [M + MeOH +
tage over the methods developed so far lies in the simple route Na+] 235.0582, found 235.0576.
procedure employment of a readily available and inexpensive
2-(4-Methoxyphenoxy)acetaldehyde (7b); brown oil; Rf = 0.13 (1:3
AcOEt/hexanes); 1H NMR (600 MHz, CDCl3) δ = 9.85 (t, J = 1.1 Hz,
1H), 6.86–6.85 (m, 4H), 4.52 (d, J = 1.0 Hz, 2H), 3.77 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ = 199.8, 154.7, 151.8, 115.7, 114.9, 73.5, 55.7;
substrate. The synthetic strategy presented above can be re-
garded as a general method for preparation of piperidine core
structure having two trans-substituents at C3 and C4.
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HRMS (ESI-TOF) m/z calcd. for C10H14NaO4 [M + MeOH + Na+]
221.0790, found 221.0784.
199.4, 131.9, 129.6, 129.0, 127.4, 50.6; HRMS (ESI-TOF) m/z calcd. for
C8H8NaO [M + Na+] 143.0473, found 143.0469.
To a solution of aldehyde 7a or 7b (14.0 mmol) in 50 mL of dry
toluene, nitromethane (7.58 mL, 140 mmol, 10.0 equiv.) and
N,N,N,N-tetramethylguanidine (177 μL, 1.4 mmol, 10 mol-%) were
added at 0 °C under argon. The resulting solution was stirred at the
same temperature for 90 min, until complete conversion of alde-
hyde 7a or 7b (TLC control, 1:2 AcOEt/hexanes). Then MsCl
(1.625 mL, 21 mmol, 1.5 equiv.) and Et3N (2.927 mL, 21 mmol,
1.5 equiv.) were added at 0 °C and the reaction mixture was stirred
for additional 40 min at the same temperature. Progress of the reac-
tion was monitored by TLC (1:2 AcOEt/hexanes). After complete
conversion, the reaction mixture was quenched with sat. aq. NaH-
CO3 (50 mL). and diluted with AcOEt (50 mL). After phase separa-
tion, the aqueous layer was washed with AcOEt (3 × 30 mL). The
combined organic layers were washed with brine (100 mL), dried
with anhydr. Na2SO4, and filtered. The filtrate was concentrated un-
der reduced pressure to give the crude product 5a or 5b, which was
purified by silica gel column chromatography, and then additionally
recrystallized from Et2O/hexanens (1:9).
Organocatalytic Michael Addition Reaction between 3a/b and
4a/b Catalyzed by Wang Resin-Supported Hayashi-Jorgensen
Catalyst (cat. 2). General procedure in bath.
To a solution of nitroalkene 5a or 5b (0.45 mmol, 1.0 equiv.) in 3 mL
of CDCl3, Wang resin-supported Hayashi–Jørgensen catalyst cat. 2
(68 mg, 0.068 mmol, 15 mol-%)(catalyst loading 1.0 mmol/g),
benzoic acid (11 mg, 0.09 mmol, 20 mol-%) and a solution of alde-
hyde 4a or 4b (0.68 mmol, 1.5 equiv.) in 3 mL of CDCl3 were added.
The resulting mixture was stirred at room temperature until com-
plete conversion of starting nitroalkene 5a/b (reaction progress was
1
monitored by TLC 1:3 AcOEt/hexanes and H-NMR). Then, the cata-
lyst cat. 2 was filtered; washed with CHCl3 (3 × 2 mL), and then
dried in a high vacuum to afford 68 mg (100 %) of the recovered
catalyst. The combined CHCl3 filtrates were concentrated under re-
duced pressure to give crude γ-nitroaldehyde 3a or 3b, which were
used for the next step without further purification.
Organocatalytic Michael Addition Reaction between 3a/b and
4a/b Catalyzed by Wang Resin-Supported Hayashi-Jorgensen
Catalyst (cat. 2). General procedure in continues flow.
(E)-5-((3-Nitroallyl)oxy)benzo[d][1,3]dioxole (5a); yellow crystal;
m.p. 92–93° C; isolated yield 62 % (4 steps, starting from sesamol);
Rf = 0.48 (1:2 AcOEt/hexanes); column chromatography (1:4 AcOEt/
hexanes); 1H NMR (600 MHz, CDCl3) δ = 7.37 (dt, J = 13.3, 3.5 Hz,
1H), 7.30 (dt, J = 13.3, 2.1 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.51 (d,
J = 2.5 Hz, 1H), 6.33 (dd, J = 8.5, 2.5 Hz, 1H), 5.95 (s, 2H), 4.73 (dd,
J = 3.4, 2.1 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ = 152.9, 148.6,
142.7, 140.3, 136.7, 108.1, 105.9, 101.4, 98.3, 64.7; HRMS (ESI-TOF)
m/z calcd. for C10H9NNaO5 [M + Na+] 246.0378, found 246.0373.
The Wang resin-supported Hayashi–Jørgensen catalyst cat. 2
(13.4 mg, 0.0134 mmol)(catalyst loading 1.0 mmol/g), was placed in
the fritted PTFE tube (0.3 mm ID, 6 cm length, 4.24 μL). The station-
ary phase was swollen and equilibrated by pumping CHCl3 at a flow
rate of 0.1 mL min–1 for 30 min through the system. Then a solution
of nitroalkane 5a or 5b (0.09 mmol, 1.0 equiv.), aldehyde 4a or 4b
(0.135 mmol, 1.5 equiv.) and benzoic acid (0.018 mmol, 20 mol-%)
in CHCl3 (5 mL) was pumped at a flow rate of 0.005 mL min–1 for
16 h 40 min. The solution flowing out of the system was collected
for the time period indicated for each round (see Table 1). All vola-
tile components of the collected mixture were removed on at re-
duced pressure and the obtained residue was used to determined
conversion and diastereoselectivity by 1H NMR spectroscopy. Pure
conjugate addition product 3a or 3b was used for the next step
without further purification.
(E)-1-Methoxy-4-((3-nitroallyl)oxy)benzene (5b); yellow crystal;
m.p; 64–65° C isolated yield 48 % (4 steps, starting from 4-methoxy-
phenol); Rf = 0.47 (1:2 AcOEt/hexanes); column chromatography (1:4
AcOEt/hexanes); 1H NMR (600 MHz, CDCl3) δ = 7.38 (dt, J = 13.3,
3.5 Hz, 1H), 7.32 (dt, J = 13.3, 2.1 Hz, 1H), 6.87–6.85 (m, 4H), 4.75
(dd, J = 3.5, 2.2 Hz, 2H), 3.78 (s, 3H); 13C NMR (151 MHz, CDCl3) δ =
154.7, 151.6, 140.2, 137.0, 115.7, 114.9, 64.5, 55.7; (ESI-TOF) m/z
calcd. for C10H11NNaO4 [M + Na+] 232.0586, found 232.0580.
(2S,3R)-4-(Benzo[d][1,3]dioxol-5-yloxy)-2-(4-fluorophenyl)-3-
(nitromethyl)butanal; (3a-syn) and (3a-anti); Inseparable mixture
of diastereomers syn/anti; yellow oil; Rf = 0.31 (1:4 AcOEt/hexanes);
Synthesis of Aldehyde 4a and 4b. General Procedure.
To a solution of Dess–Martin periodinane (3.563 g, 8.4 mmol,
1.2 equiv.) in dry CH2Cl2 (20 mL), solution of 2-(4-fluoro-
phenyl)ethan-1-ol or 2-phenylethan-1-ol (7.0 mmol) in dry CH2Cl2
(20 mL) was added dropwise under argon at 0 °C. The reaction
mixture was stirred at the same temperature for ca. 30 min. After
complete conversion of substrate (TLC control, 1:3 AcOEt/hexanes),
the reaction was quenched with sat. aq. NaHCO3 (20 mL) and sat.
aq. Na2S2O3 (20 mL). The aqueous layer was washed with Et2O (2 ×
20 mL). The combined organic layers were washed sequentially with
sat. aq. NaHCO3 (20 mL), H2O (3 × 20 mL) and brine (20 mL), dried
with Na2SO4, and filtered. The filtrate was concentrated under re-
duced pressure to give the aldehyde 4a or 4b, which was used
directly to the next step without purification.
1
major isomer 3a-syn: H NMR (600 MHz, CDCl3) δ = 9.73–9.71 (m,
1H), 7.24–7.07 (m, 4H), 6.64 (d, J = 8.5 Hz, 1H), 6.34 (d, J = 2.5 Hz,
1H), 6.14 (dd, J = 8.5, 2.5 Hz, 1H), 5.91–5.90 (m, 2H), 4.77 (dd, J =
13.1, 7.5 Hz, 1H), 4.69 (dd, J = 13.1, 4.5 Hz, 1H), 4.01 (d, J = 9.4 Hz,
1H), 3.78 (dd, J = 9.7, 3.6 Hz, 1H), 3.53 (dd, J = 9.7, 5.0 Hz, 1H), 3.31–
3.25 (m, 1H); 13C NMR (151 MHz, CDCl3) δ = 197.7, 162.8 (d, J =
248.8 Hz), 153.3, 148.3, 142.4, 131.5 (d, J = 8.2 Hz), 127.6, 116.7 (d,
J = 21.6 Hz), 108.0, 105.8, 101.3, 98.1, 74.3, 66.2, 56.3, 38.0; minor
isomer 3a-anti: 1H NMR (600 MHz, CDCl3) δ = 9.70 (d, J = 1.3 Hz,
1H), 7.24–7.06 (m, 4H), 6.70 (dd, J = 8.2, 4.1 Hz, 1H), 6.47 (d, J =
2.5 Hz, 1H), 6.30 (dd, J = 8.5, 2.5 Hz, 1H), 5.93 (s, 2H), 4.35 (d, J =
3.2 Hz, 1H), 4.35–4.34 (m, 1H), 4.14–4.09 (m, 1H), 4.07 (dd, J = 9.7,
1.0 Hz, 1H), 4.00–3.98 (m, 1H), 3.45–3.39 (m, 1H); 13C NMR (151 MHz,
CDCl3) δ = 197.0, 162.9 (d, J = 249.4 Hz), 153.3, 148.4, 142.4, 131.4
(d, J = 8.2 Hz), 127.6, 117.0 (d, J = 21.6 Hz), 108.0, 105.9, 101.3, 98.2,
74.1, 66.5, 56.3, 37.9; HRMS (ESI-TOF) m/z calcd. for C10H16FNNaO6
[M + Na+] 384.0858, found 384.0854; HPLC (Chiralcel OZ-H, 10 %
iPrOH 90 % n-hexane, flow rate: 1.0 mL min–1,λ = 220 nm, 5 °C;
69 min, 76 min minor isomer (anti), 83 min, 95 min major isomer
(syn).
2-(4-Fluorophenyl)acetaldehyde (4a); colorless oil; Rf = 0.48 (1:3
AcOEt/hexanes); 1H NMR (600 MHz, CDCl3) δ = 9.74 (t, J = 2.2 Hz,
1H), 7.20–7.16 (m, 2H), 7.08–7.03 (m, 2H), 3.68 (d, J = 2.1 Hz, 2H);
13C NMR (151 MHz, CDCl3) δ = 199.0, 162.2 (d, J = 246.0 Hz), 131.2
(d, J = 8.0 Hz), 127.6 (d, J = 2.8 Hz), 115.9 (d, J = 21.5 Hz), 49.6;
HRMS (ESI-TOF) m/z calcd. for C8H7FNaO [M + Na+] 161.0379, found
161.0374.
2-Phenylacetaldehyde (4b); colorless oil; Rf = 0.50 (1:3 AcOEt/hex-
1
anes); H NMR (400 MHz, CDCl3) δ = 9.75 (t, J = 2.4 Hz, 1H), 7.44–
(2S,3R)-4-(4-Methoxyphenoxy)-3-(nitromethyl)-2-phenylbutan-
7.20 (m, 5H), 3.69 (d, J = 2.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ = al (3b-syn) and (3b-anti); Inseparable mixture of diastereomers;
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syn/anti; yellow oil; Rf = 0.32 (1:4 AcOEt/hexanes); major isomer 3b-
syn: H NMR (600 MHz, CDCl3) δ = 9.73–9.72 (m, 1H), 7.40–7.32 (m,
ture of diastereomers syn/anti; yellow oil; Rf = 0.33 (1:3 AcOEt/hex-
anes); HRMS (ESI-TOF) m/z calcd. for C19H18FNNaO6 [M + Na+]
398.1016, found 398.1010.
1
3H), 6.84–6.82 (m, 2H), 6.79–6.74 (m, 2H), 6.69–6.66 (m, 2H), 4.79
(dd, J = 13.1, 7.4 Hz, 1H), 4.71 (dd, J = 13.1, 4.6 Hz, 1H), 4.02–3.99
(m, 1H), 3.81 (dd, J = 9.7, 3.7 Hz, 1H), 3.73 (s, 3H), 3.56 (dd, J = 9.7,
5.3 Hz, 1H), 3.35–3.29 (m, 1H); 13C NMR (151 MHz, CDCl3) δ = 198.1,
154.4, 152.1, 133.0, 129.9, 129.6, 128.7, 115.7, 114.7, 74.4, 66.1, 57.2,
55.7, 38.1; 3b-anti: 1H NMR (600 MHz, CDCl3) δ = 9.71 (d, J = 1.4 Hz,
1H), 7.45–7.33 (m, 4H), 7.25–7.21 (m, 2H), 7.21–7.17 (m, 2H), 6.83 (s,
1H), 4.37 (dd, J = 13.6, 8.3 Hz, 1H), 4.33 (dd, J = 13.6, 4.3 Hz, 1H),
4.14 (dd, J = 9.8, 5.0 Hz, 1H), 4.07 (dd, J = 9.7, 1.2 Hz, 1H), 4.04–4.00
(m, 1H), 3.76 (s, 3H), 3.50–3.44 (m, 1H); 13C NMR (151 MHz, CDCl3)
δ = 197.4, 154.5, 152.2, 131.9, 129.9, 129.7, 128.9, 115.7, 114.8, 74.3,
66.4, 57.1, 55.7, 37.8; (ESI-TOF) m/z calcd. for C18H19NNaO5 [M +
Na+] 352.1161, found 352.1155; OZ-H, 10 % iPrOH 90 % n-hexane,
flow rate: 1.0 mL min–1,λ = 220 nm, 5 °C; 32 min, 38 min minor
isomer (anti), 45 min, 53 min major isomer (syn).
(3S,4R)-5-(4-Methoxyphenoxy)-4-(nitromethyl)-3-phenylpent-
anal (2b-syn) and (2b-anti); Inseparable mixture of diastereomers
syn/anti; yellow oil; Rf = 0.35 (1:3 AcOEt/hexanes); (ESI-TOF) m/z
calcd. for C20H25NNaO6 [M + MeOH + Na+] 398.1580, found
398.1558.
General Procedure for Reductive Cyclization Reaction. Synthe-
sis of (+)-Paroxetine 1a and 1b.
To a solution of aldehyde 2a or 2b (0.42 mmol) in 2 mL of MeOH,
acetic acid (2.0 mL) was added, the mixture was cooled to 0 °C, and
then Zn powder (686 mg, 10.5 mmol, 25.0 equiv.) was added in
portion. The reaction was warmed gradually to room temperature
and stirred overnight. Then the reaction was quenched with 4
M
aq. NaOH to pH = 12, and diluted with AcOEt (5 mL). After phase
separation, the aqueous layer was washed with AcOEt (5 × 3 mL).
The combined organic layers were dried with Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure to give the
crude mixture of piperidines 1a-trans and 1a-cis or 1b-trans and
1b-cis, which were separated by silica gel column chromatography
(5:95 Et3N/AcOEt).
Synthesis of Paroxetine and Femoxetine. General Procedure.
Synthesis of Enol Ether 8a/b. General Procedure.
To a solution of (methoxymethyl)triphenylphosphonium chloride
(1.7 g, 5.0 mmol, 5.0 equiv.) in 10 mL of dry THF, LiHMDS solution
(1.0
M in THF)(4.8 mL, 4.8 mmol, 4.8 equiv.) was added dropwise
under argon at 0 °C. The reaction mixture was stirred for 30 min at
the same temperature, and then a solution of crude γ-nitroaldehyde
3a or 3b (1.0 mmol) in dry THF (10 mL) was added dropwise. The
resulting mixture was stirred at the same temperature for ca.
30 min, until TLC analysis (1:4 AcOEt/hexanes) revealed consump-
tion of the 3a/b. After that, the reaction was quenched with sat. aq.
NH4Cl (20 mL). The aqueous layer was washed with AcOEt (3 ×
10 mL). The combined organic layers were washed with brine
(30 mL), dried with Na2SO4, and filtered. The filtrate was concen-
trated under reduced pressure to give the residue, which was puri-
fied by short silica gel column chromatography (1:8 AcOEt/hexanes)
to afford inseparable mixture of E/Z-enol ether 8a-syn/anti (68 %
after two steps) or 8b-syn/anti (62 % after two steps), which was
used directly for the next step.
(+)-Paroxetine (1a-trans); yellow oil isolated yield 52 % (after 2
steps, starting from 2a); Rf = 0.08 (5:95 Et3N/AcOEt); [α]D22= +78.9
(c= 2.3; CHCl3); 1H NMR (600 MHz, C6D6) δ = 6.79–6.75 (m, 2H),
6.73–6.68 (m, 2H), 6.47 (d, J = 8.5 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H),
5.99 (dd, J = 8.5, 2.5 Hz, 1H), 5.24 (d, J = 1.4 Hz, 1H), 5.23 (d, J =
1.3 Hz, 1H), 3.32 (dd, J = 9.4, 2.9 Hz, 1H), 3.24 (dd, J = 12.0, 3.5 Hz,
1H), 3.18 (dd, J = 9.3, 7.2 Hz, 1H), 2.80 (d, J = 11.9 Hz, 1H), 2.43 (t,
J = 11.4 Hz, 1H), 2.38–2.33 (m, 1H), 2.28–2.22 (m, 1H), 1.85–1.79 (m,
1H), 1.47–1.41 (m, 2H); 13C NMR (126 MHz, CDCl3) δ = 161.89 (d, J =
243.9 Hz), 155.0, 148.8, 142.2, 140.5 (d, J = 3.2 Hz), 129.06 (d, J =
7.7 Hz), 115.52 (d, J = 21.0 Hz), 108.2, 105.9, 101.1, 98.2, 69.7, 50.6,
47.2, 44.8, 43.1, 35.6; HRMS (ESI-TOF) m/z calcd. for C19H21FNO3 [M
+ H+] 330.1505, found 330.1504.
5-(((2R,3R)-3-(4-Fluorophenyl)-5-methoxy-2-(nitromethyl)pent-
4-en-1yl)oxy)benzo[d][1,3]dioxole; E/Z-(8a-syn) and E/Z-(8a-
anti); Inseparable mixture of diastereomers; yellow oil; Rf = 0.52 (1:4
AcOEt/hexanes); HRMS (ESI-TOF) m/z calcd. for C20H20FNNaO6 [M +
Na+] 412.1172, found 412.1151.
4-epi-(+)-Paroxetine (1a-cis); yellow oil; isolated yield 12 % (after
2 steps, starting from 2a); Rf = 0.11 (5:95 Et3N/AcOEt); [α]D22= +49.9
(c= 0.6; CHCl3); 1H NMR (600 MHz, C6D6) δ = 6.76–6.72 (m, 2H),
6.71–6.67 (m, 2H), 6.47 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H),
6.11 (dd, J = 8.5, 2.4 Hz, 1H), 5.23 (d, J = 1.2 Hz, 1H), 5.22 (d, J =
1.2 Hz, 1H), 4.17 (t, J = 9.4 Hz, 1H), 3.38 (dd, J = 9.1, 3.4 Hz, 1H),
3.26 (d, J = 11.8 Hz, 1H), 2.85 (d, J = 11.7 Hz, 1H), 2.52 (dt, J = 13.0,
3.9 Hz, 1H), 2.47 (dd, J = 11.8, 2.5 Hz, 1H), 2.30 (td, J = 11.7, 2.5 Hz,
1H), 2.06–2.00 (m, 1H), 1.57 (ddd, J = 25.0, 12.7, 4.2 Hz, 1H), 1.21–
1.20 (m, 1H); 13C NMR (126 MHz, C6D6) δ = 161.8 (d, J = 244.0 Hz),
155.2, 148.8, 142.0, 139.8 (d, J = 3.2 Hz), 128.81 (d, J = 7.6 Hz),
115.28 (d, J = 21.0 Hz), 108.2, 106.3, 101.0, 98.4, 65.7, 48.5, 47.2,
43.0, 40.5, 26.8; HRMS (ESI-TOF) m/z calcd. for C19H21FNO3 [M + H+]
330.1505, found 330.1504.
1-Methoxy-4-(((2R,3R)-5-methoxy-2-(nitromethyl)-3-phenyl-
pent-4-en-1-yl)oxy)benzene; E/Z-(8b-syn) and E/Z-(8b-anti); In-
separable mixture of diastereomers; yellow oil; Rf = 0.53 (1:4 AcOEt/
hexanes); HRMS (ESI-TOF) m/z calcd. for C20H23NNaO5 [M + Na+]
380.1474, found 380.1463.
Synthesis of Aldehyde 2a/b. General Procedure.
Obtained enol ether 8a or 8b was dissolved in THF (4 mL) and 5
M
aq. HCl (1 mL) was added. The reaction mixture was refluxing until
TLC analysis revealed complete hydrolysis of the starting enol ether
8a/b (ca. 1 hours). Then the reaction was cooled to room tempera-
ture, diluted with AcOEt (10 mL) and neutralized with sat. aq.
NaHCO3 (20 mL). After phase separation, the aqueous layer was
washed with AcOEt (3 × 10 mL). The combined organic layers were
washed with brine (30 mL), and then dried with Na2SO4, and fil-
tered. The filtrate was concentrated under reduced pressure to give
the crude aldehyde 2a or 2b, which was used directly to the next
step without purification.
(3R,4S)-3-((4-Methoxyphenoxy)methyl)-4-phenylpiperidine;
(1b-trans); colorless oil; isolated yield 45 % (after 2 steps, starting
from 2b); Rf = 0.09 (5:95 Et3N/AcOEt); [α]D22= +65.5 (c= 2.9; CHCl3);
1H NMR (600 MHz, C6D6) δ = 7.12–7.03 (m, 4H), 7.01–6.97 (m, 1H),
6.63–6.61 (m, 2H), 6.61–6.58 (m, 2H), 3.51 (dd, J = 9.4, 2.9 Hz, 1H),
3.38 (dd, J = 12.0, 3.5 Hz, 1H), 3.34 (dd, J = 9.3, 7.7 Hz, 1H), 3.25 (s,
3H), 2.84 (d, J = 12.0 Hz, 1H), 2.51 (t, J = 11.4 Hz, 1H), 2.46–2.35 (m,
2H), 2.07–2.01 (m, 1H), 1.61–1.54 (m, 2H); 13C NMR (151 MHz, C6D6)
δ = 154.0, 153.3, 144.7, 128.5, 126.3, 115.3, 114.5, 69.3, 54.8, 50.6,
(3S,4R)-5-(Benzo[d][1,3]dioxol-5-yloxy)-3-(4-fluorophenyl)-4- 47.1, 45.5, 42.8, 35.5; (ESI-TOF) m/z calcd. for C19H24NO2 [M + H+]
(nitromethyl)pentanal; (2a-syn) and (2a-anti); Inseparable mix- 298.1807, found 298.1812.
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(3R,4S)-3-((4-Methoxyphenoxy)methyl)-4-phenylpiperidine; under reduced pressure to give the crude product, which was puri-
(1b-cis); colorless oil; isolated yield 14 % (after 2 steps, starting from
2b); Rf = 0.11 (5:95 Et3N/AcOEt); [α]D22= +59.2 (c= 0.9; benzene); 1H
NMR (600 MHz, C6D6) δ = 6.90–6.86 (m, 2H), 6.80–6.77 (m, 1H), 6.77–
6.74 (m, 2H), 6.43–6.40 (m, 2H), 6.39–6.36 (m, 2H), 4.06 (t, J = 9.5 Hz,
1H), 3.32 (dd, J = 9.1, 3.0 Hz, 1H), 3.14 (d, J = 11.8 Hz, 1H), 3.00 (d,
J = 4.8 Hz, 3H), 2.64 (d, J = 11.7 Hz, 1H), 2.47 (dt, J = 13.0, 4.1 Hz,
1H), 2.31 (dd, J = 11.8, 2.4 Hz, 1H), 2.12 (td, J = 11.7, 2.6 Hz, 1H),
2.00–1.94 (m, 1H), 1.49 (ddd, J = 24.9, 12.7, 4.2 Hz, 1H), 1.11 (dd, J =
12.8, 2.6 Hz, 1H); 13C NMR (151 MHz, C6D6) δ = 153.9, 153.5, 144.0,
128.2, 127.1, 126.0, 115.5, 114.5, 65.0, 54.8, 48.3, 47.1, 43.6, 40.3,
26.5; (ESI-TOF) m/z calcd. for C19H24NO2 [M + H+] 298.1807, found
298.1775.
fied by silica gel column chromatography.
Benzyl (3R,4R)-3-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-
fluorophenyl)piperidine-1-carboxylate (9a-cis); colorless oil; iso-
lated yield 71 %; column chromatography (1:6 AcOEt/hexanes);
[α]D23= +42.3 (c= 0.4; CHCl3); ee 53 % (determined by HPLC); 1H
NMR (500 MHz, CDCl3) δ = 7.25–7.19 (m, 4H), 7.19–7.14 (m, 3H),
7.02 (t, J = 8.6 Hz, 2H), 6.59 (d, J = 8.5 Hz, 1H), 6.25 (mj, 1H), 6.05
(d, J = 7.5 Hz, 1H), 5.87 (s, 2H), 5.17–4.93 (m, 2H), 4.64–4.58 (m, 1H),
4.54–4.43 (m, 1H), 3.76 (t, J = 9.4 Hz, 1H), 3.53–3.38 (m, 1H), 3.15–
3.06 (m, 2H), 2.97–2.85 (m, 1H), 2.38–2.26 (m, 1H), 2.06–1.94 (m, 1H),
1.78 (d, J = 11.2 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ = 161.6 (d,
J = 245.2 Hz), 154.2, 148.1, 141.6, 138.2 (d, J = 2.5 Hz), 128.53 (d,
J = 7.9 Hz), 128.4, 127.8, 115.4 (d, J = 21.2 Hz), 107.8, 101.0, 67.2,
46.0, 44.3, 42.5, 40.0, 29.7; HRMS (ESI-TOF) m/z calcd. for
C27H26FNNaO5 [M + Na+] 486.1693, found 486.1676; HPLC (Chiralcel
OD-H, 10 % iPrOH 90 % n-hexane, flow rate: 1.0 mL min–1, λ =
220 nm); 33 min minor isomer (3S,4S), 42 min major isomer (3R,4R).
General procedure for N-methylation reaction. Synthesis of (+)-
Femoxetine 10b.
To a solution of piperidine 1b-trans or 1b-cis (60 mg, 0.2 mmol) in
MeOH (2 mL), 37 % aq. solution of formaldehyde (23 μL, 0.31 mmol,
1.5 equiv.) and acetic acid (one drop) were added. The resulting
solution was then cooled to 0 °C, NaCNBH3 (38 mg, 0.61 mmol,
3.0 equiv.) was added, and the reaction mixture was warmed to
room temperature and stirred overnight. After complete conversion
of the starting amines 1b-trans/cis (TLC control, 5:95 MeOH/
CH2Cl2), the reaction mixture was diluted with CH2Cl2 (10 mL) and
washed with 15 % aq. solution of NaOH (5 mL) and sat. aq. NaCl
(5 mL). The organic layer was dried with Na2SO4 and filtered. The
filtrate was concentrated under reduced pressure to give the crude
product, which was purified by silica gel column chromatography
(5:95 MeOH/CH2Cl2) to afford 60 mg (96 %) of (+)-femoxetine (10b-
trans) or 59 mg (95 %) of 4-epi-(+)-femoxetine (10b-cis).
Benzyl (3R,4S)-3-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-
fluorophenyl)piperidine-1-carboxylate (9a-trans); colorless oil;
isolated yield 71 %; column chromatography (1:6 AcOEt/hexanes);
[α]D22= +24.1 (c= 1.6; CHCl3); ee 80 % (determined by HPLC);
1H NMR (500 MHz, CDCl3) δ = 7.41–7.30 (m, 5H), 7.16–7.10 (m, 2H),
7.01–6.95 (m, 2H), 6.62 (d, J = 8.5 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H),
6.13 (dd, J = 8.4, 2.1 Hz, 1H), 5.88 (s, 1H), 5.18 (s, 2H), 4.51 (s, 1H),
4.33 (s, 1H), 3.61 (dd, J = 9.4, 2.5 Hz, 1H), 3.46 (dd, J = 9.4, 6.4 Hz,
1H), 2.90 (t, J = 12.1 Hz, 1H), 2.71 (t, J = 10.0 Hz, 1H), 2.09–1.98 (m,
1H), 1.87–1.80 (m, 1H), 1.79–1.67 (m, 1H); 13C NMR (126 MHz, CDCl3)
δ = 161.6 (d, J = 244.8 Hz), 155.3, 148.2, 141.7, 138.9 (d, J = 3.2 Hz),
136.8, 128.7 (d, J = 7.8 Hz), 128.5, 128.0, 127.9, 115.5 (d, J = 21.2 Hz),
107.8, 105.6, 101.1, 98.0, 68.7, 67.2, 47.4, 44.5, 43.9, 29.7; HRMS (ESI-
TOF) m/z calcd. for C27H26FNNaO5 [M + Na+] 486.1693, found
486.1691; HPLC (Chiralcel OD-H, 10 % iPrOH 90 % n-hexane, flow
rate: 1.0 mL min–1, λ = 220 nm); 30 min major isomer (3R,4S), 35 min
minor isomer (3S,4R).
(+)-Femoxetine (10b-trans); colorless oil; [α]D22= +76.2 (c= 2.0;
1
CHCl3); H NMR (500 MHz, CDCl3) δ = 7.30–7.26 (m, 2H), 7.23–7.17
(m, 3H), 6.78–6.73 (m, 2H), 6.69–6.65 (m, 2H), 3.73 (s, 3H), 3.62 (dd,
J = 9.4, 3.0 Hz, 1H), 3.49 (dd, J = 9.4, 7.5 Hz, 1H), 3.25 (dd, J = 11.3,
2.2 Hz, 1H), 2.99 (d, J = 11.2 Hz, 1H), 2.44 (td, J = 11.7, 4.2 Hz, 1H),
2.37 (s, 3H), 2.35–2.27 (m, 1H), 2.11–2.00 (m, 2H), 1.94 (ddd, J = 24.7,
12.4, 3.9 Hz, 1H), 1.85 (ddd, J = 13.3, 6.7, 2.7 Hz, 1H); 13C NMR
(126 MHz, CDCl3) δ = 153.7, 153.1, 144.1, 128.6, 127.5, 126.5, 115.4,
114.5, 69.5, 59.7, 56.3, 55.7, 46.5, 44.4, 41.9, 34.3; (ESI-TOF) m/z calcd.
for C20H26NO2 [M + H+] 312.1964, found 312.1953.
Benzyl (3R,4R)-3-((4-methoxyphenoxy)methyl)-4-phenylpiper-
idine-1-carboxylate (9b-cis); colorless oil; isolated yield 73 %; col-
umn chromatography (1:8 AcOEt/hexanes); [α]D22= +61.1 (c= 1.4;
CHCl3); ee 52 % (determined by HPLC); 1H NMR (400 MHz, CDCl3)
δ = 7.41–7.12 (m, 10H), 6.71 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 8.6 Hz,
2H), 5.18–4.88 (m, 2H), 4.64 (d, J = 13.4 Hz, 1H), 4.59–4.39 (m, 1H),
3.81 (t, J = 9.6 Hz, 1H), 3.73 (s, 3H), 3.58–3.44 (m, 1H), 3.11 (d, J =
12.9 Hz, 2H), 3.01–2.86 (m, 1H), 2.36 (s, 1H), 2.14–1.95 (m, J = 9.3 Hz,
1H), 1.95–1.71 (m, J = 12.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ =
155.9, 155.8, 153.7, 152.9, 142.6, 128.6, 128.4, 1278, 127.2, 126.6,
115.3, 114.5, 67.1, 55.7, 46.0, 44.4, 43.2, 40.0; HRMS (ESI-TOF) m/z
calcd. for C27H29NNaO4 [M + Na+] 454.1994, found 454.1968; HPLC
4-epi-(+)-Femoxetine (10b-cis); colorless oil; [α]D22= +23.9 (c= 0.8;
1
CHCl3); H NMR (500 MHz, CDCl3) δ = 7.35–7.29 (m, 2H), 7.25–7.19
(m, 3H), 6.74–6.69 (m, 2H), 6.64–6.60 (m, 2H), 4.22 (t, J = 9.5 Hz, 1H),
3.72 (s, 3H), 3.52 (dd, J = 9.1, 3.4 Hz, 1H), 3.21 (d, J = 11.3 Hz, 1H),
3.04 (d, J = 7.4 Hz, 1H), 2.96–2.90 (m, 1H), 2.40–2.34 (m, 1H), 2.30
(s, 3H), 2.21–2.16 (m, 1H), 2.14–2.06 (m, 1H), 1.83–1.76 (m, 1H); 13C
NMR (126 MHz, CDCl3) δ = 153.5, 153.2, 128.4, 127.3, 126.3, 115.5,
114.4, 65.8, 57.7, 56.4, 55.7, 46.5, 42.5, 40.5, 29.7, 26.0; (ESI-TOF) m/z
calcd. for C20H26NO2 [M + H+] 312.1964, found 312.1961.
(Chiralcel AS-H, 10 % iPrOH 90 % n-hexane, flow rate: 1.0 mL min–1
λ = 220 nm); 19 min minor isomer (3S,4S), 21 min major isomer
(3R,4R).
,
General Procedure for Cbz Protection. Synthesis of 9a-trans/cis
and 9a-trans/cis.
Benzyl (3R,4S)-3-((4-methoxyphenoxy)methyl)-4-phenylpiper-
idine-1-carboxylate (9b-trans); colorless oil; isolated yield 72 %;
column chromatography (1:8 AcOEt/hexanes); [α]D22= +22.0 (c= 1.2;
CHCl3); ee 75 % (determined by HPLC); 1H NMR (400 MHz, CDCl3)
δ = 7.43–7.14 (m, 10H), 6.75 (d, J = 9.1 Hz, 2H), 6.67 (d, J = 9.0 Hz,
1H), 5.19 (s, 2H), 4.62–4.52 (m, J = 11.6 Hz, 1H), 4.40–4.28 (m, 1H),
3.73 (s, 3H), 3.65 (dd, J = 9.5, 2.7 Hz, 1H), 3.50 (dd, J = 9.4, 6.9 Hz,
1H), 2.90 (t, J = 12.2 Hz, 2H), 2.70 (t, J = 9.8 Hz, 1H), 2.18–2.05 (m,
1H), 1.91–1.66 (m, 2H); 13C NMR (101 MHz, CDCl3) δ = 155.3, 153.9,
152.9, 143.3, 136.9, 128.7, 128.5, 128.0, 127.9, 127.4, 127.0, 126.8,
To a solution of piperidine 1a-trans/cis or 1b-trans/cis (0.3 mmol)
in 3 mL of dry CH2Cl2, Et3N (42 μL, 0.3 mmol, 1.0 equiv.) and benzyl
chloroformate (43 μL, 0.3 mmol, 1.0 equiv.) were added at 0 °C
under argon. The reaction mixture was warmed gradually to room
temperature and stirred overnight. After complete conversion of
the starting piperidine 1a-trans/cis or 1b-trans/cis (TLC control,
5:95 Et3N/AcOEt), the reaction mixture was diluted with CH2Cl2
(5 mL) and quenched with sat. 1
M aq. HCl (3 mL). After phase
separation, the organic layer was washed with brine (50 mL), and 115.5, 114.6, 68.6, 67.1, 55.7, 47.5, 44.8, 44.6, 41.8; HRMS (ESI-TOF)
then dried with Na2SO4, and filtered. The filtrate was concentrated
m/z calcd. for C27H29NNaO4 [M + Na+] 454.1994, found 454.1985;
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1.0 mL min–1, λ = 220 nm); 20 min major isomer (3R,4S), 25 min
minor isomer (3S,4R).
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Acknowledgments
The author is grateful to Polish National Science Centre for fi-
nancial support of the research (Fuga 4 Grant No. DEC-2015/
16/S/ST5/00440), JM thanks the Foundation for Polish Science
for financial support (TEAM/2017-4/38).
Keywords: Paroxetine · Femoxetine · Total synthesis ·
Organocatalysis · Flow Chemistry · Immobilised Catalysts
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Received: September 20, 2019
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Total Synthesis
P. Szcześniak,* S. Buda,
L. Lefevre, O. Staszewska-Krajewska,
J. Mlynarski ....................................... 1–11
Total Asymmetric Synthesis of (+)-
Paroxetine and (+)-Femoxetine
Total, asymmetric synthesis of (+)- ues flow. High efficiency and selecti-
Paroxetine and (+)-Femoxetine is re- vity in the Michael addition was
ported. The key step is organocatalytic achieved by application of Wang resin-
Michael addition of aldehydes to trans- supported Hayashi–Jørgensen catalyst.
nitroalkenes realized in bath or contin-
DOI: 10.1002/ejoc.201901389
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim