Enantioselective β-hydroxy thioesters formation via decarboxylative aldol reactions of malonic acid half thioesters with aldehydes promoted by chloramphenicol derived sulfonamides

Article abstract of DOI:10.1016/j.tet.2017.05.066

A highly enantioselective synthesis of chiral β-hydroxy thioesters that uses a decarboxylative aldol reaction of malonic acid half thioesters and aldehydes catalyzed by a chloramphenicol base-derived bifunctional organocatalyst is reported. The resulting

Full text of DOI:10.1016/j.tet.2017.05.066

Accepted Manuscript
Enantioselective β-hydroxy thioesters formation via decarboxylative aldol reactions
of malonic acid half thioesters with aldehydes promoted by chloramphenicol derived
sulfonamides
Yafeng Wang, Guanxin Huang, Sha Hu, Kaijun Jin, Yan Wu, Fener Chen
PII:
S0040-4020(17)30567-7
10.1016/j.tet.2017.05.066
TET 28732
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 March 2017
Revised Date: 15 May 2017
Accepted Date: 19 May 2017
Please cite this article as: Wang Y, Huang G, Hu S, Jin K, Wu Y, Chen F, Enantioselective β-hydroxy
thioesters formation via decarboxylative aldol reactions of malonic acid half thioesters with aldehydes
promoted by chloramphenicol derived sulfonamides, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.066.
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Enantioselective β-Hydroxy thioesters Formation via
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Decarboxylative Aldol Reactions of Malonic Acid Half
Thioesters with Aldehydes Promoted by Chloramphenicol
derived Sulfonamides
Yafeng Wang, Guanxin Huang, Sha Hu, Kaijun Jin, Yan Wu* and Fener Chen*
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, People’s Republic of China
bEngineering Center of Catalysis and Synthesis for Chiral Molecules at Fudan University

1
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Tetrahedron
journal homepage: www.elsevier.com
Enantioselective β-Hydroxy thioesters Formation via Decarboxylative Aldol
Reactions of Malonic Acid Half Thioesters with Aldehydes Promoted by
Chloramphenicol derived Sulfonamides[1]
Yafeng Wang, Guanxin Huang, Sha Hu, Kaijun Jin, Yan Wu* and Fener Chen*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, People’s Republic of China
b Engineering Center of Catalysis and Synthesis for Chiral Molecules at Fudan University
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly enantioselective synthesis of chiral β-hydroxy thioesters that uses a decarboxylative
aldol reaction of malonic acid half thioesters and aldehydes catalyzed by a chloramphenicol
base-derived bifunctional organocatalyst is reported. The resulting chiral β-hydroxy thioesters
were obtained in high yields (up to 82%) with good to excellent enantioselectivities (up to 94%
ee). The synthetic application of the methodology is illustrated by the asymmetric synthesis of
the selective serotonin reuptake inhibitor dapoxetine.
Available online
Keywords:
Chloramphenicol base-sulfonamides catalysts
Aldol reaction
Asymmetric catalysis
Chiral β-hydroxy thioesters
1. Introduction
Chiral β-hydroxy thioesters[2] are important synthetic building
blocks in many pharmaceuticals and natural products, including
erythromycin (1), oxytetracycline (2), triamcinolone diacetate
(3), tephrosin (4), atorvastatin (5) and fluoxetine (6). In the past
two decades, tremendous efforts have been devoted to the
construction of this class of β-hydroxy thioester motifs using a
highly enantioselective catalytic approach. For example, Ikariya
and co-workers[3] reported work on the asymmetric synthesis of
β-hydroxy thioesters using an asymmetric Mukaiyama aldol
reaction catalyzed by a BINOL-Ti complex. Subsequently,
Shair[4] and Cozzi[5] and their co-workers independently
investigated a direct aldol reaction with malonic acid half
thioesters (MAHTs) using a chiral Cu/bis(oxazoline) catalyst to
give the corresponding β-hydroxy thioesters; this method
required the use of metal catalysts. Recently, Shibata[6] disclosed
a metal-free decarboxylative addition reaction of MAHTs with
isatins for the synthesis of β-hydroxy thioesters that is catalyzed
by cinchona-derived squaramide. Most importantly, when using
cinchona-based bifunctional thioureas or sulfonamides as
catalysts, the groups of Song[7] and Wennemers[8] obtained β-
hydroxy thioesters with up to 96% and 99% ee, respectively.
Despite considerable progress, however, the inaccessibility and
high cost of the catalysts used in these protocols limits their use
in industrial applications. The ultimate goal of developing a
practical and highly effective catalytic system remains elusive
forthe construction of chiral β-hydroxy thioester scaffolds using
the asymmetric decarboxylative aldol reaction.

2
Tetrahedron
Figure 1. Pharmaceuticals and natural products derived from β-hydroxy
esters from MAHTs and aldehydes using our chiral chloram-
ACCEPTED MANUSCRIPT
thioesters.
phenicol derived sulfonamide catalysts in a decarboxylative aldol
reaction.
Chloramphenicol base is a byproduct of chloramphenicol
production and an important chiral scaffold. Many homogeneous
catalysts based on this structural motif have been reported and
used in a wide variety of efficient enantioselective and non-
enantioselective asymmetric reactions. These reactions have been
applied to many pharmaceuticals and natural products, including
the asymmetric ring opening of prochiral cyclic anhydrides,
asymmetric transfer hydrogenation/dynamic kinetic resolution of
α-amino-β-ketoesters, and catalytic enantioselective aldol reac-
tions of α,β-unsaturated aldehydes with diketenes (Scheme 1).
Continuing our work[9] on the development of organocatalysts
and their applications in asymmetric synthesis, we herein report
the highly efficient enantioselective synthesis of β-hydroxy thio-
2. Results/Discussion
We commenced our evaluation of the catalytic ability of
chiral chloramphenicol derived sulfonamide catalysts 10a-10g,
Table 1. Asymmetric decarboxylative aldol reaction between MAHT 8a and
aldehyde 7a catalyzed by various chloramphenicol derived bifunctional
catalysts
Scheme 1. Various asymmetric reactions catalyzed by our chloramphenicol
derived catalysts

3
7-9) and temperature (entries 10-11). MTBE/THF (9:1) was the
[b]
Entry
Catalyst
10a
10b
10c
10d
10e
10f
Time (d)
Yield[a] (%)
Ee (%)
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best solvent system among those that we screened. The catalyst
loading had a marked effect on the reaction, with 50 mol%
organocatalyst giving the best balance in terms of isolated yields
and ee values. The reaction temperature had a considerable
impact on the reaction rate, isolated yield and ee value. The aldol
reaction proceeded slowly in very low yield and enantio-
selectivity when it was carried out at −10℃ (entry 11). When
the temperature was increased to 0℃(entry 8), the reaction gave a
76% yield with 88% ee. A slight acceleration in the reaction rate
and ee value was observed in the presence of 4 Å molecular
sieves (entry 13, Table 2). We therefore decided to run the aldol
reaction at 0℃, with 50 mol% of the catalyst and 4 Å molecular
sieves in MTBE/THF (9:1).
1
2
5
8
8
5
5
6
8
6
6
6
6
42
53
20
25
60
85
78
80
75
95
78
74
74
51
62
65
65
86
5
3
4
5
6
7
10g
11
8
A series of β-hydroxy thioesters was obtained from a variety
of aldehydes and MAHTs with the aim of extending the scope of
the methodology under the optimized conditions. As shown in
Scheme 2, we found that electron-rich thioesters 9a and 9b give
high yields (80%, 73%) and excellent ee values (90%, 90%).
Electron-deficient thioesters afforded products with ee values
lower than 84%. In general, electron-donating groups at the
ortho, para or meta positions of the phenyl ring of the aldehydes
(9f-k) enable the decarboxylative aldol reaction to proceed
effectively in high yield (70%-76%) and excellent enantiomeric
excess(90%-94% ee). The enantiomeric excess decreases when
strongly electron-withdrawing groups, such as p-nitro and p-
cyano groups, are attached to the phenyl ring of the aldehyde.
In addition, weakly electron-withdrawing groups are tolerated on
the phenyl ring of the aldehyde under the optimized conditions,
providing desired products 9o-q with 88%-90% ee. The electron-
9
12
11
2
10
11
13
14
7
[a]Yield of isolated product. [b] Determined by HPLC.
11-14 by using thioester 8a and aldehyde 7a as model substrates
for the decarboxylative aldol reaction. In the presence of organo-
catalysts 10a-10g, 11-14 and using MTBE/THF=9:1 as the
solvent, desired product 9a was obtained in good to excellent
yields and poor to high ee values (Table 1, entries 1-11). In terms
of both isolated yield and ee, the best result was obtained with
catalyst 10g.
With this preliminary result in hand, we investigated further
parameters that may affect the efficiency of this transformation,
including solvent (entries 1-6, Table 2), catalyst loading (entries
Table 2. Optimization of the reaction conditions
Entry
Solvent
Catalyst
loading
(%)
30
T
(oC)
Time
(d)
Yield[
a] (%)
Ee[b]
(%)
1
2
MTBE/THF(9:1)
MTBE
0
0
8
8
78
80
83
72
10
74
56
76
80
82
47
85
80
68
86
80
72
86
54
82
82
88
80
84
55
80
90
88
30
3
THF
30
0
8
4
AcOEt
30
0
8
5
DCM
30
0
8
6
acetone
30
0
8
7
MTBE/THF(9:1)
MTBE/THF(9:1)
MTBE/THF(9:1)
MTBE/THF(9:1)
MTBE/THF(9:1)
MTBE/THF(9:1)
MTBE/THF(9:1)
MTBE/THF(9:1)
20
0
13
8
8
50
0
9
70
0
7
10
11
12
13
14
50
15
-10
15
0
4
50
15
3
50[c]
50[c]
40[c]
6
Scheme 2. Substrate scope for β-hydroxy thioesters. Reaction conditions:
Aldehyde (0.2 mmol), catalyst (10 g. 0.1 mmol), 4 Å molecular sieves (0.1 g)
and MAHT (1 mmol) in MTBE/THF (9:1, 1 mL) at 0 ℃.
0
7
[a] Yield of isolated product. [b] Determined by HPLC. [c] cat (%) + 4 Å
molecular sieves.

4
Tetrahedron
and activates the aldehyde. Intermediate I is converted to
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complex II as a result of the orientation determined by the three
hydrogen-bonds. The β-hydroxy thioester product is generated
from 9', which results from the decarboxylation of intermediate
II. Importantly, only CO2 is generated as a byproduct in this
decarboxylative aldol reaction.
We demonstrate the value of our methodology by carrying
out the asymmetric synthesis of (+)-dapoxetine, a selective
serotonin reuptake inhibitor, from primary alkyl substrates in
very few steps. The reduction of chiral β-hydroxy thioester 9a
with LiBH4, which was prepared in situ from KBH4 and
anhydrous LiCl in THF at 70 , provided (R)-1-phenylpropane-
1,3-diol 15 in 85% yield. The 1,3-diol smoothly underwent
hydroxyl tosylation with TsCl to form (R)-3-hydroxy-3-phenyl-
propyl-4-methylbenzenesulfonate(16), which then successfully
underwent nucleophilic substitution with 1-naphthol in the
presence of K2CO3 to afford (R)-3-(naphthalen-1-yloxy)-1-
pheny lpropan-1-ol(17) in excellent yield. The (S)-3-(naphthalen-
1-yloxy)-1-phenylpropan-1-amine(18) was formed by electro-
philic substitution, azidated, and reduced of the O-mesylated
derivative (17). Finally, (+)-dapoxetine 19 was generated in 68%
yield by refluxing with aqueous formaldehyde solution and
formic acid for 10 h (Scheme 3).
Figure 2. Plausible mechanism for the decarboxylative aldol
reaction
3. Conclusion
withdrawing p-bromo group at the 2-positon of the aldehyde had
the biggest influence on the aldol reaction, and led to very low
enantioselectivities (70% ee). The reaction of 1-naphthaldehyde
afforded product 9l in high yield (70%) with excellent
enantioselectivity (90% ee).
In summary, chiral bifunctional chloramphenicol derived
sulfonamide organocatalyst 10g displayed high catalytic activity
in the asymmetric aldol reaction of MAHTs with aldehydes.
Various β-hydroxy thioesters were obtained in high yields and
excellent enantioselectivities under mild conditions. The reaction
was successfully applied to the construction of 1,3-diols in the
synthesis of (+)-dapoxetine without loss of enantioselectivity.
Further investigations aimed at exploring the scope of this
methodology are currently in progress in our laboratory.
Considering the mechanism reported previously by the
groups of Song[7] and Wennemers[8], we propose the mechanism
shown in Figure 2. The tertiary amine of the chloramphenicol
base forms two hydrogen-bonds with the MAHTs because of its
basicity. The sulfonamide group acts as a hydrogen-bond donor
4. Experimental section
Unless otherwise specified, all reagents and solvent were
obtained from commercial sources and used without further
purification. MTBE was distilled from calcium hydride; THF
was distilled from sodium–benzophenone. 1H (400 MHz) and 13
C
(100 MHz) NMR were recorded on a Bruker Avance 400
spectrometer using TMS or CDCl3 as internal standards. Optical
rotations were measured by a JASCO P1020 digital polarimeter.
EI-MS were recorded on an Agilent 6890N/5975 spectrometer
and ESI-MS were recorded on a Waters Micromass Quattro
Micro spectrometer. HRMS were recorded on
a Bruker
micrOTOF spectrometer.HPLC analysis were performed with
Daicel Chiralpak AD-H column (25 cm × 4.6 mm × 5 µm) and
Chiralpak OD-H column (25 cm × 4.6 mm × 5 µm). The
enantiomericratios, expressed as % ee, were determined by
HPLC analysis as specified in the individual experimental
descriptions and verified using the appropriate racemic mixtures.
General procedure for preparation of chloramphenicol
derived bifunnctional organocatalysts.
All the chloramphenicol derived bifunnctional organocatalysts
10a-10g, 11-14 were prepared by known procedure[9b]. The
characterization results of new catalysts 10f and 10g were as
below.
N-((1R,2R)-1-(4-nitrophenyl)-2-(pyrrolidin-1-yl)-3-(trityloxy) p-
ropyl)-naphthalene-1-sulfonamide (10f).
Yellow solid, mp 98-100oC. 1HNMR (400 MHz, CDCl3): δ =8.00
(s, 1H), 7.84 (dd, J = 7.5, 6.0 Hz, 2H), 7.75 – 7.54 (m, 6H), 7.19
Scheme 3. Asymmetric synthesis of (+)-dapoxetine 19

5
– 7.05 (m, 18H), 4.21 (d, J = 9.1 Hz, 1H), 3.10 (dd, J = 10.4, 5.3
(R)-S-p-tolyl 3-hydroxy-3-phenylpropanethioate(9a).
ACCEPTED MANUSCRIPT
Hz, 1H), 2.98 (d, J = 8.3 Hz, 2H), 2.56 (d, J = 18.5 Hz, 4H), 1.70
(d, J = 6.4 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ= 146.94 ,
146.60 , 143.04 , 136.34 , 134.53 , 131.70 , 129.14 , 129.00 ,
128.90 , 128.76 , 128.43 , 127.84 , 127.71 , 127.63 , 127.17 ,
123.08 , 122.32 , 87.60 , 63.82 , 59.02 , 58.43 , 57.56 , 48.19 ,
23.65 , 18.42 . HRMS (ESI) calcd for C42H39N3O5S [M + H]+
698.2683 , found 698.2701.
White solid, mp 85-87 C. [α]D20 = + 18.24 (c 0.104, CHCl3).
1HNMR (400 MHz, CDCl3): δ =7.37 – 7.19 (m, 9H), 5.18 (dd,
J = 8.9, 3.6 Hz, 1H), 3.04 (qd, J = 16.0, 6.2 Hz, 2H), 2.36 (s, 3H).
13CNMR (100 MHz, CDCl3): δ =197.82 , 142.15 , 139.99 ,
134.40 , 130.09 , 128.55 , 127.87 ,125.63 , 123.48 , 70.70 , 51.94
, 21.30 .HRMS (ESI) calcd for C16H16O2S [M + H]+ 207.0944,
found 273.0955. ee of 9a : 90%, determined by HPLC analysis,
Daicel, Chiralpak AD-H column (25 cm × 4.6 mm × 5 µm), n-
hexane/isopropanol = 95/5, 1 mL/min, 216 nm, 26°C, tR (major)
= 24.682 min, tR (minor) = 28.651 min.
o
2,4,6-triisopropyl-N-((1R,2S)-1-(4-nitrophenyl)-5,5,5-triphen-yl-
2-(pyrrolidin-1-yl)pentyl)benzenesulfonamide (10g).
1
Light yellow solid, mp 93-95oC. HNMR (400 MHz, CDCl3):
δ= 7.81 (d, J = 8.3 Hz, 2H), 7.18 (s, 17H), 6.98 (s, 2H), 5.27 (s,
1H), 4.53 (d, J = 9.4 Hz, 1H), 3.99 (dt, J = 13.1, 6.5 Hz, 2H), 3.23
(dd, J = 9.7, 4.6 Hz, 1H), 3.04 (dd, J = 17.5, 7.4 Hz, 2H), 2.83 (d,
J = 6.1 Hz, 3H), 2.69 (d, J = 6.7 Hz, 2H), 1.76 (d, J = 2.7 Hz,
4H), 1.25 (d, J = 6.6 Hz, 6H), 1.19 (d, J = 6.8 Hz, 6H), 1.10 (d, J
= 6.6 Hz, 6H).13CNMR (100 MHz, CDCl3): δ= 152.95, 149.79,
147.18, 146.94, 143.13, 133.65, 128.93, 128.49, 127.73, 127.18,
123.17, 122.89, 87.62, 64.08, 59.26, 57.49, 48.16, 34.15, 29.61,
29.09, 25.07, 24.60, 23.85, 23.67, 23.57. HRMS (ESI) calcd for
C47H55N3O5S [M + H]+ 774.3943, found 774.3943.
(R)-S-p-tolyl 3-hydroxy-3-phenylpropanethioate(9b).
White solid, mp 126-130°C. [α]D20 = + 18.24 (c 0.104, CHCl3 ).
1
Ref[7]. [α]D20 = + 15.4 (c 0.10, CHCl3). HNMR (400 MHz,
CDCl3): δ =7.43 – 7.28 (m, 7H), 6.95 (d, J = 8.8 Hz, 2H), 5.21
(dd, J = 8.8, 3.6 Hz, 1H), 3.83 (s, 3H), 3.06 (qd, J = 16.0, 6.2 Hz,
2H). ee of 9b : 90%, determined by HPLC analysis, Daicel,
Chiralpak AD-H column (25 cm × 4.6 mm × 5 µm), n-
hexane/isopropanol = 95/5, 1 mL/min, 216 nm, 26°C, tR (major)
= 32.859 min, tR (minor) = 37.942 min.
(R)-S-(4-fluorophenyl) 3-hydroxy-3-phenylpropanethioate (9c).
White solid, mp 96-98oC. [α]D20 = + 14.00 (c 0.10, CHCl3).
General procedure for preparation of malonic acid half
thioesters (MATHs).
1
Ref[7]. [α]D20 = + 17.8 (c 0.10, CHCl3). HNMR (400 MHz,
MAHTs 20a, 20b, 20c, 20d, 20e were prepared by known
procedure[10]
.
The characterization results of 20a, 20b, 20c,
CDCl3):δ= 7.44 – 7.27 (m，7H), 7.12 (t, J = 8.6 Hz, 2H), 5.22
(dd, J = 9.0, 3.5 Hz, 1H), 3.08 (ddd, J = 19.5, 15.9, 6.3 Hz, 2H).
ee of 9c : 72%, determined by HPLC analysis, Daicel, Chiralpak
AD-H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol
= 95/5, 1 mL/min, 216 nm, 26°C, tR (major) = 17.445 min, tR
(minor) = 19.392 min.
20d, 20e were as below.
3-oxo-3-(p-tolylthio)propanoic acid(20a).
1HNMR (400 MHz, CDCl3): δ =10.27 (s, 1H), 7.34 (d, J = 7.8
Hz, 2H), 7.25 (d, J= 7.8 Hz, 2H), 3.71 (s, 2H), 2.39 (s,
3H).13CNMR (100 MHz, CDCl3): δ =190.25 , 171.30 , 140.36 ,
134.36 , 130.19 , 122.93 , 48.18 , 21.29 .HRMS (ESI) calcd for
C10H10O3S [M + H]+ 211.0423, found 211.0423.
(R)-S-(2-chlorophenyl) 3-hydroxy-3-phenylpropanethioate (9d).
1
[α]D20 = +22.92 (c 0.288, CHCl3). HNMR (400 MHz, CDCl3):
δ= 7.52 (t, J = 8.2 Hz, 2H), 7.36 (dd, J = 16.1, 8.5 Hz, 7H), 5.24
(d, J = 8.5 Hz, 1H), 3.11 (ddd, J = 18.5, 15.9, 5.8 Hz,
2H).13CNMR (100 MHz, CDCl3): δ =195.12 , 142.02 , 138.50 ,
136.99 , 131.35 , 130.28 , 128.59 , 127.95 , 127.33 , 125.66 ,
70.68 , 52.14 .HRMS (ESI) calcd for C15H13ClO2S [M + H]+
315.0213, found 315.0217. ee of 9d : 81%, determined by HPLC
analysis, Daicel, Chiralpak AD-H column (25 cm × 4.6 mm × 5
µm), n-hexane/isopropanol = 97/3, 1 mL/min, 216 nm, 30°C, tR
(major) = 42.497 min, tR (minor) = 45.272 min.
3-((4-methoxyphenyl)thio)-3-oxopropanoic acid(20b).
1HNMR (400 MHz, CDCl3): δ= 9.69 (s, 1H), 7.27 (d, J = 8.5 Hz,
2H), 6.87 (d, J = 8.5 Hz, 2H), 3.73 (s, 3H), 3.61 (s, 2H).
3-((4-fluorophenyl)thio)-3-oxopropanoic acid(20c).
1HNMR (400 MHz, CDCl3): δ =10.68 (s, 1H), 7.42 (dd, J = 8.3,
5.4 Hz, 2H), 7.13 (t, J = 8.5 Hz, 2H), 3.72 (s, 2H).
3-((2-chlorophenyl)thio)-3-oxopropanoic acid(20d).
(R)-S-(4-chlorophenyl) 3-hydroxy-3-phenylpropanethioate (9e).
1HNMR (400 MHz, CDCl3): δ= 12.95 (dd, J = 4.0, 1.8 Hz, 1H),
7.65 (dd, J = 19.9, 7.7 Hz, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.46 (t, J
= 7.5 Hz, 1H), 3.87 (s, 2H). 13C NMR (100 MHz, CDCl3): δ=
188.81, 168.89 , 167.54 , 138.00 , 137.76 , 132.52 , 130.67 ,
128.48 , 126.80 , 49.66 . HRMS (ESI) calcd for C9H7ClO3S [M +
Na]+ 252.9697, found 252.9697.
1
[α]D20 = +18.18 (c 0.242, CHCl3). HNMR (400 MHz, CDCl3):
δ =7.37 (dt, J = 14.6, 9.2 Hz, 9H), 5.22 (dd, J = 8.9, 3.0 Hz, 1H),
3.08 (ddd, J = 19.2, 15.9, 6.1 Hz, 2H). ee of 9e : 84%, determined
by HPLC analysis, Daicel, Chiralpak AD-H column (25 cm × 4.6
mm × 5 µm), n-hexane/isopropanol = 98/2, 1 mL/min, 216 nm,
30°C, tR (major) = 35.706 min, tR (minor) = 41.740 min.
3-((4-chlorophenyl)thio)-3-oxopropanoic acid(20e).
(R)-S-p-tolyl 3-hydroxy-3-(3-methoxyphenyl)propanethioate (9f).
1HNMR (400 MHz, CDCl3): δ =13.05-12.73 (m, 1H), 7.60 (s,
2H), 7.50 (s, 2H), 3.85 (s, 2H).
White solid, mp 51-53oC. [α]D20 = + 22.03 (c 0.236, CHCl3).
1HNMR (400 MHz, CDCl3): δ =7.28 (dt, J = 12.7, 8.1 Hz, 5H),
6.99 – 6.83 (m, 3H), 5.20 (dd, J = 8.9, 3.6 Hz, 1H), 3.83 (s, 3H),
3.07 (qd, J = 15.9, 6.3 Hz, 2H), 2.40 (s, 3H).13CNMR (100 MHz,
CDCl3): δ= 197.70 , 159.76 , 143.85 , 139.93 , 134.36 , 130.05 ,
129.55 , 123.48 , 117.85 , 113.46 , 111.01 , 70.57, 55.17 , 51.91 ,
21.26 . HRMS (ESI) calcd for C17H18O3S [M + H]+ 303.1049,
found 303.1063. ee of 9f : 92%, determined by HPLC analysis,
Daicel, Chiralpak AD-H column (25 cm × 4.6 mm × 5 µm), n-
hexane/isopropanol = 90/10, 1 mL/min, 216 nm, 30°C, tR (major)
= 17.508 min, tR (minor) = 20.737 min.
General procedure for catalytic aldol reaction
The procedure was used for all the substrates. To a stirring
solution of MAHT (8, 1mmol), catalyst (10g, 774mg, 0.1mmol)
and 4Å molecular sieve (0.1g) in anhydrous MTBE/THF (9:1,
1ml), aldehyde (7, 0.2mmol) was added at 0oC and stirred for 8
days. The β-hydroxy thioester (9) was achieved by flash
chromatography (Petroleum Ether/EtOAc = 10:1 to 4:1 ).

6
Tetrahedron
(R)-S-p-tolyl 3-hydroxy-3-(p-tolyl)propanethioate(9g).
= 90/10, 1 mL/min, 216 nm, 30°C, tR (major) = 18.684 min, tR
ACCEPTED MANUSCRIPT
(minor) = 21.201 min.
White solid, mp 89-90oC. [α]D20 = + 10.83 (c 0.24, CHCl3).
1HNMR (400 MHz, CDCl3): δ =7.34 – 7.24 (m, 6H), 7.20 (d, J =
7.9 Hz, 2H), 5.20 (dd, J = 9.0, 3.5 Hz, 1H), 3.07 (ddd, J = 19.5,
15.9, 6.3 Hz, 2H), 2.41 (s, 3H), 2.38 (s, 3H).13C NMR (100 MHz,
CDCl3): δ =197.79 , 139.94 , 139.22 , 137.58 , 134.40 , 130.07 ,
129.21 , 125.58 , 123.55 , 70.58 , 51.97 , 21.29 , 21.08 .HRMS
(ESI) calcd for C17H18O2S [M + H]+ 287.1100, found 287.1100.
ee of 9g : 94%, determined by HPLC analysis, Daicel, Chiralpak
AD-H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol
= 90/10, 1 mL/min, 216 nm, 30°C, tR (major) = 12.425 min, tR
(minor) = 13.713 min.
(R)-S-p-tolyl 3-hydroxy-3-(naphthalen-1-yl)propanethioate (9l).
White solid, mp 122-124oC. [α]D20 = + 8.93 (c 0.168, CHCl3).
1HNMR (400 MHz, CDCl3): δ= 7.87 (d, J = 7.8 Hz, 4H), 7.57 –
7.46 (m, 3H), 7.29 (dd, J = 28.6, 7.9 Hz, 4H), 5.40 (dd, J = 8.8,
3.6 Hz, 1H), 3.17 (qd, J = 16.0, 6.2 Hz, 2H), 2.41 (s,
3H).13CNMR (100 MHz, CDCl3): δ 197.70 , 139.92 , 139.53 ,
134.35 , 133.18 , 132.96 , 130.04 , 128.34 , 127.95 , 127.61 ,
126.17 , 125.94 , 124.45 , 123.57 , 123.45 , 77.32 , 77.00, 76.68 ,
70.76 , 51.86 , 21.25 .HRMS (ESI) calcd for C20H18O2S [M +
NH4]+ 340.1366, found 340.1366. ee of 9l : 90%, determined by
HPLC analysis, Daicel, Chiralpak AD-H column (25 cm × 4.6
mm × 5 µm), n-hexane/isopropanol = 90/10, 1 mL/min, 216 nm,
30°C, tR (major) = 17.873 min, tR (minor) = 22.399 min.
(R)-S-p-tolyl 3-hydroxy-3-(o-tolyl)propanethioate(9h).
White solid, mp 43-45oC. [α]D20 = + 27.78 (c 0.180, CHCl3).
1HNMR (400 MHz, CDCl3): δ= 7.47 (d, J = 7.4 Hz, 1H), 7.29 –
7.09 (m, 7H), 5.39 (dd, J = 8.9, 3.2 Hz, 1H), 3.06 – 2.87 (m, 2H),
2.35 (s, 3H), 2.31 (s, 3H).13CNMR (100 MHz, CDCl3): δ= 198.09
, 140.22, 140.09 , 134.48 , 134.19 , 130.54 , 130.18 , 127.72 ,
126.49 , 125.30 , 123.57 , 67.46 , 50.82 , 21.38 , 19.02 . HRMS
(ESI) calcd for C17H18O2S [M + H]+ 287.1100, found 287.1100.
ee of 9h : 92%, determined by HPLC analysis, Daicel, Chiralpak
AD-H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol
= 90/10, 1 mL/min, 216 nm, 30°C, tR (major) = 10.774 min, tR
(minor) = 12.807 min.
(R)-S-p-tolyl 3-(4-cyanophenyl)-3-hydroxypropanethioate (9m).
White solid, mp 122-124oC. [α]D20 = + 15.84 (c 0.284, CHCl3).
1HNMR (400 MHz, CDCl3): δ= 7.66 (d, J = 8.2 Hz, 2H), 7.50 (d,
J = 8.2 Hz, 2H), 7.27 (q, J = 8.3 Hz, 4H), 5.33 – 5.20 (m, 1H),
3.11 – 2.98 (m, 2H), 2.40 (s, 3H). 13CNMR (100 MHz, CDCl3): δ
=197.59 , 147.37 , 140.25 , 134.32 , 132.35 , 130.17 , 126.35 ,
123.00 , 111.56 ,69.89 , 51.38 , 21.29 .HRMS (ESI) calcd for
C17H15NO2S [M + H]+ 298.0896, found 298.0896. ee of 9m :
74%, determined by HPLC analysis, Daicel, Chiralpak OD-H
column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol =
90/10, 1 mL/min, 216 nm, 30°C, tR (minor) = 11.343 min, tR
(major) = 13.651 min.
(R)-S-p-tolyl 3-hydroxy-3-(3-phenoxyphenyl)propanethioate(9i).
White solid, mp 60-62oC. [α]D20 = + 13.14 (c 0.236, CHCl3).
1HNMR (400 MHz, CDCl3): δ= 7.41 – 7.22 (m, 7H), 7.10 (dt, J =
21.1, 7.5 Hz, 5H), 6.96 (dd, J = 8.1, 1.9 Hz, 1H), 5.19 (dd, J =
8.5, 3.8 Hz, 1H), 3.06 (qd, J = 16.0, 6.2 Hz, 2H), 2.40 (s,
3H).13CNMR (100 MHz,CDCl3): δ =197.73 , 157.50 , 156.95 ,
144.25 , 140.01 , 134.38 , 130.09 , 129.88 , 129.74 , 123.39 ,
123.34 , 120.37 , 118.92 , 118.11 , 116.06 , 70.36 , 51.77 , 21.29 .
HRMS (ESI) calcd for C22H20O3S [M + H]+ 365.1206, found
365.1206. ee of 9i : 90%, determined by HPLC analysis, Daicel,
Chiralpak AD-H column (25 cm × 4.6 mm × 5 µm), n-
hexane/isopropanol = 90/10, 1 mL/min, 216 nm, 30°C, tR (major)
= 15.302 min, tR (minor) = 18.69 min.
(R)-S-p-tolyl 3-hydroxy-3-(4-nitrophenyl)propanethioate (9n).
White solid, mp 113-114oC. [α]D20 = + 16.01 (c 0.606, CHCl3).
1HNMR (400 MHz, DMSO): δ =8.20 (d, J = 8.5 Hz, 2H), 7.67 (d,
J = 8.5 Hz, 2H), 7.26 (s, 4H), 5.97 (d, J = 4.8 Hz, 1H), 5.19 (dd, J
= 12.1, 5.4 Hz, 1H), 3.10 – 2.96 (m, 2H), 2.33 (s, 3H).13CNMR
(100 MHz, DMSO): δ 194.28 , 151.92 , 146.56 , 139.27 , 134.13
, 129.87 , 127.02 , 123.84 , 123.23 , 68.58 , 52.00 , 20.69 . HRMS
(ESI) calcd for C16H15NO4S [M + H]+ 318.0795, found 318.0803.
ee of 9n : 70%, determined by HPLC analysis, Daicel, Chiralpak
OD-H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol
= 90/10, 1 mL/min, 216 nm, 30°C, tR (minor) = 33.757 min, tR
(major) = 41.5 min.
(R)-S-p-tolyl 3-(4-(tert-butyl)phenyl)-3-hydroxypropanethioate
(9j).
White solid, mp 74-76oC. [α]D20 = + 9.37 (c 0.128, CHCl3).
1HNMR (400 MHz, CDCl3): δ =7.39 (d, J = 8.3 Hz, 2H), 7.33 –
7.27 (m, 4H), 7.24 (d, J = 8.1 Hz, 2H), 5.19 (dd, J = 9.1, 3.3 Hz,
1H), 3.07 (ddd, J = 19.4, 16.0, 6.3 Hz, 2H), 2.39 (s, 3H), 1.32 (s,
9H).13CNMR (100 MHz, CDCl3): δ= 197.91 , 150.95 , 140.00 ,
139.16 , 134.44 , 130.11 , 125.51 , 125.43 , 123.58 , 70.55 , 51.92
, 34.54 , 31.32 , 21.33 .HRMS (ESI) calcd for C20H24O2S [M +
H]+ 329.1570, found 329.1584. ee of 9j : 92%, determined by
HPLC analysis, Daicel, Chiralpak AD-H column (25 cm × 4.6
mm × 5 µm), n-hexane/isopropanol = 90/10, 1 mL/min, 216 nm,
30°C, tR (major) = 9.242 min, tR (minor) = 10.837 min.
(R)-S-p-tolyl 3-(4-fluorophenyl)-3-hydroxypropanethioate (9o).
White solid, mp 107-108oC. [α]D20 = + 9.09 (c 0.154, CHCl3).
1HNMR (400 MHz, CDCl3): δ= 7.40 – 7.22 (m, 6H), 7.06 (t, J =
8.7 Hz, 2H), 5.19 (dd, J = 8.7, 3.7 Hz, 1H), 3.05 (qd, J = 16.0, 6.3
Hz, 2H), 2.40 (s, 3H).13CNMR (100 MHz, CDCl3): δ =197.85 ,
140.16 , 138.04 , 138.01 , 134.46 , 130.21 , 127.51 , 127.4,
123.43 , 115.57 , 115.36 , 70.17 , 51.98 , 21.38 . HRMS (ESI)
calcd for C16H15FO2S[M + H]+ 291.0850, found 291.0850. ee of
9o : 90%, determined by HPLC analysis, Daicel, Chiralpak AD-
H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol =
95/5, 1 mL/min, 216 nm, 30°C, tR (major) = 23.314 min, tR
(minor) = 26.357 min.
(R)-S-p-tolyl 3-hydroxy-3-(4-methoxyphenyl)propanethioate(9k).
White solid, mp 89-90oC. [α]D20 = + 5.24 (c 0.102, CHCl3).
1HNMR (400 MHz, CDCl3): δ= 7.35 – 7.23 (m, 6H), 6.91 (d, J =
8.6 Hz, 2H), 5.17 (dd, J = 8.9, 3.5 Hz, 1H), 3.82 (s, 3H), 3.06
(ddd, J = 19.4, 15.9, 6.3 Hz, 2H), 2.40 (s, 3H).13CNMR (100
MHz, CDCl3): δ =197.74 , 159.24 , 139.93 , 134.38 , 130.06 ,
126.93 , 123.54 , 113.91 , 70.34 , 55.23 , 51.96 , 21.28 .HRMS
(ESI) calcd for C17H18O3S [M + H]+ 303.1049, found 303.1043.
ee of 9k : 90%, determined by HPLC analysis, Daicel, Chiralpak
AD-H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol
(R)-S-p-tolyl 3-(4-chlorophenyl)-3-hydroxypropanethioate (9p).
White solid, mp 128-130oC. [α]D20 = + 12.28 (c 0.228, CHCl3).
1HNMR (400 MHz, DMSO): δ =7.40 (s, 4H), 7.26 (s, 4H), 5.73
(d, J = 4.6 Hz, 1H), 5.10 – 4.98 (m, 1H), 3.04 – 2.92 (m, 2H),
2.34 (s, 3H).13CNMR (100 MHz, DMSO): δ= 194.47, 143.17 ,
139.20 , 134.12 , 131.57 , 129.84 , 127.97 , 127.65 , 123.95 ,
68.72 , 52.42 , 20.70 .HRMS (ESI) calcd for C16H15ClO2S[M +
H]+ 307.0554, found 307.0554. ee of 9p : 90%, determined by

7
HPLC analysis, Daicel, Chiralpak AD-H column (25 cm × 4.6
mm × 5 µm), n-hexane/isopropanol = 95/5, 1 mL/min, 216 nm,
30°C, tR (major) = 23.989 min, tR (minor) = 27.243 min.
allowed to stried at r.t. for 24h. It was then extracted with ethyl
ACCEPTED MANUSCRIPT
acetate, washed with brine (20 mL), dried with Na2SO4 and
evaporated in vacuo. The crude product was purified by flash
chromatography (Petroleum Ether/EtOAc = 10:1 to 4:1 ) to give
(16, 2.95g, 93%) as a colorless oil. [α]D20 = + 17.60 (c 1,
CHCl3). Ref[11b]. [α]D24 = + 12.2 (c 5.53, CHCl3).1HNMR (400
MHz, CDCl3): δ =7.77 (d, J = 8.2 Hz, 2H), 7.35 – 7.23 (m, 7H),
4.78 (t, J = 6.7 Hz, 1H), 4.27 (dt, J = 9.9, 6.7 Hz, 1H), 4.08 – 4.01
(m, 1H), 2.44 (s, 3H), 2.01 (dd, J = 12.7, 6.1 Hz, 2H).
(R)-S-p-tolyl 3-(4-bromophenyl)-3-hydroxypropanethioate (9q).
White solid, mp 144-145oC. [α]D20 = + 12.78 (c 0.352, CHCl3).
1HNMR (400 MHz, DMSO): δ =7.59-7.15 (m, 8H), 5.73 (s, 1H),
5.03 (s, 1H), 2.98 (s, 2H), 2.33 (s, 3H).13CNMR (100 MHz,
DMSO): δ =194.45 , 143.59 , 139.19 , 134.12 , 130.89 , 129.84 ,
128.01 , 123.94 , 120.08 , 68.76 , 52.38 , 20.71 . HRMS (ESI)
calcd for C16H15BrO2S [M + NH4]+ 368.0314, found 368.0312. ee
of 9q : 88%, determined by HPLC analysis, Daicel, Chiralpak
OD-H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol
= 90/10, 1 mL/min, 216 nm, 30°C, tR (minor) = 17.811 min, tR
(major) = 20.363 min.
(R)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol (17).
A mixture of 16 (2.95g, 9.6mmol), 1-naphthol(1.53g, 10.6mmol)
and K2CO3 (4.00g, 28.9mmol) in acetone was refluxed for 5h.
The reaction mixture was cooled to room temperature and
acetone was evaporated. Then water (20 mL) was added and
extracted with ethyl acetate (20 mL × 3), washed with brine,
dried with Na2SO4 and evaporated in vacuo. The crude product
was purified by flash chromatography (Petroleum Ether/EtOAc =
10:1 to 4:1 ) to give 17 as a white solid (2.55g, 95%) .
(R)-S-p-tolyl 3-(2-bromophenyl)-3-hydroxypropanethioate (9r).
White solid, mp 110-112oC. [α]D20 = + 61.90 (c 0.126, CHCl3).
1HNMR (400 MHz, CDCl3): δ =7.59 (dd, J = 37.2, 7.8 Hz, 2H),
7.40 – 7.13 (m, 6H), 5.52 (d, J = 9.2 Hz, 1H), 3.27-3.10 (m, 2H),
2.91 (dd, J = 16.1, 9.4 Hz, 1H), 2.40 (s, 3H).13CNMR (100 MHz,
CDCl3): δ =198.04 , 141.02 , 140.02 , 134.41 , 132.64 , 130.10 ,
129.13 , 127.80 , 127.33 , 123.38 , 121.27 , 69.69 , 49.95 ,
21.30 . HRMS (ESI) calcd for C16H15BrO2S [M + NH4]+
368.0314, found 368.0320. ee of 9r : 70%, determined by HPLC
analysis, Daicel, Chiralpak OD-H column (25 cm × 4.6 mm × 5
µm), n-hexane/isopropanol = 90/10, 1 mL/min, 216 nm, 30°C, tR
(minor) = 10.593 min, tR (major) = 12.079 min.
The optical purity of 17 was further increased to 99% ee by
twice recrystallization from dichloromethane and n-hexane.
[α]D20 = -24.9 (c 1, CHCl3). Ref[11c]. [α]D20 = -30.5 (c 0.5,
CHCl3).1HNMR (400 MHz, CDCl3):δ =8.34 – 8.26 (m, 1H), 7.89
– 7.80 (m, 1H), 7.58 – 7.29 (m, 9H), 6.82 (d, J = 7.5 Hz, 1H),
5.13 (dd, J = 7.8, 5.2 Hz, 1H), 4.34 (dd, J = 13.7, 7.7 Hz, 1H),
4.18 (dd, J = 11.4, 6.8 Hz, 1H), 2.55 (s, 1H), 2.47 – 2.29 (m, 2H).
ee of 17 : >99%, determined by HPLC analysis, Daicel,
Chiralpak OD-H column (25 cm × 4.6 mm × 5 µm), n-
hexane/isopropanol = 92/8, 1 mL/min, 210 nm, 30°C, tR (major)
= 15.42min.
(R)-S-p-tolyl 3-(3-bromophenyl)-3-hydroxypropanethioate(9s).
White solid, mp 84-85oC. [α]D20 = + 15.71 (c 0.49, CHCl3).
1HNMR (400 MHz, CDCl3): δ= 7.56 (s, 1H), 7.44 (d, J = 7.7 Hz,
1H), 7.33 – 7.21 (m, 6H), 5.17 (dd, J = 8.3, 4.0 Hz, 1H), 3.13 (s,
1H), 3.10 – 2.97 (m, 2H), 2.40 (s, 3H).13CNMR (100 MHz,
CDCl3): δ =197.69 , 144.44 , 140.08 , 134.37 , 130.87 , 130.11 ,
128.78 , 124.23 , 123.24 , 122.64 , 69.94 , 51.67 , 21.29 .
HRMS (ESI) calcd for C16H15BrO2S [M + NH4]+ 368.0314, found
368.0305. ee of 9s : 86%, determined by HPLC analysis, Daicel,
Chiralpak OD-H column (25 cm × 4.6 mm × 5 µm), n-
hexane/isopropanol = 90/10, 1 mL/min, 216 nm, 30°C, tR (minor)
= 16.301 min, tR (major) = 24.209 min.
(S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine (18).
To a solution of alcohol 17 (1 g, 3.6 mmol) in DCM (10 mL) was
added triethylamine (0.91 g, 9 mol) and DMAP (4-dimethyl-
aminopyridine, 0.01g, 0.08mmol) at 0 oC. Methanesulfonyl
chloride (1.03 g, 9 mmol) was added dropwise to the reaction
o
o
mixture at 0 C over 20 min. The mixture was stirred at 0 C for
0.5 h. The reaction mixture was washed with saturated NaHCO3
aqueous (3 x 5 mL), dired over Na2SO4 and concentrated under
reduced pressure to give orange oil. The crude product was used
in the next step without any further purification. The orange oil
was dissolved in DMF (10 mL), sodium azide (0.48 g, 7.2 mmol)
was added to the reaction mixture in batches at room
temperature. The reaction mixture was stirred at 50oC for 16 h. 5
mL H2O was added to quench the reaction, and the mixture was
extracted with CH2Cl2 (20 mL). The organic phase was washed
by H2O (5 x 10 mL), brine, dried over Na2SO4 and concentrated
under reduced pressure to give orange oil. The crude product was
used in the next step without any further purification. The residue
was dissolved in the mixture of MeOH/i-PrOH/THF 3:5:8 (16
General procedure for preparation of (+)-dapoxetine
(R)-1-phenylpropane-1,3-diol(15).
A mixture of KBH4 (3.24g, 60mmol) and LiCl (2.54g, 60mmol)
was stirred in boiling anhydrous THF under N2 for 2h. The
reaction mixture was cooled to room temperature, and a solution
of 9a (5.44g, 20mmol) in THF was added dropwise at 0 oC over 1
h. Striing was continued at room temperature for an additioal 3h.
Then water was added and stirred for 1h, extracted with DCM,
the combined organic phase was washed with water, dried with
Na2SO4 and evaporated in vacuo. The crude product was
purified by flash chromatography (Petroleum Ether/EtOAc =
10:1 to 4:1 ) to give (15, 2.58g, 85%) as a colorless oil. [α]D20 =
+ 62.42 (c 0.564, CHCl3). Ref[11a]. [α]D20 = + 59.1 (c 1.00,
mL). To the solution was added
triethylamine (0.73 g, 7.2
mmol) at room temperature, followed by (0.03g, 0.36mmol) 1,3-
propanedithiol. The reaction mixture was cooled to 0 oC, (1.36 g,
36 mol) sodium borohydride was added to the reaction mixture at
0 oC in batches. After addition, the reaction mixture was stirred at
o
0 C for 2 h. The reaction mixture was quenched by water (10
mL), the solvent was removed under reduced pressure. The
residue was dissolved by CH2Cl2 (30 mL), the organic phase was
washed with H2O (3 x 10 mL), brine, dried over Na2SO4 and
concentrated under reduced pressure to give yellow oil. The
crude product was purified by flash chromatography using
PE/EA 2:1 to give 18 as colorless oil (0.52 g, yield 52%).[α]D20
= + 53.46 (c 1.62, CHCl3). Ref[11d]. [α]D22 = 8.2 (c 0.3,
CHCl3).1HNMR (400 MHz, CDCl3): δ= 8.27 (d, J = 4.7 Hz,
1H), 7.79 (s, 1H), 7.37 (ddd, J = 42.9, 29.5, 4.5 Hz, 9H), 6.72 (d,
1
CHCl3). HNMR (400 MHz, CDCl3): δ =7.39 – 7.22 (m，5H),
4.84 (dd, J = 8.5, 4.0 Hz， 1H), 3.85 (s, 2H), 3.78 – 3.62 (m,
2H), 1.98 – 1.77 (m, 2H).
(R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (16).
To a stirring solution of 15 (1.58g, 10mmol) in DCM at 0 oC was
added triethylamine (2.1g, 20mmol) and a solution of tosyl
chloride (2.18g, 11mmol) in DCM. The reaction mixture was

8
Tetrahedron
ACCEPTED MANUSCRIPT
Wang HF, Yan LJ, Xiong FJ, Wu Y, Chen FE, RSC Adv. 2016; 6:
75470-75477; g) Wang XL, Xu LJ, Yan LJ, Wang HF, Han S, Wu
Y, Chen FE, Tetrahedron. 2016;72:1787-1793; h) Wang XL, Xu
LJ, Xiong FJ, Wu Y, Chen FE, RSC Adv. 2016; 6: 37701-37709; i)
Wang HF, Yan LJ, Wu Y, Chen FE, Tetrahedron. 2017; 7: 2793-
2800;
J = 6.7 Hz, 1H), 4.32 (s, 1H), 4.19 (s, 1H), 4.07 (s, 1H), 2.27
(dd, J = 17.9, 5.8 Hz, 2H).
ee of 18 : 92%, determined by HPLC analysis, Daicel, Chiralpak
OD-H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol
= 80/20 with 0.1% Et3N, 0.8 mL/min, 254 nm, 35°C, tR (minor) =
13.589 min, tR (major) = 17.649min.
10. Tao GW, Rui HW, Ru ZM. Chin. J. Org. Chem.. 2008; 28: 2001-
2005
11. a) Johan P, Tahar A, Virginie RV, Annie-Claude G, Philippe J,
Eric L. Tetrahedron: Asymmetry. 2011; 22: 562-574; b) Teruaki
M, Koji T, Takeshi O. Chem. Lett. 1985; 9: 1359-62; c) Gopal K,
Ratnesh S, Varun K, Mangilal C, Vipin NA.Tetrahedron Lett.
2013; 54: 5991-5993; d) Joo KS, Hong JT, Sook MI, Su KI, Hoon
JY. Tetrahedron Lett. 2012; 53: 3680 - 3685.
(+)-dapoxetine(19).
A mixture of 18 (0.5g, 1.8mmol), 37%-40% formaldehyde
aqueous solution (0.59ml, 7.2mmol) and formic acid (0.55ml,
14.4mmol) was refluxed for 12h. The reaction mixture was
cooled to room temperature and adjusted to pH 8-9 with N N
NaOH solution. Then extracted with DCM (10 mL × 3),
dried with Na2SO4 and evaporated in vacuo. The crude product
was purified by flash chromatography (Petroleum Ether/EtOAc
= 10:1 to 4:1 ) to give (19, 0.38g, 68%) . [α]D20 = + 69.2 (c 1,
CHCl3). Ref[11a]. [α]D20 = + 65.9 (c 1.00, CHCl3). 1HNMR (400
MHz, CDCl3): δ=8.00 (d, J = 7.2 Hz, 1H), 7.81 – 7.48 (m,
3H), 7.15-7.37 (m, 5H), 6.89 (ddd, J = 25.2, 12.8, 4.6 Hz, 3H),
4.81 – 4.50 (m, 1H), 4.06 (dd, J = 4.5, 3.3 Hz, 1H), 3.27 (d, J =
6.8 Hz, 2H), 2.69-2.22 (m, 1H), 1.58 (s, 6H).
ee of 19 : 92%, determined by HPLC analysis, Daicel, Chiralpak
OD-H column (25 cm × 4.6 mm × 5 µm), n-hexane/isopropanol
= 99/1 with 0.1% Et3N, 1 mL/min, 254 nm, 35°C, tR (minor) =
7.968 min, tR (major) = 8.758min.
References and notes
1. This is a continuous endeavor. Part 11 are in submission. For Part
10 see: Wang HF, Yan LJ, Wu Y, Chen FE, Tetrahedron. 2017; 7:
2793-2800.
2. (a) Li HJ, Tian HY, Wu YC, Chen YJ, Liu L, Wang D, Li CJ,
Adv. Synth. Catal. 2005; 347: 1247-1256; (b) Fortner KC, Shair
MD, J. Am. Chem. Soc. 2007; 129: 1032-1033; (c) Berrue F,
Antoniotti S, Tomas OP, Amade P, Eur. J. Org. Chem. 2007:
1743-1748; (d) Zhou GQ, Yost JM, Colotart DM, Synthesis. 2007;
3: 478-482; (e) Tarsis E, Gromova A, Lim D, Zhou GQ, Coltart
DM, Org. Lett. 2008; 10: 4819-4822; (f) Schipper DJ, Rousseaux
S, Fagnou K, Angew. Chem. Int. Ed. 2009; 48: 8343-8347; (g)
Obrien JM, Lee KS, Hoveyda AH, J. Am. Chem. Soc. 2010; 132:
10630-10633; (h) Sauer SJ, Garnsey MR, Cotart DM, J. Am.
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