Practical synthetic process for enantiopure 1-benzyl-3-hydroxypyrrolidine

Article abstract of DOI:10.1016/j.tetasy.2008.06.003

The synthesis of (S)-1-benzyl-3-hydroxypyrrolidine (S)-5 comprised the asymmetric hydroboration of 1-benzyl-3-pyrroline 4, followed by oxidation and chiral purification via diastereomeric salt formation. The asymmetric borane reagent was generated 'in situ' from NaBH₄, BF₃-OEt₂, and (+)-α-pinene 1 (85% ee) and reacted with 4, prepared from cis-1,4-butenediol 3, to give crude product (S)-5. The following chiral purification via diastereomeric salt formation proceeded to afford (S)-5 with >99% ee. The optimized process was successfully scaled up to an industrial scale to produce a 252 kg batch of (S)-5.

Full text of DOI:10.1016/j.tetasy.2008.06.003

Tetrahedron: Asymmetry 19 (2008) 1465–1469
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Tetrahedron: Asymmetry
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Practical synthetic process for enantiopure 1-benzyl-3-hydroxypyrrolidine
*
Masao Morimoto , Kenichi Sakai
Specialty Chemicals Research Laboratory, Toray Fine Chemicals Co., Ltd, Minato-ku, Nagoya, Aichi 455-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 May 2008
Accepted 2 June 2008
The synthesis of (S)-1-benzyl-3-hydroxypyrrolidine (S)-5 comprised the asymmetric hydroboration of 1-
benzyl-3-pyrroline 4, followed by oxidation and chiral purification via diastereomeric salt formation. The
asymmetric borane reagent was generated ‘in situ’ from NaBH4, BF3–OEt2, and (+)-a-pinene 1 (85% ee)
and reacted with 4, prepared from cis-1,4-butenediol 3, to give crude product (S)-5. The following chiral
purification via diastereomeric salt formation proceeded to afford (S)-5 with >99% ee. The optimized pro-
cess was successfully scaled up to an industrial scale to produce a 252 kg batch of (S)-5.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
a resolution process of (S)-enriched 5 with Ts-(S)-Phe via diaste-
reomeric salt formation.15
Enantiopure 1-benzyl-3-hydroxypyrrolidine 5 is well known as
a useful intermediate for various drugs and clinical drug candi-
dates,1 such as Darifenacin, Barnidipine, and Panipenem. Thus, a
great variety of methods have been reported as follows: the reduc-
tion of the imide precursor with an alkaline metal hydride,2 asym-
metric hydroboration of 1-benzyl-3-pyrroline;3 resolution of
racemic 1-benzyl-3-hydroxypyrrolidine (RS)-5 with enantiopure
lactic acid,4 phenylalanine derivative,5 or isoquinoline carboxylic
acid derivative,6 asymmetric hydrolysis with an esterase enzyme;7
enzymatic asymmetric reduction of racemic 1-benzyl-3-pyrrolidi-
none;8 stereoselective inversion of the mesylate or ester of enan-
tiopure 1-benzyl-3-hydroxypyrrolidine followed by hydolysis;9
resolution of (RS)-5 via cluster-formation,10 ring-closure of
4-halo-3-hydroxybutane derivatives11 or 1-bromo-3-butene-
2-one;12 ring-closure of malic acid followed by hydride reduc-
tion;13 and enzymatic hydroxylation of 1-benzylpyrrolidine.14
At an early stage of process development, we established the
2. Results and discussion
The hybrid process is mainly built up over three stages: (a) syn-
thesis of 1-benzyl-3-pyrroline 4; (b) asymmetric hydroboration to
4 with borane species 2a, 2b, and 2c, followed by alkaline
oxidation; and (c) enantiomeric purity improvement of (S)-en-
riched 5 (84% ee) via diastereomeric salt formation, as illustrated
in Scheme 1.
2.1. Synthesis of 1-benzyl-3-pyrroline 4
Starting material, cis-1,4-butenediol 3 was chlorinated with
thionyl chloride to give cis-1,4-dichlorobutene followed by cycliza-
tion with benzylamine to give 4.16 However, residual non-reacted
benzylamine deactivated the borane species 2a, 2b, and 2c in the
next step, because of an unfavorable side reaction, nitrogen–boron
complex formation. Accordingly, the effective removal of excessive
benzylamine was crucial and so liquid–liquid extraction was car-
ried out, as shown in Table 1. Considering both the yield of 4 and
removal efficiency of benzylamine, liquid–liquid extraction was
performed at pH 7.2–7.5. It was found that the recovered benzyl-
amine could be reused in the cyclization reaction of the next batch
without any further purification. The isolated 4 was purified by
distillation under reduced pressure, minding both its atmosphere
and temperature, since intermediate 4 was found to be easily oxi-
dized into 1-benzylpyrrole in the presence of a trace amount of
oxygen or by heat.17
resolution of (RS)-5 with naturally-denied L-phenylalanine p-tolu-
enesulfonamide (Ts-(S)-Phe) as a resolving agent, while consider-
ing economical points of view and ease of scale-up to an
industrial scale.5 However, the productivity of the resolution pro-
cess was insufficient because recrystallization of the salt had to
be repeated to obtain >99% ee and no effective racemization of
the counter enantiomer could be established. Therefore, the maxi-
mum yield by direct resolution of (RS)-5 via diastereomeric salt
formation is 50% of the racemic form. In order to overcome this
low productivity, we sought a practical strategy suited for an
industrial-scale production. As a result, we successfully contrived
a hybrid process composed of the asymmetric hydroboration of
1-benzyl-3-pyrroline 4 and enantiomeric purity improvement by
2.2. Asymmetric hydroboration–oxidation
It is known that enantiopure diisopinocampheylborane 2c,
* Corresponding author.
which was prepared by the reaction between (+)-a-pinene 1 with
E-mail address: masao_morimoto@tfc.toray.co.jp (M. Morimoto).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.003

1466
M. Morimoto, K. Sakai / Tetrahedron: Asymmetry 19 (2008) 1465–1469
H
B
BH2
c, d
BH3
1
2a
2b
2c
OH
OH
e
f
a, b
HO
OH
N
N
N
CH2Ph
CH2Ph
CH2Ph
(>99% ee)
(84% ee)
3
4
crude (S)-5
(S)-5
Scheme 1. Reaction conditions: a) SOCl2/C5H5N, b) PhCH2NH2, c) NaBH4/THF, d) BF3-OEt2, e) H2O2/NaOHaq. f) chiral purification via salt formation, (S)-phenylalanine p-
toluenesulfonamide (Ts-(S)-Phe)/denatured EtOH.
Table 1
Table 2
pH dependency of liquid–liquid extraction
Effect of activating agent of NaBH4 on reactivity
Entry
pH
Recovery of 4a (%)
Removal of benzyl amineb (%)
Entry Activating Solvent
agent
Yield of
Yield of
Enantiomeric
purity of crude
limonenea crude
1
2
3
4
5
6.5
7.0
7.2
7.5
8.0
29
58
73
77
85
>99
99
99
98
94
(%)
(S)-5 (%) (S)-5 (% ee)
1
2
3
4
5
6
7
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
BF3–OEt2
Diglymeb
Trace
Trace
22
15
15
80
53
81
75
Monoglymec
THF
d
d
—
—
—
—
—
—
—
—
d
d
1,4-Dioxane
Isopropylether
Tetrahydropyrane
THF
a
d
d
Yield was calculated on the amount of 4 contained in the cyclization solution.
Yield was calculated on the amount of benzylamine contained in the cyclization
b
d
d
8
nde
92
82
solution.
a
b
c
Yield of limonene generated by isomerization of 1 in the synthesis of 2c.
Diethylene glycol dimethyl ether.
Monoethylene glycol dimethyl ether.
over 99% ee and 1M BH3–THF, smoothly underwent asymmetric
hydroboration to the intermediate 4 at ꢀ25 °C. Subsequent oxida-
tion with H2O2 easily affords enantiopure (S)-1-benzyl-3-hydroxy-
pyrrolidine (S)-5, with approximately 100% ee successfully.3
Regardless of the scientific elegance, however, the reaction condi-
tions are suitable for laboratory experiment, but not for an indus-
trial-scale production without any sufficient improvement. This is
because diborane reagents 2a and 2c (Scheme 1) are not only very
expensive, but also unsafe during transportation and storage due
to a lack of stability,18 although they are commercially available.19
Moreover, manufacturing at ꢀ25 °C is not always available at or-
dinary multi-purpose facilities.
In order to achieve asymmetric hydroboration on an industrial
scale, various parameters were examined. We characterized the
two key points: (1) to employ in situ generated borane from inex-
pensive starting materials, and (2) to carry out asymmetric hyd-
roboration at around 0 °C.
d
Asymmetric hydroboration with 4 was not carried out when isomers of 1 such
as limonene were observed in the synthesis of 2c.
e
Not detected.
mixture composed of 1, NaBH4, and THF, and stirred for 12 h to
give a milky white slurry. To the slurry 4 was added dropwise,
and the resulting mixture was stirred for 8 h to complete reaction.
The experiments were performed employing the BF3–OEt2/4 molar
ratio as a parameter. The most efficient reaction conditions were
found in a case using a twofold equivalent of the BF3–OEt2 to 4
as observed in the former example (Fig. 1).20 It is generally known
that adducts of borane species with amines exhibit no hydrobora-
tion activity.20b Therefore, coordination of 4 would lead to a loss in
the hydroboration abilities of an equivalent borane species comp-
ring 2a, 2b, and 2c to 4.
First, we employed 1 (85% ee) which is commercially available
and economical. A type of activating agent, sodium borohydride
(NaBH4) was optimized (Table 2). The results suggested that
borontrifluoride–etherate (BF3–OEt2) and THF were the best com-
bination to effectively generate borane active species (Table 2, en-
try 7), where in situ generated diborane immediately hydroborated
with 1 to provide 2c and so forth. Meanwhile, when more cost-
effective H2SO4 was employed as an activating agent, diglyme gave
the best results compared with the other solvents, such as monog-
lyme, THF, 1,4-dioxane, isopropyl ether, and tetrahydropyran.
However, it was not as good as that obtained in the case of BF3–
OEt2 and THF (Table 2).
The changes in enantiomeric purity of the resulting crude (S)-5
with reaction time at ꢀ25, 0, and 25 °C were examined, and are
shown in Figure 2.
As seen in Figure 2, it was proven that the enantiomeric purity
of crude (S)-5 continued to decrease with reaction time at 0 °C and
25 °C, whereas it remained almost unchanged at ꢀ25 °C. The yield
of (S)-5 between ꢀ22 and 25 °C reached around 92% after 8 h. It
was concluded that the optimization of reaction conditions is cru-
cial for establishing the asymmetric hydroboration process with
high enantiomeric selectivity.
These test results indicated that the enantiomeric purity of
crude (S)-5 decreased with reaction time and could be compre-
hended by the addition–elimination equilibrium reactions be-
tween 4 and three borane species. In general, any 2c which
formed at an initial time could not keep its structure for a long time
at around 0 °C due to the steric hindrance of the two pinanyl
Next, the reaction conditions such as reagent molar ratios and
reaction time were optimized to maximize both the chemical yield
and chiral purity of the resulting crude (S)-5 at around 5 °C. A typ-
ical procedure is as follows: BF3–OEt2 was added into the reaction

M. Morimoto, K. Sakai / Tetrahedron: Asymmetry 19 (2008) 1465–1469
1467
Table 3
100
95
90
85
80
75
70
65
60
Chiral purification via diastereomeric salt formation followed by recrystallization
Entry
Operation
Yield (%)
Diastereomeric excess (% de)
1
2
Salt formationa
87b
97d
98
>99
Recrystallizationc
a
An equivalent of Ts-(S)-Phe to crude (S)-5 with 81% ee was used.
Yield (%) = (amount of 5 in the salt obtained) ꢁ 100/(amount of crude (S)-5
b
charged).
c
Recrystallization of the salt obtained in the salt formation.
Yield (%) = (amount of the salt obtained) ꢁ 100/(amount of the salt charged).
d
De% is based on enantiomeric excess of (S)-5 in the salt.
2.4. Production of (S)-5 on an industrial scale
1.50
2.00
2.50
BF3-OEt2/4 (mol/mol)
At first, cis-1,4-dichlorobutene was produced from cis-1,4-
butenediol 3 (460 kg) and thionyl chloride under the optimized
condition. Subsequently, the resulting intermediate was reacted
with benzylamine, followed by extraction and distillation to afford
346 kg (net 331 kg) of 1-benzyl-3-pyrroline 4, as described in Sec-
tion 2.1.
chiral purity
chemical yield
Figure 1. Effect of BF3–OEt2/4 molar ratio.
Next, we demonstrated the asymmetric hydroboration using a
multi-purpose facility, 10 kL reactor, at 0 °C for 8 h. The resulting
reaction mixture was treated with aqueous sodium hydroxide fol-
lowed by oxidation with hydrogen peroxide. The separated organic
layer was extracted with diluted sulfuric acid, and crude (S)-5 was
isolated from the resulting aqueous layer by reverse-extraction
with toluene under alkaline conditions with sodium hydroxide.
As a result, crude (S)-5, 320 kg(net), was obtained in 88% yield
(on the basis of 4) with an enantiomeric purity of 84% ee, without
any deterioration in the enantiomeric purity of 1 (85% ee). This re-
sult indicates that the industrial-scale hydroboration is advanta-
geous, because the process avoids air contamination.
Isolated crude (S)-5 (84% ee) was treated with Ts-(S)-Phe in
EtOH to successfully provide enantiopure (S)-5 (>99% ee) via dia-
stereomeric salt formation, 5/Ts-(S)-Phe = 1/1 (mol/mol). Commer-
cially available and inexpensive alcohol denatured solvent24 with
2-PrOH was used in the production. The resulting diastereomeric
salt was recrystallized to give 99.3% de. Subsequently, the removal
of the chiral purifying agent Ts-(S)-Phe was performed, followed by
distillation to afford 252 kg of (S)-5 (99.3% ee). No boron contami-
nation is expected in the final product, judging from the by-
products such as NaBF4 and NaB(OH)4 which can be removed
by extraction, resolution followed by recrystallization, and
distillation.
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
50
reaction time (h)
-22ºC
0ºC
25ºC
Figure 2. Effect of reaction time and temperature.
groups. Also, it has been reported that a pinanyl group on a boron
atom is apt to release an -pinene molecule in the presence of
a
amine,21 that is, longer reaction times led to an increase in the
amount of thermodynamically stable 2a and 2b, which are unfa-
vorable for asymmetric hydroboration22 and cause a decrease in
the amount of unstable 2c. Accordingly, it was concluded that
stopping the reaction at 8 h (>90% yield) would give the best solu-
tion to realize a better result for industrial production employing a
common facility without powerful cooling equipment.
3. Conclusion
For producing (S)-1-benzyl-3-hydroxypyrroline 5, a versatile
key intermediate for various chiral drugs, a hybrid process com-
posed of the asymmetric hydroboration of 1-benzyl-3-pyrroline 4
and chiral purification of crude (S)-5 via diastereomeric salt forma-
tion was developed. In the key step, the asymmetric hydroboration
successfully proceeded to provide crude (S)-5 (84% ee), without a
decrease in the enantiomeric excess (% ee) of 1 (85% ee) used as
a chiral template, followed by chiral purity improvement via dia-
stereomeric salt formation with Ts-(S)-Phe. The proposed hybrid
process has been performed in an industrial plant and successfully
produced 252 kg of (S)-5 with 99.3% ee.
2.3. Chiral purification via diastereomeric salt formation
Crude (S)-5 [81% ee, containing 90.5% of (S)-form] was purified
via salt formation with Ts-(S)-Phe23 from denatured EtOH24 with
MeOH and n-PrOH, where the crude (S)-5/Ts-(S)-Phe ratio was
1.0/1.0 (mol/mol).5 Representative results are indicated in Table
3. Total yield of the resolution followed by recrystallization was
84%, based on the total amount of crude (S)-5 charged. Meanwhile,
in the direct resolution, the total yield of the resolution followed by
two recrystallizations was 30% based on the total amount of the
racemate (RS)-5 (theoretical maximum yield = 50%). It was found
that a hybrid process composed of asymmetric hydroboration
and chiral purification via salt formation was more cost-effective
than a direct resolution process.
4. Experimental
4.1. General
Ts-(S)-Phe was synthesized from (S)-phenylalanine and p-tolu-
enensulfonyl chloride according to the literature.23 The other re-
agents were purchased from commercial suppliers and used

1468
M. Morimoto, K. Sakai / Tetrahedron: Asymmetry 19 (2008) 1465–1469
without further purification. For example,
a
-pinene 1 and dena-
(0.40 equiv) and cooled to 0–5 °C under stirring. To the cooled
mixture was carefully added 1329 kg of thionyl chloride
(2.1 equiv to 3) dropwise and the reaction mixture was warmed
up to 50 °C. The resulting solution was concentrated under re-
duced pressure and the residual oil layer was extracted with tol-
uene (806 kg) to afford a solution containing 442 kg of cis-1,4-
dichlorobutene (1820 kg). To the separated organic layer was
added the mixture of toluene, 1343 kg of benzylamine, and
215 kg of water, with the pH of the solution maintained from 9
to 12 by adding 48% aq NaOH (total 933 kg). After the confirma-
tion of disappearance of cis-1,4-dichlorobutene by GC analysis,
2847 kg of water and 780 kg of 35% HCl were added to adjust
the pH to 7.2. The organic layer was distilled at 75 °C under re-
duced pressure (133 Pa) to afford 346 kg of 4 (95.5% a/a (GC),
yield 40% on the basis of 3).
tured ethanol24 were manufactured in Bordas (Spain), and Japan
Alcohol Co. Ltd, respectively. All reactions were conducted under
an air-free atmosphere with nitrogen unless noted otherwise. All
of the industrial productions were performed in a glass-lined reac-
tor. Reactions were monitored by GC or HPLC for completion by a
small sample from the reaction mixture and analyzed. The diaste-
reomeric excesses (% de) of the diastereomeric salts were deter-
mined with the enantiomeric excess (% ee) of (S)-5 isolated from
the salt. Enantiomeric excess (% ee) = jA ꢀ Bj ꢁ 100/(A + B), where
A and B are contents of both enantiomers, respectively. GC analyses
were performed according to the following conditions. cis-1,4-
Dichlorobutene assay: 5% Thermon-3000/Chromosorb W (80–100
mesh), i.d. 3.2 mm ꢁ 2 m, FID detector. Chemical assays of 4 and
5: Unisole 10T + KOH(10 + 3%)/Uniport HP(80–100 mesh), i.d.
3.2 mm ꢁ 1 m. Chemical purities of 4 and 5: NEUTRABOND-1, i.d.
0.25 mm ꢁ 60 m. Enantiomeric excess of (S)-5 was determined
by HPLC: CAPCELLPAK SG-120 i.d. 4.6 mm ꢁ 250 mm, 0.03% aque-
ous NH3/MeOH = 50/50 (v/v), UV detector (243 nm). Sample prep-
aration of (S)-5 for chiral purity was individually treated with O,O0-
ditoluoyl (2S,3S)-tartaric anhydride to give its diastereomeric
derivatives prior to analysis. 1H and 11B NMR spectra were
IR (neat) (cmꢀ1) 3065, 3026, 2938, 2873, 2781, 1604, 1586,
1493, 1472, 1453, 1376, 1350, 1337, 1294, 1244, 1209, 1156,
1127, 1073, 1028, 1010, 977, 929, 906, 851, 743, 699, 654, 467.
1H NMR (400 MHz, CDCl3) d (ppm) 7.41–7.29 (m, 5H), 5.83 (s,
2H), 3.86 (s, 2H), 3.53 (s, 4H).
4.3.2. 1-Benzyl-(3S)-hydroxypyrrolidine crude (S)-5
recorded on
a JEOL JNM-AL400 spectrometer (400 MHz and
2915 kg of THF, 1114 kg of 1 (85.8% ee, 4.0 equiv to 4), and
116 kg of NaBH4 (1.5 equiv to 4) were fed into 10 kL reactor. To
the reaction mixture were added dropwise 285 kg of THF and
580 kg of BF3–OEt2 (2.0 equiv to 4), while keeping the tempera-
ture between ꢀ2 and 6 °C for 12 h. Next, 341 kg of 4 was added
at below 5 °C and the resulting solution was kept stirring. After
the yield of crude (S)-5 was confirmed to be over 90% by GC anal-
ysis after 8 h, 508 kg of water and 818 kg of 48% aq NaOH were
added carefully, followed by oxidation with 924 kg of 35% aq
H2O2. After the addition of 1250 kg of 20% aq Na2SO3, the oil layer
was acidified with 539 kg of 30% aq H2SO4 and mixed with
1312 kg of toluene and 984 kg of H2O. To the resulting aqueous
layer were added 240 kg of 48% aqueous NaOH and 3280 kg of
toluene to extract crude (S)-5. The concentration of the oil
layer gave 352 kg of crude (S)-5 [91.1% a/a (GC), 84.1% ee, yield
87.6% on the basis of 4]. Otherwise, NaBF4 generated in the
oxidation was treated with CaCl2 to be transformed to harmless
CaF2.
128 MHz for a proton and boron, respectively). Melting points
were determined with a YAMATO apparatus MODEL MP-21 and
are uncorrected. IR spectrum was measured on a PERKIN ELMER
SYSTEM 2000 spectrometer. Commercially available anhydrous
THF was used as an NMR solvent. (+)-a-Pinene 1 was dried over
LiAlH4 prior to NMR measurement and used without any pretreat-
ment. Borane reagent for NMR measurement was prepared from
NaBH4 and BF3–OEt2 as mentioned above, and transferred into bor-
on-free NMR tube for 11B NMR.
4.2. Optimization of the reaction conditions of the asymmetric
hydroboration
To a 300 mL flask were added 74 g of THF, 28.6 g of 1, and 2.93 g
of NaBH4. Subsequently, 14.9 g of BF3–OEt2 was added dropwise at
1 °C and stirred overnight. Next, 8.3 g of 4 (0.5 equiv on the basis of
BF3–OEt2) was added dropwise at the same temperature. A small
portion of the resulting slurry was applied to 11B NMR spectrum
measurement. The activating agent was optimized by employing
BF3–OEt2 and H2SO4 in an ether solvent, such as THF, diglyme,
monoglyme, 1,4-dioxane, isopropyl ether, or tetrahydropyran,
where the molar ratios of NaBH4/BF3–OEt2 and NaBH4/H2SO4 were
3/4 and 2/1, respectively, according to theoretical molar ratios. The
molar ratio of BF3–OEt2/4 was optimized in the range of 1.6 and 2.5
with respect to enantiomeric purity and chemical yield of the
resulting crude (S)-5. Also, the dependency of the enantiomeric
purity of crude (S)-5 and the reaction time were monitored by
HPLC analysis. Furthermore, borane species active in the hydrobo-
ration solution were observed on 11B NMR. As a result, four main
peaks were observed at 55, 37, 18, and 0 ppm in the reacted solu-
tion of NaBH4 with BF3–OEt2, which could be attributed to 2c,
monoisopinocampheyl boronic acid, 2b, and BF3, respectively.
Next, upon addition of 4, a broad peak at 81 ppm appeared, which
was attributed to trialkylborane formed from 2c and 4. 11B NMR
(128 MHz) d (ppm) for the reacted solution of NaBH4 with BF3–
OEt2: 54.8, 48.7, 36.8, 31.8, 17.5, 2.2, 0.0. After addition of 4:
80.5, 55.9, 2.4, 0.8.
4.3.3. 1-Benzyl-(3S)-hydroxypyrrolidine enantiopure (S)-5
To a 3 kL reactor were added 909 kg of denatured ethanol,24
74 kg of water, and 620 kg of Ts-(S)-Phe [chemical purity 95.3%
by HPLC, 1.0 equiv to crude (S)-5] as a chiral purifying agent.
After the addition of crude (S)-5, the resulting slurry was com-
pletely dissolved at 70 °C, followed by gradual cooling to 5 °C.
The precipitated crude salt crystals were centrifuged to afford
941 kg of wet cake (95.8% de). The crude cake was recrystallized
from water to produce 911 kg of wet cake (99.4% de), which was
added to 1496 kg of H2O and 170 kg of H2SO4, followed by addi-
tion of 900 kg of H2O. The resulting solution was treated with
300 kg of 48% aq NaOH and extracted with 1080 kg of toluene
twice. The separated organic layer was concentrated and distilled
at 115–120 °C under reduced pressure (90–240 Pa) to afford
252 kg of (S)-5 (CP >99.9% (GC), enantiomeric purity 99.4% ee,
yield 68.9% on the basis of 4). The 1H NMR spectrum of (S)-5
was consistent with those in the literature.12,25 IR (neat) 3381,
3062, 3028, 2944, 2797, 1604, 1585, 1494, 1477, 1454, 1376,
1347, 1254, 1208, 1128, 1094, 1028, 1001, 971, 909, 883, 850,
828, 751, 699, 632, 476, 468, 467. 1H NMR (CDCl3) d (ppm)
7.31–7.22 (m, 5 H), 4.31–4.28 (m, 1H), 3.61 (s, 2H), 2.86–2.80
(m, 1H), 2.64 (d, 1H, J = 10 Hz), 2.52 (dd, 1H, J = 10.2 Hz, 5.4 Hz),
2.29 (dd, 1H, J = 15.6 Hz, 8.0 Hz), 2.21–2.12 (m, 1H), 1.74–1.67
(m, 1H).
4.3. Industrial production of (S)-5
4.3.1. 1-Benzyl-3-pyrroline 4
To a 10 kL reactor were added 1380 kg of toluene, 460 kg of
cis-1,4-butenediol 3, (5.22 kmol) and 165 kg of pyridine

M. Morimoto, K. Sakai / Tetrahedron: Asymmetry 19 (2008) 1465–1469
1469
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19. Diisopinocampheylborane, ChiPros (BASF), is available on an industrial scale.
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23. Ts-(S)-Phe was prepared according to J. Am. Chem. Soc. 1937, 59, 1116. Ts-(S)-
Phe: Mp 164–165 °C. IR (KBr) 3319, 3259, 3064, 3027, 2926, 2658, 2584, 1714,
1694, 1597, 1496, 1456, 1423, 1389, 1344, 1331, 1309, 1294, 1224, 1189, 1157,
1091, 1030, 1020, 935, 903, 846, 819, 758, 751, 730, 704, 666, 556, 493. 1H
NMR (400 MHz, CDCl3) d (ppm) 7.59 (d, 2H, J = 8.4 Hz), 7.24–7.20 (m, 5H),
7.09–7.07 (m,2H), 4.19 (t, 1H, J = 6 Hz), 3.09 (dd, 1H, J = 14 Hz, 5.2 Hz), 2.99 (dd,
1H, J = 14 Hz, 5.2 Hz), 2.40 (s, 3H).
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resolution experiment was carried out under the racemate (RS)-5/Ts-(S)-Phe/
H2SO4 = 1.0/0.8/0.1 (mol/mol/mol) conditions, where H2SO4 was employed as a
supplemented acid to neutralize the resolution system and reduce the amount
of Ts-(S)-Phe without lowering the resolution efficiency in comparison with
that of (RS)-5/Ts-(S)-Phe = 1.0/1.0 (mol/mol). The resolution gave the
diastereomeric salt with 68% de in 51% yield (E 69%), which was calculated
based on the total amount of (R)-5 and (S)-5 in the obtained salt on charged
(RS)-5. This was followed by two recrystallization to purify to give more than
99% de in 59% yield, based on the obtained salt on charged salt. Total yield
besed on (S)-form in the charged (RS)-5 was 60%, equal to 30% on (RS)-5.
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24. Solmix AP-1 (Japan Alcohol Coorporation) consists of 85.5% of ethanol, 13.3% of
isopropylalcohol and 1.1% of methanol.
25. Nemia, M. M. B.; Lee, J.; Joullie, M. M. Synth. Commun. 1983, 13, 1117.