Efficient synthesis of optically active 4,5-dihydroxy-2,3,4,5-tetrahydro-IH-1-benzazepine derivatives utilizing lipase-catalyzed transesterification

Article abstract of DOI:10.3987/COM-06-S(O)42

As an efficient and enantioselective synthesis of the 4,5-dihydroxybenzazepine compounds, the syntheses of optically active 5-0-protected tranAs an efficient and enantioselective synthesis of the 4,5-dihydroxybenzazepine compounds, the syntheses of optica

Full text of DOI:10.3987/COM-06-S(O)42

HETEROCYCLES, Vol. 69, 2006
333
HETEROCYCLES, Vol. 69, 2006, pp. 333 - 350. © The Japan Institute of Heterocyclic Chemistry
Received, 18th July, 2006, Accepted, 21st August, 2006, Published online, 25th August, 2006. COM-06-S(O)42
EFFICIENT SYNTHESIS OF OPTICALLY ACTIVE 4,5-DIHYDROXY-
2,3,4,5-TETRAHYDRO-1H-1-BENZAZEPINE DERIVATIVES UTILIZING
LIPASE-CATALYZED TRANSESTERIFICATION
Tadaaki Ohtani, * Kazuyoshi Kitano, Jun Matsubara, Yoshikazu Kawano,
Makoto Komatsu, Minoru Uchida, Fujio Tabusa, and Yoshimitsu Nagaoa
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd.,
Kagasuno 463-10 Kawauchi-cho, Tokushima 771-0192, Japan
aGraduate School of Phamaceutical Sciences, The University of Tokushima,
Sho-machi, Tokushima 770-8505, Japan
Abstract – As an efficient and enantioselective synthesis of the 4,5-dihydroxy-
benzazepine compounds, the syntheses of optically active 5-O-protected trans-
4,5-dihydroxybenzazepine derivatives were accomplished. The trans-7-chloro-
4-hydroxy-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-
benzazepine [(±)-4] was kinetically resolved by lipase-catalyzed trans-
esterification. The optically active 4* was isomerized into the cis compound (6*)
utilizing the Mitsunobu esterification followed by hydrolysis. The chiral
compounds (4* and 6*) were converted to the 4,5-bismethoxymethoxy
compounds (7*–10*), which were the intermediates for the compounds (2a, b
and 3a, b).
INTRODUCTION
The benzazepene derivatives (tolvaptan, 11) have been applied as drug for vasopressin V2 receptor
antagonist.1, 2 In its metabolic study, we found the 4,5-dihydroxybenzazepine compounds (2a and 3a) as
metabolites (Figure 1). In a previous paper, we reported the synthesis of optically active compounds by
lipase-catalyzed enantioselective transesterification.3 During the course of our investigation on the
lipase-catalyzed asymmetric resolution, we have already reported the synthesis of the chiral diols (2b and
3b) by utilizing the kinetic resolution of each of the trans- and cis-4,5-dihydroxy compounds.3c In this
report, we focused our attention on the development of a more effective method for the synthesis of the
compounds having a 4,5-dihydroxybenzazepine skelton, in optically active forms.

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HETEROCYCLES, Vol. 69, 2006
OH
HO
HO
OH
OH
5
4
2
X
X
Cl
3
1
N
N
N
O
O
O
R
NH
O
R
NH
Me
NH
O
O
Me
Me
Me
2a (X=Cl, R=Me)
2b (X=R=H)
3a (X=Cl, R=Me)
3b (X=R=H)
tolvaptan (1)
Figure 1
Our strategy is summarized in Scheme 1. In order to simplify the synthesis of the chiral 4,5-dihydroxy-
benzazepine derivatives, we planed the optical resolution of an applicable intermediate for both of the
trans- and cis-4,5-dihydroxy compounds. Here, we chose the 5-O-protected trans-4,5-dihydroxybenz-
azepine compound [(±)-4], which has a 7-chloro moiety and is protected by a tosyl group on the nitrogen
atom and by a methoxymethyl group on the 5-hydroxyl group, as the common starting material. If the
optical resolution of the trans-monohydroxy compound [(±)-4] is achieved, it is also applicable to the
synthesis of the chiral cis-monohydroxy compound (6*) by utilizing isomerization of the chiral
trans-monohydroxy compound (4*). These compounds (4* and 6*) can be converted to the compounds
(7* and 8*) as the intermediates of 2a and 3a, and the following dechlorinations of the compounds (7*
and 8*) will afford the compounds (9* and 10*) as the intermediates of 2b and 3b, respectively.
MOMO
MOMO
MOMO
MOMO
OH
OAc
!
OMOM
!
OH
!
lipase catalyzed
kinetic acetylation
!
!
!
Cl
Cl
Cl
Cl
+
N
N
N
N
Ts
Ts
Ts
Ts
!
!
!
(±)-4
5
7
4
MOMO
OH
MOMO
MOMO
MOMO
OMOM
!
OMOM
!
OMOM
!
!
!
!
!
!
Cl
Cl
N
N
N
N
Ts
Ts
Ts
Ts
!
!
!
!
6
8
10
9
Scheme 1
RESULTS AND DISCUSSION
First, we studied the optical resolution of the trans-4-hydroxy-5-methoxymethoxybenzazepine derivative
[(±)-4]. The regio- and diastereoselective synthesis of (±)-4 is summarized in Scheme 2. The ketone (11)1

HETEROCYCLES, Vol. 69, 2006
335
reacted with chloromethyl methyl ether (MOMCl) by treatment with sodium hexamethyldisilazide
(NHMDS) in THF-DMPU (1:1) to give the enol ether (12) in 98% yield. The hydroboration of 12
followed by treatment with alkaline hydrogen peroxide afforded (±)-4 in 79% yield.
Scheme 2
MOMO
O
MOMO
OH
1) NHMDS, THF-DMPU
(1:1), !78°C, 1 h
Cl
Cl
Cl
1) BH3, THF, rt, over night
2) NaOOH, rt, 7.5 h, 79%
2) MOMCl, !78 °C, 30 mim
N
N
N
then rt, 30 mim, 98%
Ts
Ts
Ts
11
12
(±)-4
The screening tests of a variety of lipases on their catalyzed transesterification of (±)-4 were carried out,
and the results are listed in Table 1. Most of the lipases were inactive on this reaction (Entries 1–4 and 6),
however, lipase QLM showed a good reactivity and selectivity (Entry 5).
a
Table 1 Screening tests of lipases on their catalyzed transesterification of (±)-4
MOMO
MOMO
MOMO
OAc
OH
OH
Cl
Cl
Cl
lipase
+
AcOCH=CH2
40 °C, 1 d
N
N
N
Ts
Ts
Ts
(±)-4
5a
4b
Acetate (5a)
Yield (%)d % ee
Alcohol (4b)
Yield (%)d % ee
Lipaseb
E valuec
Entry
2
1
95
87
98
99
2
40
15
AK Amano
AL
1
2
3
1
OF
<1
8
51
>99
92
0.1
8
3
4
5
6
PL
98
107
>459
28
43
1
>99
93
57
76
QLM
Novozym 435
99
1
a. All reactions were carried out by stirring a mixture of the substrate (20 mg) and lipase (20 mg) in
vinyl acetate (2 mL) at 40 °C for 1 day.
b. AK Amano (Amano enzyme Inc., Pseudomonas fluorescens), AL (Meito sangyo, Achromobacter sp.),
OF (Meito sangyo, Candida cylindracea), PL, QLM (Meito Sangyo, Alcaligenes sp.), Novozym 435
(Novo Nordisk, Aspergillus orizae).
c. The E value is the ratio of the specificity constant of two enantiomers calculated according to ref. 4.
d. Calculated yield.
As the next tests, we examined the solvent effect using lipase QLM as the catalyst at its enzymatic
optimum temperature (65 °C). The results of these experiments under the various conditions of solvent
type and the ratio of solvent and vinyl acetate are summarized in Table 2. Althrough the solvent effect
was slight, to reduce the amount of vinyl acetate, we selected isopropyl ether as the solvent for
preparation of the chiral alcohol (4b) (Entry 5) and acetonitrile as the solvent for preparation of the chiral
acetate (5a) (Entry 13).

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HETEROCYCLES, Vol. 69, 2006
a
Table 2 Lipase-catalyzed transesterification of (±)-4 in organic solvent
MOMO
MOMO
MOMO
Lipase QLMb
OAc
OH
OH
Cl
Cl
Cl
AcOCH=CH2 (VA)
+
solvent
65 °C, 1 d
E > 435 c
N
N
N
Ts
Ts
Ts
(±)-4
5a
4b
Acetate (5a)
Yield (%)d % ee
Alcohol (4b)
Yield (%)d % ee
Solvent
(Solvent / VA )
Entry
50
98.4
50
99.1
none
1
2
3
(1/1)
(3/1)
50
51
51
51
50
50
50
50
50
50
50
50
98.0
97.2
97.8
96.7
98.7
98.9
98.7
99.1
98.6
97.8
99.3
99.7
50
49
49
49
50
50
50
50
50
50
50
50
99.6
99.6
99.6
>99.9
99.1
99.6
99.7
99.6
99.6
99.2
98.6
99.4
Hexane
4
5
6
7
8
9
iso-Pr2O (1/1)
(3/1)
CCl4
(1/1)
(3/1)
(1/1)
(3/1)
PhMe
AcOEt
10
11
12
13
(1/1)
(3/1)
(1/1)
(3/1)
CH3CN
a. All reactions were carried out by stirring a mixture of the substrate (20 mg) and Lipase QLM (20 mg)
in a vinyl acetate-solvent (2 mL) at 65 °C for 1 day.
b. Meito Sangyo, Alcaligenes sp..
c. The E value is the ratio of the specificity constant of two enantiomers calculated according to ref. 4.
d. Calculated yield.
The absolute configurations of the newly formed chiral carbon atoms in the above optically active
compounds were determined as follows. The alcohol (4b), which was not an acetylated compound based
on the above enzymatic reactions, was treated with 1,1’-thiocarbonyldiimidazole followed by the addition
of MeOH, and then reduced by tributyltin hydride in the presence of AIBN to give the known (R)-133d in
35% yield (Eq. 1). Therefore, 4b and 5a were assigned the (4S,5S) and the (4R,5R) configurations,
respectively.
MOMO
MOMO
OH
Cl
Cl
1) Im2CS, DMF, 80 °C, 3 h
(Eq. 1)
2) MeOH, 60 °C, 3 h
3) Bu3SnH, AIBN, PhMe
reflux, 4 h, 35%
N
N
Ts
Ts
4b
(R)-13
Next, the optimal conditions were applied to the preparative scale reaction (Scheme 3). The racemate
[(±)-4] was kinetically acetylated in the presence of lipase QLM [10 weight % of (±)-4] in a mixture of

HETEROCYCLES, Vol. 69, 2006
337
vinyl acetate and isopropyl ether (1:3, 10 times volume) at 65 °C for 1 day to give the acetylated product
(5a, 97% ee) in 47% yield and the optically pure alcohol (4b, >99% ee) in 46% yield. The hydrolysis of
5a gave 4a (97%ee) in 98% yield. To increase the optical purity, 4a was treated with lipase QLM (20
weight %) in a mixture of vinyl acetate and acetonitrile (1:3, 10 times volume) at 65 °C for 1 day to
afford 5a (>99% ee, 94% yield) and 4a (44% ee, 5% yield). The optically pure alcohol (4a) (>99% ee)
was obtained by the hydrolysis of 5a (>99% ee).
Scheme 3
MOMO
MOMO
MOMO
Lipase QLM,
OAc
OH
OH
Cl
Cl
Cl
AcOCH=CH2 (VA)
+
iso-Pr2O (IPE)
65 °C, 1 d
(VA / IPE = 1 / 3)
N
N
N
Ts
Ts
Ts
5a (47%)
(±)-4
4b (46%)
(97% ee)
(>99% ee)
MOMO
Lipase QLM
OH
Cl
AcOCH=CH2 (VA)
CH3CN (AN)
1N NaOH
5a (94%)
(>99% ee)
4a (5%)
(44% ee)
5a
(97% ee)
+
EtOH
rt, 30 mim, 98%
N
65 °C, 1 d
(VA / AN = 1 / 3)
Ts
4a (97% ee)
1N NaOH
4a (>99% ee)
EtOH
rt, 30 mim, quant.
Secondly, in order to apply the above-mentioned resolution system to the synthesis of the cis-4,5-
dihydroxybenzazepine derivatives, we investigated the isomerization of the trans-compounds (4a,b)
utilizing the Mitsunobu reaction (Scheme 4). The chiral alcohols (4a,b) reacted with 4-nitrobenzoic acid
in the presence of triphenylphosphine and diethyl azodicarboxylate (DEAD) to give the 4-nitrobenzoates
(14a,b) in good yields. The chiral cis-compounds (6a,b) were quantitatively obtained by hydrolysis of the
corresponding esters (14a,b).
Scheme 4
O
MOMO
MOMO
DEAD, PPh3,
O
OH
Cl
Cl
Cl
Cl
4-NO2-C6H4CO2H
1N NaOH
4a
THF
rt, 3 h, 89%
THF
rt, 3 h, 99%
(>99% ee)
N
N
NO2
Ts
Ts
14a
MOMO
6a
O
MOMO
DEAD, PPh3,
4-NO2-C6H4CO2H
O
OH
1N NaOH
4b
(>99% ee)
THF
rt, 3 h, 87%
THF
rt, 3 h, 99%
N
N
NO2
Ts
Ts
14b
6b

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HETEROCYCLES, Vol. 69, 2006
As the available intermediates for the compounds (2a,b and 3a,b), we synthesized the corresponding
4,5-bismethoxymethoxy compounds (Scheme 5). The monomethoxymethoxy compounds (4a,b and 6a,b)
were treated with MOMCl in the presence of diisopropylethylamine to give the bismethoxymethoxy
compounds (7 and 8) for the intermediates of 2a and 3a. The hydrogenation of 7 and 8 in the presence of
5% Pd/C and sodium acetate afforded the dechlorination compounds (9 and 10) for the intermediates of
2b and 3b.
Scheme 5
MOMO
MOMO
MOMO
OH
!
OMOM
!
OMOM
!
H2 (1 atm), 5% Pd/C
NaOAc
EtOH
!
!
!
Cl
Cl
MOMCl, i-Pr2NEt
CH2Cl2
refl., 4 h
N
N
N
rt, 4 h
Ts
Ts
Ts
4a [trans-, (4R,5R)]
4b [trans-, (4S,5S)]
6a [cis-, (4S,5R)]
6b [cis-, (4R,5S)]
(4R,5R)-7 (97%)
(4S,5S)-7 (93%)
(4S,5R)-8 (98%)
(4R,5S)-8 (97%)
(4R,5R)-9 (97%)
(4S,5S)-9 (97%)
(4S,5R)-10 (98%)
(4R,5S)-10 (99%)
Finally, we accomplished the first synthesis of the optically active metabolites (2a and 3a) of tolvaptan
(1), as shown in Scheme 6. Detosylation of 7 and 8 using magnesium in MeOH quantitatively afforded 15
and 16, respectively. Acylation of these compounds (15 and 16) with the acid chloride (17) followed by
removal of the bismethoxymethyl ether moieties gave the target compounds [(4R,5R)-2a, (4S,5S)-2a,
(4S,5R)-3a and (4R,5S)-3a]. Regarding the previously reported chiral compounds (2b and 3b), we have
also applied a similar procedure.
Scheme 6
Me
MOMO
MOMO
OMOM
!
OMOM
!
COCl
!
!
Cl
Cl
Me O
pyridine
Mg
+
N
CH2Cl2
rt, over night
MeOH
refl., 1.5"2.5 h
N
N
H
H
Ts
17
(4R,5R)-15 (96%)
(4S,5S)-15 (93%)
(4S,5R)-16 (99%)
(4R,5S)-16 (99%)
(4R,5R)-7 (trans isomer)
(4S,5S)-7
(4S,5R)-8 (cis isomer)
(4R,5S)-8
MOMO
OMOM
HO
!
OH
!
!
Cl
Cl
!
conc. HCl
MeOH
60 °C, 3.5"4.5 h
N
N
O
O
O
Me
O
Me
Me
N
Me
N
H
H
(4R,5R)-18 (81%)
(4S,5S)-18 (85%)
(4S,5R)-19 (86%)
(4R,5S)-19 (83%)
(4R,5R)-2a (83% yield, >99% ee) (trans diol)
(4S,5S)-2a (82% yield, >99% ee)
(4S,5R)-3a (87% yield, >99% ee) (cis diol)
(4R,5S)-3a (89% yield, >99% ee)

HETEROCYCLES, Vol. 69, 2006
339
In conclusion, we have established the efficient synthesis of optically active 4,5-dihydroxybenzazepine
compounds utilizing the lipase-catalyzed kinetic resolution of (±)-4. The enzymatic esterification of (±)-4
proceeded with excellent enantioselectivities. The Mitsunobu reaction of the chiral trans-compounds
(4a,b) was applicable for the synthesis of the corresponding cis-isomers (6a,b). In this manner, we
succeeded in the syntheses of all four diastereomers of the 4,5-dihydroxybenzazepine derivatives by
derivation from the racematic compound [(±)-4].
EXPERIMENTAL
All melting points were determined using a Yamato MP-21 apparatus and are uncorrected. The IR spectra
were obtained using a Perkin-Elmer Spectrum 1000 FT-IR spectrophotometer. The 1H NMR (250 MHz)
and 13C NMR (62.5 MHz) spectra were recorded by a Bruker AVANCE DPX 250 spectrometer.
Chemical shifts are given in δ values (ppm) using tetramethylsilane (TMS) as the internal standard. The
HRMS spectra were recorded by a JEOL JMS-SX 102A mass spectrometer. Optical rotations were
measured using a JASCO DIP-370 digital polarimeter. Elemental analyses were performed using a
Yamaco CHN CORDER MT-5. All reactions were monitored by TLC employing a 0.25 mm silica gel
plate (Merck 5715; 60 F254) and/or a 0.20 mm NH-silica gel plate (Fuji Silysia Chemical; NH). Column
chromatography was carried out on silica gel [Kanto Chemical Silica Gel 60 (spherical); 63-210 µm and
Biotage KP-SilTM Silica; 40-63 µm] and NH-silica gel (Fuji Silysia Chemical Chromatorex NH-DM1020;
100 µm). All reagents were used as purchased.
7-Chloro-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3-dihydro-1H-1-benzazepine (12)
A solution of sodium 1,1,1,3,3,3-hexamethyldisilazide (NHMDS) in THF (1.0 M, 6.9 mL, 6.9 mmol) was
added to a stirring solution of 7-chloro-5-oxo-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
(11) (2.0 g, 5.7 mmol) in THF (20 mL) and DMPU (20 mL) at –78°C under a nitrogen atmosphere, and
the mixture was stirred at –78°C for 1 h. Chloromethyl methyl ether (MOMCl, 0.53 mL, 7.0 mmol) was
added to the above mixture and the mixture was stirred at –78°C for 30 mim and then rt for 30mim. The
reaction mixture was poured into a saturated NaHCO3 solution and then extracted with AcOEt. The
extract was washed with water (2 times) and brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (silica gel; eluent, hexane/AcOEt = 17/3 – 4/1) to give
12 (2.2 g, 98%) as a yellow oil. 1H NMR (CDCl3) δ (ppm): 2.25 (2H, q, J = 6.3 Hz), 2.38 (3H, s), 3.36
(3H, s), 3.84-4.05 (2H, m), 4.60 (2H, s), 5.14 (1H, t, J = 6.3 Hz), 7.13-7.22 (2H, m), 7.31 (1H, dd, J = 2.5,
8.3 Hz), 7.40-7.55 (4H, m, including 7.48, d, J = 2.5 Hz and 7.51, d, J = 8.5 Hz). 13C NMR (CDCl3) δ
(ppm): 21.4, 25.4, 54.1, 56.0, 94.5, 105.1, 127.1, 127.6, 128.7, 129.2, 132.2, 133.8, 135.5, 136.2, 137.4,

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HETEROCYCLES, Vol. 69, 2006
142.9, 149.7. IR (neat): 2946, 2890, 1645, 1482, 1347, 1162, 1090, 1019, 814, 668 cm-1. HRFAB-MS
calcd for C19H21NO4ClS (M+H)+: 394.0880, found: 394.0904.
trans-7-Chloro-4-hydroxy-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benz-
azepine [(±)-4]
A solution of borane-THF complex (0.92 mol/L, 12 mL, 11 mmol) was added to a stirring solution of 12
(2.2 g, 5.6 mmol) in THF (25 mL) at rt under a nitrogen atmosphere and the mixture was stirred overnight
at rt. 1N NaOH solution (12 mL) and 30% H2O2 (12 mL) were added and the mixture was stirred at rt for
7.5 h. The reaction mixture was poured into water and extracted with AcOEt (2 times). The extract was
washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography (silica gel; eluent, hexane/AcOEt = 7/3 – 13/7) to give (±)-4 (1.8 g, 79%) as a colorless
viscous oil. 1H NMR (CDCl3) δ (ppm): 1.51-1.72 (1H, m), 1.80-1.98 (1H, m), 2.41 (3H, s), 3.28-3.55 (6H,
m, including 3.36, s), 3.57-3.69 (1H, m), 3.98-4.16 (2H, m, including 4.06, d, J = 6.5 Hz), 4.54 (1H, d, J
= 6.5 Hz), 7.23-7.32 (3H, m), 7.33-7.38 (1H, m), 7.43 (1H, d, J = 8.5 Hz), 7.54-7.63 (2H, m). 13C NMR
(CDCl3) δ (ppm): 21.4, 31.0, 44.2, 56.0, 70.2, 81.6, 96.8, 125.4, 126.9, 128.4, 129.8, 131.9, 133.5, 133.7,
137.0, 138.5, 143.8. IR (neat): 3530, 2947, 2890, 1483, 1348, 1162, 1104, 1040, 667 cm-1. HRFAB-MS
calcd for C19H22NO5ClS M+: 411.0907, found: 411.0905.
General procedure of screening test on the reaction of lipase-catalyzed transesterification
A mixture of (±)-4 (20 mg) and lipase (20 mg) in vinyl acetate (2 mL) or in a mixture of vinyl acetate and
solvent (2 mL, the ratio of 1/1 or 1/3) was stirred at the appropriate temperature (40 or 65°C) for 1 day.
The mixture was filtered and the insoluble material washed with AcOEt. The filtrate was concentrated in
vacuo. The residue was purified by column chromatography (silica gel; eluent, hexane/AcOEt = 7/3 –
1/1) to give 5a and 4b. The obtained 5a and 4b were analyzed by HPLC using CHIRALCEL OJ-R
(CH3CN/H2O = 9/11) and CHIRALCEL OD (hexane/iso-PrOH = 9/1).
(R)-7-Chloro-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
[(R)-13]
A solution of 4b (92 mg, 0.22 mmol) and 1,1’-thiocarbonyldiimidazole (120 mg, 0.673 mmol) in DMF (2
mL) was stirred at 80°C for 3 h. After evaporation of DMF, MeOH (4 mL) was added to the mixture and
the solution was stirred at 60°C for 3 h. After removal of MeOH, the residue was purified by column
chromatography (silica gel; eluent, hexane/AcOEt = 9/1 – 3/1) to give the xanthate as a colorless oil. A
solution of the above-mentioned product, tributyltin hydride (0.10 mL, 0.37 mmol) and AIBN (3.0 mg, 18
µmol) in PhMe (4 mL) was refluxed for 4 h under an argon atmosphere. After removal of PhMe, the

HETEROCYCLES, Vol. 69, 2006
341
residue was purified by column chromatography (silica gel; eluent, hexane/CH2Cl2/AcOEt = 23/10/1 –
67/27/1 and then NH-silica gel; eluent, hexane/AcOEt = 9/1 – 4/1) to give (R)-13 (30 mg, 35%) as a
26
27
colorless oil. [α]D = +42° (c 1.5, CHCl3) [lit.,3d [α]D = +38.6° (c 1.0, CHCl3)]. 1H NMR (CDCl3) δ
(ppm): 1.37-1.79 (2H, m), 1.81-2.04 (2H, m), 2.41 (3H, s), 2.99-3.23 (1H, m), 3.28 (3H, s), 3.97-4.27 (2H,
m), 4.31 (1H, d, J = 6.8 Hz), 4.53 (1H, d, J = 6.8 Hz), 7.20 (1H, dd, J = 2.5, 8.5 Hz), 7.23-7.34 (3H, m),
7.42 (1H, d, J = 2.5 Hz), 7.56-7.66 (2H, m). HRFAB-MS calcd for C19H22NO4ClS M+: 395.0958, found:
395.0939.
Preparative scale resolution of (±)-4
A mixture of (±)-4 (3.02 g, 7.33 mmol), lipase QLM (300 mg) in vinyl acetate–iso-Pr2O (30 mL, the ratio
of 1/3) was stirred at 65°C for 1day. The reaction mixture was filtered through a pad of Celite and the
insoluble material was washed with AcOEt. The filtrate was concentrated in vacuo. The residue was
purified by column chromatography (NH-silicagel; eluent, CH2Cl2 and then silica gel; eluent,
hexane/AcOEt = 4/1 – 1/1) to give 5a (1.58 g, 47%) as a colorless viscous oil and 4b (1.40 g, 46%) as a
colorless viscous oil, which were 5a (97%ee) and 4b (>99%ee) by HPLC analysis using the
above-mentioned conditions, respectively.
1N NaOH solution (5.2 mL) was added to a solution of 5a (97%ee, 1.58 g, 3.48 mmol) in EtOH (16 mL)
and the mixture was stirred at rt for 30 mim. The reaction mixture was poured into water and then
extracted with AcOEt. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (NH-silica gel; eluent, CH2Cl2) to give 4a (1.41 g,
98%, 97%ee) as a colorless viscous oil.
A mixture of 4a (97%ee, 1.41 g, 3.42 mmol), lipase QLM (280 mg) in vinyl acetate–CH3CN (14 mL, the
ratio of 1/3) was stirred at 65°C for 1day. The reaction mixture was filtered through a pad of Celite and
the insoluble material was washed with AcOEt. The filtrate was concentrated in vacuo. The residue was
purified by column chromatography (NH-silicagel; eluent, CH2Cl2 and then silica gel; eluent,
hexane/AcOEt = 7/3 – 1/1) to give 5a (1.46 g, 94%, >99%ee) as a colorless viscous oil and 4a (73 mg,
5%, 44%ee) as a colorless viscous oil.
1N NaOH solution (4.4 mL) was added to a solution of 5a (>99%ee, 1.34 g, 2.95 mmol) in EtOH (14
mL) and the mixture was stirred at rt for 30 mim. The reaction mixture was poured into water and then
extracted with AcOEt. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (NH-silica gel; eluent, CH2Cl2) to give 4a (1.21 g,
quant., >99%ee) as a colorless viscous oil. The spectral data are listed below.
(4R,5R)-7-Chloro-4-hydroxy-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-
benzazepine (4a)

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[α]D28 = –75° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.51-1.73 (1H, m), 1.82-1.97 (1H, m), 2.41 (3H,
s), 3.30-3.56 (6H, m, including 3.36, s), 3.56-3.69 (1H, m), 3.97-4.15 (2H, m, including 4.07, d, J = 6.5
Hz), 4.54 (1H, d, J = 6.5 Hz), 7.23-7.32 (3H, m), 7.33-7.38 (1H, m), 7.44 (1H, d, J = 8.5 Hz), 7.54-7.63
(2H, m). 13C NMR (CDCl3) δ (ppm): 21.5, 31.1, 44.2, 56.0, 70.3, 81.7, 96.9, 125.4, 126.9, 128.4, 129.8,
132.0, 133.5, 133.8, 137.1, 138.5, 143.8. IR (neat): 3522, 2948, 2890, 1484, 1348, 1163, 1104, 1041, 668
cm-1. HRFAB-MS calcd for C19H22NO5ClS M+: 411.0907, found: 411.0905.
(4S,5S)-7-Chloro-4-hydroxy-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-
benzazepine (4b)
[α]D27 = +76° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.51-1.72 (1H, m), 1.81-1.97 (1H, m), 2.41 (3H,
s), 3.29-3.55 (6H, m, including 3.36, s), 3.56-3.68 (1H, m), 3.99-4.15 (2H, m, including 4.07, d, J = 6.5
Hz), 4.54 (1H, d, J = 6.5 Hz), 7.22-7.32 (3H, m), 7.33-7.38 (1H, m), 7.43 (1H, d, J = 8.5 Hz), 7.53-7.64
(2H, m). IR (neat): 3524, 2947, 2890, 1484, 1348, 1163, 1104, 1040, 668 cm-1. HRFAB-MS calcd for
C19H22NO5ClS M+: 411.0907, found: 411.0905.
(4R,5R)-4-Acetoxy-7-chloro-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-
benzazepine (5a)
[α]D27 = –129° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.63-2.13 (5H, m, including 2.03, s), 2.42 (3H,
s), 3.24 (3H, s), 3.46-3.95 (2H, m), 4.15-4.32 (2H, m, including 4.19, d, J = 6.8 Hz), 4.39 (1H, d, J = 6.8
Hz), 4.77-4.99 (1H, m), 7.23-7.37 (4H, m), 7.40 (1H, d, J = 8.5 Hz), 7.58-7.70 (2H, m). IR (neat): 2945,
2846, 1741, 1484, 1351, 1240, 1166, 1094, 1046, 667 cm-1. HRFAB-MS calcd for C21H24NO6ClS M+:
453.1013, found: 453.0980.
(4S,5R)-7-Chloro-5-methoxymethoxy-4-(p-nitrobenzoyloxy)-1-(p-toluenesulfonyl)-2,3,4,5-tetra-
hydro-1H-1-benzazepine (14a)
Diethyl azodicarboxylate (40 wt% in PhMe, 1.8 mL, 4.0 mmol) was added to a solution of 4a (844 mg,
2.05 mmol), 4-nitrobenzoic acid (682 mg, 4.08 mmol) and PPh3 (1.07 g, 4.08 mmol) in THF (17 mL) and
the mixture was stirred at rt for 3 h under an argon atmosphere. The reaction mixture was poured into a
saturated NaHCO3 solution and extracted with AcOEt. The extract was washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel;
eluent, hexane/AcOEt = 4/1 – 7/3 and then NH-silica gel; eluent, CH2Cl2) to give 14a (1.02 g, 89%) as a
27
colorless amorphous solid. [α]D = +46° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.96-2.57 (5H, m,
including, 2.44, s), 3.03-3.58 (4H, m, including 3.31, s), 3.91-4.45 (2H, m, including 4.40, d, J = 6.8 Hz),
4.48-4.68 (2H, m, including 4.61, d, J = 6.8 Hz), 5.39-5.58 (1H, m), 7.23-7.37 (4H, m), 7.45-7.55 (1H, m),

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7.62-7.72 (2H, m), 7.74-7.91 (2H, m), 8.14-8.24 (2H, m). IR (KBr): 3111, 2952, 1728, 1529, 1348, 1271,
1162, 1101, 1034, 720 cm-1. Anal. Calcd for C26H25N2O8ClS: C, 55.66; H, 4.49; N, 4.99. Found: C,
55.46; H, 4.35; N, 4.97.
(4R,5S)-7-Chloro-5-methoxymethoxy-4-(p-nitrobenzoyloxy)-1-(p-toluenesulfonyl)-2,3,4,5-tetra-
hydro-1H-1-benzazepine (14b)
As a colorless amorphous solid, 14b (913 mg, 87%) was obtained by the same treatment of 4b (770 mg,
1.87 mmol) as in the case of 14a. [α]D27 = –47° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.96-2.56 (5H,
m, including 2.44, s), 3.02-3.59 (4H, m, including 3.31, s), 3.90-4.44 (2H, m, including 4.40, d, J = 6.8
Hz), 4.50-4.67 (2H, m, including 4.61, d, J = 6.8 Hz), 5.39-5.60 (1H, m), 7.24-7.37 (4H, m), 7.44-7.55
(1H, m), 7.62-7.72 (2H, m), 7.74-7.91 (2H, m), 8.14-8.25 (2H, m). IR (KBr): 3111, 2952, 1728, 1531,
1348, 1271, 1162, 1101, 1034, 720 cm-1. Anal. Calcd for C26H25N2O8ClS: C, 55.66; H, 4.49; N, 4.99.
Found: C, 55.41; H, 4.34; N, 4.96.
(4S,5R)-7-Chloro-4-hydroxy-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-
benzazepine (6a)
1N NaOH solution (3.2 mL) was added to a solution of 14a (887 mg, 1.58 mmol) in THF (18 mL) and the
mixture was stirred at rt for 3 h. The reaction mixture was poured into a saturated NaHCO3 solution and
then extracted with AcOEt. The extract was washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography (NH-silica gel; eluent, CH2Cl2) to give 6a
27
(641 mg, 99%) as a colorless amorphous solid. [α]D = –53° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm):
1.65-1.88 (1H, m), 1.89-2.03 (1H, m), 2.04-2.24 (1H, m), 2.42 (3H, s), 3.20-3.56 (4H, m, including 3.31,
s), 3.82-4.12 (2H, m), 4.26 (1H, br s), 4.36 (1H, d, J = 6.8 Hz), 4.59 (1H, d, J = 6.8 Hz), 7.19-7.33 (4H, m,
including 7.23, dd, J = 2.3, 8.5 Hz), 7.41 (1H, d, J = 2.3 Hz), 7.57-7.67 (2H, m). 13C NMR (CDCl3) δ
(ppm): 21.5, 32.7, 44.4, 55.8, 69.1, 78.0, 95.5, 126.8, 127.8, 128.3, 129.8, 130.7, 133.9, 135.6, 137.9,
138.1, 143.8. IR (KBr): 3509, 2950, 2890, 1479, 1344, 1159, 1091, 1034, 918, 840, 722, 665 cm-1. Anal.
Calcd for C19H22NO5ClS: C, 55.40; H, 5.38; N, 3.40. Found: C, 55.02; H, 5.21; N, 3.45.
(4R,5S)-7-Chloro-4-hydroxy-5-methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-
benzazepine (6b)
As a colorless amorphous solid, 6b (568 mg, 99%) was obtained by the same treatment of 14b (782 mg,
1.39 mmol) as in the case of 6a. [α]D27 = +53° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.67-1.88 (1H,
m), 1.89-2.03 (1H, m), 2.04-2.22 (1H, m), 2.42 (3H, s), 3.22-3.56 (4H, m, including 3.31, s), 3.83-4.12
(2H, m), 4.26 (1H, br s), 4.36 (1H, d, J = 6.8 Hz), 4.59 (1H, d, J = 6.8 Hz), 7.19-7.33 (4H, m, including

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7.23, dd, J = 2.3, 8.5 Hz), 7.41 (1H, d, J = 2.3 Hz), 7.57-7.67 (2H, m). IR (KBr): 3502, 2951, 2890, 1479,
1344, 1160, 1091, 1034, 918, 840, 722, 665 cm-1. Anal. Calcd for C19H22NO5ClS: C, 55.40; H, 5.38; N,
3.40. Found: C, 55.04; H, 5.15; N, 3.39.
(4R,5R)-4,5-Bis(methoxymethoxy)-7-chloro-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benz-
azepine [(4R,5R)-7]
A solution of 4a (525 mg, 1.27 mmol), MOMCl (0.48 mL, 6.3 mmol) and iso-Pr2NEt (1.3 mL, 7.5 mmol)
in CH2Cl2 (5 mL) was refluxed for 4 h. The reaction mixture was poured into a 0.2 N HCl solution and
then extracted with CH2Cl2. The extract was washed with a saturated NaHCO3 solution, brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel;
27
eluent, hexane/AcOEt = 4/1 – 7/3) to give (4R,5R)-7 (559 mg, 97%) as a colorless oil. [α]D = –78° (c
1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.44-1.99 (2H, m), 2.41 (3H, s), 3.24 (3H, s), 3.33 (3H, s),
3.53-3.94 (3H, m), 4.01-4.30 (2H, m, including 4.24, d, J = 6.5 Hz), 4.36 (1H, d, J = 6.5 Hz), 4.62 (1H, d,
J = 6.8 Hz), 4.67 (1H, d, J = 6.8 Hz), 7.18-7.35 (4H, m), 7.36-7.49 (1H, m), 7.56-7.69 (2H, m). IR (neat):
2947, 2890, 1484, 1351, 1165, 1104, 1089, 1033, 667 cm-1. HRFAB-MS calcd for C21H26NO6ClS M+:
455.1169, found: 455.1129.
(4S,5S)-4,5-Bis(methoxymethoxy)-7-chloro-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benz-
azepine [(4S,5S)-7]
As a colorless oil, (4S,5S)-7 (481 mg, 93%) was obtained by the same treatment of 4b (464 mg, 1.13
27
1
mmol) as in the case of (4R,5R)-7. [α]D = +76° (c 1.0, CHCl3). H NMR (CDCl3) δ (ppm): 1.43-1.98
(2H, m), 2.41 (3H, s), 3.24 (3H, s), 3.33 (3H, s), 3.52-3.93 (3H, m), 4.00-4.29 (2H, m, including 4.24, d, J
= 6.5 Hz), 4.36 (1H, d, J = 6.5 Hz), 4.62 (1H, d, J = 6.8 Hz), 4.67 (1H, d, J = 6.8 Hz), 7.19-7.35 (4H, m),
7.37-7.48 (1H, m), 7.56-7.70 (2H, m). IR (neat): 2948, 2892, 1484, 1351, 1165, 1105, 1089, 1034, 667
cm-1. HRFAB-MS calcd for C21H26NO6ClS M+: 455.1169, found: 455.1129.
(4S,5R)-4,5-Bis(methoxymethoxy)-7-chloro-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benz-
azepine [(4S,5R)-8]
As colorless needles, (4S,5R)-8 (547 mg, 98%) was obtained by the same treatment of 6a (506 mg, 1.23
27
mmol) as in the case of (4R,5R)-7. [α]D = –60° (c 1.0, CHCl3). mp 103-104°C (hexane-CH2Cl2). 1H
NMR (CDCl3) δ (ppm): 1.78-1.98 (1H, m), 1.99-2.20 (1H, m), 2.41 (3H, s), 3.10-3.45 (7H, m, including
3.26, s, and 3.30, s), 3.96-4.07 (1H, m), 4.07-4.37 (3H, m, including 4.31, d, J = 6.8 Hz), 4.49 (1H, d, J =
6.8 Hz), 4.58 (1H, d, J = 6.8 Hz), 4.67 (1H, d, J = 6.8 Hz), 7.16-7.32 (4H, m, including 7.20, dd, J = 2.3,
8.5 Hz), 7.45 (1H, d, J = 2.3 Hz), 7.57-7.66 (2H, m). IR (KBr): 2952, 2928, 2896, 1479, 1349, 1161, 1049,

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1022, 915, 845, 722, 664 cm-1. Anal. Calcd for C21H26NO6ClS: C, 55.32; H, 5.75; N, 3.07. Found: C,
55.07; H, 5.60; N, 3.06.
(4R,5S)-4,5-Bis(methoxymethoxy)-7-chloro-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benz-
azepine [(4R,5S)-8]
As colorless needles, (4R,5S)-8 (521 mg, 97%) was obtained by the same treatment of 6b (487 mg, 1.18
27
mmol) as in the case of (4R,5R)-7. [α]D = +57° (c 1.0, CHCl3). mp 102-104°C (hexane-CH2Cl2). 1H
NMR (CDCl3) δ (ppm): 1.78-1.98 (1H, m), 1.98-2.19 (1H, m), 2.41 (3H, s), 3.11-3.44 (7H, m, including
3.26, s, and 3.30, s), 3.95-4.07 (1H, m), 4.08-4.37 (3H, m, including 4.31, d, J = 6.8 Hz), 4.49 (1H, d, J =
6.8 Hz), 4.58 (1H, d, J = 6.8 Hz), 4.67 (1H, d, J = 6.8 Hz), 7.16-7.32 (4H, m, including 7.20, dd, J = 2.3,
8.5 Hz), 7.45 (1H, d, J = 2.3 Hz), 7.57-7.67 (2H, m). IR (KBr): 2952, 2928, 2896, 1479, 1349, 1160, 1049,
1022, 914, 847, 722, 664 cm-1. Anal. Calcd for C21H26NO6ClS: C, 55.32; H, 5.75; N, 3.07. Found: C,
55.08; H, 5.62; N, 3.07.
(4R,5R)-4,5-Bis(methoxymethoxy)-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
[(4R,5R)-9]
A mixture of (4R,5R)-7 (350 mg, 0.768 mmol), 5% Pd/C (35 mg) and NaOAc (189 mg, 2.30 mmol) in
EtOH (7 mL) was stirred at rt for 4 h under a hydrogen atmosphere. The reaction mixture was filtered and
the insoluble material was washed with EtOH. The filtrate was concentrated in vacuo and the residue was
suspended in AcOEt. The AcOEt suspension was washed with a saturated NaHCO3 solution, brine, dried
over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel;
27
eluent, hexane/AcOEt = 4/1 – 3/2) to give (4R,5R)-9 (315 mg, 97%) as a colorless oil. [α]D = –103° (c
1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.53-2.04 (2H, m), 2.40 (3H, s), 3.25 (3H, s), 3.33 (3H, s),
3.55-3.92 (3H, m), 4.14-4.42 (3H, m, including 4.26, d, J = 6.5 Hz and 4.38, d, J = 6.5 Hz), 4.63 (1H, d, J
= 6.8 Hz), 4.69 (1H, d, J = 6.8 Hz), 7.18-7.37 (5H, m), 7.38-7.52 (1H, m), 7.60-7.71 (2H, m). IR (neat):
2946, 2890, 1348, 1162, 1092, 1032, 920, 765, 716, 662 cm-1. HRFAB-MS calcd for C21H27NO6S M+:
421.1559, found: 421.1542.
(4S,5S)-4,5-Bis(methoxymethoxy)-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
[(4S,5S)-9]
As a colorless oil, (4S,5S)-9 (306 mg, 97%) was obtained by the same treatment of (4S,5S)-7 (343 mg,
27
0.752 mmol) as in the case of (4R,5R)-9. [α]D = +106° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm):
1.52-2.02 (2H, m), 2.40 (3H, s), 3.25 (3H, s), 3.33 (3H, s), 3.55-3.93 (3H, m), 4.14-4.42 (3H, m,

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including 4.26, d, J = 6.5 Hz and 4.38, d, J = 6.5 Hz), 4.63 (1H, d, J = 6.8 Hz), 4.69 (1H, d, J = 6.8 Hz),
7.19-7.37 (5H, m), 7.38-7.51 (1H, m), 7.60-7.71 (2H, m). IR (neat): 2946, 2890, 1349, 1163, 1092, 1033,
918, 766, 716, 662 cm-1. HRFAB-MS calcd for C21H27NO6S M+: 421.1559, found: 421.1577.
(4S,5R)-4,5-Bis(methoxymethoxy)-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
[(4S,5R)-10]
A mixture of (4S,5R)-8 (250 mg, 0.548 mmol), 5% Pd/C (25 mg) and NaOAc (135 mg, 1.65 mmol) in
EtOH (5 mL) and THF (1 mL) was stirred at rt for 4 h under a hydrogen atmosphere. The following
treatment was carried out the same as in the case of (4R,5R)-9 to give (4S,5R)-10 (226 mg, 98%) as a
27
colorless oil. [α]D = –86° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm): 1.80-2.22 (2H, m), 2.41 (3H, s),
3.13-3.54 (7H, m, including 3.27, s, and 3.30, s), 3.88-4.24 (2H, m), 4.34 (1H, d, J = 6.8 Hz), 4.38-4.46
(1H, m), 4.50 (1H, d, J = 6.8 Hz), 4.57 (1H, d, J = 6.8 Hz), 4.70 (1H, d, J = 6.8 Hz), 7.16-7.37 (5H, m),
7.40-7.52 (1H, m), 7.59-7.71 (2H, m). IR (neat): 2948, 2890, 1345, 1161, 1091, 1029, 716 cm-1.
HRFAB-MS calcd for C21H27NO6S M+: 421.1559, found: 421.1584.
(4S,5S)-4,5-Bis(methoxymethoxy)-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
[(4R,5S)-10]
As a colorless oil, (4R,5S)-10 (228 mg, 99%) was obtained by the same treatment of (4R,5S)-8 (250 mg,
26
0.548 mmol) as in the case of (4S,5R)-10. [α]D = +84° (c 1.0, CHCl3). 1H NMR (CDCl3) δ (ppm):
1.80-2.23 (2H, m), 2.41 (3H, s), 3.10-3.55 (7H, m, including 3.27, s, and 3.30, s), 3.90-4.23 (2H, m), 4.34
(1H, d, J = 6.8 Hz), 4.38-4.47 (1H, m), 4.50 (1H, d, J = 6.8 Hz), 4.57 (1H, d, J = 6.8 Hz), 4.70 (1H, d, J =
6.8 Hz), 7.18-7.36 (5H, m), 7.40-7.50 (1H, m), 7.60-7.70 (2H, m). IR (neat): 2949, 2890, 1346, 1161,
1091, 1033, 716 cm-1. HRFAB-MS calcd for C21H27NO6S M+: 421.1559, found: 421.1584.
(4R,5R)-4,5-Bis(methoxymethoxy)-7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepine [(4R,5R)-15]
A mixture of (4R,5R)-7 (835 mg, 1.83 mmol) and magnesium (450 mg, 18.5 mg·atm) in MeOH (10 mL)
was refluxed for 2.5 h. The reaction mixture was poured into a 10% citric acid solution and then extracted
with CH2Cl2 (2 times). The extract was washed with a saturated NaHCO3 solution, brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel;
26
eluent, hexane/AcOEt = 7/3 – 3/2) to give (4R,5R)-15 (532 mg, 96%) as a yellow oil. [α]D = –164° (c
1.0, MeOH). 1H NMR (CDCl3) δ (ppm): 1.84-2.01 (1H, m), 2.07-2.27 (1H, m), 3.07-3.23 (1H, m),
3.26-3.48 (7H, m, including 3.35, s, and 3.36, s), 3.75 (1H, br s), 3.93-4.04 (1H, m), 4.58 (1H, d, J = 6.8
Hz), 4.63 (1H, d, J = 6.8 Hz), 4.69-4.79 (3H, m, including 4.71, d, J = 6.8 Hz and 4.75, d, J = 6.8 Hz),
6.60 (1H, d, J = 8.3 Hz), 7.05 (1H, dd, J = 2.5, 8.3 Hz), 7.23 (1H, d, J = 2.5 Hz). 13C NMR (CDCl3) δ

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347
(ppm): 30.6, 42.1, 55.56, 55.62, 75.3, 79.1, 94.8, 96.0, 120.4, 124.8, 128.3, 128.4, 130.5, 146.7. IR (neat):
3371, 2947, 2896, 1494, 1151, 1105, 1035, 918, 819 cm-1. HRFAB-MS calcd for C14H20NO4Cl
M+: 301.1081, found: 301.1078.
(4S,5S)-4,5-Bis(methoxymethoxy)-7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepine [(4S,5S)-15]
As a yellow oil, (4S,5S)-15 (622 mg, 93%) was obtained by the same treatment of (4S,5S)-7 (1.01 g, 2.22
mmol) as in the case of (4R,5R)-15. [α]D26 = +163° (c 1.0, MeOH). 1H NMR (CDCl3) δ (ppm): 1.84-2.01
(1H, m), 2.09-2.26 (1H, m), 3.07-3.23 (1H, m), 3.27-3.47 (7H, m, including 3.35, s, and 3.36, s), 3.75 (1H,
br s), 3.93-4.04 (1H, m), 4.58 (1H, d, J = 6.8 Hz), 4.63 (1H, d, J = 6.8 Hz), 4.69-4.82 (3H, m, including
4.71, d, J = 6.8 Hz and 4,75, d, J = 6.8 Hz), 6.60 (1H, d, J = 8.3 Hz), 7.05 (1H, dd, J = 2.5, 8.3 Hz), 7.23
(1H, d, J = 2.5 Hz). IR (neat): 3370, 2947, 2890, 1493, 1150, 1105, 1034, 918, 819 cm-1. HRFAB-MS
calcd for C14H20NO4Cl M+: 301.1081, found: 301.1096.
(4S,5R)-4,5-Bis(methoxymethoxy)-7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepine [(4S,5R)-16]
As a pale yellow oil, (4S,5R)-16 (445 mg, 99%) was obtained by the same treatment of (4S,5R)-8 (674 mg,
27
1.48 mmol) as in the case of (4R,5R)-15. [α]D = –195° (c 1.0, MeOH). 1H NMR (CDCl3) δ (ppm):
1.92-2.22 (2H, m), 3.02-3.23 (2H, m), 3.37 (3H, s), 3.38 (3H, s), 3.79 (1H, br s), 4.01-4.15 (1H, m),
4.60-4.70 (2H, m), 4.73-4.83 (3H, m), 6.64 (1H, d, J = 8.3 Hz), 7.05 (1H, dd, J = 2.5, 8.3 Hz), 7.34 (1H, d,
J = 2.5 Hz). 13C NMR (CDCl3) δ (ppm): 32.9, 43.3, 55.3, 55.5, 75.4, 79.2, 95.0, 95.3, 120.6, 125.5, 127.8,
129.1, 129.9, 147.2. IR (neat): 3359, 2948, 2890, 1491, 1150, 1100, 1028, 917, 820 cm-1. HRFAB-MS
calcd for C14H20NO4Cl M+: 301.1081, found: 301.1067.
(4R,5S)-4,5-Bis(methoxymethoxy)-7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepine [(4R,5S)-16]
As a pale yellow oil, (4R,5S)-16 (915 mg, 99%) was obtained by the same treatment of (4R,5S)-8 (1.40 g,
27
3.07 mmol) as in the case of (4R,5R)-15. [α]D = +198° (c 1.0, MeOH). 1H NMR (CDCl3) δ (ppm):
1.92-2.22 (2H, m), 3.03-3.23 (2H, m), 3.37 (3H, s), 3.38 (3H, s), 3.79 (1H, br s), 4.01-4.14 (1H, m),
4.61-4.69 (2H, m), 4.74-4.83 (3H, m), 6.63 (1H, d, J = 8.3 Hz), 7.05 (1H, dd, J = 2.5, 8.3 Hz), 7.34 (1H, d,
J = 2.5 Hz). IR (neat): 3358, 2947, 2890, 1492, 1149, 1100, 1028, 917, 820 cm-1. HRFAB-MS calcd for
C14H20NO4Cl M+: 301.1081, found: 301.1096.
(4R,5R)-4,5-Bis(methoxymethoxy)-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-1H-1-benzazepine [(4R,5R)-18]
A suspension of 2-methyl-4-(2-methylbenzoylamino)benzoic acid (650 mg, 2.41 mmol), SOCl2 (0.23 mL,
2.7 mmol) and NMP (1 drop) in CH2Cl2 (7 mL) was refluxed for 30 mim to give the acid chloride (17).

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The acid chloride (17) solution was added to a solution of (4R,5R)-15 (483 mg, 1.60 mmol) and pyridine
(2.2 mL, 27 mmol) in CH2Cl2 (5 mL) at 0°C and the mixture was stirred overnight at rt. The reaction
mixture was poured into a 0.3N HCl solution and then extracted with CH2Cl2. The extract was washed
with a saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (NH-silica gel; eluent, hexane/AcOEt = 7/3 – 13/7) to give
27
1
(4R,5R)-18 (717 mg, 81%) as a yellow amorphous solid. [α]D = –98° (c 1.0, MeOH). H NMR
(DMSO-d6, 100°C) δ (ppm): 1.60-2.12 (2H, m), 2.25-2.44 (6H, m), 3.07-4.31 (9H, m, including 3.29, s,
and 3.32, s), 4.56-4.91 (5H, m), 6.68-7.66 (10H, m), 9.86 (1H, br s). IR (KBr): 3289, 1634, 1531, 1487,
1317, 1104, 1034, 918, 734 cm-1. HRFAB-MS calcd for C30H34N2O6Cl (M+H)+: 553.2105, found:
553.2103.
(4S,5S)-4,5-Bis(methoxymethoxy)-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-1H-1-benzazepine [(4S,5S)-18]
As a yellow amorphous solid, (4S,5S)-18 (907 mg, 85%) was obtained by the same treatment of
27
1
(4S,5S)-15 (578 mg, 1.92 mmol) as in the case of (4R,5R)-18. [α]D = +98° (c 1.0, MeOH). H NMR
(DMSO-d6, 100°C) δ (ppm): 1.60-2.12 (2H, m), 2.27-2.44 (6H, m), 3.09-4.34 (9H, m, including 3.29, s,
and 3.32, s), 4.54-4.93 (5H, m), 6.67-7.68 (10H, m), 9.86 (1H, br s). IR (KBr): 3295, 1634, 1532, 1487,
1317, 1104, 1034, 918, 733 cm-1. HRFAB-MS calcd for C30H34N2O6Cl (M+H)+: 553.2105, found:
553.2145.
(4S,5R)-4,5-Bis(methoxymethoxy)-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-1H-1-benzazepine [(4S,5R)-19]
As a pale yellow amorphous solid, (4S,5R)-19 (703 mg, 86%) was obtained by the same treatment of
27
(4S,5R)-16 (445 mg, 1.47 mmol) as in the case of (4R,5R)-18. [α]D = –156° (c 1.0, MeOH). 1H NMR
(DMSO-d6, 100°C) δ (ppm): 1.83-2.22 (2H, m), 2.35 (3H, s), 2.36 (3H, s), 2.84-4.45 (9H, m, including
3.25, s, and 3.34, s), 4.59 (1H, d, J = 6.5 Hz), 4.67 (1H, d, J = 6.5 Hz), 4.70 (1H, d, J = 6.5 Hz), 4.79-5.07
(2H, m, including 4.85, d, J = 6.5 Hz), 6.70-7.72 (10H, m), 9.87 (1H, br s). IR (KBr): 3289, 1634, 1532,
1486, 1317, 1150, 1102, 1028, 918, 822, 733 cm-1. HRFAB-MS calcd for C30H34N2O6Cl (M+H)+:
553.2105, found: 553.2103.
(4R,5S)-4,5-Bis(methoxymethoxy)-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-1H-1-benzazepine [(4R,5S)-19]
As a pale yellow amorphous solid, (4R,5S)-19 (658 mg, 83%) was obtained by the same treatment of
27
(4R,5S)-16 (432 mg, 1.43 mmol) as in the case of (4R,5R)-18. [α]D = +159° (c 1.0, MeOH). 1H NMR

HETEROCYCLES, Vol. 69, 2006
349
(DMSO-d6, 100°C) δ (ppm): 1.86-2.20 (2H, m), 2.35 (3H, s), 2.36 (3H, s), 2.83-4.44 (9H, m, including
3.25, s, and 3.34, s), 4.59 (1H, d, J = 6.5 Hz), 4.67 (1H, d, J = 6.5 Hz), 4.69 (1H, d, J = 6.5 Hz), 4.78-5.06
(2H, m, including 4.85, d, J = 6.5 Hz), 6.67-7.71 (10H, m), 9.87 (1H, br s). IR (KBr): 3295, 1634, 1532,
1485, 1317, 1150, 1102, 1028, 918, 822, 733 cm-1. HRFAB-MS calcd for C30H34N2O6Cl (M+H)+:
553.2105, found: 553.2108.
(4R,5R)-7-Chloro-4,5-dihydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra-
hydro-1H-1-benzazepine [(4R,5R)-2a]
A solution of (4R,5R)-18 (679 mg, 1.23 mmol) and conc. HCl (2 mL) in MeOH (10 mL) was stirred at
60°C for 3.5 h. The reaction mixture was poured into water and then extracted with CH2Cl2 (2 times). The
extract was washed with a saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography (silica gel; eluent, CH2Cl2/MeOH = 30/1 –
20/1) to give (4R,5R)-2a (473 mg, 83%) as a colorless amorphous solid, which was >99% ee by HPLC
27
analysis using CHIRALCEL OD-RH (CH3CN/MeOH/H2O = 8/5/7). [α]D = –170° (c 1.0, MeOH). 1H
NMR (DMSO-d6, 100°C) δ (ppm): 1.58-2.06 (2H, m), 2.34 (3H, s), 2.36 (3H, s), 2.79-4.39 (3H, m),
4.54-4.81 (2H, m), 5.23-5.47 (1H, m), 6.59-7.66 (10H, m), 9.86 (1H, br s). IR (KBr): 3296, 1634, 1486,
1404, 1318, 1180, 1099, 1055, 910, 821, 733 cm-1. HRFAB-MS calcd for C26H26N2O4Cl (M+H)+:
465.1581, found: 465.1582.
(4S,5S)-7-Chloro-4,5-dihydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra-
hydro-1H-1-benzazepine [(4S,5S)-2a]
As a colorless amorphous solid, (4S,5S)-2a (595 mg, 82%, >99% ee) was obtained by the same treatment
of (4S,5S)-18 (866 mg, 1.57 mmol) as in the case of (4R,5R)-2a. [α]D27 = +167° (c 1.0, MeOH). 1H NMR
(DMSO-d6, 100°C) δ (ppm): 1.60-2.05 (2H, m), 2.34 (3H, s), 2.36 (3H, s), 2.81-4.39 (3H, m), 4.54-4.80
(2H, m), 5.26-5.47 (1H, m), 6.62-7.64 (10H, m), 9.86 (1H, br s). IR (KBr): 3290, 1634, 1487, 1404, 1318,
1180, 1099, 1055, 911, 822, 733 cm-1. HRFAB-MS calcd for C26H26N2O4Cl (M+H)+: 465.1581, found:
465.1584.
(4S,5R)-7-Chloro-4,5-dihydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra-
hydro-1H-1-benzazepine [(4S,5R)-3a]
As a colorless amorphous solid, (4S,5R)-3a (436 mg, 87%), which was >99% ee by HPLC analysis using
CHIRALCEL OD-RH (CH3CN/MeOH/H2O = 8/5/7), was obtained by the same treatment of (4S,5R)-19
27
(596 mg, 1.08 mmol) as in the case of (4R,5R)-2a. [α]D = –124° (c 1.0, MeOH). 1H NMR (DMSO-d6,
100°C) δ (ppm): 1.55-2.14 (2H, m), 2.34 (3H, s), 2.36 (3H, s), 2.71-4.46 (4H, m), 4.78-4.97 (1H, m),

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HETEROCYCLES, Vol. 69, 2006
5.21-5.34 (1H, m), 6.60-7.68 (10H, m), 9.86 (1H, br s). IR (KBr): 3298, 1634, 1404, 1317, 1058, 909,
822, 733 cm-1. HRFAB-MS calcd for C26H26N2O4Cl (M+H)+: 465.1581, found: 465.1584.
(4R,5S)-7-Chloro-4,5-dihydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-
1H-1-benzazepine [(4R,5S)-3a]
As a colorless amorphous solid, (4R,5S)-3a (829 mg, 89%, >99% ee) was obtained by the same treatment
27
of (4R,5S)-19 (1.10 g, 1.99 mmol) as in the case of (4R,5R)-2a. [α]D = +122° (c 1.0, MeOH). 1H NMR
(DMSO-d6, 100°C) δ (ppm): 1.55-2.16 (2H, m), 2.34 (3H, s), 2.36 (3H, s), 2.69-4.45 (4H, m), 4.78-4.98
(1H, m), 5.20-5.33 (1H, m), 6.59-7.69 (10H, m), 9.86 (1H, br s). IR (KBr): 3290, 1634, 1403, 1317, 1058,
909, 822, 732 cm-1. HRFAB-MS calcd for C26H26N2O4Cl (M+H)+: 465.1581, found: 465.1582.
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