An efficient synthesis of optical isomers of vasopressin V2 receptor antagonist OPC-41061 by lipase-catalyzed enantioselective transesterification

Article abstract of DOI:10.3987/COM-99-S(I)2

The optically active enantiomers of 7-chloro-5-hydroxy-1-[2- methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro- 1H- 1-benzazepine (OPC-41061, 1) were enantioselectively synthesized. The chiral acetate ((R)-(-)-3) and the chiral alcohol ((S)-(+)-2) were prepared via the resolution of the racemic alcohol ((±)-2) using the lipase-mediated transesterification with vinyl acetate. Compounds ((R)-(-)-3) and ((S)-(+)-2) were converted to optically active 1.

Full text of DOI:10.3987/COM-99-S(I)2

HETEROCYCLES, Vol. 54, No. 1, 2001, pp. 131 - 138, Received, 15th November, 1999
AN EFFICIENT SYNTHESIS OF OPTICAL ISOMERS OF
VASOPRESSIN V2 RECEPTOR ANTAGONIST OPC-41061 BY LIPASE-
CATALYZED ENANTIOSELECTIVE TRANSESTERIFICATION
Jun Matsubara,* Seiji Morita, Hiroshi Yamashita, Kenji Otsubo, Kazuyoshi
Kitano, Tadaaki Ohtani, Yoshikazu Kawano, Masahiko Bando, Masaru Kido,
Minoru Uchida, and Fujio Tabusa
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd.,
Kagasuno 463-10, Kawauchi-cho, Tokushima 771-0192, Japan
Abstract
-
The optically active enantiomers of 7-chloro-5-hydroxy-1-[2-
methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine
(OPC-41061, 1) were enantioselectively synthesized. The chiral acetate ((R)-(–)-3)
and the chiral alcohol ((S)-(+)-2) were prepared via the resolution of the racemic
alcohol ((±)-2) using the lipase-mediated transesterification with vinyl acetate.
Compounds ((R)-(–)-3) and ((S)-(+)-2) were converted to optically active 1.
INTRODUCTION
The benzazepine derivative 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-1H-1-benzazepine (OPC-41061, 1)1 is a new vasopressin V2 receptor antagonist and is now
under clinical trial as a novel aquaretic agent. This compound has an asymmetric carbon at the 5-position
of the benzazepine ring. In order to clarify the mechanism of action and the pharmacological profile of 1,
obtaining the optically active isomer was essential.
OH
Cl
N
CH3
O
O
CH3
N
H
1 (OPC-41061)
Figure 1
There are many useful methods of preparing optically active secondary alcohols. Lipase-catalyzed
transesterification is one of the most useful technologies. We have already reported the asymmetric
synthesis of the key intermediate and the metabolites of OPC-290302 via lipase-catalyzed

transesterification.3 In this paper, we wish to report an efficient synthesis of optically active 1 using the
lipase-catalyzed transesterification.
RESULTS AND DISCUSSION
First, to prepare both enantiomers of 1, we examined the lipase-catalyzed transesterification of the key
intermediate ((±)-2) with vinyl acetate. Based on the screening test (Table 1), most of the lipases except
for lipase OF showed good selectivity. Especially, the selectivity of Lipozyme IM was excellent (Entry 6).
When we prepare the compound on a practical scale, reactivity is also regarded as the important factor.
Taking both the selectivity and the reactivity into consideration, using lipase QL (Entry 1) was the best
condition for preparing (R)-(–)-3 and (S)-(+)-2.
a
Table 1 Lipase-catalyzed transesterification
OH
OAc
OH
Cl
Cl
Cl
Lipase
AcOCH=CH
+
2
N
N
N
Ts
Ts
Ts
38°C, 40 h
(S)-(+)-2
(R)-(-)-3
(±)-2
(S)-(+)-2
Yield (%)c ee (%)d
(R)-(-)-3
Yield (%)c ee (%)d
Entry
Lipaseb
E valuee
QL
QL
1
2f
3
4
5
6
7
8
9
51
32
9
95
98
49
68
91
81
---
89
91
96
90
99
45
9
206
155
72
QLG
97
PL
97
23
---
13
10
4
19
0
82
OF
---
---
Lipozyme IM
Novozym 435
SP 524
> 99
99
11
9
453
220
103
220
4
98
Toyozyme LIP
10
99
10
a. All reactions were carried out by stirring a mixture of (±)-2 (52 mg), lipase (52 mg), and vinyl
acetate (2 mL) at 38°C for 40 h, except for Entry 2. b. PL, QL (Meito Sangyo, Alcaligenes sp.),
QLG (Meito Sangyo, immobilized, Alcaligenes sp.), OF (Meito Sangyo, Candida cylindracea),
Lipozyme IM (Novo Nordisk, Mucor miehei), Novozym 435, SP 524 (Novo Nordisk, Aspergillus
oryzae), Toyozyme LIP (Toyo Boseki, Pseudomonas sp.). c. HPLC yield. d. Enantiomeric
purities were determined by HPLC analysis using a column packed with CHIRALCEL OJ (Daicel
Chemical). e. The E value is the ratio of the specificity constant of two enantiomers calculated
according to ref. 4. f. Reaction at room temperature (24°C).

We applied the optimal conditions on a practical scale (35.0 g of the substrate) to convert the substrate
into the target compound. Transesterification of (±)-2 with vinyl acetate and lipase QL gave the acetate
((R)-(–)-3) (48% yield and 95% ee) and the unreacted alcohol ((S)-(+)-2) (52% yield and 93% ee). The
crude (S)-(+)-2 (93% ee) was recrystallized from EtOAc – hexane to give optically pure crystals (99% ee).
Treatment of (S)-(+)-2 with chloromethyl methyl ether in the presence of sodium hydride gave the
methoxymethyl compound, which was reacted with magnesium in MeOH to give the benzazepine ((S)-
(–)-5) in 68% yield (from (S)-(+)-2). Benzoylation of (S)-(–)-5 with 2-methyl-4-[(2-methylbenzoyl)-
amino]benzoyl chloride in the presence of pyridine afforded the benzoyl derivative ((S)-(–)-6) in
quantitative yield. The target compound ((S)-(–)-1) was obtained by deprotection of (S)-(–)-6 with
hydrochloric acid in 74% yield, and the high enantiomeric excess was retained (>99% ee). On the other
hand, the alcohol ((R)-(–)-2) was derived by hydrolysis of the acetate ((R)-(–)-3) with potassium carbonate,
and recrystallized from EtOAc – hexane to give optically pure crystals (>99% ee). The antipodal
enantiomer ((R)-(+)-1) (>99% ee) was synthesized similarly from (R)-(–)-2. (Scheme 1).
OH
OH
OAc
OMOM
Cl
Cl
Cl
Cl
Lipase QL
recryst.
67%
MOMCl, NaH
DMF
(S)-(+)-2
(99% ee)
+
AcOCH=CH
N
Ts
2
N
Ts
N
Ts
N
Ts
92%
(S)-(+)-2
52% (93% ee)
(R)-(-)-3
48% (95% ee)
(±)-2
(S)-(-)-4
H C
3
H C
O
3
O
OMOM
OMOM
OH
NH
Py, CH Cl
2
Cl
Cl
Cl
1) HCl, MeOH
2) recryst.
Mg
Cl
MeOH
74%
2
N
H
N
CH
N
CH
3
3
quant.
O
O
CH
O
O
CH
3
74%
3
(S)-(-)-5
N
N
H
H
(S)-(-)-6
(S)-(-)-1
(>99% ee)
OAc
OH
OH
Cl
Cl
Cl
1) K CO , MeOH
2
3
2) recryst.
70%
N
Ts
N
Ts
N
CH
3
O
O
CH
3
(R)-(-)-2
(>99% ee)
(R)-(-)-3
N
H
(R)-(+)-1
(>99% ee)
Scheme 1
Thus we accomplished the enantioselective synthesis of both enantiomers of 1. This method was effective
for preparing both enantiomers of the target compounds in good yield and high enantiomeric excess.
The absolute configurations of the above optically active compounds were determined as follows. The X-
Ray crystal structure for (+)-2 is shown in Figure 2. The absolute configuration of the 5-position was
determined to be S by Bijvoet’s anomalous-dispersion method.5 Consequently, the compounds ((–)-4, (–)-
5, (–)-6, and (–)-1) derived from (+)-2 were of the S configuration.

OH
Cl
N
O S O
CH3
(S)-(+)-2
X-Ray crystal structure for (+)-2
Figure 2
In conclusion, we have established the enantioselective synthesis of optically active OPC-41061 ((S)-(–)-1
and (R)-(+)-1) from the key intermediates ((S)-(+)-2 and (R)-(–)-2) obtained by means of lipase-catalyzed
kinetic resolution.
EXPERIMENTAL
Melting points were determined with a Yamato MP-21 apparatus and are uncorrected. NMR spectra were
recorded on a Bruker AVANCE DPX 250 spectrometer. MS spectra were obtained on Finnigan MAT
GCQ instrument. IR spectra were recorded on a Perkin Elmer FT-IR spectrophotometer Spectrum 1000.
Optical rotations were measured on a JASCO DIP-370 digital polarimeter. Silica gel (Fuji silysia
chemical Ltd., BW-127ZH) was used for column chromatography.
General procedure of lipase catalyzed transesterification
A mixture of (±)-2 (52 mg), vinyl
acetate (2 mL) and lipase QL (52 mg) was stirred at 38°C. The ratio of the substrate and the acetylated
product was monitored by HPLC (DAICEL CHIRALCEL OJ was used for (S)-(+)-2 and (R)-(–)-3 with
hexane : iso-PrOH : Et2NH = 800 : 200 : 1 as the eluent) or the reaction was quenched after appropriate
time. When about a half of the substrate was acetylated, the mixture was filtered and evaporated. The
residue was chromatographed on silica gel with a mixed solvent (hexane : EtOAc = 4 : 1) to afford both
the optically active alcohol and the acetylated product.
(S)-7-Chloro-5-hydroxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine [(S)-(+)-2]
A mixture of (±)-2 (35.0 g, 100 mmol) and lipase QL (22.0 g) in vinyl acetate (350 mL) was stirred at
38°C for 48 h. The mixture was filtrated by a pad of Celite and the insoluble material was washed with
CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography
(silica gel; eluent, hexane : EtOAc = 4 : 1) to give (S)-(+)-2 (18.1 g, 52%) and (R)-(–)-3 (19.0 g, 48%),
which were (S)-(+)-2 (93% ee) and (R)-(–)-3 (95% ee) by HPLC analysis using CHIRALCEL OJ

(hexane : iso-PrOH : Et2NH = 800 : 200 : 1). The crude (S)-(+)-2 was recrystallized from EtOAc – hexane
27
to give (S)-(+)-2 (12.2 g, 35%, 99% ee) as colorless prisms, mp 143 – 144°C. [a ]D +9.5° (c 1.0, CHCl ).
3
1H NMR (CDCl ) d: 1.50 – 2.20 (4 H, m), 2.44 (3 H, s), 3.00 – 3.30 (1 H, m), 3.90 – 4.20 (1 H, m), 4.50 –
3
4.65 (1 H, m), 7.05 (1 H, d, J = 8.4 Hz), 7.15 (1 H, dd, J = 8.4 Hz, 2.3 Hz), 7.29 (2 H, dd, J = 8.3 Hz, 2.1
-1
Hz), 7.53 (1 H, d, J = 2.3 Hz), 7.65 (2 H, d, J = 8.3 Hz). IR (KBr): 3526, 1482, 1340, 1159 cm . Anal
Calcd for C17H18NO3ClS: C, 58.03; H, 5.16; N, 3.98. Found: C, 57.88. H, 5.20; N, 4.08.
(R)-5-Acetoxy-7-chloro-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine [(R)-(–)-3]
The crude (R)-(–)-3 was recrystallized from MeOH to give (R)-(–)-3 as colorless needles, mp 109 – 111°C.
1
[a ]D28 –8.9° (c 1.0, CHCl ). H NMR (CDCl ) d: 1.50 – 2.00 (4 H, m), 2.13 (3 H, s), 2.43 (3 H, s), 3.00 –
3
3
3.30 (1 H, m), 3.90 – 4.20 (1 H, m), 5.42 (1 H, d, J = 9.0 Hz), 7.15 – 7.40 (5 H, m), 7.67 (2 H, d, J = 8.3
-1
Hz). IR (KBr): 2932, 1745, 1341, 1243, 1225, 1164, 1038 cm . Anal Calcd for C H20NO4ClS: C, 57.94;
19
H, 5.12; N, 3.56. Found: C, 57.90; H, 5.05; N, 3.59.
(R)-7-Chloro-5-hydroxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine [(R)-(–)-2]
A mixture of (R)-(–)-3 (19.0 g, 48.2 mmol, 95% ee) and K CO3 (6.66 g, 48.2 mmol) in MeOH (160 mL)
2
was stirred at rt for 30 min. After removal of MeOH, the residue was poured into water and the solution
was extracted with CH2Cl . The extract was dried over Na2SO4 and concentrated in vacuo. The residue
2
was recrystallized from EtOAc – hexane to give (R)-(–)-2 (11.8 g, 70%, >99% ee) as colorless prisms, mp
27
150°C. [a ]D –9.4° (c 1.0, CHCl3). IR (KBr): 3520, 1482, 1341, 1159 cm-1. Anal Calcd for
C17H18NO3ClS: C, 58.03; H, 5.16; N, 3.98. Found: C, 58.13. H, 5.20; N, 4.15.
(S)-7-Chloro-5-methoxymethyloxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine [(S)-
(–)-4]
A 60% dispersion of NaH in oil (0.19 g, 4.8 mmol) was added to a ice-cooled solution of (S)-
(+)-2 (1.41 g, 4.0 mmol, 99% ee) in DMF (15 mL) and the mixture was stirred at the same temperature for
30 min. Chloromethyl methyl ether (0.46 mL, 6.0 mmol) was added to the mixture and stirred at rt for 18
h. The reaction mixture was poured into water and the solution was extracted with EtOAc – toluene. The
extract was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography (silica gel; eluent, hexane : EtOAc = 3 : 1) to give (S)-(–)-4 (1.45 g, 92%) as colorless oil.
1
[a ]D27 –39.2° (c 1.0, CHCl ). H NMR (CDCl ) d: 1.40 – 2.10 (4 H, m), 2.41 (3 H, s), 3.00 – 3.25 (1 H,
3
3
m), 3.28 (3 H, s), 4.00 – 4.20 (2 H, m), 4.30 (1 H, d, J = 6.7 Hz), 4.53 (1 H, d, J = 6.7 Hz), 7.15 – 7.35 (4
H, m), 7.41 (1 H, d, J = 2.4 Hz), 7.61 (2 H, d, J = 8.3 Hz). IR (neat) : 2936, 1600, 1480, 1349, 1161, 1093,
-1
1034 cm . Anal Calcd for C19H22NO4ClS: C, 57.64; H, 5.60; N, 3.54. Found: C, 57.58. H, 5.70; N, 3.45.
(R)-7-Chloro-5-methoxymethyloxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
[(R)-(+)-4]
The title compound was prepared from (R)-(–)-2, NaH and chloromethyl methyl ether by
the procedure described for the preparation of (S)-(–)-4. The product was purified by column
27
chromatography to give (R)-(+)-4 (quant.) as colorless oil. [a ]D +38.6° (c 1.0, CHCl ). IR (neat): 2938,
3
-1
1600, 1480, 1341, 1154, 1094, 1030 cm . Anal Calcd for C H22NO4ClS: C, 57.64; H, 5.60; N, 3.54.
19

Found: C, 57.61. H, 5.67; N, 3.52.
(S)-7-Chloro-5-methoxymethyloxy-2,3,4,5-tetrahydro-1H-1-benzazepine [(S)-(–)-5]
Magnesium
(0.61 g, 25.1 mmol) was added to a solution of (S)-(–)-4 (0.99 g, 2.5 mmol) in MeOH (18 mL) and the
mixture was refluxed for 2 h. After removal of MeOH, the residue was diluted with CH2Cl , and then
2
Celite was added to the mixture. The insoluble material was filtrated and the filtrate was concentrated in
vacuo. The residue was purified by column chromatography (silica gel; eluent, hexane : EtOAc = 3 : 1) to
27
1
give (S)-(–)-5 (0.45 g, 74%) as colorless oil. [a ]D –212° (c 1.0, MeOH). H NMR (CDCl ) d: 1.70 –
3
2.10 (4 H, m), 2.85 – 3.25 (2 H, m), 3.39 (3 H, s), 4.62 (1 H, d, J = 6.8 Hz), 4.66 (1H, br s), 4.71 (1 H, d, J
= 6.8 Hz), 6.64 (1 H, d, J = 8.3 Hz), 7.03 (1 H, dd, J = 8.3 Hz, 2.4 Hz), 7.31 (1H, d, J = 2.4 Hz). IR (neat):
-1
35
3372, 2938, 2818, 1493, 1150, 1033 cm . HRMS Calcd for C12H16NO2 Cl: 241.0871, Found: 241.0889.
(R)-7-Chloro-5-methoxymethyloxy-2,3,4,5-tetrahydro-1H-1-benzazepine [(R)-(+)-5]
The title
compound was prepared from (R)-(+)-4 and magnesium by the procedure described for the preparation of
(S)-(–)-5. The product was purified by column chromatography to give (R)-(+)-5 (88%) as colorless oil.
28
-1
[a ]D +202° (c 1.0, MeOH). IR (neat): 3372, 2936, 1494, 1150, 1035 cm . HRMS Calcd for
35
C12H16NO2 Cl: 241.0871, Found: 241.0860.
(S)-7-Chloro-5-methoxymethyloxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-1H-1-benzazepine [(S)-(–)-6]
A solution of 2-methyl-4-(2-methylbenzoylamino)benzoyl
chloride (0.17 g, 0.60 mmol) in CH2Cl (10 mL) was added dropwise to a ice-cooled solution of (S)-(–)-5
2
(0.12 g, 0.50 mmol) and pyridine (0.22 mL, 2.73 mmol) in CH2Cl (5 mL) and the mixture was stirred at
2
the same temperature for 0.5 h, and then at rt for 2 h. The reaction mixture was washed with 10% citric
acid aqueous solution and saturated K2CO3 aqueous solution. The mixture was dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (silica gel; eluent, CH Cl :
2
2
27
MeOH = 30 : 1) to give (S)-(–)-6 (0.28 g, quant.) as pale brown amorphous. [a ]D –126° (c 1.0, MeOH).
1H NMR (CDCl ) d: 1.50 – 2.35 (4 H, m), 2.40 (3 H, s), 2.46 (3 H, s), 2.75 – 3.00 (1 H, m), 3.42 (3H, s),
3
4.50 – 4.90 (3 H, m), 4.90 – 5.15 (1 H, m), 6.58 (1 H, d, J = 8.3 Hz), 6.77 (1 H, d, J = 8.2 Hz), 6.94 (1 H,
-1
dd, J = 8.3 Hz, 2.4 Hz), 7.00 – 7.70 (7 H, m). IR (KBr): 3300, 2925, 1636, 1524, 1400, 1314, 1030 cm .
35
HRMS Calcd for C28H30N2O4 Cl (MH+): 493.1896, Found: 493.1895.
(R)-7-Chloro-5-methoxymethyloxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-
tetrahydro-1H-1-benzazepine [(R)-(+)-6]
The title compound was prepared from (R)-(+)-5, 2-
methyl-4-(2-methylbenzoylamino)benzoyl chloride and pyridine by the procedure described for the
preparation of (S)-(–)-6. The product was purified by column chromatography to give (R)-(+)-6 (74%) as
-1
yellow amorphous. [a ]D27 +122° (c 1.0, MeOH). IR (KBr): 3295, 2920, 1650, 1527, 1400, 1315, 1030 cm .
35
HRMS Calcd for C28H30N2O4 Cl (MH+): 493.1896, Found: 493.1902.
(S)-7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-

benzazepine [(S)-(–)-1]
A conc. HCl (4.0 mL) was added to a solution of (S)-(–)-6 (1.48 g, 3.0
mmol) in MeOH (20 mL) and the mixture was stirred at 55°C for 1.5 h. MeOH was evaporated and the
residue was extracted with CH2Cl . The extract was dried over Na2SO4 and concentrated in vacuo. The
2
residue was purified by column chromatography (silica gel; eluent, CH2Cl : MeOH = 50 : 1) and
2
recrystallized from EtOH – H2O to give (S)-(–)-1 (1.00 g, 74%) as white powder, which was >99% ee by
HPLC analysis using CHIRALCEL OD (hexane : iso-PrOH : Et2NH = 600 : 400 : 1), mp 148 – 150°C.
26
1
[a ]D –159° (c 0.1, MeOH). H NMR (CDCl ) d: 1.50 – 2.40 (4 H, m), 2.44 (3 H, s), 2.47 (3 H, s), 2.60
3
– 2.95 (1 H, m), 4.70 – 5.10 (2 H, m), 6.54 (1 H, d, J = 8.3 Hz), 6.64 (1 H, d, J = 8.4 Hz), 6.92 (1 H, d, J =
-1
8.3 Hz), 7.00 – 7.70 (7 H, m). IR (KBr): 3425, 1627, 1522, 1400, 1315 cm . Anal Calcd for
C26H25N2O3Cl·1/4H2O: C, 68.87; H, 5.67; N, 6.18. Found: C, 68.84; H, 5.76, N, 5.81.
(R)-7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-
benzazepine [(R)-(+)-1]
The title compound was prepared from (R)-(+)-6, and conc. HCl by the
procedure described for the preparation of (S)-(–)-1. The product was recrystallized from EtOH – H2O to
26
give (R)-(+)-1 (70%, >99% ee) as white powder, mp 149 – 152°C. [a ]D +165° (c 0.1, MeOH). IR (KBr):
-1
3425, 1621, 1526, 1400, 1316 cm . Anal Calcd for C H25N2O3Cl·1/4H2O: C, 68.87; H, 5.67; N, 6.18.
26
Found: C, 68.78; H, 5.72, N, 5.86.
X-Ray analysis of (+)-2:
Suitable crystals of (+)-2 for an X-Ray diffraction study were grown from a
EtOAc – hexane solution. All data were obtained Rigaku AFC-5S automated four circle diffractometer
with graphite-monochromated Cu Ka radiation. Crystal data : C17H18NO3ClS, Mr=351.85, orthorhombic,
space group P212121, a=12.917(6)Å, b=15.046(6)Å, c=8.723(4)Å, V=1695(2)Å3, Z=4.0, Dx=1.378 g/cm3,
-1
Dm=1.384(4) g/cm3, F(000)=736, and m(CuKa)= 32.658 cm . The intensities were measured using w/2q
scan, and measurements were conducted on one component of Bijvoet pairs. Three standard reflections
were monitored every 150 measurements. The data were corrected for Lorentz and polarization factors.
Absorption and decay correlation was not applied. Of the 3320 independent reflections which collected,
3128 reflections with I>3.0s(I) were used for structure determination and refinement. The structure was
solved by direct method using TEXSAN crystallographic software package.6 All non-H atoms were found
in Fourier map. All H atoms were found in difference fourier map and refined isotropically. The
refinement of atomic parameters were carried out by the full matrix least-squares refinement, using
anisotropically temperature factors for all non-H atoms. The final refinement converged with R=0.048 and
Rw=0.046 for 208 parameters. Then, 25 of Bijvoet pairs having large intensity and high measurement
accuracy were selected. The absolute configuration of (+)-2 was determined as S by the Bijvoet’s
anomalous-dispersion method.5
REFERENCES AND NOTES
1. K. Kondo, H. Ogawa, H. Yamashita, H. Miyamoto, M. Tanaka, K. Nakaya, K. Kitano, Y. Yamamura,
S. Nakamura, T. Onogawa, T. Mori, and M. Tominaga, Bioorg. Med. Chem., 1999, 7, 1743.
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Nishi, Chem. Pharm. Bull., 1995, 43, 1724.
3. a) S. Morita, J. Matsubara, K. Otsubo, K. Kitano, T. Ohtani, Y. Kawano, and M. Uchida,
Tetrahedron Asymmetry, 1997, 8, 3707. b) K. Kitano, J. Matsubara, T. Ohtani, K. Otsubo, Y.
Kawano, S. Morita, and M. Uchida, Tetrahedron Lett., 1999, 40, 5235.
4. C. Chen, Y. Fujimoto, G. Girdaukas, and C. J. Sih, J. Am. Chem. Soc., 1982, 104, 7294.
5. J. M. Bijvoet, A. F. Peerdeman, and A. J. von Bommel, Nature, 1951, 168, 271.
6. "TEXSAN, TEXRAY Structure Analysis Package," Molecular Structure Corporation (1995). Single
Crystal Structure Analysis Software. Version 1.7. MSC, 3200A Research Forest Drive, The
Woodlands, TX 77381, USA.
7. The author has deposited atomic coordinates for this structure with the Cambridge Crystallographic
Data Center. The coordinates can be obtained on request from The Director, Cambridge
Crystallographic Data Center, University Chemical Laboratory, Lensfield Road, Cambridge CB12
1EW, UK.