An efficient method for the preparation of enantiomerically pure N- acylarylsulfonamides having an asymmetric center at the α-position: Condensation of acid chlorides and arylsulfonamides under solid-liquid two- phase conditions

Article abstract of DOI:10.1055/s-2000-6270

A convenient synthetic method for the preparation of enantiomerically pure N-acylarylsulfonamides having an asymmetric center at the α-position of the carbonyl group is described. Chiral phenylacetic acids are first converted to the corresponding acid chl

Full text of DOI:10.1055/s-2000-6270

784
PAPER
An Efficient Method for the Preparation of Enantiomerically Pure
N-Acylarylsulfonamides Having an Asymmetric Center at the a-Position:
Condensation of Acid Chlorides and Arylsulfonamides Under Solid-Liquid
Two-Phase Conditions
Natsuki Ishizuka,* Ken-ichi Matsumura, Kunio Hayashi, Katsunori Sakai, Teruo Yamamori
Shionogi Research Laboratories, Shionogi & Co. Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan
Fax +81(6)64580987; E-mail: natsuki.ishizuka@shionogi.co.jp
Received 18 January 2000; revised 28 February 2000
Abstract: A convenient synthetic method for the preparation of
enantiomerically pure N-acylarylsulfonamides having an asymmet-
ric center at the a-position of the carbonyl group is described. Chiral
phenylacetic acids are first converted to the corresponding acid
chlorides, which in turn are condensed with arylsulfonamides in the
presence of powdered alkaline hydroxide in CH2Cl2, giving the cor-
responding N-acylarylsulfonamides with good optical and chemical
yields. A more convenient one-pot procedure is also possible.
Key words: chiral N-acylarylsulfonamides, chiral phenylacetic ac-
id, racemization, solid-liquid two-phase conditions, powdered alka-
line hydroxide
Scheme
N-Acylsulfonamides, forming a class of acidic functional
groups, have been widely employed as carboxylic acid
describe a simple and economically feasible method for
the preparation of 4 as a model of such chiral N-acylaryl-
sulfonamides, which include the condensation of acid
chloride 2, readily available from the corresponding opti-
cally active phenylacetic acid derivative 1, and arylsul-
fonamide 3 in the presence of powdered alkaline
hydroxide in CH2Cl2. The product 4 thus obtained is enan-
bioisosteres in medicinal chemistry.1 They have similar
pKa values to those of the corresponding carboxylic
acids2 and offer the possibility for a wide range of struc-
tural modifications. Acylation of sulfonamides with acid
chlorides,3 acid anhydrides4 or reactive esters5 have tradi-
tionally been used for the preparation of N-acylsulfona-
mides.6 More recently, direct condensation of carboxylic
tiomerically pure enough for further elaboration.
acids and sulfonamides in the presence of condensing
agents, such as carbonyldiimidazole (CDI),7 2-chloro-N-
methylpyridinium iodide (CMPI)8 or carbodiimides,9
have also been employed for this purpose.
The results of the direct condensation of (R)-1a and 3 in
the presence of condensing agents (route A) are summa-
rized as Entries 1-6 in Table 1. Each reaction was carried
out by reported methods. The optical purity of each of the
starting materials and the products were determined by
chiral HPLC analysis. The CDI method of Drummond
and Johnson7 resulted in good yield of 4a, but the product
was completely racemized (Entry 1). CMPI method8 also
gave the racemate (Entry 2). On the other hand, carbodi-
imide-DMAP (4-dimethylaminopyridine) methods9a,b at
room temperature afforded 89-91% ee of (R)-4a in 70-
88% yields after silica gel chromatography (Entries 3 and
4). Lowering the temperature to 0 ∞C improved the optical
purity of the product, giving 99% ee of (R)-4a; however
the yield was only 34% after 10 h and a considerable
amount of the starting material was recovered (Entry 5).
Replacing DMAP with less basic 1-hydroxybenzotriazole
(HOBt) 9c resulted in significant loss of reaction rate even
at room temperature, giving 40% ee of the product in 19%
yield after 24 hours (Entry 6).
During the course of development of our endotheline re-
ceptor antagonists, we found that N-acylarylsulfonamide
(R)-4a is a potent endotheline-A receptor antagonist.10
This compound has one asymmetric center at the a-posi-
tion of the carbonyl group. In order to prepare (R)-4a,
enantiomerically pure (R)-1a was allowed to react with ar-
ylsulfonamide 3 in the presence of various condensing
agents (Scheme). Although these methods gave 4a in
good to excellent yields, the product was completely or
partially racemized in all cases. Acylation of 3 with the
corresponding acid chloride (R)-2a in the presence of tri-
ethylamine also resulted in the racemized product (vide
infra).
The increasing importance of preparing the enantiomeri-
cally pure form of biologically active compounds in drug
development studies11 prompted us to survey a hitherto
undocumented efficient method for the synthesis of chiral
N-acylarylsulfonamide having an asymmetric center at
the a-position of the carbonyl group.12 In this paper, we
We next turned our attention to the stepwise methods
which include conversion of 1 to acid chloride 2 (route B).
Synthesis 2000, No. 6, 784–788 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Method for the Preparation of Enantiomerically Pure N-Acylarylsulfonamides
785
Table 1 Results of Condensation of Chiral Phenylacetic Acids 1 or Chlorides 2 with 3
Entry R1
R2
Starting
Reagentb
Solvent
Conditions
Product ee
(%)c
Yield
Materiala
(%)c
1
2
3
4
5
6
7
8
9
(R)-1a
CDI, DBU
CMPI, Et3N
DCC, DMAP
EDC, DMAP
EDC, DMAP
EDC, HOBt
THF
r.t., 1 h; r.t., 1h (R)-4a
r.t., 1 h
r.t., 2 h
r.t., 2 h
0°C, 24 h
r.t., 24 h
0°C, 2.5 h
0°C, 1.5 h
0°C, 1.5 h
2
0
89
91
99
74
55
88
70
34
19
37
90
85d
92
83
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
40
13
(R)-2a
Et3N
powdered KOH
powdered KOH
powdered KOH
powdered KOH
(one-pot)
99
100d
99
10
11
CH2Cl2 (wet)e 0°C, 1.5 h
CH2Cl2
0°C, 2 h
98
12
13
14
15
16
17
18
19
20
powdered NaOH
powdered NaOH
powdered LiOH
powdered LiOH•H2O CH2Cl2
CDI, DBU
EDC, DMAP
EDC, DMAP
powdered KOH
powdered KOH
(one-pot)
CH2Cl2
0°C, 1.5 h
99
99
95
97
42
98
11
100
100
88
85
84
61
81
19
87
77
93
CH2Cl2 (wet)e 0°C, 1.5 h
CH2Cl2
0°C, 2.5 h
0°C, 2.5 h
r.t., 1h; r.t., 1h (R)-4b
r.t., 2 h
r.t., 24 h
0°C, 1 h
OMe
(R)-1b
(R)-2b
(+)-2c
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0°C, 1 h
21
powdered KOH
CH2Cl2
0°C, 1 h
(+)-4c
(S)-4d
100
80
22
23
(S)-2d
powdered KOH
powdered KOH
(one-pot)
CH2Cl2
CH2Cl2
0°C, 3 h
0°C, 3 h
95
96
54
52
a For optical purity of 1a−d, see experimental section.
b Abbreviations used: CDI = 1,1’-carbonyldiimidazole; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; CMPI = 2-chloro-N-methylpyridinium
iodide; DCC = dicyclohexylcarbodiimide; EDC = 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride; DMAP = 4-dimethyl-
aminopyridine; HOBt = 1-Hydroxybenzotriazole.
c Unless otherwise stated, optical purity and yield were determined after chromatographic separation of the product.
d Optical purity and isolated yield were determined after recrystallization as HCl salt.
e Saturated with H2O (0.2% w/v).
The acid chloride (R)-2a was readily obtained on treat- When Et3N was used as a base,3a only 13% ee of (R)-4a
ment of (R)-1a with oxalyl chloride in CH2Cl2 at 0 ∞C fol- was obtained in 37% yield (Entry 7). The time course
lowed by evaporation of the volatile portion at room study of racemization of (R)-2a and (R)-4a in CH2Cl2 at 0
temperature.13 It was then allowed to react with 3 in ∞C revealed that (R)-2a was stable in the absence of Et3N,
CH2Cl2 at 0 ∞C in the presence of various bases. The re- but rapidly racemized in its presence. On the other hand,
sults are summarized as Entries 7-15 in Table 1.
(R)-4a was recovered unchanged even after 2.5 hours (Ta-
ble 2). Clearly, the presence of Et3N enhanced the racem-
ization of (R)-2a.14
These results prompted us to survey inorganic bases as an
alternative to Et3N, and satisfactory results were obtained
by using powdered alkaline hydroxides as the base. In a
typical procedure, (R)-2a was allowed to react with 3 (1.1
equiv) in the presence of powdered potassium hydroxide
(3.3 equiv)15 in CH2Cl2 at 0 ∞C, to give 99% ee of (R)-4a
in 90% yield after column chromatography (Entry 8). The
analytically pure (R)-4a (100% ee) was also obtained in
85% yield simply by extraction followed by recrystalliza-
tion as the HCl salt (Entry 9). Similar results were also ob-
tained using powdered sodium or lithium hydroxide as
base (Entries 12 and 14). Essentially identical results were
Table 2 Time Course of Optical Purity of (R)-2a and (R)-4a in
Dichloromethane at 0°C
Substrate
Time (h)
ee (%)
(R)-2a
0.5
1.0
2.0
0.5
1.0
1.5
1.0
2.0
2.5
98
98
98
18
8
(R)-2a + Et3N
(R)-4a + Et3N
0
99
98
98
Synthesis 2000, No. 6, 784–788 ISSN 0039-7881 © Thieme Stuttgart · New York

786
N. Ishizuka et al.
PAPER
The optical purity of each starting material and product was inde-
pendently determined under one of the following conditions.
obtained even in the presence of small amount of water as
demonstrated by the reactions carried out in wet CH2Cl2
(Entries 10 and 13) or the reaction with hydrated lithium Condition A: column, Sumichiral OA4900 (4.6 î 250 mm, Sumito-
mo Chemical); solvent, 20 mM NH4OAc in MeOH; flow rate, 1.0
hydroxide (Entry 15). These results indicate that the con-
mL/min; detection wavelength, 286 or 240 nm; Condition B: col-
densation reaction can be carried out under conventional
umn, CHIRALPAK OJ-R (4.6 î 150 mm, Daicel Chemical); sol-
vent, MeCN/H2O/TFA (70:30:0.1, v/v), flow rate, 0.5 mL/min;
reaction conditions without exclusion of contaminated
water.
detection wavelength 230 nm; Condition C: column, CHIRALPAK
In a similar manner, enantiomerically pure 1b-d16,17 were
AD (4.6 î 250 mm, Daicel Chemical); solvent, hexane/EtOH/TFA
converted to the corresponding acid chlorides 2b-d.18
(90:10:0.1, v/v); flow rate, 0.5 mL/min; detection wavelength, 254
nm.
They were then allowed to react with 3 under conditions
similar to those of entry 8.19 The results are summarized
(R)-(-)-a-(6-Methyl-2-propyl-3-pyridyloxy)-1,3-benzodioxol-5-
as Entries 19-23 together with those of some direct meth-
ods (Entries 16-18). The CDI method resulted in substan-
tial loss of optical purity of the product (Entry 16).
acetic Acid [(R)-1a]20
Racemic 1a was prepared from ethyl a-bromo-1,3-benzodioxole-5-
acetate21 and 6-methyl-2-propylpyridin-3-ol22 similar to a reported
Although the carbodiimide-DMAP method gave 98% ee procedure.12c Compound 1a (66.04 g, 201 mmol) and (1S,2S)-(+)-2-
amino-1-phenylpropane-1,3-diol (33.61 g, 201 mmol) were dis-
solved in hot i-PrOH (149 mL), and then EtOAc (223 mL) was add-
ed. The resulting precipitate was collected and recrystallized twice
from i-PrOH, giving the corresponding amine salt (35.5g, 99% ee,
of the product at room temperature for 2 hours, the yield
was far from satisfactory (Entry 17). In this case, longer
reaction time led to considerable loss of optical purity
(Entry 18). In contrast, the present method provided the
products in good to excellent optical and chemical yields
(Entries 19, 21 and 22).
71% yield) as colorless crystals. To a suspension of the amine salt
in H2O (355 mL) was added 1 N HCl (71.5 mL) at 0 ∞C. The mixture
was extracted with CHCl3/MeOH (9:1) and the organic layer was
washed with H2O and brine, dried (MgSO4), and concentrated in
vacuo. The residue was recrystallized from EtOH to give (R)-1a
A more convenient one-pot procedure was also possible.
In a typical procedure, chiral 1 was treated with oxalyl
chloride (1.1 equiv) in CH2Cl2 at room temperature for 1
hour. Without isolation of 2, the sulfonamide 3 (1.1
equiv) and powdered potassium hydroxide (3.3 equiv)19
were successively added to the reaction mixture at 0 ∞C.
Satisfactory optical and chemical yields comparable to
those of the stepwise procedures were obtained in all cas-
es (Entry 8 vs 11, 19 vs 20 and 22 vs 23).
20
(17.5 g, 53% from 1a) as colorless crystals; mp 156-158 ∞C; [a]D
-109.8 (c = 1.00, MeOH); HPLC (condition A at 286 nm): tR = 12.2
min; 100% ee.
1H NMR (CD3OD): d = 0.97 (t, 3 H, J = 7.4 Hz), 1.62-1.85 (m, 2
H), 2.52 (s, 3 H), 2.80-3.07 (t, 2 H, J = 8.2 Hz), 5.59 (s, 1 H), 5.96
(s, 2 H), 6.81-7.53 (m, 5 H).
(+)-(4-Methyphenoxy)-a-phenylacetic Acid [(+)-1c]
Racemic a-(4-methyphenoxy)phenylacetic acid (1.50 g, 6.19
mmol) and (1S,2S)-(+)-2-amino-1-phenylpropane-1,3-diol (1.04 g,
6.19 mmol) were dissolved in hot EtOH (9 mL). The mixture was
allowed to cool to r.t., and the resulting precipitate was collected
and recrystallized from EtOH twice to give the corresponding
amine salt (717 mg, 57%) as colorless crystals. To a suspension of
the amine salt (547 mg, 1.34 mmol) in H2O (5.5 mL) was added 1
N HCl (1.34 mL) at 0∞C. After similar workup as in the case of (R)-
1a, the product was recrystallized from hexane to give (+)-1c (296
mg, 42%) as colorless crystals; mp 109.5-110.5 ∞C; [a]D25 +126.2
(c = 1.00, MeOH); HPLC (condition A at 240 nm): tR = 17.9 min;
100% ee.
In summary, we have described a convenient synthetic
method for the preparation of enantiomerically pure N-
acylarylsulfonamide 4 starting from chiral phenylacetic
acid 1. The asymmetry can be retained during the course
of the reaction. The key feature is the condensation of acid
chloride 2 and arylsulfonamide 3 under the solid-liquid
two-phase conditions in the presence of powdered alka-
line hydroxide as base. The operation and isolation of the
products are simple, and the reagents are all inexpensive.
Thus, this method should be widely applicable to the syn-
thesis of various N-acylarylsulfonamide derivatives with
an asymmetric center at the a-position of the carbonyl
group.
1H NMR (CDCl3): d = 2.27 (s, 3 H), 5.60 (s, 1 H), 6.84 (d, 2 H,
J = 8.6 Hz), 7.06 (d, 2 H, J = 8.6 Hz), 7.36-7.44 (m, 3 H), 7.54-
7.59 (m, 2 H).
(R)-1b and (S)-1c were prepared according to literature meth-
ods.16,17
All reactions were carried out under N2. The solvents were dried
over molecular sieve 4 A. Wet CH2Cl2 was prepared by shaking
CH2Cl2 with H2O in separatory funnel and separating the layers. Re-
agent grade KOH (85%) and NaOH (96%) pellets were pulverized
using laboratory blender (Phoenix, Blender KB-1) and stocked in a
sealed vessel. Anhyd and hydrated LiOH were pulverized using a
mortar. Contamination of H2O for dried and wet CH2Cl2 and pow-
dered KOH were determined by Karl-Fischer analysis, to be <0.1%
(w/v), 0.20% (w/v) and 12.1% (w/w), respectively. Melting points
were determined on a Yanagimoto hot plate apparatus and are un-
(R)-(–)-a-Methoxyphenylacetic Acid [(R)-1b]
22
Colorless crystals; mp 66-68 °C; [a]D -151.7 (c = 1.38, EtOH);
HPLC (condition A at 240 nm): tR = 17.9 min; 100% ee (Lit.16 mp
65-66 °C; [a]D20 -150.7 (c = 0.57, EtOH))
(S)-(+)-a-Cyclohexylphenylacetic Acid [(S)-1c]
25
Colorless crystals; mp 100-101.5 °C; [a]D +40.8 (c = 1.00,
MeOH); HPLC (condition B): tR = 3.6 min; 99% ee (Lit.17 mp 100-
102 °C; [a]D25 +38.7 (c = 20, CHCl3)).
1
corrected. H NMR spectra were recorded on a Varian VXR-300
(R)-(-)-N-(4-Isopropylphenylsulfonyl)-a-(6-methyl-2-propyl-3-
pyridyloxy)-1,3-benzodioxol-5-acetamide [(R)-4a]20; Typical
Procedures
spectrometer and are reported in ppm (d) relative to TMS as an in-
ternal standard. Column chromatography was performed with Mer-
ck silica gel 60 (70-230 mesh). Preparative TLC was performed
(a) CDI Method7 (Table 1, Entry 1)
with Merck precoated TLC plates silica gel 60 F254
.
Synthesis 2000, No. 6, 784–788 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Method for the Preparation of Enantiomerically Pure N-Acylarylsulfonamides
787
After a mixture of 1,1’-carbonyldiimidazole (108 mg, 0.668 mmol)
and (R)-1a (200 mg, 0.607 mmol) in THF (3 mL) was stirred at r.t.
for 1 h, 3 (133 mg, 0.668 mmol) and DBU (100 mL, 0.668 mmol)
were successively added and stirring was continued for an addition-
al 1 h at r.t. The mixture was poured into H2O and extracted with
EtOAc. The organic layer was washed with H2O, brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (CHCl3/MeOH, 95:5) to give
(R)-4a as a colorless oil (228 mg, 74%, 2% ee).
of (R)-4a (283 mg, 85%) as colorless crystals; mp 171-175 ∞C;
22
[a]D -75.8 (c = 1.00, MeOH); HPLC (condition A at 286 nm):
tR = 21.4 min; 100% ee.
1H NMR(CDCl3): d = 0.96 (t, 3 H, J = 7.4 Hz), 1.27 (d, 6 H, J = 6.4
Hz), 1.61-1.80 (m, 2 H), 2.64 (s, 3 H), 2.93-3.07 (m, 3 H), 5.82 (s,
1 H), 5.99 (s, 2 H), 6.76-6.93 (m, 3 H), 7.42 (d, 2 H, J = 8.2 Hz),
7.51-7.56 (m, 1 H), 7.74-7.82 (m, 3 H).
(g) Powdered Alkaline Hydroxide Method; One-Pot Procedure (En-
try 11)
(b) CMPI Method8 (Entry 2)
Oxalyl chloride (59 mL, 0.668 mmol) was dropwise added to a sus-
pension of (R)-1a (200 mg, 0.607 mmol) in CH2Cl2 (4 mL) at 0 ∞C,
and stirred at the same temperature for 1 h. To the solution were
added successively 3 (133 mg, 0.668 mmol) and powdered KOH
(85%; 132 mg, 2.00 mmol). The resulting suspension was stirred at
0 ∞C for 2 h, and then H2O and 1 N HCl (0.79 mL) were added. The
usual workup and purification as given in (a) afforded (R)-4a (258
mg, 83%) as a colorless oil; [a]D25 -16.4 (c = 1.00, MeOH); HPLC
(condition A at 240 nm); tR = 31.9 min; 100% ee, mp 89–91 °C.
A solution of 3 (12 mg, 0.061 mmol) and Et3N (15 mg, 0.146 mmol)
in CH2Cl2 (1 mL) was added to a suspension of (R)-1a (20 mg,
0.061 mmol) and 2-chloro-N-methylpyridinium iodide (19 mg,
0.073 mmol) in CH2Cl2 (2 mL), and the mixture was stirred at r.t.
for 1 h. After similar workup as given in (a), the crude product was
purified by preparative TLC (CHCl3/MeOH, 95:5) to give 4a (17
mg, 55%, 0% ee).
(c) Carbodiimide-DMAP Method9a,b (Entry 4)
EDC (N-ethyl-N'-(3,3-dimethylamino)propylcarbodiimide hydro-
chloride, 96 mg, 0.501 mmol) was added to a mixture of (R)-1a
(150 mg, 0.455 mmol), 3 (100 mg, 0.501 mmol) and DMAP (61 mg,
0.501 mmol) in CH2Cl2 (3 mL) and the mixture was stirred at r.t. for
2 h. The sulfonamide (R)-4a was obtained by a similar workup and
purification as (a) (162 mg, 70%, 91% ee).
Chiral 4b-4d
These were prepared in a similar manner to Methods (f) or (g).18,19
(R)-N-(4-Isopropylbenzenesulfonyl)-a-methoxyphenylacetam-
ide [(R)-4b]
Crude (R)-4b (100% ee). An analytical sample was obtained by re-
crystallization from acetone/isopropyl ether: colorless crystals.
1H NMR (CDCl3): d = 1.25 (m, 6 H), 2.90-3.04 (m, 1 H), 3.34 (s, 3
H), 4.59 (s, 1 H), 7.22-7.35 (m, 7 H), 7.94 (d, 2 H, J = 7.8 Hz), 9.12
(br, 1 H).
(d) Carbodiimide-HOBt Method9c (Entry 6)
EDC (128 mg, 0.668 mmol) was added to a mixture of (R)-1a (200
mg, 0.607 mmol), 3 (133 mg, 0.668 mmol) and 1-hydroxybenzotri-
azole (90 mg, 0.668 mmol) in CH2Cl2 (4 mL) and the mixture was
stirred at r.t. for 24 h. The sulfonamide (R)-4a was obtained by a
similar workup and purification as (a) (59 mg, 19%, 40% ee).
(+)-N-(4-Isopropylbenzenesulfonyl)-a-(4-methylphenoxy)phe-
nylacetamide [(+)-4c]
Crude (+)-4c (100% ee). An analytical sample was obtained by re-
crystallization from EtOAc/hexane; colorless crystals; mp 137-
138.5 ∞C; [a]D25 +14.5 (c = 1.00, MeOH); HPLC (condition A at 240
nm): tR = 36.1 min; 100% ee.
1H NMR (CDCl3): d = 1.25-1.28 (m, 6 H), 2.26 (s, 3 H), 2.90-3.04
(m, 1 H), 5.42 (s, 1 H), 6.73 (d, 2 H, J = 8.6 Hz), 7.01 (d, 2 H, J = 8.6
Hz), 7.30-7.36 (m, 7 H), 7.88 (d, 2 H, J = 8.6 Hz), 9.04 (br, 1 H),
(e) Et3N Method3a (Entry 7)
Oxalyl chloride (57 mL, 0.637 mmol) was added dropwise to a sus-
pension of (R)-1a (200 mg, 0.607 mmol) in CH2Cl2 (2 mL) at 0 ∞C.
After stirring at 0 ∞C for 1 h, the mixture was concentrated in vacuo
at r.t. to give (R)-2a as a colorless oil. This material was used with-
out further purification. To a solution of 3 (133 mg, 0.668 mmol)
and Et3N (186 mL, 1.34 mmol) in CH2Cl2 (2 mL) was added (R)-2a
in CH2Cl2 (2 mL) at 0 ∞C dropwise, and the mixture was stirred at 0
∞C for 2.5 h. (R)-4a was obtained after a similar workup and purifi-
cation as (a) (114 mg, 37%, 13% ee).
(S)-N-(4-Isopropylbenzenesulfonyl)-a-cyclohexylphenyl-
acetamide [(S)-4d]
Crude (S)-4d (95% ee). An analytical sample was obtained after
column chromatography on silica gel (CH3Cl/MeOH, 95/5); color-
less foam; [a]D26 +92.8 (c = 1.00, MeOH); HPLC (condition C):
tR = 13.9 min; 95% ee.
(f) Powdered Alkaline Hydroxide Method; Stepwise Procedure
(Entries 8 and 9)
Oxalyl chloride (57 mL, 0.637 mmol) was dropwise added to a sus-
pension of (R)-1a (200 mg, 0.607 mmol) in CH2Cl2 (2 mL) at 0 ∞C.
After stirring at 0 ∞C for 1 h, the mixture was concentrated in vacuo
at r.t. to give (R)-2a as a colorless oil. Powdered KOH (85%; 132
mg, 2.00 mmol) and 3 (133 mg, 0.668 mmol) were stirred in CH2Cl2
(2 mL) at r.t. for 1 h in advance. A solution of (R)-2a in CH2Cl2 (2.5
mL) was added dropwise at 0 ∞C and the mixture was stirred for 1.5
h. After H2O (2 mL) and 1 N HCl (0.79 mL) were added to the mix-
ture, the usual workup and purification as (a) afforded (R)-4a (280
mg, 90%) as a colorless oil; [a]D23 -76.2 (c = 1.00, MeOH); HPLC
(condition A at 286 nm): tR = 21.4 min; 99% ee.
1H NMR (CDCl3): d = 0.61-0.72 (m, 1 H), 0.80-0.93 (m, 1 H),
1.05-1.10 (m, 2 H), 1.19 (br, 2 H), 1.27 (d, 6 H, J = 7.2 Hz), 1.58
(br, 4 H), 1.90-2.05 (m, 1 H), 2.93-3.02 (m, 1 H), 3.00 (d, 1 H,
J = 9.9 Hz), 7.05-7.09 (m, 2 H), 7.21-7.23 (m, 3 H), 7.31 (d, 2 H,
J = 8.3 Hz), 7.80 (d, 2 H, J = 8.3 Hz), 8.23 (br, 1 H).
Acknowledgement
The authors are grateful to Dr. T. Konoike, T. Yorifuji, Y. Ide and
T. Oya, Process R&D Laboratories, for their help. Thanks are also
to Dr. H. Shindo, Bulk Chemicals Manufacturing Technical Depart-
ment, for Karl-Fischer analysis.
1H NMR (DMSO-d6): d = 0.85 (t, 3 H, J = 7.3 Hz), 1.20 (d, 6 H,
J = 6.8 Hz), 1.50-1.70 (m, 2 H), 2.33 (s, 3 H), 2.60-2.75 (m, 2 H),
2.90-3.10 (m, 1 H), 5.60 (s, 1 H), 6.04 (m, 2 H), 6.80-7.00 (m, 5
H), 7.41 (d, 2 H, J = 8.4 Hz), 7.69 (d, 2 H, J = 8.4 Hz).
References
(R)-4a•HCl (Table 1, Entry 9)
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Crude (R)-4a obtained after extraction was dissolved in EtOAc (3
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Synthesis 2000, No. 6, 784–788 ISSN 0039-7881 © Thieme Stuttgart · New York

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N. Ishizuka et al.
PAPER
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in Entry 8 (see experimental).
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(20) The absolute configurations of (R)-1a and (R)-4a were
determined by X-ray crystallographic analysis as their
diastereomeric salts with chiral amines, which will be reported
elsewhere.
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Article Identifier:
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