Novel protocol for the asymmetric synthesis of 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one via bakers' yeast reduction

Article abstract of DOI:10.3987/COM-05-S(K)57

A novel protocol for the asymmetric synthesis of 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is reported. Darzens condensation reactions of anisaldehyde with dichloroacetates, followed substitution reaction of sodium o-nitrophenylthiolate and bakers' yeast reduction furnished 2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)-propionates. Further reduction of a nitro group and cyclization gave the title compound.

Full text of DOI:10.3987/COM-05-S(K)57

HETEROCYCLES, Vol. 66, 2005
147
HETEROCYCLES, Vol. 66, 2005, pp. 147 – 151. © The Japan Institute of Heterocyclic Chemistry
Received, 14th September, 2005, Accepted, 28th October, 2005, Published online, 1st November, 2005. COM-05-S(K)57
NOVEL PROTOCOL FOR THE ASYMMETRIC SYNTHESIS OF
3-HYDROXY-2-(4-METHOXYPHENYL)-2,3-DIHYDRO-1,5-
BENZOTHIAZEPIN-4(5H)-ONE VIA BAKERS’ YEAST REDUCTION
Takuzo Komiyama, Yutaka Takaguchi,and Sadao Tsuboi*
Department of Material and Energy Science, Graduate School of Environmental
Science, Okayama University, Okayama 700-8530, Japan
E-mail address: stsuboi6@cc.okayama-u.ac.jp
Abstract
–
A
novel protocol for the asymmetric synthesis of
is
3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
reported. Darzens condensation reactions of anisaldehyde with dichloroacetates,
followed substitution reaction of sodium o-nitrophenylthiolate and bakers’ yeast
reduction furnished 2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)-
propionates. Further reduction of a nitro group and cyclization gave the title
compound.
Derivatives of 1,5-benzothiazepin are well known calcium channel blockers and represented by diltiazem
[(2S,3S)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-
4(5H)-one]. Diltiazem is one of the most potent calcium antagonist and used as a remedy for hypertension
and angina.1 In contrast, its enantiomer, (2R,3R)-form compound, has a weak activity as an
antihypertensive agent. However it has more brain-waves awakening activity.2 Because of their potent
biological activity, various synthetic approaches have been reported toward to the asymmetric synthesis
of diltiazem and its isomer.3
OMe
OMe
S
N
bakers'
yeast
S
NO2
S
S
NO2
OAc
CO2R
CO2R
OH
O
N
H
OH
O
O
MeO
MeO
1
2
3
NMe2
Diltiazem
Scheme 1.
This paper is dedicated to the memory of the Emeritus Professor Kenji Koga of Tokyo University.

148
HETEROCYCLES, Vol. 66, 2005
Our group has studied about the utilization of bakers’ yeast for the synthesis of optically active
compounds.4 So, in this report, we demonstrate the mild and inexpensive protocol for the synthesis of
3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (3), which is a precursor of
cis or trans isomer of diltiazem via bakers’ yeast reduction of prepared β-arylthio-α-keto esters (1)
(Scheme 1).
Substrates of bakers’ yeast reaction, β-arylthio-α-keto esters (1) were prepared easily as shown in
Scheme 2. Darzens condensation reaction of anisaldehyde with dichloroacetates gave β-chloro-α-keto
esters (4)5 and further treatment with sodium o-nitrophenylthiolate furnished the β-arylthio-α-keto esters
(1).
O2N
S
NO2
CHCl2CO2R
+
Cl
t-BuOK
SNa
CO2R
CHO
CO2R
THF, -40 oC
toluene, rt
O
MeO
O
4
MeO
MeO
1
Scheme 2.
Then, we attempted to bakers’ yeast reduction of prepared compound β-arylthio-α-keto esters (1).
Treatment of β-arylthio-α-keto esters (1a-e) with bakers’ yeast furnished corresponding 2-hydroxy-
3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionates (2a-e) (Table 1).6 Treatment of glycidic ester
(1a) with bakers’ yeast in water for 5 days provided reduced product (1a) in 41% yield after purification
by silica gel flash chromatography (Entry 1). And an anti-form product was obtained selectively (syn/
anti =20: 80) with the reasonable stereoselectivity (syn: 76% ee, anti: 71% ee). Then we tried to change
the ester group of substrates (Entries 2-4). We found that a syn-form product ratio increased by employing
the substrate having the bulky ester group. Furthermore, the syn-form product was obtained in good
selectivity with good stereoselectivity (96% ee) by the use of tert-butyl ester (Entry 5). Although there is
no report about the bakers’ yeast reduction of β-arylthio-α-keto ester, this change of diastereoselectivity
depending on the ester group has reported in the case of β-keto-α-sulfenyl esters. As for the change of
diastereoselectivity, our case exhibited more conspicuously.8
Then the obtained anti-form of β-arylthio-α-hydroxy ester (anti-2a) was converted to trans-form
benzothiazepine (trans-3) by the reduction of the nitro group and cyclization (Scheme 3). The absolute
configuration of trans-3 was confirmed by comparison of its specific rotation with authentic data.3g

HETEROCYCLES, Vol. 66, 2005
149
Table 1. Bakers’ yeast reduction of β-arylthio-α-keto esters (1)
bakers' yeast
S
NO2
S
NO2
S
NO2
+
CO2R
CO2R
water
CO2R
OH
anti-2
OH
syn-2
O
MeO
MeO
MeO
1
Ee (%)c)
Entry
Conditions
Substrate/ R Temp. (oC) Time (day)
Product/
Yielda) (%)
Syn:
antib)
1
2
3
4
5
1a/ Me
1b/ n-Bu
1c/ i-Pr
35
35
38
38
35
5
6
4
4
6
2a/ 41 (48)
20:80
syn : 76
anti : 71
syn : 92
anti : 91
syn : 92
anti : 87
syn : 96
anti : 93
syn : 96
anti : 60
2b/ 61 (65)
2c/ 43 (59)
2d/ 45 (59)
2e/ 28 (36)
35:65
37:63
46:54
85:15
1d/ i-Bu
1e/ t-Bu
a) Yield which calculated based on recovery is given in a parenthesis.
b) Diastereo ratio was determined by the 300MHz NMR analysis.
c) Ee was determined by the 500MHz NMR analysis after converted to MTPA ester.
OMe
.
FeSO4 7H2O
S
p-TSA
NH4OH
S
NO2
S
NH2
OH
CO2Me
xylene
70 %
EtOH/ H2O
70 %
CO2Me
N
H
O
OH
OH
MeO
trans-3 (2S, 3R)
[α]D= -443o (c, 0.1, DMF)
lit., [α]D= -837o (c, 1.0, DMF)
MeO
anti-2a
3g
OMe
.
FeSO4 7H2O
S
NH4OH
ref. 3h
S
NH2
S
NO2
CO2Bu-t
OH
CO2Bu-t
EtOH/ H2O
84 %
N
H
O
OH
OH
syn-2e
MeO
MeO
cis-3 (2R, 3R)
5 (2R, 3R): [α]D= -128o (c, 0.07, CHCl3)
lit., 5 (2S, 3S): [α]D= +133o (c, 1.0, CHCl3)
3h
Scheme 3.

150
HETEROCYCLES, Vol. 66, 2005
The obtained syn-form of β-arylthio-α-hydroxy ester (syn-2e) was also reduced to a compound (5) and
confirmed its absolute configuration by comparison of its specific rotation with authentic data.3h Further
cyclization of the compound (5) can be prepared cis-form benzothiazepine (cis-3).3h
In conclusion, we have developed the novel method for the synthesis of 3-hydroxy-2-(4-
methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one via bakers’ yeast reduction. The important
and new discovering in this report is the efficiency of bakers’ yeast reduction of β-arylthio-α-keto esters
for the preparation of optically active β-arylthio-α-hydroxy esters. Each diastereomer of β-arylthio-
α-hydroxy ester can be prepared selectively by changing its ester group. Other features and advantage of
our method against previously reported one for the preparation of 3-hydroxy-2-(4-methoxyphenyl)-
2,3-dihydro-1,5-benzothiazepin-4(5H)-one is ease of experimental operations, using inexpensive reagents
and mild reaction conditions.
REFERENCES AND NOTES
1. (a) H. Kugita, H. Inoue, M. Ikezaki, M. Konda, and S. Takeo, Chem. Pharm. Bull., 1971, 19, 595; (b)
T. Nagao, M. Sato, H. Nakajima, and A. Kiyomoto, Chem. Pharm. Bull., 1973, 21, 92.
2. H. Inoue, S. Takeo, M. Kawatsu, A. Kiyomoto, H. Nakajima, H. Kugita, and M. Ikesaki,
JP-53018038, 1978 (Chem. Abstr., 1978, 90, 6431).
3. (a) K. G. Wtson, Y. M. Fung, M. Gredley, G. J. Bird, W. R. Jackson, H. Gountzos, and B. R.
Matthews, J. Chem. Soc., Chem. Commun., 1990, 1018; (b) H. Akita, I. Umezawa, H. Matsukura,
and T. Oishi, Chem. Pharm. Bull., 1991, 39, 1632; (c) A. Schwartz, P. B. Madan, E. Mohacsi, J. P.
O’Brien, L. J. Todaro, and D. L. Coffen, J. Org. Chem., 1992, 57, 851; (d) L. T. Kanerva and O.
Sundholm, J. Chem. Soc., Perkin Trans. 1, 1993, 1385; (e) K. Matsuki, M. Sobukawa, A. Kawai, H.
Inoue, and M. Takeda, Chem. Pharm. Bull., 1993, 41, 643; (f) B. B. Lohray, B. Jayachandran, V.
Bhushan, E. Nandanan, and T. Ravindranathan, J. Org. Chem., 1995, 60, 5983; (g) S. Yamada, Y.
Mori, K. Morimatsu, Y. Ishizu, Y. Ozaki, R. Yoshioka, T. Nakatani, and H. Seko, J. Org. Chem.,
1996, 61, 8586; (h) B. M. Adger, J. V. Barkley, S. Bergeron, M. W. Cappi, B. E. Flowerdew, M. P.
Jackson, R. McCague, T. C. Nugent, and S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1997, 3501;
(i) R. Imashiro and T. Kuroda, Tetrahedron Lett., 2001, 42, 1313.
4. S. Tsuboi, H. Furutani, M. H. Ansari, T. Sakai, M. Utaka, and A. Takeda, J. Org. Chem., 1993, 58,
486.
5. (a) A. Takeda, S. Tsuboi, S. Wada, and H. Kato, Bull. Chem. Soc. Jpn., 1972, 45, 1217; (b) S. Tsuboi,
H. Furutani, A. Takeda, K. Kawazoe, and S. Sato, Bull. Chem. Soc. Jpn., 1987, 60, 2475.
6. Typical procedure (synthesis of 2e from 1e): To a stirring mixture of KH2PO4 (40 mg), NH4H2PO4

HETEROCYCLES, Vol. 66, 2005
151
(40 mg), MgSO4 (20 mg), CaCO3 (12 mg), glucose (1.0 g), and water (24 ml) was added bakers’
yeast (1.0 g) at 35 oC. After stirring for 30 min, α-keto-β-arylthio ester (1e) (60 mg, 0.15 mmol) was
o
added and the reaction mixture was stirred at 35 C. And bakers’ yeast (1.0 g) and glucose (1.0 g)
were added every 24 h during after 2 days. After 6 day stirring, the reaction mixture was treated with
celite for 1 h and filtrated. Then the filtrate was extracted four times with EtOAc and washed with
brine. The combined organic extracts were dried over MgSO4 and evaporated. The residual crude
products were purified by column-chromatography (hexane: EtOAc= 15: 1) to give
β-arylthio-α-hydroxy ester (2e) (17 mg, 28%).
7. Compound (syn-2e): 1H-NMR (300 MHz, CDCl3): δ 1.42 (s, 9H), 3.29 (br, 1H), 3.79 (s, 3H), 4.46 (d,
1H, J=3.6 Hz), 4.68 (d, 1H, J=3.6 Hz), 6.85-6.87 (m, 2H), 7.17-7.24 (m, 1H), 7.26-7.49 (m, 4H),
8.01-8.04 (m, 1H); IR (neat, cm-1) 3475, 2977, 1728, 1511, 1251 cm-1. Anal. Calcd for C20H23NO6S:
C, 59.24; H, 5.72; N, 3.45. Found: C, 59.39; H, 5.66; N, 3.72.
8. T. Fujisawa, T. Ito, and T. Sato, Tetrahedron Lett., 1984, 25, 5083.