Asymmetric reduction of a 1,5-benzothiazepine derivative with sodium borohydride-(S)-α-amino acids: An efficient synthesis of a key intermediate of diltiazem

Article abstract of DOI:10.1021/jo960950w

A key intermediate of diltiazem synthesis, (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one [(2S,3S)-1], has been efficiently synthesized by an asymmetric reduction of the prochiral ketone, 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (3), with NaBH₄ and chiral α-amino acids. As the chiral sources, β-branched-chain amino acids, such as (S)-valine, (S)-isoleucine, and (S)-tert-leucine, were found to be effective. In particular, using (S)-tert-leucine as a ligand resulted in the formation of (2S,3S)-1 with excellent enantioselectivity. (95% ee for cis-isomers). The addition of AcOH to the reaction permitted further improvement of both conversion and stereoselectivity. As a result, optically pure (2S,3S)-1 could be isolated in 86% yield. This asymmetric reduction proceeded via dynamic kinetic resolution and made it possible to control the two adjacent asymmetric carbons through keto-enol tautomerism.

Full text of DOI:10.1021/jo960950w

8586
J . Org. Chem. 1996, 61, 8586-8590
Asym m etr ic Red u ction of a 1,5-Ben zoth ia zep in e Der iva tive w ith
Sod iu m Bor oh yd r id e-(S)-r-Am in o Acid s: An Efficien t Syn th esis of
a Key In ter m ed ia te of Diltia zem
Shin-ichi Yamada,* Yoshikazu Mori,† Katsuji Morimatsu,† Yoshinori Ishizu,‡ Yasuhiko Ozaki,
Ryuzo Yoshioka, Tadashi Nakatani,§ and Hiroyasu Seko†
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., 16-89, Kashima-3-chome,
Yodogawa-ku, Osaka 532, J apan
Received May 22, 1996X
A key intermediate of diltiazem synthesis, (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-
benzothiazepin-4(5H)-one [(2S,3S)-1], has been efficiently synthesized by an asymmetric reduction
of the prochiral ketone, 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (3), with NaBH4
and chiral R-amino acids. As the chiral sources, â-branched-chain amino acids, such as (S)-valine,
(S)-isoleucine, and (S)-tert-leucine, were found to be effective. In particular, using (S)-tert-leucine
as a ligand resulted in the formation of (2S,3S)-1 with excellent enantioselectivity. (95% ee for
cis-isomers). The addition of AcOH to the reaction permitted further improvement of both conversion
and stereoselectivity. As a result, optically pure (2S,3S)-1 could be isolated in 86% yield. This
asymmetric reduction proceeded via dynamic kinetic resolution and made it possible to control the
two adjacent asymmetric carbons through keto-enol tautomerism.
In tr od u ction
method. However, even these optical resolutions have
an inevitable disadvantage in that the theoretical maxi-
mum yield of the desired isomer does not exceed 50%.
Lately, asymmetric syntheses5 have been extensively
studied from the view point of their high efficiency. In
these, biochemical asymmetric reduction of the prochiral
ketone 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4-
(2H,5H)-dione (3)6 to (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-
methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [(2S,3S)-
1] was reported.7 As for the chemical reduction of the
ketone, Morimoto et al. also reported that reduction with
NaBH4 gave the cis-hydroxy benzothiazepine stereose-
lectively.8
Generally, NaBH4 is used as a mild and selective
reducing agent, and reducing reagents modified with
chiral sources are very useful for the asymmetric reduc-
tion of ketones. For example, use of phase transfer
catalysts,9 protein,10 amino acids,11 monosaccharide de-
rivatives,12 and carboxylic acids12f,13 as chiral sources have
been reported in ketone reductions. This information
Today diltiazem (4),1 a representative calcium antago-
nist, is used throughout the world as a remedy for angina
and hypertension. Diltiazem is a 1,5-benzothiazepine
derivative and has two asymmetric carbon atoms at the
C-2 and C-3 positions. Among the possible diastereo-
mers, the (2S,3S)-isomer exhibits strong coronary va-
sodilating activity; therefore, stereoselective synthesis of
the (2S,3S)-isomer has been attracting great attention.
Diltiazem has been prepared through chemical2 or
enzymatic3 optical resolutions of its intermediates. Re-
cently, enzymatic preparation4 of an intermediate, (2R,3S)-
3-(4-methoxyphenyl)glycidic acid methyl ester, has been
utilized in industrial production as a more economical
† Present address: Production Technology Division.
‡ Present address: Patent Division.
§ Present address: Osaka Plant.
X Abstract published in Advance ACS Abstracts, October 15, 1996.
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S0022-3263(96)00950-4 CCC: $12.00 © 1996 American Chemical Society

Asymmetric Reduction with Sodium Borohydride-(S)-R-Amino Acids
J . Org. Chem., Vol. 61, No. 24, 1996 8587
Sch em e 1
This successful result prompted us to examine the effect
of aromatic side chain amino acids on stereoselectivities.
Unfortunately, phenylalanine and phenylglycine were not
as effective as we expected (entries 12 and 13).
From the above results, we have selected (S)-tert-
leucine as a favorable chiral source for asymmetric
reduction.
Effect of Ad d itives. In order to obtain the desired
(2S,3S)-1 in higher yield, we investigated this reaction
in more detail. Figure 1 shows the typical time course
of the asymmetric reduction at 0 °C, and the following
phenomena were found: (a) the reaction proceeded to a
conversion of 60% immediately after the beginning and
at this time the ratio of (2S,3S)-1 was nearly 90%; (b)
the rate of the reaction became slow and the ratio of
(2S,3S)-1 decreased with extended time; (c) the reaction
was almost completed after 16 h, but the ratio of
(2S,3S)-1 dropped to only 76%. These results suggested
us that, to obtain (2S,3S)-1 in higher yield, the reaction
must proceed with the high selectivity observed at the
beginning of the reaction. Therefore, the effect of addi-
tives was examined to improve the selectivity.
Table 2 shows the results when 1 equiv of various
additives was added to the reaction. As can be seen,
MeOH and H2O did not improve the selectivity. Triethyl-
amine improved the selectivity, but the conversion was
not high. Interestingly, AcOH exhibited a fairly good
effect in both the conversion and the selectivity. Conse-
quently, various addition methods of AcOH were exam-
ined in detail, as shown in Table 3. When 1 equiv of
AcOH was added at the beginning of the reaction, the
conversion was 86% and the selectivity of (2S,3S)-1 was
76% (entry 1). However, in the case of AcOH addition
after 0.5 h, the yield and selectivity increased to 95 and
82%, respectively (entry 2). Moreover, divided addition
of 1 equiv of AcOH gave an apparent elevation of
selectivity (entries 3-5). Under these conditions, the
reactions were almost complete in 3 h with good stereo-
selectivity. Thus the divided addition of AcOH was found
to be effective for the improvement of both conversion
and stereoselectivity.
Effect of Tem p er a tu r e. In the final stage of our
investigation, we evaluated the effect of the reaction
temperature. Using the divided addition method with
AcOH, the asymmetric reductions were carried out at
various temperatures (Table 4). A characteristic ten-
dency of the reaction was noticed. That is, at 20 °C the
reduction was complete within 3 h but with only 80%
(2S,3S)-1 selectivity (entry 1). In contrast, as the reaction
temperature was lowered, the selectivity increased and
the rate of reaction became slow (entries 2-4). Accord-
ingly, it seemed reasonable that the reaction should be
performed at lower temperature with prolonged reaction
time, so as to finish with a higher (2S,3S)-1 ratio.
Finally, we were able to achieve the reaction with 98%
conversion and 91% (2S,3S)-1 selectivity when it was
carried out at -30 °C for 60 h with divided addition of
AcOH (entry 5). Figure 2 shows the improved time
course under these reaction conditions.
motivated us to study the asymmetric reduction of 3 with
NaBH4 and chiral sources. The present paper describes
an efficient synthesis of a diltiazem intermediate via a
highly enantioselective reduction with chirally modified
NaBH4 (Scheme 1).
Resu lts
Sea r ch of Ch ir a l Sou r ces. The ketone 3 was pre-
pared by oxidation6,8 of the racemic alcohol (2RS,3RS)-
114,15 followed by ester hydrolysis. With chiral reducing
agents prepared from NaBH4 and various R-amino acids,
3 was asymmetrically reduced to the corresponding
stereoisomer of 1.
As can be seen in Table 1, enantioselectivities were
observed when R-amino acids possessing hydrocarbon
side chains16 were used. Cis-isomers predominated
except for proline, and the use of (S)-amino acids gave
the desired (2S,3S)-1 as a major product.
We have also directed our attention to the relationship
between the structure of the alkyl side chains and the
selectivity of stereoisomers. That is, using (S)-alanine
as a ligand gave little asymmetric induction (entry 2),
whereas a substantial increase in the ratio of (2S,3S)-1
was realized when longer straight or γ-branched-chain
amino acids were employed (entries 3-6). Furthermore,
â-branched-chain amino acids, (S)-valine, (S)-isoleucine,
and (S)-tert-leucine, induced relatively high stereoselec-
tivities (entries 7-9). In particular, (S)-tert-leucine
exhibited an excellent result with a stereoselectivity of
89% in favor of (2S,3S)-1 (95% ee for cis-isomers).
Similarly, the reducing agent from (R)-tert-leucine pro-
vided (2R,3R)-1 with an equally high ratio (entry 10).
Isola tion of (2S,3S)-1 a n d Recover y of (S)-ter t-
Leu cin e. Because we have found satisfactory conditions
for the reaction, actual isolation of (2S,3S)-1 was at-
tempted. The reducing agent, NaBH4-(S)-tert-leucine,
was used at 1.5 equiv to the ketone 3, and the reaction
was conducted at -30 °C for 60 h with addition of AcOH.
After removing the (S)-tert-leucine from the reaction
mixture, the crude product was purified in 2-propanol
to isolate optically pure (2S,3S)-1 in 86% yield. Further-
(14) Kugita, H.; Inoue, H.; Ikezaki, M.; Takeo, S. Chem. Pharm. Bull.
1970, 18, 2028.
(15) Hashiyama, T.; Inoue, H.; Konda, M.; Takeda, M. J . Chem. Soc.,
Perkin Trans. 1 1984, 1725.
(16) In the cases of aspartic acid, glutamic acid, asparagine,
glutamine, lysine, serine, threonine, and tyrosine, no asymmetric
induction was detected. There was a possibility that chiral reducing
agents from these amino acids were not produced, because no hydrogen
evolution was observed and these amino acids did not dissolve in the
reaction with NaBH4.

8588 J . Org. Chem., Vol. 61, No. 24, 1996
Yamada et al.
Ta ble 1. Asym m etr ic Red u ction of 3 w ith th e Rea gen ts P r ep a r ed fr om Na BH4 a n d Op tica lly Active r-Am in o Acid sa
ratio of stereoisomer 1b
cis
trans
amino acid
RCH(NH2)COOH
structure of
side chain R
conversionb
(%)
entry
(2S,3S)c
(2R,3R)c
(2R,3S)d
(2S,3R)d
1e
2
3
4
5
6
7
8
9
10
11
12
13
none
(S)-alanine
(S)-R-aminobutyric acid
(S)-norvaline
(S)-norleucine
(S)-leucine
90
78
55
52
50
58
64
62
65
65
52
40
48
46
46
57
57
57
58
74
74
89
2
46
42
21
22
22
21
10
8
2
89
1
31
19
4
7
4
5
7
7
7
7
3
3
1
8
1
8
5
CH3
CH2CH3
15
14
14
14
13
15
8
CH2CH2CH3
CH2CH2CH2CH3
CH2CH(CH3)2
CH(CH3)2
CH(CH3)CH2CH3
C(CH3)3
(S)-valine
(S)-isoleucine
(S)-tert-leucine
(R)-tert-leucine
(S)-proline
(S)-phenylalanine
(S)-phenylglycine
C(CH3)3
1
CH2CH2CH2(NR)
CH2Ph
29
37
61
69
24
15
Ph
a
b
Conditions NaBH4-amino acid (1.5 mmol), 3 (1 mmol), 0 °C, 1 h, THF. Determined by HPLC analysis. c Authentic samples were
d
prepared according to refs 2a and 2b. Authentic samples were prepared by asymmetric reduction of 3 with NaBH4-(S)- and (R)-proline
system (See experimental Section for details). e Reduction was carried out with NaBH4 alone.
reaction satisfies the following two requirements: (1) the
racemization between (2S)-3 and (2R)-3 is rapid; (2) the
rate constant k1 is much larger than k2. It can therefore
be concluded that the desired (2S,3S)-1 was produced
selectively among the four possible stereoisomers via
dynamic kinetic resolution17 (Scheme 2).
The possible reasons for the improvement in the
reaction by AcOH addition are as follows: (1) This
reaction apparently proceeds via dynamic kinetic resolu-
tion with racemization at the C-2 position. AcOH may
promote the racemization between (2R)-3 and (2S)-3; (2)
There was a possibility that the chiral reducing agent
became deactivated during the reaction but might be
reactivated by addition of AcOH.
In regard to the side-chain structures of R-amino acids
as chiral sources, it is noteworthy that branches at the
â-position exerted marked effects on providing high
stereoselectivities. The steric bulkiness near the asym-
metric carbon atom may play an important role in
distinguishing not only the enantioface of the ketone but
also the configuration at the C-2 position.
Up to now, attempts at isolating the reducing agent
were unsuccessful. The structure of the reducing agent
and the reaction mechanism remain to be examined.
F igu r e 1. Time course of the asymmetric reduction of 3 with
NaBH4-(S)-tert-leucine at 0 °C. Conversion (dashed line); ratio
of (2S,3S)-1 (solid line).
Ta ble 2. Effect of Ad d itives on Asym m etr ic Red u ction a
ratio of stereoisomer 1b
Con clu sion s
cis
trans
conversionb
(%)
entry additive
(2S,3S) (2R,3R) (2R,3S) (2S,3R)
We have discovered a new chiral reducing agent
NaBH4-(S)-tert-leucine which was very efficient in syn-
thesizing a diltiazem intermediate. The asymmetric
reduction proceeded via dynamic kinetic resolution and
made it possible to control the configurations of the two
adjacent asymmetric carbon atoms at the same time. This
method may be one of the more promising routes to
diltiazem developed to date.
1
2
3
4
5
none
MeOH
H2O
Et3N
AcOH
97
97
98
80
95
76
71
73
82
82
16
20
19
11
6
6
6
6
7
11
2
3
2
1
1
a
Conditions: NaBH4-(S)-tert-leucine (1.5 mmol), 3 (1 mmol),
additive (1 mmol), 0 °C, 16 h, THF. Determined by HPLC
analysis.
b
Exp er im en ta l Section
more, efficient recovery of the chiral source (S)-tert-
leucine is important for an economical synthetic method.
(S)-tert-Leucine could be recovered almost quantitatively
without racemization, and use of recycled material for
the asymmetric reduction caused no problem.
Gen er a l Meth od s. Melting points are uncorrected. All of
the solvents except THF and reagents were commercial
products used without further purification. THF was distilled
from sodium benzophenone ketyl before use. Analytical thin-
layer chromatography (TLC) was performed on E. Merck
precoated silica gel 60 F254 plates. Flash column chromatog-
raphy was carried out on Merck silica gel 60 (230-400 mesh).
Conversions from 3 to 1 were analyzed by reversed-phase
HPLC. [Column: Waters Puresil 5 µm C18 120 Å 4.6 × 150
Discu ssion
As described above, the yield of (2S,3S)-1 was 86% in
the asymmetric reduction. To obtain (2S,3S)-1 in over
50% yield, it is necessary that the C-3 ketone is not only
reduced asymmetrically, but that the configuration at the
C-2 position is preferably controlled. Accordingly, this
(17) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumoba-
yashi, H. J . Am. Chem. Soc. 1989, 111, 9134.

Asymmetric Reduction with Sodium Borohydride-(S)-R-Amino Acids
Ta ble 3. Effect of AcOH Ad d ition on Asym m etr ic Red u ction a
ratio of stereoisomer 1b
trans
J . Org. Chem., Vol. 61, No. 24, 1996 8589
cis
additive, AcOH
(equiv × times)
addition
time (h)
reaction
time (h)
conversionb
(%)
entry
(2S,3S)
(2R,3R)
(2R,3S)
(2S,3R)
1
2
3
4
5
1.0 × 1
1.0 × 1
0.5 × 2
0.33 × 3
0.25 × 4
0
0.5
20
16
5
3
3
86
95
95
96
96
76
82
87
88
88
7
6
4
3
3
15
11
8
8
8
2
1
1
1
1
0.5, 1.0
0.5, 1.0, 1.5
0.25, 0.5, 1.0, 1.5
a
b
Conditions: NaBH4-(S)-tert-leucine (1.5 mmol), 3 (1 mmol), 0 °C, THF. Determined by HPLC analysis.
Ta ble 4. Effect of Tem p er a tu r e on Asym m etr ic Red u ction a
ratio of stereoisomer 1b
cis trans
additive, AcOH
(0.33 equiv × 3 times)
addition time (h)
reaction
temperature (°C)
reaction
time (h)
conversionb
(%)
entry
(2S,3S)
(2R,3R)
(2R,3S)
(2S,3R)
1
2
3
4
5
20
0
-15
-30
-30
0.5, 1, 1.5
0.5, 1, 1.5
0.5, 1, 1.5
0.5, 1, 1.5
1, 4, 20c
3
3
3
3
60
100
96
89
81
98
80
88
90
91
91
10
3
2
2
2
10
8
7
7
7
1
1
1
0
0
a
b
Conditions: NaBH4-(S)-tert-leucine (1.5 mmol), 3 (1 mmol), THF. Determined by HPLC analysis. c AcOH (0.5 equiv) was added
three times.
(2RS)-2-(4-Met h oxyp h en yl)-1,5-b en zot h ia zep in e-3,4-
(2H,5H)-d ion e (3). A suspension of 2 (17.1 g, 0.05 mol) in
MeOH (51 mL) was cooled in an ice bath, and then a solution
of NaOH (5.0 g, 0.125 mol) in H2O (63 mL) was added. The
ice bath was removed, and the solution was allowed to stir at
rt for 2 h. The reaction was neutralized by the addition of 2
N HCl (50 mL) and extracted with AcOEt. The organic phase
was washed twice with H2O, dried over MgSO4, and concen-
trated to yield a viscous oil. The resulting oil was triturated
in Et2O to give 12.98 g (86.7%) of 3 as a yellow crystalline
solid. The 1H NMR spectrum of 3 in CDCl3 revealed a mixture
of keto and enol forms: mp 163-165 °C; IR (KBr, cm-1) 1725,
1655, 1470; 1H NMR (CDCl3) δ. 3.80 and 3.83 (s, 3H), 5.45 (s,
1H), 6.64 (s, 1H), 6.86-7.78 (m, 8H), 8.95 and 9.00 (s, 1H);
MS m/z 299 (M+). Anal. Calcd for C16H13NO3S: C 64.20; H
4.38; N 4.68. Found: C 64.31; H 4.36; N 4.53.
P r ep a r a tion of th e Au th en tic Sa m p les [(2S,3R)-1 a n d
(2R,3S)-1]. tr a n s-(2S,3R)-2,3-Dih yd r o-3-h yd r oxy-2-(4-
m eth oxyp h en yl)-1,5-ben zoth ia zep in -4(5H)-on e [(2S,3R)-
1]. A reducing agent was prepared by stirring the mixture of
NaBH4 (284 mg, 7.5 mmol) and (R)-proline (950 mg, 8.25
mmol) in THF (50 mL) at reflux temperature for 3 h under
N2. The reaction mixture was cooled to 0 °C, and then 3 (1497
mg, 5.0 mmol) was added. After stirring for 3 h at 0 °C, the
reaction mixture was allowed to warm to rt. THF was
evaporated in vacuo, and the yellow residue was triturated in
H2O (50 mL). The crystalline material formed was collected
by filtration and washed with H2O to give crude product, which
was purified by flash chromatography using hexane and ethyl
acetate (1:1-1:1.5) as eluent to yield (2S,3R)-1 (590 mg,
39.2%). This was recrystallized from EtOH (20 mL) to give
optically pure (2S,3R)-1 (365 mg, 24.2%). The absolute con-
figuration was determined to be (2S,3R) by X-ray crystal-
F igu r e 2. Time course of the asymmetric reduction of 3 with
NaBH4-(S)-tert-leucine at -30 °C with AcOH addition. Three
portions of AcOH (0.5 equiv × 3) were added after 1, 4, and
20 h from the beginning of the reaction. Conversion (dashed
line); ratio of (2S,3S)-1 (solid line).
mm; Mobile Phase: CH3CN/10 mM KH2PO4 (pH 3) ) 50/50;
flow rate: 0.5 mL/min; detection: UV 250 nm; temperature:
40 °C]. Four stereoisomers of 1 were analyzed by chiral HPLC.
[Column: DAICEL CHIRALCEL OD 4.6 × 250 mm; mobile
phase: n-hexane/EtOH ) 85/15; flow rate: 0.5 mL/min; detec-
tion: UV 250 nm; temperature: 35 °C; tR: (2R,3R) 22 min,
(2S,3S) 28 min, (2R,3S) 32 min, (2S,3R) 35 min].
lographic analysis: mp 196-198 °C; [R]20 ) -837 (c 1.0,
D
1
DMF); IR (KBr, cm-1) 1690, 1515, 1475; H NMR (DMSO-d6)
δ. 3.72 (s, 3H), 4.07 (dd, J ) 10.2 Hz, 8.3 Hz, 1H), 4.35 (d, J
) 10.2 Hz, 1H), 5.33 (d, J ) 8.3 Hz, 1H), 6.83-7.56 (m, 8H),
10.21 (s, 1H); MS m/z 301 (M+). Anal. Calcd for C16H15NO3S:
C 63.77; H 5.02; N 4.65. Found: C 63.81; H 4.85; N 4.42. The
analytical data for this compound were in agreement with
those reported by Tanaka et al.18
3-Acet oxy-2-(4-m et h oxyp h en yl)-1,5-b en zot h ia zep in -
4(5H)-on e (2). A modified literature procedure8 was used to
prepare 2. cis-(2RS,3RS)-2,3-Dihydro-3-hydroxy-2-(4-meth-
oxyphenyl)-1,5-benzothiazepin-4(5H)-one [(2RS,3RS)-1] (60.3
g, 0.2 mol) was dissolved in DMSO (156.3 g, 2.0 mol) and Ac2O
(51.1 g, 0.5 mol). A catalytic amount of pyridine (2.37 g, 0.03
mol) was added to the mixture. After the solution was stirred
at rt for 24 h, H2O (122 mL) was added over 10 min, and then
further stirring was continued for 30 min. The crystalline
material formed was collected by filtration, washed with
MeOH, and dried to afford 57.44 g (84.1%) of the desired
product 2: mp 203-206 °C; IR (KBr, cm-1) 1765, 1650, 1480;
1H NMR (DMSO-d6) δ. 2.04 (s, 3H), 3.79 (s, 3H), 6.97-7.68
(m, 8H), 10.82 (s, 1H); MS m/z 341 (M+). Anal. Calcd for
C18H15NO4S: C 63.33; H 4.43; N 4.10. Found: C 63.07; H 4.56;
N 4.00.
t r a n s-(2R ,3S )-2,3-Dih yd r o-3-h yd r oxy-2-(4-m e t h oxy-
p h en yl)-1,5-b en zot h ia zep in -4(5H )-on e
[(2R,3S)-1].
(2R,3S)-1 was prepared similarly using (S)-proline instead of
(R)-proline.
Gen er a l P r oced u r e for Asym m etr ic Red u ction of 3
w ith th e Rea gen ts P r ep a r ed fr om Na BH4 a n d Op tica lly
(18) Tanaka, T.; Inoue, H.; Date, T.; Okamura, K.; Aoe, K.; Takeda,
M.; Kugita, H.; Murata, S.; Yamaguchi, T.; Kikkawa, K.; Nakajima,
S.; Nagao, T. Chem. Pharm. Bull. 1992, 40, 1476.

8590 J . Org. Chem., Vol. 61, No. 24, 1996
Yamada et al.
Sch em e 2
after 1, 4, and 20 h from the beginning of the reaction (total
90 mg, 1.5 mmol). Conversions and ratios of (2S,3S)-1 were
analyzed by HPLC after 10 min, 1 h, 4 h, 19 h, 28 h, 44 h, and
60 h.
Active r-Am in o Acid s (Ta ble 1). A reducing agent was
prepared by stirring the mixture of NaBH4 (57 mg, 1.5 mmol)
and optically active R-amino acid (1.65 mmol) in THF (15 mL)
at 60-65 °C for 3 h under N2 (hydrogen evolution). The
reaction mixture was cooled to 0 °C, and then 3 (299 mg, 1
mmol) was added. After stirring for 1 h, the conversion and
the ratio of the four stereoisomers of 1 were analyzed by HPLC.
Tim e Cou r se of th e Asym m etr ic Red u ction of 3 w ith
Na BH4-(S)-ter t-Leu cin e (F igu r e 1). A reducing agent was
prepared by stirring the mixture of NaBH4 (57 mg, 1.5 mmol)
and (S)-tert-leucine (216 mg, 1.65 mmol) in THF (15 mL) at
60-65 °C for 3 h under N2. The reaction mixture was cooled
to 0 °C, and then 3 (299 mg, 1.0 mmol) was added. After
stirring for 10 min, 1 h, 2 h, 8 h, and 16 h, the conversions
and ratios of (2S,3S)-1 were analyzed by HPLC.
Gen er a l P r oced u r e for Asym m etr ic Red u ction of 3
w ith Na BH4-(S)-ter t-Leu cin e in th e P r esen ce of a n
Ad d itive (Ta ble 2). The preparation of the chiral reducing
agent, NaBH4-(S)-tert-leucine, was similar to that described
above. The reaction mixture was cooled to 0 °C and then 3
(299 mg, 1.0 mmol) was added. After stirring for 0.5 h, the
additive (1.0 mmol) was added and then further stirring was
continued for 15.5 h at 0 °C. Then conversion and ratio of
four stereoisomers of 1 were analyzed by HPLC.
Gen er a l P r oced u r e for Asym m etr ic Red u ction of 3
w ith Na BH4-(S)-ter t-Leu cin e u n d er Va r iou s AcOH Ad -
d ition Con d ition s (Ta ble 3). The preparation of the chiral
reducing agent, NaBH4-(S)-tert-leucine, was similar to that
described above. The reaction mixture was cooled to 0 °C, and
then 3 (299 mg, 1.0 mmol) was added. The mixture was stirred
at 0 °C with addition of AcOH. Then the conversion and the
ratio of the four stereoisomers of 1 were analyzed by HPLC.
Gen er a l P r oced u r e for Asym m etr ic Red u ction of 3
w ith Na BH4-(S)-ter t-Leu cin e a t Va r iou s Rea ction Tem -
p er a tu r es (Ta ble 4). The preparation of the chiral reducing
agent, NaBH4-(S)-tert-leucine, was similar to that described
above. The reaction mixture was adjusted to a fixed temper-
ature, and then 3 (299 mg, 1.0 mmol) was added. The mixture
was stirred at the same temperature with addition of AcOH.
Then the conversion and the ratio of the four stereoisomers of
1 were analyzed by HPLC.
Isola tion of (2S,3S)-1. cis-(2S,3S)-2,3-Dih yd r o-3-h y-
d r oxy-2-(4-m et h oxyp h en yl)-1,5-b en zot h ia zep in -4(5H )-
on e [(2S,3S)-1]. A reducing agent was prepared by stirring
the mixture of NaBH4 (189 mg, 5.0 mmol) and (S)-tert-leucine
(722 mg, 5.5 mmol) in THF (50 mL) at 60-65 °C for 3 h under
N2. (If a lump of NaBH4 remained unreacted, it was crushed
with a spatula and reacted for an additional time). The
reaction mixture was cooled to -30 °C, 3 (997 mg, 3.33 mmol)
was added, and the mixture was stirred for 60 h at -30 °C. In
the course of the reaction, three portions of AcOH (100 mg×3)
were added after 1, 17, and 45 h (total 300 mg, 5.0 mmol).
The reaction was allowed to warm to rt, THF was evaporated
in vacuo, and the pale yellow residue was triturated in H2O
(50 mL). The crystalline material formed was collected by
filtration and washed with H2O to give the crude product (969
mg, 96.6%). This material consisted of a 93:7 mixture of cis:
trans isomers, and the optical purity of the cis-isomers was
95% ee according to HPLC analysis. The crude product was
refluxed for 3 h in 2-propanol (12 mL), cooled to 5 °C, and
filtered to give optically pure (2S,3S)-1 (867 mg, 86.4%): mp
200-202 °C; [R]22D ) +115.6 (c 0.5, DMF); IR (KBr, cm-1) 1680,
1510, 1475; 1H NMR (DMSO-d6) δ. 3.76 (s, 3H), 4.29 (dd, J )
6.4 Hz, 6.6 Hz, 1H), 4.74 (d, J ) 6.4 Hz, 1H), 5.05 (d, J ) 6.6
Hz, 1H), 6.87-7.62 (m, 8H), 10.31 (s, 1H); MS m/z 301(M+).
Anal. Calcd for C16H15NO3S: C 63.77; H 5.02; N 4.65.
Found: C 63.59; H 5.07; N 4.55.
Recover y of (S)-ter t-Leu cin e. To the mother liquor,
which was obtained after the isolation of the crude (2S,3S)-1
described above, was added 6 N HCl (20 mL), and then the
solution was stirred for 1.5 h at 70 °C. After cooling to rt, the
solution was washed with CHCl3 (20 mL) to remove organic
contaminants. The aqueous layer was concentrated in vacuo,
and again the residue was dissolved in H2O (40 mL), and
treated with cation-exchange resin (SK-1B, 20 mL). The resin
was washed with H2O (80 mL), and the amino acid was eluted
with 5% NH4OH (80 mL). The eluent was evaporated in vacuo
to recover 712 mg (98.6%) of (S)-tert-leucine: [R]25 ) +31.2
D
(c 1.0, AcOH) [lit.19 [R]25 ) +30.0 (c 1.0, AcOH)]
D
Tim e Cou r se of th e Asym m etr ic Red u ction of 3 w ith
Na BH4-(S)-ter t-Leu cin e w ith AcOH Ad d ition (F igu r e 2).
The preparation of the chiral reducing agent, NaBH4-(S)-tert-
leucine, was similar to that described above. The reaction
mixture was cooled to -30 °C, 3 (299 mg, 1.0 mmol) was added,
and the mixture was stirred for 60 h at -30 °C. In the course
of the reaction, three portions of AcOH (30 mg×3) were added
Ack n ow led gm en t. The authors thank the staff of
the Analytical Department for elemental analyses and
spectral measurements. We are also grateful to Dr. T.
Tosa, R&D Executive of this company, and to Dr. M.
Ikezaki, Director of this laboratory, for their encour-
agement.
(19) Viret, J .; Patzelt, H.; Collet, A. Tetrahedron Lett. 1986, 27, 5865.
J O960950W