Kinetic resolutions of indan derivatives using bacteria

Article abstract of DOI:10.1271/bbb.66.464

Racemic indan derivatives have been resolved by the hydrolysis of amide bonds using Corynebacterium ammoniagenes IFO12612 to produce (5)-amine and (R)-amides. In the kinetic resolution of 1 (N-[2-(6-methoxyindan-1-yl)ethyl] acetamide), it was possible to run the reaction to 44% conversion on a 10-g scale, obtaining (S)-amine 4 ((S)-2-(6-methoxy-indan-1-yl)ethylamine) at >99% enantiomeric excess (ee) and (R)-1 at 98% ee.

Full text of DOI:10.1271/bbb.66.464

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Kinetic Resolutions of Indan Derivatives Using
Bacteria
Naoki TARUIa, Hayao WATANABEa, Kohji FUKATSUa, Shigenori OHKAWAa & Kazuo
NAKAHAMAa
a Pharmaceutical Research Division, Takeda Chemical Industries, Ltd. 2-17-85,
Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
Published online: 22 May 2014.
To cite this article: Naoki TARUI, Hayao WATANABE, Kohji FUKATSU, Shigenori OHKAWA & Kazuo NAKAHAMA (2002) Kinetic
Resolutions of Indan Derivatives Using Bacteria, Bioscience, Biotechnology, and Biochemistry, 66:2, 464-466, DOI: 10.1271/
bbb.66.464
To link to this article: http://dx.doi.org/10.1271/bbb.66.464
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Biosci. Biotechnol. Biochem., 66 (2), 464–466, 2002
Note
Kinetic Resolutions of Indan Derivatives Using Bacteria
Naoki TARUI,† Hayao WATANABE, Kohji FUKATSU, Shigenori OHKAWA
,
and Kazuo NAKAHAMA
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi,
Yodogawa-ku, Osaka 532-8686, Japan
Received August 29, 2001; Accepted October 10, 2001
Racemic indan derivatives have been resolved by the
hydrolysis of amide bonds using Corynebacterium am-
at 379C for 24 h with shaking. Each reaction mixture
was extracted with ethyl acetate (0.5 ml). The organic
layer was evaporated to dryness under reduced pres-
moniagenes IFO12612 to produce (
amides. In the kinetic resolution of 1 (
indan-1-yl)ethyl]acetamide), it was possible to run the
S
)-amine and (
R)-
N
-[2-(6-methoxy-
sure and the residue was dissolved in methanol (50 ml)
and analyzed by thin layer chromatography (TLC).
reaction to 44
)-amine 4 ((
99% enantiomeric excess (ee) and (R)-1 at 98% ee.
%
S
conversion on a 10-g scale, obtaining
)-2-(6-methoxy-indan-1-yl)ethylamine)
×
TLC plates (100 200 mm silica gel 60 F254, layer
(
at
S
thickness of 0.25 mm, Merck, BDH) were chro-
matographed in pre-equilibrated draught-proof
À
glass chambers containing 200 ml of chloroform
W
Key words: chiral indan derivative; kinetic resolu-
tion; Corynebacterium ammoniagenes
IFO12612
methanol triethylamine (90:7:3). Spots were seen
W
with ultraviolet (UV) light. For measurment of the
conversion and the enatiomeric excess of (
S
)-amine 4
l) was suspend-
l) and ˆltered through a
m cellulose acetate ˆlter (Advantec Toyo, Ltd.,
and (
ed in methanol (950
0.45
R)-1, the reaction mixture (50 m
Lipases and microorganisms are useful in the enan-
tioselective synthesis of chiral intermediates of drugs,
and many examples of the hydrolysis of ester and
amide bonds of unnatural substrates have been
demonstrated.1–5)
Chiral indans are useful as intermediates for the
synthesis of melatonin receptor agonists.6) However,
enzymatic resolution of the amides carrying chirality
in indans has not been reported. Here we report the
enzymatic resolution of indan racemic derivatives by
bacteria (Fig. 1).
m
m
Tokyo), and the ˆltrate was analyzed by high pres-
sure liquid chromatography (HPLC). HPLC analysis
was done using an L7100 system (Hitachi, Ltd.,
Tokyo) with a CHIRAL-AGP column (Sumitomo
Chemical, Ltd., Tokyo). For the HPLC analysis,
10 m
M
sodium acetate buŠer (pH 6.8) and 2-
propanol at a ratio of 95:5 were used as the mobile
phase, the ‰ow rate was 0.5 ml min, and detection
W
was at 280 nm. Retention times were 5.16 min for
We screened 53 commercially available enzymes
(lipases, proteases, esterases, acylases) and 340 bac-
(
R
)-1, 7.11 min for (
15.6 min for (
)-3, 10.7 min for (
S
)-1, 8.64 min for (
)-3, 8.74 min for
)-amine, and 12.5 min for ( )-
R)-2,
S
)-2, 6.23 min for (R
terial strains for the ability to produce (
S
)-amine and
(
S
R
S
(R)-amide with high enantioselectivity using 1 (N-
[2-(6-methoxy-indan-1-yl)ethyl]acetamide)7) as a sub-
strate. An enzyme (5 mg) suspended in 0.5 ml of suit-
able buŠer suitable buŠer, 0.1
7.0, 8.0, or 8.5) or 0.1 Bis-Tris-HCl buŠer (pH
6.0), and a solution (25 l) of 1 (20 mg) in methanol
(1 ml) were mixed, and the reaction mixture was incu-
bated at 37 C for 24 h with shaking. The culture
M
Tris-HCl buŠer (pH
M
m
9
(40 ml in 200-ml Erlenmeyer ‰asks) for inoculation
of Trypticase Soy Broth (Becton Dickinson, USA)
was taken from a stock slope grown on Trypticase
Soy Agar (Becton Dickinson, USA). The culture was
allowed to grow at 28
9
C for 24 h with shaking. The
culture (0.5 ml) and the substrate solution (25
m
l)
were mixed and the reaction mixture was incubated
Fig. 1. Kinetic Resolution of Racemic Amides by Bacteria.
Naoki takeda.co.jp
†
To whom correspondence should be addressed. Naoki TARUI, Fax: +81-6-6300-6254; E-mail: Tarui
ä
＠
Abbreviations: ee, enantiomeric excess; TLC, thin layer chromatography; UV, ultraviolet; HPLC, high pressure liquid chromatography

Kinetic Resolution of Indan Derivatives
465
Table 1. Microbial Kinetic Resolution of Each Substratea)
Substarte
R
Conversionb)
(
S
)-Amine
ee)
(
R
)-Amide
Strain
(
z
)
(
z
(
z
ee)
C. ammoniagenes IFO12612
S. marcescens IFO12648
K. planticola IFO3317
CH3
CH2CH3
CF3
61
22
56
74
99
72
À
99
26
93
À
C. ammoniagenes IFO12612
S. marcescens IFO12648
K. planticola IFO3317
14
9
8
À
À
À
99
99
99
14
8
10
C. ammoniagenes IFO12612
S. marcescens IFO12648
K. planticola IFO3317
26
100
100
46
0
0
8
0
0
a)
b)
Each reaction mixture, comprised of 25 ml of substrate solution (20 mg ml methanol) and 0.5 ml of culture, was incubated at 379C for 24 h with shaking.
W
The reaction mixture was analyzed by HPLC.
Conversion ( concentration of amines initial concentration of substrate (1 mg ml) 100
×
＝
z
)
W
W
amine.
Commercially available enzymes, examined here,
had no hydrolytic activity. From the screening, three
bacterial strains, Corynebacterium ammoniagenes
IFO12612, Serratia marcescens IFO12648, and Kleb-
siella planticola IFO3317 were selected. We examined
the diŠerences in enantioselectivity between the vari-
ous substrates,7) and the ˆndings are summarized in
Table 1. The bacteria showed a high enantioselectivi-
ty towards
1 and 2 (N-[2-(6-methoxy-indan-1-
yl)ethyl] propanamide) and a lower hydrolytic activi-
ty toward 2 compared to 1. Furthermore, to assess
whether the tri‰uoromethyl substituent would have
an electronic eŠect, the kinetic resolution of 3
(2,2,2-tri‰uoro-N-[2-(6-methoxy-indan-1-yl)ethyl]
acetamide) was done. C. ammoniagenes IFO12612
had a lower enantioselectivity toward 3 than 1. S.
marcescens IFO12648, and K. planticola IFO3317
had no enantioselectivity toward 3.
The kinetic resolution of 1 on a 10-g scale was done
using C. ammoniagenes IFO12612. The slope culture
was transferred to a 200-ml Erlenmeyer ‰ask contain-
ing Trypticase Soy Broth (40 ml) and was shaken at
Fig. 2. Course of the Enantioselective Hydrolysis of 1 by C. am-
moniagenes IFO12612.


#
Symbols:
)-1 ( ee).
, conversion (
z
);
, (
S
)-amine 4 (
z
ee);
,
(
R
z
289C for 24 h to obtain the seed culture. A portion (1
ml) of the seed culture was transferred to Trypticase
Soy Broth (40 ml) in a 200-ml Erlenmeyer ‰ask. The
[
a
]
0.3, CHCl3), lit.7)
＝
„61.69 (c [a]
＝
Hg365
Hg365
culture was shaken at 28
9
C for 24 h to obtain the
9
„61.3 (c 0.3, CHCl3); NMR (200 MHz, CDCl3) dH
main culture. The substrate 1 (10.32 g) was dissolved
in 516 ml of methanol. A portion (2 ml) of the sub-
strate solution was added to each main culture and
1.50–1.80 (2 H, m), 1.93–2.11 (1 H, m), 1.97 (3 H,s),
2.24–2.40 (1 H, m), 2.67–2.90 (2 H, m), 3.02–3.20
(1 H, m), 3.32–3.44 (2 H, m), 3.79 (3 H, s), 5.51
＝
(1 H, m, br s), 6.67–6.76 (2 H, m), 7.11 (1 H, d, J
the reaction was done at 28
9C with shaking. The
course of the hydrolysis of 1 is shown in Fig. 2. After
30 h, the reaction mixture was adjusted to pH 5 with
2 N HCl and extracted with ethyl acetate. The organ-
ic layer was evaporated to dryness under reduced
pressure to yield a residue. The residue was puriˆed
with silica gel column chromatography by eluting
8.0 Hz). Found: C, 72.11; H, 8.09; N, 5.86. Calcd.
for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. The aque-
ous phase was adjusted to pH 9 with 30
z NaOH and
extracted with ethyl acetate. The organic layer was
evaporated under reduced pressure to yield a residue.
The residue was dissolved in ethanol and diethyl
ether, and 5 N HCl was added to aŠord a crystalline
solid. The crystalline solid was recrystallized from
with 5
evaporated under reduced pressure to aŠord (
a crystalline solid (4.6 g, 45 yield, 99
z
methanol in ethyl acetate. The eluate was
)-1 as
ee):
R
z
z
À
ethanol-diethyl ether, yielding 4 ((S)-2-(6-methoxy-

466
N. TARUI et al.
atropisomers: Synthesis of a key intermediate of the
farnesyl protein transferase inhibitor, SCH66336. J.
Org. Chem., 65, 5451–59 (2000).
indan-1-yl)ethylamine)hydrochloride as a crystalline
＝
„30.09(c
solid (2.2 g, 21
z
yield, 98z
ee) [
0.15, H2O); NMR
dH 1.57–1.88 (2 H, m),
a
]
D
0.15, H2O), lit.7) [
a
]
9
„30.0 (c
＝
D
3) Lin, C. N. and Tsai, S. W., Dynamic kinetic resolution
of suprofen thioester via coupled trioctylamine and
lipase catalysis. Biotechnol. Bioeng., 69, 31–8 (2000).
4) Gotor, V., Non-conventional hydrolase chemistry:
Amide and carbamate bond formation catalyzed by
lipases. Bioorg. Med. Chem., 7, 2189–97 (1999).
5) Zhang, M. and Kazlauskas, R., First preparation of
(200 MHz, DMSO-d6
)
2.01–2.36 (2 H, m), 2.62–2.92 (4 H, m), 3.07–3.23
(1 H, m), 3.73 (3 H, s), 6.68–6.78 (2 H, m), 7.12
＝
8.2 Hz), 8.14 (2 H, br s). Found: C,
(1 H, d,
J
63.14; H, 7.70; N, 6.14. Calcd. for C12H18ClNO: C,
63.29; H, 7.97; N, 6.15.
These analytical data were in good agreement with
enantiopure indane monomer, (
S)-(„)- and (R)-(+)-
those of authentic reference substances.7) The ob-
2,3-dihydro-3-(4 -hydroxyphenyl)-1,1,3-trimethyl-1H-
?
inden-5-ol, via a unique enantio- and regioselective
enzymatic kinetic resolution. J. Org. Chem., 64,
7498–7503 (1999).
tained (S)-amine 4 and (R)-1 were available as inter-
mediates for the synthesis of melatonin receptor
agonists.
6) Kato, K., Hirai, K., Uchikawa, O., Fukatsu, K.,
Ohkawa, S., Hinuma, S., and Miyamoto, M.,
Neuropharmacological properties of TAK-375, a novel
melatonin ML receptor agonist. Jpn. J. Pharmacol.,
85, supplement I 257 (2001).
7) Nakahama, K., Watanabe, H., Tarui, N., and
Ohkawa, S., Japan Kokai Tokkyo Koho, 09-140396
(June 3, 1997).
References
1) Schmid, R. D. and Verger, R., Lipases: Interfacial
Enzymes with Attractive Applications. Angew. Chem.
Int. Ed. Engl., 37, 1608–1633 (1998).
2) Morgan, B., Zaks, A., Dodds, D. R., Liu, J. C., Jain,
R., Megati, S., Njoroge, F. G., and Girijavallabhan,
V. M., Enzymatic kinetic resolution of piperidine