Convenient synthesis of 7′ and 6′-bromo-D-tryptophan and their derivatives by enzymatic optical resolution using D-aminoacylase

Article abstract of DOI:10.1016/S0040-4020(02)00909-2

Compounds 7′ and 6′-bromo-D-tryptophan (1 and 2) which are important derivatives for the synthesis of the chloropeptin and kistamycin A, respectively, were conveniently synthesized by optical resolution from N-acetyl-7′ and 6′-bromo-DL-tryptophan ((RS)-5 and (RS)-14) using D-aminoacylase.

Full text of DOI:10.1016/S0040-4020(02)00909-2

Tetrahedron 58 (2002) 7851–7861
Convenient synthesis of 70 and 60-bromo-D-tryptophan and their
derivatives by enzymatic optical resolution using D-aminoacylase
*
Yaeko Konda-Yamada, Chiharu Okada, Kiminari Yoshida, Yasuyuki Umeda, Shiho Arima,
Noriko Sato, Toshitsugu Kai, Hiroaki Takayanagi and Yoshihiro Harigaya
School of Pharmaceutical Sciences, Kitasato University, 9-1 Shirokane 5 chome, Minato-ku, Tokyo 108-8641, Japan
Received 18 January 2002; accepted 26 July 2002
Abstract—Compounds 70 and 60-bromo-D-tryptophan (1 and 2) which are important derivatives for the synthesis of the chloropeptin and
kistamycin A, respectively, were conveniently synthesized by optical resolution from N-acetyl-70 and 60-bromo-DL-tryptophan ((RS)-5 and
(RS)-14) using D-aminoacylase. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Since then, several D-aminoacylases from microorganism
were produced and purified, and several of them were
applied to produce natural a-D-amino acid from racemic
a-amino acids by enzymatic optical resolution. But this
practical enzymatic optical resolution method has not yet
been applied to obtain unnatural a-D-amino acids although
only enzymatic deacetylation of unusual amino acid,8
b-lactam amino acid, was reported.
The enzymatic hydrolysis of N-acylamino acids has been
known for a century and was first detected in aqueous
kidney preparation.1 Based on the finding that this
enzymatic hydrolysis proceeds enantiospecifically,2
Grennstein and co-workers developed a general and
attractive procedure for the resolution of a vast number of
racemic N-acylated amino acids to the corresponding
L-amino acids catalyzed by L-aminoacylase from hog
kidney in 1949.3 As L-aminoacylase has a wide substrate
specifity and high enantioselectivity, it has been applied to
the optical resolution of many natural4 as well as unnatural
and rarely occurring a-amino acids.5 But the above-
mentioned enzymatic hydrolysis was used mainly to obtain
L-amino acids, and D-amino acids were recovered by
chemical hydrolysis of N-acyl-D-amino acid isolated as
non-hydrolyzed isomers. Thus, partial racemization is
unavoidable and high optical purity of the D-amino acid
cannot been attained.
Recently, several bioactive natural organic compounds
which contain D-amino acids have been reported.9–11 We
are interested in the synthesis of chloropeptin9 which has an
anti-HIV activity, and we are also interested in the structure
of kistamycin10 which is known as an anti-influenza A virus
agent. Both of them contain various D-amino acids as
components. We have investigated the total synthesis of the
chloropeptin and already reported its left-hand segment.12
We are now progressing the synthesis of the right-hand
segment of chloropeptin and also kistamycin which contains
a C–C bond between 4-hydroxy-D-phenyl glycine and the
D-tryptophan moiety. The 70 and 60-halogeno-D-tryptophan
are needed to synthesize the right-hand segments of
chloropeptin and kistamycin, respectively.
Against this background, investigations of D-specific
aminoacylases have been carried out, and work on the use
of D-specific aminoacylases with racemic N-benzoyl amino
acids to obtain D-amino acids directly without chemical
hydrolysis was first carried out by Kameda and co-workers
in 1952.6 However, the D-aminoacylase productivity of the
strain was not satisfactory. In 1980, Sugie and co-workers
reported the finding of a D-specific aminoacylase suitable
for the production of natural D-amino acids together with
the application of the D-aminoacylase to optical resolution
of several natural DL-amino acids.7
The aim of the present work 0is to construct conveniently two
u0nusual D-amino acids, 7 -bromo-D-tryptophan (1) and
6 -bromo-D-tryptophan (2), by enzymatic optical resolution
using D-aminoacylase from Achromobacter xylosoxydans
aubap. Xylosoxydans.
2. Results and discussion
2.1. Synthesis of 70-bromo-D-tryptophan ((R)-1) using
L-aminoacylase
Keywords: 70 and 60-bromo-D-tryptophan; synthesis; D-aminoacylase;
optical resolution.
*
Corresponding author. Tel.: þ81-3-5791-6377; fax: þ81-3-3444-4742;
e-mail: konday@pharm.kitasato-u.ac.jp
At first, we planned to synthesize 70-bromo-D-tryptophan
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00909-2

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Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
((R)-1) from racemic N-acetyltryptophan ((RS)-5) by optical
resolution using L-aminoacylase, followed by acid
hydrolysis of the obtained N-acetyl-D-tryptophan ((R)-5).
7-Bromoindole (4) which is the starting material for (RS)-5
was easily obtained from 2-bromonitrobenzene by the
literature method.13 Substitution reaction of 4 with L-serine
in AcOH–Ac2O at 708C according to the literature
procedure14 gave racemic N-acetyltryptophan ((RS)-5) in
84% yield. Optical resolution was performed by treatment
with (RS)-5 and L-aminoacylase in the presence of cobalt
dichloride in phosphate buffer (pH 7.4) at 378C. Extraction
with an organic solvent afforded N-acetyl-D-tryptophan
((R)-5) in 42% yield and the water part was chromato-
graphed to afford 70-bromo-D-tryptophan ((S)-1) in 39%
yield. It was reported that deacetylation of an N-acetyl-
tryptophan derivative using aqueous HBr proceeds without
racemization.15 Then, hydrolysis of the acetyl group of (R)-
5 with aqueous HBr afforded 70-bromo-D-tryptophan ((R)-1)
in 87% yield. The formation of the compound (R)-1 has not
yet been reported though its L-form was already reported.16
Optical rotation of (R)-1 showed þ11.488 (lit.16, S-form:
27.68). The protection of the amino group with the
carbobenzoxy (Cbz) group was performed by treatment
with carbobenzoxy chloride (Cbz-Cl) under alkali con-
ditions. Several attempts to extract 70-bromo-N-Cbz-D-
tryptophan ((R)-6) with an organic solvent after acidifica-
tion of the reaction mixture failed, which is attributable to
lability of the tryptophan moiety. Then, filtration of the
precipitate of N-Cbz-tryptophan directly which results after
acidification afforded (R)-6 in 47.1% yield, successfully
(Scheme 1).
appropriate amount of the chiral shift reagent showed two
peaks (1:1) of methyl signal which resulted in a racemate,
whereas the H NMR spectrum of (R)-8 and (S)-8 in the
1
presence of the chiral shift reagent under the same
conditions as (RS)-8 showed each one peak of the methyl
signal in corresponding position to that of the racemate.
1
Each H NMR spectral data were described in Section 4.
Further, (R)-5 was condensed with (R)-(þ)-phenylethyl-
amine by treatment with 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide (EDCI) to afford phenylethylamide
(R)-5-amide in 73% yield, and none of it’s diastereomer
(S)-5-amide (which was described in Scheme 4) was
obtained These results prove that (R)-5 is optically pure,
and our enzymatic optical resolution using L-aminoacylase
proceeded stereospecifically (Scheme 2).
2.2. Synthesis of 70-bromo-D-tryptophan ((R)-1) using
D-aminoacylase
However, acid hydrolysis of (R)-5 is often accompanied
with by-products in addition to the desired compound (R)-1,
which results from lability of N-acylated tryptophan, and the
yield and reproducitbility were often not satisfactory. So,
another route was developed to increase the yield and purity
of compound (R)-1. This route involves direct transform-
ation of (RS)-5 to (R)-1 in one step by using D-aminoacylase
supplied from Amano Enzyme Inc. Incubation of (RS)-5
with D-aminoacylase in the presence of cobalt dichloride in
phosphate buffer at pH 7.4 for 24 h at 378C and0 extraction
with an organic solvent afforded N-acetyl-7 -bromo-L-
tryptophan ((S)-5) from the organic layer quantitatively,
and the water part was chromatogaphed to afford optically
pure (R)-1 quantitatively from inorganic salts by using
SEPABEADS SP207 resin. Protection of the amino group
by treatment with Cbz-Cl in a similar way as mentioned
above gave (R)-6 in 99% yield. Finally, the carboxyl group
was transformed to t-butyl ester. At first, (R)-6 was treated
with di-tert-butyl dicarbonate (Boc2O) in the presence
of dimethylaminopyridine (DMAP) which is a general
Optical purity was determined by 1H NMR technique using
a chiral shift reagent with methyl esters. Compounds (R)-5,
(S)-5 (which was described in Section 2.2) and (RS)-5 were
derivated to methyl ester by treatment with trimethylsilyl-
diazomethane (TMSCHN2) to afford (R)-8, (S)-8 and (RS)-8
in 100, 66, 96%, yields, respectively. The 1H NMR
spectrum of (RS)-8 in CDCl3 in the presence of an
Scheme 1.

Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
7853
Scheme 2.
procedure for formation of t-butyl ester. However, compli-
cated substances were obtained, which result from the
reaction of the NH group on indole and also carbamate with
Boc2O together with esterification of the carboxyl group.
So, (R)-6 was treated with tert-butyl bromide in the presence
of benzyltriethylammonium chloride (BTEAC) as a phase
were achieved conveniently each in two and three steps
from 7-bromoindole in 42 and 27% yields, respectively, by
optical resolution using a D-aminoacylase. The reaction
conditions and isolation procedures are both simple and are
suitable for large-scale preparation.
17
transfer catalyst and K2CO3 as a base to afford t-butyl
Optical purity was determined, and it was confirmed that
this enzymatic optical resolution stereospecifically occurred
as described below. Carboxylic acid (R)-6 was condensed
with (R)-(þ)-1-phenylethylamine by treatment with EDCI
to afford amide 9 in 69% yield and none of it’s
diastereomeric amide 10 was obtained. Compound 10 was
obtained as follows. Conversion of 70-bromo-L-tryptophan
((S)-1), which was obtained by enzymatic resolution using
L-aminoacylase, to carbamate (S)-6 by treatment with
Cbz-Cl, followed by condensation with (R)-(þ)-1-phenyl-
ethylamine in a similar way to provided diastereomeric
ester ((R)-7) in 65%. In this reaction, potassium salt of the
carboxylate is formed as an intermediate, then only t-butyl
esterification occurs, selectively. This esterification method
was revealed to be very appropriate for t-butyl esterification
of reactive and labile N-acyltryptophan analogies which are
important for peptide synthesis (Scheme 3).
Thus, synthesis of 70-bromo-N-Cbz-D-tryptophan ((R)-6)
and 70-bromo-N-Cbz-D-tryptophan t-butyl ester ((R)-7)
which are both useful derivatives for peptide synthesis
Scheme 3.

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Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
Scheme 4.
D-tryptophan ((R)-1) and N-acetyl-70-bromo-L-tryptophan
((S)-5) and enzymatic resolution by L-aminoacylase proceed
enatiomerically to give optic0ally pure 70-bromo-L-trypto-
phan ((S)-1) and N-acetyl-7 -bromo-D-trtptophan ((R-5),
simultaneously (Scheme 4).
amide 10 in 64% yield and none of it’s diastereomeric
amide 9 was obtained. Furthermore, optically purity of
remained N-acetyl-70-bromo-L-tryptophan ((S)-5) obtained
from organic layer by optical enzymatic resolution of (RS)-5
using D-aminoacylase was determined as follows. Com-
pound (S)-5 was similary derivated to it’s (R)-(þ)-phenyl
ethylamide to afford (S)-5-amide in 67% yield and none of
its diastereomer ((R)-5)-amide was obtained in this reaction.
2.3. Synthesis of 60-bromo-D-tryptophan using
D-aminoacylase
Next, 60-bromo-D-tryptophan ((R)-2) was similarly synthe-
sized by enzymatic optical resolution using D-aminoacylase
These results prove enzymatic resolution by D-aminoacyl-
ase proceed enatiomerically to give optically pure 70-bromo-
Scheme 5.

Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
7855
Scheme 6.
as a key reaction. 60-Bromoindole (13) was synthesized in
two steps according to the literature.18 4-Bromo-2-nitro-
toluene (11) was treated with N,N-dimethylformamide
dimethyl acetal (DMF-DMA) and pyrrolidine at 1108C.
The crude enamine 12 was subjected to reductive cycliza-
tion with zinc in acetic acid to afford 13 in 57% yield for two
steps from 11. Substitution reaction of 13 with L-serine in 0a
similar way as described above gave racemic N-acetyl-6 -
bromotryptophan ((RS)-14) in 96% yield, followed by
optical resolution using D-aminoacylase afforded 60-bromo-
D-tryptophan ((R)-2) in 38% yield and (S)-14 was recovered
in 45% yield. Compound (R)-2 was converted to 60-bromo-
N-Cbz-D-tryptophan ((R)-15) in 62% yield by using same
condition as described (Scheme 5).
16 and 17, respectively, in 98 and 82% yields and none of
diasteromeric amide was obtained in each condensation
reaction. Optically purity of remained N-acetyl-60-bromo-L-
tryptophan ((S)-14) obtained from organic layer by optical
enzymatic resolution of (RS)-14 using D-aminoacylase was
determined as follows. Compound (S)-14 was similary
derivated to it’s (R)-(þ)-1-phenyl ethylamide to afford
(S)-14-amide in 58% yield and none of its diastereomer (R)-
14-amide was obtained in this reaction. Diasteremer (R)-14-
amide was obtained as follows. Compound (R)-14 obtained
by optical enzymatic resolution using L-aminoacylase was
similarly derivated to it’s (R)-(þ)-1-phenyl ethylamide
(R)-14-amide in 73% yield.
These results prove enzymatic resolution by D-aminoacyl-
ase proceed enatiomerically to give optically pure 60-bromo-
D-tryptophan ((R)-2) and N-acetyl-70-bromo-L-tryptophan
((S)-14) (Scheme 6).
Optical purity of (R)-15 was determined as follows. Optical
resolution of (RS)-14 by treatment with L-aminoacylase in a
similar manner as described above afforded 60-bromo-L-
tryptophan ((S)-2) and (R)-14 in 45 and 46% yields,
respectively. Conversion of (S)-2 to N-Cbz derivative
similarly gave (S)-15 in 78% yield. Condensation reaction
of each carboxylic acid (R)-15 and (S)-15 with (R)-(þ)-1-
phenylethylamine by treatment with EDCI afforded amide
3. Conclusion
Compounds 70 and 60-bromo-D-tryptophan, their N-Cbz

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Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
derivatives and t-butyl ester were conveniently synthesized
enantiospecifically by optical resolution using D-amino-
acylase from N-acetyl-70 and 60-bromo-DL-tryptophan in
short steps. Each step proceeds to give high yields which are
adequate for large-scale preparation.
volume to give crystals, which were collected by filtration
and dried. The crystals were combined to give (RS)-5 as
light yellow crystals (1.39 g, 84.3%). The organic layer was
dried over Na2SO4, concentrated to give the residue
(210 mg), which was purified by preparative TLC (CHCl3/-
MeOH¼10:1) to recovered 4 (151 mg). Rf: 0.71 (CHCl3/-
MeOH¼10:1); mp: 209–2128C (H2O); IR (KBr): nmax
cm21: 1630 (NHCO), 1730 (COOH), 3400 (indole-NH); 1H
NMR (400 MHz, CD3COCD3) dH: 1.91 (3H, s, CH3), 3.21
(1H, ddd, J¼1.0, 7.5, 15.0 Hz, 3-Ha), 3.34 (1H, ddd, J¼1.0,
5.5, 15.0 Hz, 3-Hb), 4.81 (1H, dd, J¼5.5, 8.0, 9.0 Hz, 2-H),
6.99 (1H, t, J¼8.0 Hz, 50-H), 7.31 (1H, d, J¼1.0 Hz, 20-H),
7.32 (1H, dd, J¼1.0, 8.0 Hz, 60-H), 7.35 (brd, J¼8.0 Hz,
NHCO), 7.63 (1H, d, J¼8.0 Hz, 40-H), 10.28 (1H, brs, 10-H);
13C NMR (100 MHz, CD3COCD3) dC: 22.69 (q, CH3),
28.22 (t, 3-C), 53.77 (d, 2-C), 105.07 (s, 70-C), 112.67 (s,
30-C), 118.91 (d, 40-C), 120.96 (d, 50-C), 124.67 (d, 60-C),
125.49 (d, 20-C), 130.36 (s, 30a-C), 135.76 (s, 70a-C), 170.44
(s, NHCO), 173.33 (s, 1-C); HRFAB-MS m/z: 324.0112
[M]þ, calcd for C13H13O3N2Br79: 324.0110 [M].
4. Experimental
4.1. General
Melting points were taken on a Yanagimoto hot-stage and
are uncorrected. 1H and 13C NMR were recorded on Varian
VXR-300, XL-400 spectrometers. The signals were
assigned by 1H–1H COSY, DEPT, HMQC, HMBC
experiments. Mass spectra were obtained on a JEOL-
JMX-DX 300 mass spectrometer (low-resolution mass
spectrometry) and JEOL-JMS-AX505 HA mass spec-
trometer (high-resolution mass spectrometry). Routine
monitoring of reactions was carried out using Merck 60
GF254 silica gel, glass-supported plates (TLC). Flash
column chromatography was performed on silica gel 60 H
(Merck). Thin-layer chromatography was done on silica gel
60 PF254 (Merck).
4.1.3. N-Acetyl-70-bromo-D-tryptophan ((R)-5) and 70-
bromo-L-tryptophan ((S)-1). L-Aminoacylase (1500 U/g,
80 mg) in phosphate buffer solution (pH 7.41, 4 ml) and
CoCl2·6H2O (0.2 mg) were added to a solution of (RS)-5
(80 mg, 0.247 mmol) in phosphate buffer solution (8 ml).
The solution was shaken for 24 h at 378C. The reaction
mixture was adjusted to pH 5 with 10% HCl, filtered
through celite pad. The filtrate was washed with AcOEt
(30 ml£3). The water layer was purified by column
chromatography (Sepabeads SP207, 150 ml of H2O,
followed by 200 ml of MeOH). Concentration of eluate of
MeOH afforded (S)-1 (27 mg, 39%) as a white powder. The
organic layer was dried over Na2SO4, concentrated in vacuo
to give (R)-5 (33 mg) in 42% yield as light yellow granules.
(S)-1: mp: 220–2228C [a]2D5¼223.998 (c¼0.15, MeOH);
Rf: 0.47 (1-BuOH/AcOH/H2O¼4:1:5); 1H NMR (400 MHz,
CD3OD) dH: 3.17 (1H, dd, J¼9.0, 15.0 Hz, 3-Ha), 3.49 (1H,
dd, J¼4.0, 15.0 Hz, 3-Hb), 3.850 (1H, dd, J¼4.0, 9.0 Hz,
2-H), 6.98 (1H, t, J¼8.0 Hz, 5 -H), 7.29 (1H, s, 20-H),
7.30 (1H, d, J¼8 Hz, 60-H), 7.70 (1H, dd, J¼1.0, 8.0 Hz,
40-H); HRFAB-MS m/z: 283.0072 [M]þ, calcd for
C11H12O2N2Br79: 283.0082 [M]. (R)-5: mp 128–1308C;
[a]2D5¼221.988 (c¼1.01, acetone); HRFAB-MS m/z:
325.0156 [MþH]þ, calcd for C13H14O3N2Br79: 325.0159
[MþH]. The data of Rf, 1H NMR were consistent with those
of (RS)-5.
4.1.1. 7-Bromoindole (4). Vinyl magnesium bromide
solution in THF (0.95 mol/l, 63.3 ml, 60.0 mmol) was
added to a solution of 2-bromonitrobenzene (3) (4.04 g,
20.0 mmol) in THF (40 ml) at 2408C under argon and
stirred for 20 min. The reaction mixture was poured into
saturated ammonium chloride (50 ml) and THF was
concentrated in vacuo. The residual aqueous solution was
extracted with AcOEt (200 ml£3). The organic layer
was dried over Na2SO4 and concentrated in vacuo to give
a pale yellow oil (4.52 g) and this was purified by flash
column chromatography (hexane) to afford pale yellow
plates 4 (2.11 g, 53.8%). Rf: 0.56 (hexane/AcOEt¼3:1); mp:
35–368C (CHCl3); IR (KBr): nmax cm21: 510, 580 (Ar–Br),
1580, 1620 (arom), 3420 (NH); 1H NMR (400 MHz,
CDCl3) dH: 6.66 (1H, dd, J¼2.0, 3.0 Hz, 3-H), 7.04 (1H,
t, J¼7.5 Hz, 5-H), 7.25 (1H, t, J¼3.0 Hz, 2-H), 7.39 (1H, d,
J¼7.5 Hz, 4-H), 7.63 (1H, d, J¼7.5 Hz, 6-H), 8.33 (1H, brs,
1-H); 13C NMR (100 MHz, CDCl3) dC: 103.79 (d, 2-C),
104.61 (s, 7-C), 119.91 (d, 6-C), 120.95 (d, 5-C), 124.28 (d,
4-C), 124.65 (d, 3-C), 128.96 (s, 3a-C), 134.53 (s, 7a-C);
HREI-MS: m/z: 194.9680 [M]þ, calcd for C8H6NBr79:
194.9684 [M].
4.1.4. 70-Bromo-D-tryptophan ((R)-1) from L-aminoacyl-
ase route. 48% Aqueous hydrogen bromide (0.17 ml,
1.42 mmol) was added to a solution of (R)-5 (96.0 mg,
0.296 mmol) in H2O (0.7 ml), and stirred for 3 h at 1008C.
The reaction mixture was adjusted to pH 5 with 20%
aqueous NaOH, ice-cooled to give precipitates, then the
precipitates were filtered. The filtrate was concentrated to
1/2 volume, ice-cooled to give precipitates which were
filtered. Combined light yellow powders give (R)-1
(72.4 mg, 86.6%). [a]2D6¼þ11.488 (c¼1.01, MeOH); the
data of Rf and 1H NMR were consistent with those of (S)-1.
13C NMR (100 MHz, CD3OD) dC: 28.44 (t, 3-C), 56.61
(d, 2-C), 105.68 (s, 70-C), 111.03 (s, 30-C), 118.91 (d, 40-C),
121.35 (d, 50-C), 125.300 (d, 60-C), 126.31 (d, 20-C), 130.13
(s, 30a-C), 136.76 (s, 7a -C), 174.15 (s, 1-C); HRFAB-MS
4.1.2. N-Acetyl-70-bromo-DL-tryptophan ((RS)-5). L-Serine
(1.06 g, 10.3 mmol) was dissolved in a solution of 4 (1.00 g,
5.13 mmol) in AcOH (12.0 ml) and Ac2O (4.0 ml). After the
solution was stirred at 758C for 2 h under argon, the mixture
was diluted with diethyl ether (100 ml) and adjusted to pH
11 with 30% NaOH (40 ml). The water layer was further
washed with diethyl ether (150 ml£3), then ice-cooled. The
organic layer was further extracted with 1N NaOH
(30 ml£2) and a small amount of Na2S2O4 was added to
the combined alkali solution, which was then neutralized
with conc. HCl, concentrated to 1/2 volume in vacuo to give
precipitates, then acidified with 5% HCl to adjust to pH 3
using congo red as indicator, stored in refrigerator for 24 h.
The resulted precipitates were collected by filtration and
dried to give crystals. The filtrate was concentrated to 1/2

Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
7857
m/z: 282.0092 [M]þ, calcd for C11H11O2N2Br79: 282.0004
[M].
(0.43 ml) and stirred for 30 min at room temperature under
argon. The solution was evaporated in vacuo to give a
yellow solid (24.7 mg). This was purified by preparative
TLC (CHCl3/MeOH¼7:1) to afford (RS)-8 (18.7 mg,
96.4%) as white crystals. The data of Rf and 1H NMR
were consistent with those of (R)-8. HRFAB-MS m/z:
339.0334 [MþH]þ, calcd for C14H16O3N2Br79: 339.0344
[MþH].
4.1.5. 70-Bromo-N-carbobenzyloxy-D-tryptophan ((R)-6).
Cbz-Cl (18.5 ml, 0.155 mmol) in diethyl ether (0.2 ml) was
dropped to a solution of (R)-1 (36.4 mg, 0.129 mmol) in
10% aqueous Na2CO3 (1.8 ml) at 08C, and stirred for 5 h.
The reaction mixture was acidified with 10% citric acid,
extracted with CHCl3 (10 ml£3). The organic layer was
washed with water, dried over Na2SO4, evaporated to give
light yellow gels, which were purified by preparative TLC
(CHCl3/MeOH¼5:1) to afford (R)-6 (25.7 mg, 47.1%) as
yellow amorphous solid. Rf: 0.87 (1-BuOH/AcOH/H2-
O¼4:1:5); [a]2D3¼227.278 (c¼0.99, CHCl3); 1H NMR
(400 MHz, CD3COCD3) dH: 3.23 (1H, dd, J¼8.0,
15.0 Hz, 3-Ha), 3.38 (1H, dd, J¼5.0, 15.0 Hz, 3-Hb), 4.58
(1H, dd, J¼5.0, 8.0 Hz, 2-H), 5.01, 5.06 (each 1H, d,
J¼13.0 Hz, CH2-Ph), 6.48 (1H, d, J¼8.0 Hz, NHCO), 6.97
(1H, t, J¼8.0 Hz, 50-H), 7.31 (5H, m, Ph), 7.31 (1H, d,
J¼8.0 Hz, 60-H), 7.35 (1H, d, J¼2.5 Hz, 20-H), 7.65 (1H, d,
J¼8.0 Hz, 40-H), 10.25 (1H, s, 10-H); HRFAB-MS m/z:
416.0358 [M]þ, calcd for C19H17O4N2Br79: 416.0372 [M].
4.1.9. 1H NMR spectral data for (R)-8, (S)-8 in the
presence of the chiral shift reagent. Ttris[3-(heptafluoro-
propyl-hydroxymethylene)-(þ)-camphorato], europium(III)
derivative made in Aldrich Chemical Company, Inc. was
used as a chiral shift reagent and the shift reagent (6 mg)
was added in each 0.022 M solution of (R)-8 and (S)-8 in
1
CDCl3. H NMR (400 MHz, CDCl3) (R)-8: dH 3.63 (1H,
brd, J¼15.0 Hz, 3-Ha), 3.80 (3H, s, CH3), 4.12 (1H, br,
3-Hb), 6.23 (1H, br, 2-H), 6.91 (1H, m,0NHCO), 7.14 (1H, t,
J¼8.0 Hz, 50-H), 7.38 (1H, brs, 2 -H), 7.44 (1H, d,
J¼8.0 Hz,0 40-H), 7.98 (1H, brd, J¼8.0 Hz, 60-H), 8.47
(1H, brs, 1 -H). (S)-8: 1H NMR (400 MHz, CDCl3) dH: 3.57
(1H, dd, J¼3.5, 14.0 Hz, 3-Ha), 3.79 (3H, s, CH3), 4.55 (1H,
br, 3-Hb), 6.01 (1H, br, 2-H), 6.71 (1H, 0br, NHCO), 7.09
(1H, t, J¼7.5 Hz, 50-H), 7.29 (1H, brs, 2 -H0), 7.41 (1H, d,
J¼7.5 Hz, 40-H), 7.84 (1H, brd, J¼7.5 Hz, 6 -H), 8.45 (1H,
brs, 10-H). HRFAB-MS m/z: 428.090 [MþH]þ, calcd for
C21H23O2N3Br79: 428.0974 [MþH].
4.1.6. N-Acetyl-70-bromo-D-tryptophan methyl ester
((R)-8). A solution of TMSCHN2 (40 ml, 80.5 mmol) in
benzene (0.16 ml) was dropped to a solution of (R)-5
(20.1 mg, 62.0 mmol) in MeOH (0.12 ml) and benzene
(0.43 ml) and stirred for 30 min at room temperature under
argon. The solution was evaporated in vacuo to give a
yellow solid (24.4 mg). This was purified by preparative
TLC (CHCl3/MeOH¼7:1) to afford (R)-8 (22.1 mg) quan-
titatively as a white powder. Rf: 0.65 (CHCl3/MeOH¼5:1);
mp: 150–1548C; [a]D26¼þ62.008 (c¼0.14, CHCl3); 1H
NMR (400 MHz, CDCl3) dH: 1.97 (3H, s, COCH3), 3.70
(3H, s, CH3), 3.27, 3.34 (each 1H, dd, J¼5.5, 14.5 Hz,
3-H2), 4.95 (1H, dd, J¼5.5, 7.5 Hz, 2-H), 6.00 (1H, brd,
J¼7.5 Hz, NHCO), 7.00 (1H, t, J¼7.5 Hz, 500-H), 7.04 (1H,
d, J¼2.5 Hz, 20-H), 7.35 (1H, d, J¼7.5 Hz0, 6 -H), 7.47 (1H,
d, J¼7.5 Hz, 40-H), 8.33 (1H, brs, 1 -H); 13C NMR
(100 MHz, CD3OD) dC: 23.25 (q, COCH3), 27.79 (t, 3-C),
52.42 (q, OMe), 52.96 (d, 2-C), 104.90 (s, 70-C), 111.509 (s,
30-C), 117.850 (d, 40-C), 120.91 (d, 50-C), 123.20 (d, 2 -C),
124.64 (d, 6 -C), 128.92 (s, 30a-C), 169.61 (s, NHCO),
172.24 (s, 1-C); HRFAB-MS m/z: 338.0273 [M]þ, calcd for
C14H15O3N2Br79: 338.0266 [M].
4.1.10. N-Acetyl-70-bromo-D-tryptophan (R)-(1)-1-
phenylethylamide ((R)-5-amide). (R)-(þ)-1-Phenylethyl-
amine (8.8 mg, 0.074 mmol), EDCI (28.2 mg, 0.148 mmol),
diisopropylethyllamine (19 ml, 0.148 mmol), hydroxy-
benzotriazole (9.9 mg, 0.074 mmol) were added to a
solution of (R)-5 (24 mg, 0.074 mmol) in THF (2 ml) and
stirred for 24 h at room temperature under argon. The
reaction mixture was concentrated in vacuo, purified by
preparative TLC (hexane/AcOEt¼5:1) to give (R)-5-amide
(23 mg, 73%) as white crystals. Rf: 0.25 (hexane/
AcOEt¼1:5); mp: 230–2328C. [a]2D5¼þ5.608 (c¼0.25,
1
MeOH); H NMR (300 MHz, CD3COCD3) dH: 1.35 (3H,
d, J¼7.0 Hz, CHCH3), 1.90 (3H, s, Ac), 3.08, 3.18 (2H, dd,
J¼6.5, 14.5 Hz, 3-H2), 4.73 (1H, dt, J¼7.0, 6.5 Hz, 2-H),
5.02 (1H, quintet, J¼7.0 Hz, CHMe), 6.95 (1H, t, J¼7.5 Hz,
5-H0), 7.12 (1H, d, J¼2.5 Hz, 20-H), 7.12–7.30 (5H, m,
phenyl), 7.25 (1H, d, J¼7.0 Hz, 2-NHCO), 7.30 (1H, d,
J¼7.5 Hz, 40-H), 7.58 (1H, brd, J¼8.3 Hz, 1-CONH), 7.64
(1H, d, J¼7.5 Hz, 60-H), 10.09 (1H, brs, 10-H); 13C NMR
(100 MHz, CD3COCD3) dC: 22.41 (q, CHCH3), 22.92 (q,
COCH3), 29.03 (t, 3-C), 49.15 (d, CHCH3), 54.66 (d, 2-C),
104.99 (s, 70-C), 112.095 (s, 30-C), 119.18 (d, 60-C), 120.85
(d, 50-C), 124.59 (d, 4 -C), 125.57 (d, 20-C), 126.80, 127.45,
129.03 (each d, phenyl), 129.10 (s, 30a-C), 130.40 (s, 7a0-C),
145.00, (s, phenyl), 169.93, 171.16 (each s, NHCO£2).
HRFAB-MS m/z: 428.090 [MþH]þ, calcd for
C21H23O2N3Br79: 428.0974 [MþH].
4.1.11. 70-Bromo-D-tryptophan ((R)-1) from D-amino-
acylase route. D-Aminoacylase (7.2£103 U/g, 257 mg) in
phosphate buffer solution (pH 7.41, 10 ml) and CoCl2·6H2O
(0.2 mg) were added to a solution of (RS)-5 (1.0 g,
3.09 mmol) in phosphate buffer solution (115 ml). The
solution was shaken for 24 h at 378C. The reaction mixture
was adjusted to pH 5 with 10% HCl, filtered through celite
4.1.7. N-Acetyl-70-bromo-L-tryptophan methyl ester
((S)-8). A solution of TMSCHN2 (40 ml, 80.5 mmol) in
benzene (0.16 ml) was dropped to a solution of (S)-5
(20.3 mg, 62.7 mmol) in MeOH (0.12 ml) and benzene
(0.43 ml) and stirred for 30 min at room temperature under
argon. The solution was evaporated in vacuo to give a
yellow solid (23.2 mg). This was purified by preparative
TLC (CHCl3/MeOH¼7:1) to afford (S)-8 (14.0 mg, 66.1%)
as a white granules. Mp: 155–1568C; [a]2D6¼254.008
(c¼0.19, CHCl3). The data of Rf, 1H NMR were consistent
with those data of (R)-8. HRFAB-MS m/z: 338.0273 [M]þ,
calcd for C14H15O3N2Br79: 338.0266 [M].
4.1.8. N-Acetyl-70-bromo-D, L-tryptophan methyl ester
((RS)-8). A solution of TMSCHN2 (40 ml, 80.5 mmol) in
benzene (0.16 ml) was dropped to a solution of (RS)-5
(20.0 mg, 61.7 mmol) in MeOH (0.12 ml) and benzene

7858
Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
pad. The filtrate was washed with AcOEt (115 ml£3). The
water layer was purified by column chromatography
(SEPABEADS SP207, 200 ml of H2O, followed by
200 ml of MeOH). Concentration of eluate of MeOH
afforded (R)-1 (435.4 mg), quantitatively. The organic layer
was dried over Na2SO4, concentrated in vacuo to give (S)-5
(497.1 mg) quantitatively as light yellow amorphous
crystals. (R)-1: mp: 244–2488C (MeOH); [a]2D5¼þ11.428
(c¼0.98, MeOH). HRFAB-MS m/z: 283.0079 [MþH]þ,
calcd for C11H12O2N729Br: 283.0082 [MþH]. The data of Rf
and 1H NMR were consistent with those data of (R)-1. (S)-5:
HRFAB-MS m/z: 325.0179 [MþH]þ, calcd for
C13H14O3N2Br79: 325.0188 [MþH]. The data of Rf and
1H NMR were consistent with those of (RS)-5.
4.1.14. 70-Bromo-N-carbobenzyloxy-D-tryptophan (R)-
(1)-1-phenylethylamide (9). (R)-(þ)-1-Phenylethylamine
(3.64 mg, 0.03 mmol), EDCI (5.8 mg, 0.03 mmol),
hydroxybenzotriazole (HOBT) (4.0 mg, 0.03 mmol) were
added to a solution of (R)-6 (3.64 mg, 0.03 mmol) in THF
(0.8 ml) and stirred for 1.5 h at room temperature under
argon. The reaction mixture was concentrated in vacuo,
purified by preparative TLC (hexane/AcOEt¼1:2) to 9
(9 mg, 68.5%) as a white powder. Rf: 0.71 (CHCl3/
MeOH¼5:1); mp: 198–2008C. [a]2D5¼þ24.008 (c¼0.20,
CHCl3); 1H NMR (300 MHz, CDCl3) dH: 1.32 (3H, d,
J¼7.5 Hz, CHCH3), 3.06 (1H, dd, J¼8.5, 14.3 Hz, 3-Ha),
3.27 (1H, dd, J¼4.0, 14.3 Hz, 3-Hb), 4.44 (1H, br, 2-H),
4.97 (1H, quintet, J¼7.5 Hz, CHMe), 5.10, 5.12 (each 1H,
d, J¼13.0 Hz, CH2-Ph), 5.54 (1H, brd, J¼8.5 Hz,
2-NHCO), 5.69 (1H, brd, J¼6.5 Hz, 1-NH), 6.78 (1H, d,
J¼2.5 Hz, 20-H), 6.93 (1H, d, J¼6.5 Hz, 40-H), 6.94 (2H, d,
J¼6.5 Hz, phenethylamine arom-H), 6.99 (1H, t, J¼6.5 Hz,
50-H), 7.25 (3H, m, phenethylamine arom-H), 7.34 (5H, m,
benzyl-arom-H), 7.34 (1H, hidden, 60-H), 7.63 (1H, brd,
J¼7.0 Hz, 40-H), 8.21 (1H, br, 10-H); 13C NMR (100 MHz,
CD3COCD3) dC: 21.51 (q, CHCH3), 29.06 (t, 3-C), 48.80 (d,
CHCH3), 55.47 (d, 2-C), 67.03 (t, benzyl-CH2), 104.80 (s,
70-C), 111.70 (s, 30-C), 118.17 (d, 40-C), 121.05 (d, 50-C),
123.89 (d, 20-C), 124.69, 128.57, 128.60 (each d, phenyl),
125.94 (d, 60-C), 125.94 (d, phenyl), 127.37, 128.08, 128.04
(each d, phenyl), 134.79 (s, 3a0-C), 136.18 (s, 7a0-C), 142.52
(s, phenyl), 155.89 (s, NHCOO), 169.86 (s, CONH);
HRFAB-MS m/z: 542.1099 [MþNa]þ, calcd for C27H26O3-
N3Br79Na: 542.1055 [MþNa].
4.1.12. 70-Bromo-N-carbobenzyloxy-D-tryptophan ((R)-
6) from D-aminoacylase route. Cbz-Cl (101.6 ml,
0.852 mmol) in diethyl ether (0.3 ml) was dropped to a
solution of (R)-1 (200.0 mg, 0.709 mmol) in 10% aqueous
Na2CO3 (4 ml) at 08C, and stirred for 5 h. The reaction
mixture was acidified with 10% HCl at 08C to give
precipitates which were filtered, washed with H2O (1 ml)
to afford (R)-6 (231.9 mg, 98.8%) as a light yellow powder.
Mp: 96–998C (H2O); [a]2D4¼223.198 (c¼1.00, CHCl3); 13
C
NMR (100 MHz, CD3COCD3) dC: 28.33 (t, 3-C), 55.84 (d,
2-C), 66.56 (t, CH2-Ph), 104.99 (s, 70-C), 112.85 (s, 30-C),
118.95 (d, 40-C), 120.93 (d, 50-C), 124.58 (d, 60-C), 125.52
(d, 20-C), 128.51 (d, CH2-Ph arom C-2, 6), 129.11 (d,
CH2-Ph arom C-3, 5), 130.37 (s, 30a-C), 135.60 (s, 70a-C),
138.11 (d, CH2-Ph arom C-4), 156.78 (s, NHCO), 174.58 (s,
1-C); HRFAB-MS m/z: 416.0358 [M]þ, calcd for
C19H17O4N2Br79: 416.0372 [M]; the data of Rf and 1H
NMR were consistent with those of (R)-6 obtained by using
L-aminoacylase.
4.1.15. 70-Bromo-N-carbobenzyloxy-L-tryptophan ((S)-
6). Cbz-Cl (12 mg, 0.071 mmol) in diethyl ether (0.2 ml)
was dropped to a solution of (S)-1 (18 mg, 0.071 mmol) in
10% aqueous Na2CO3 (0.6 ml) at 08C, and stirred for
30 min. The reaction mixture was acidified with 10% HCl at
08C to give precipitates which were filtered, washed with
H2O (1 ml) to afford (S)-6 (20 mg, 95%) as a light yellow
powder. [a]2D5¼þ24.008 (c¼0.20, CHCl3); HRFAB-MS
m/z: 415.0321 [M2H]2, calcd for C19H16O4N2Br79:
415.0293 [M2H]. The data of Rf and 1H NMR were
consistent with those of (R)-6.
4.1.13. 70-Bromo-N-carbobenzyloxy-D-tryptophan tert-
butyl ester ((R)-7). K2CO3 (172.8 mg, 1.25 mmol) and
tert-butyl chloride (257.7 ml, 2.31 mmol) were added to a
solution of (R)-6 (20.0 mg, 48.1 mmol), benzyltriethyl-
ammonium chloride (11.0 mg, 48.1 mmol) in dimethyl-
acetamide (0.360 ml) and stirred for 20 h at 558C. Ice water
(30 ml) was added to the reaction mixture, extracted with
AcOEt (7.5 ml£2). The organic layer was washed with H2O
(3 ml£2), dried over Na2SO4 to provide light yellow gels,
which were purified by preparative TLC (hexane/
AcOEt¼5:1£2) to give (R)-7 (14.8 mg, 65.2%) as white
gels. Rf: 0.24 (1-BuOH/AcOH/H2O¼4:1:5); [a]2D5¼
222.358 (c¼0.34, CHCl3); IR (CHCl3) nmax cm21: 1730
4.1.16. 70-Bromo-N-carbobenzyloxy-L-tryptophan (R)-
(1)-1-phenylethylamide (10). (R)-(þ)-1-Phenylethyl-
amine (3.64 mg, 0.03 mmol), EDCI (5.8 mg, 0.03 mmol),
hydroxybenzotriazole (4.0 mg, 0.03 mmol) were added to a
solution of (S)-6 (10 mg, 0.03 mmol) in THF (0.8 ml) and
stirred for 30 min at room temperature under argon. The
reaction mixture was concentrated in vacuo, purified by
preparative TLC (hexane/AcOEt¼1:2) to give10 (8.4 mg,
64.0%) as a white powder. Rf: 0.83 (CHCl3/MeOH¼5:1);
mp: 198–2008C. [a]D25¼23.528 (c¼0.17, CHCl3); 1H NMR
(300 MHz, CDCl3) dH: 1.18 (3H, d, J¼6.5 Hz, CHCH3),
3.12 (1H, dd, J¼8.0, 14.3 Hz, 3-Ha), 3.35 (1H, dd, J¼4.5,
14.3 Hz, 3-Hb), 4.47 (1H, br, 2-H), 4.93 (1H, quintet,
J¼6.5 Hz, CHMe), 5.10 (2H, s, CH2-Ph), 5.42 (1H, brd,
J¼6.0 Hz, 2-NHCO), 5.76 (1H, d, J¼7.5 Hz, 1-NH), 7.00
(1H, hidden, 50-H), 7.02 (2H, m, phenethylamine arom-H),
7.03 (1H, brs, 20-H), 7.24 (3H, m, phenethylamine arom-H),
7.33 (5H, m, benzyl arom-H), 7.36 (1H, d, J¼6.0 Hz, 60-H),
7.34 (5H, m, benzyl-a0rom-H), 7.34 (1H, hidden, 60-H), 7.62
(1H, brd, J¼7.0 Hz, 4 -H), 8.20 (1H, br, 10-H); dC: 21.36 (q,
1
(NHCOO); H NMR (300 MHz, CDCl3) dH: 1.37 (9H, s,
tBu), 3.22, 3.29 (each 1H, dd, J¼6.0, 14.0 Hz, 3-H2), 4.62
(1H, dd, J¼6.0, 8.0 Hz, 2-H), 5.07, 5.13 (each 1H, d,
J¼12.0 Hz, CH2-Ph), 5.33 (1H, d, J¼8.0 Hz, NHCO), 6.96
(1H, t, J¼8.0 Hz, 50-H), 7.05 (1H, d, J¼3.0 Hz, 20-H), 7.33
(5H, m, Ph), 7.34 (1H, d, J¼8.0 Hz, 60-H), 7.34 (1H, s,
20-H), 7.53 (1H, d, J¼8.0 Hz, 40-H), 8.25 (1H, s, 10-H); 13
C
NMR (100 MHz, CDCl3) dC: 27.92 (q, C(CH3)3), 28.21 (t,
3-C), 54.92 (d, 2-C), 66.80 (t, CH2-Ph), 82.23 (s, C(CH3)3),
104.68 (s, 70-C), 111.81 (s, 30-C), 1180.27 (d, 40-C), 120.72
(d, 50-C), 123.19 (d, 20-C), 124.49 (d, 6 -C), 128.10 (d, CH2-
Ph arom C-2, 6), 128.48 (d, CH2-Ph arom C-3, 5), 129.00 (s,
30a-C), 134.71 (s, 7a0-C), 136.38 (d, CH2-Ph arom C-4),
155.69 (s, NHCO), 170.80 (s, 1-C); HRFAB-MS m/z:
472.0996 [M]þ, calcd for C23H25O4N2Br79: 472.0998 [M].

Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
7859
CHCH3), 28.75 (t, 3-CH2), 48.95 (d, CHCH3), 55.60 (d,
2-C), 67.09 (t, benzyl-CH2), 104.84 (s, 70-C), 112.043 (s,
30-C), 118.16 (d, 40-C), 121.19 (d, 50-C), 123.80 (d, 20-C),
124.77, 128.11, 128.26, 128.059, 128.60 (each0 d, phenyl),
125.97 (d, 60-C), 134.86 (s, 3a -C), 136.10 (s, 7a -C), 142.60
(s, phenyl), 155.89 (s, NHCOO), 169.86 (s, CONH);
HRFAB-MS m/z: 542.1093 [MþNa]þ, calcd for C27H26O3-
N3Br79Na: 542.1055 [MþNa].
(7a-C); HREI-MS: m/z: 194.9697 [M]þ, calcd for
C8H6NBr79: 194.9684 [M].
4.1.19. N-Acetyl-60-bromo-DL-tryptophan ((RS)-14).
L-Serine (316.8 mg, 3.078 mmol) was dissolved in a
solution of 13 (300 mg, 1.539 mmol) in AcOH (3.6 ml)
and Ac2O (1.2 ml) and the mixture was stirred for 2 h at
738C under argon. After cooled, the reaction mixture was
diluted with diethyl ether (30 ml) and adjusted to pH 11 with
30% NaOH and further ether (45 ml) was added and
partitioned. The ether layer was further extracted with 1N
NaOH (30 ml£2) and a small amount of Na2S2O4 was added
to the combined alkali solution, which was then neutralized
with conc. HCl, concentrated to 1/2 volume, acidified with
5% HCl to adjust to pH 3 using congo red as a indicator,
extracted with AcOEt (100 ml£3). The AcOEt layer was
washed with H2O (30 ml£2), dried over Na2SO4, concen-
trated in vacuo adding benzene several times to remove the
vapor of HCl gas to give (RS)-14 (477.4 mg, 96.0%) as light
brown crystals. The ether layer was dried over Na2SO4,
concentrated to give a brown solid, which was purified by
preparative TLC (CHCl3/MeOH¼10:1) to recovered 4
(4.5 mg). (RS)-14: Rf¼0.58 (1-BuOH/AcOH/H2O¼4:1:5);
mp: 84–868C (acetone); IR (KBr): nmax cm21 3200–3500
(indole-NH, amide-NH), 2400–2600 (COOH), 1700, 1710
(COOH), 1600–1640 (NHCO), 1540 (indole); 1H NMR
(300 MHz, CD3COCD3) dH: 1.91, 1.97 (3H, each s,
COCH3), 3.19 (1H, dd, J¼7.5, 14.5 Hz, 3-Ha), 3.32 (1H,
dd, J¼5.5, 14.5 Hz, 3-Hb), 4.79 (1H, dt, J¼5.5, 7.5 Hz,
2-H), 7.16 (1H, dd, J¼2.5, 8.4 Hz, 50-H), 7.24 (1H, d,
J¼3.0 Hz, 20-H), 70.28 (1H, brd, J¼7.5 Hz, NHCO), 7.56
(1H, d, J¼0 8.4 Hz, 4 -H), 7.58 (1H, d, J¼2.5 Hz, 70-H), 10.25
(1H, br, 1 -H); 13C NMR (100 MHz, CD3COCD3) dC 22.62,
22.66 (each q, CH3), 27.96, 27.99 (each t, 3-C), 53.73, 53.82
(each, d, 2-C), 111.5, 111.3 (each s, 60-C), 114.90, 114.96
(each d, 70-C), 114.96, (s, 30-C), 120.92 (d, 40-C), 122.57 (d,
50-C), 125.40, 125.24 (each d, 20-C), 127.73, 127.76 (each s,
3a-C), 138.10 (s, 7a-C), 165.36, 165.39 (each s, NHCO),
170.46, 170.53 (each s, COOH); HRFAB-MS m/z: 325.0188
[MþH]þ, calcd for C13H14O3N2Br79: 325.0188 [MþH].
4.1.20. 60-Bromo-D-tryptophan ((R)-2). D-Aminoacylase
(0.6 U/mol, 150.4 mg) in phosphate buffer solution (pH
7.41, 8 ml) and CoCl2·6H2O (0.2 mg) were added to a
solution of (RS)-14 (600 mg, 1.846 mmol) in phosphate
buffer solution (90 ml). The solution was shaken for 23 h at
378C. The reaction mixture was adjusted to pH 5 with 5%
HCl, filtered through celite pad. The filtrate was washed
with AcOEt (100 ml£3). The water layer was purified by
column chromatography (SEPABEADS SP207, 150 ml of
H2O, followed by 200 ml of MeOH). Concentration of
eluate of MeOH afforded (R)-2 (197.3 mg, 37.7%) as white
yellow crystals. The organic layer was dried over Na2SO4,
concentrated in vacuo to give (S)-14 (267.3 mg, 44.5%) as a
yellow oil. (R)-2: Rf¼0.35 (1-BuOH/AcOH/H2O¼4:1:5);
mp: 232–2368C (MeOH); [a]2D6¼þ22.408 (c¼1.0, MeOH);
1H NMR (300 MHz, CD3OD) dH: 3.15 (1H, dd, J¼9.0,
15.0 Hz, 3-Ha), 3.46 (1H, dd, J¼4.0, 15.0 Hz, 3-Hb), 3.83
(1H, dd, J¼4.0, 9.0 Hz, 2-H), 7.15 (1H, dd, J¼2.0, 8.5 Hz,
50-H), 7.20 (1H, brs, 20-H), 7.53 (1H, d, J¼2.0 Hz, 70-H),
7.62 (1H, d, J¼8.5 Hz, 40-H); 13C NMR (100 MHz,
CD3OD) dC 28.20 (t, 3-C), 56.550 (d, 2-C), 109.99 (s,
30-C), 115.27 (s, 70-C), 116.17 (s, 6 -C), 120.95 (d, 40-C),
4.1.17. N-Acetyl-70-bromo-L-tryptophan (R)-(1)-1-
phenylethylamide ((S)-5-amide). (R)-(þ)-1-Phenylethyl-
amine (8.8 mg, 0.074 mmol), EDCI (28.2 mg, 0.148 mmol),
diisopropylethylamine (19 ml, 0.148 mmol), hydroxybenzo-
triazole (9.9 mg, 0.074 mmol) were added to a solution of
(S)-5 (24 mg, 0.074 mmol) in THF (2 ml) and stirred for
24 h at room temperature under argon. The reaction mixture
was concentrated in vacuo, purified by preparative TLC
(hexane/AcOEt¼5:1) to give (S)-5-amide (21 mg, 67.0%)
as white crystals. Rf: 0.38 (hexane/AcOEt¼1:5); mp: 240–
2428C. [a]2D5¼þ37.718 (c¼0.35, MeOH); 1H NMR
(300 MHz, CD3COCD3) dH: 1.25 (3H, d, J¼7.0 Hz,
CHCH3), 3.12, 3.21 (each 1H, dd, J¼7.0, 14.5 Hz), 4.70
(1H, m, 2-H), 4.97 (1H, quintet, J¼7.0 Hz, CHCH3), 6.90
(1H, t, J¼7.5 Hz, 50-H), 7.15–7.30 (5H,0phenyl), 7.26 (1H,
brs, 20-H), 7.33 (1H, dd, J¼0.7, 7.5 Hz, 4 -H), 7.490(1H, brd,
J¼8.0 Hz, 2-NHCO), 7.68 (1H, d, J¼7.8 Hz, 6 -H); 13C
NMR (100 MHz, CD3COCD3) dC: 22.43 (q, CHCH3), 22.86
(q, Ac), 29.00 (t, 3-C), 49.31 (d, CHCH3), 54.78 (d, 2-C),
105.01 (s, 70-C), 113.019 (s, 30-C), 119.16 (d, 60-C), 120.87
(d, 50-C), 124.61 (d, 4 -C), 125.55 (d,020-C), 126.88, 127.47,
129.04 (each d, phenyl), 126.79 (s, 3a -C), 130.47 (s, 7a0-C),
145.22 (s, phenyl), 169.93, 171.09 (each s, NHCO£2);
HRFAB-MS m/z: 428.0951 [MþH]þ, calcd for
C21H23O2N3Br79: 428.0974 [MþH].
4.1.18. 6-Bromoindole (13). Dimethylformamidedimethyl-
acetal (8.580 g, 72 mmol) and pyrrolidine (3.0 ml) were
added to a solution of 4-bromo-2-nitrotoluene (11) (5.185 g,
24 mmol) in DMF (48 ml) and the mixture was stirred for
1 h at 1108C, under argon. The reaction mixture was diluted
with ether (300 ml), washed with H2O (50 ml£2). The water
layer was extracted with ether (120 ml) and the combined
organic layer was dried over Na2SO4, concentrated in vacuo
to give 20-nitro-40-bromostyryldimethylamine (12) as a dark
violet crude substance which was used for the next reaction
without purification. Zinc powder (13.6 g) was added in
portions to a solution of 12 obtained above in 80% AcOH
(160 ml) over 1 h at 758C, then the reaction mixture was
further stirred for 2.5 h at 858C. After the mixture was ice-
cooled and filtered, the filtrate was dissolved in AcOEt
(600 ml), washed with H2O (70 ml), saturated aqueous
NaCl (70 ml), dried over Na2SO4, evaporated in vacuo to
afford a crude substance (5.512 g), which was purified by
flash column chromatography (silica gel 450 g,
hexane/AcOEt¼30:1–15:1) to provide white blue crystals
13 (2.675 g, 56.9% from 11). 12: Rf¼0.40 (hexane/
AcOEt¼5:1); 13: Rf¼0.58 (hexane/AcOEt¼5:1); mp: 95–
1
978C (CHCl3); H NMR (300 MHz, CDCl3) dH: 6.54 (1H,
m, 3-H), 7.18 (1H, t, J¼2.5 Hz, 2-H), 7.23 (1H, dd, J¼2.0,
9.1 Hz, 5-H), 7.51 (1H, d, J¼9.1 Hz, 4-H), 7.55 (1H, d,
J¼2.0 Hz, 7-H), 8.14 (1H, br, 10-H); 13C NMR (100 MHz,
CDCl3) dC 102.74 (d, 3-C), 113.91 (d, 7-C), 121.88 (d, 4-C),
123.07 (d, 5-C), 124.79 (d, 2-C), 126.66 (s, 3a-C), 136.49

7860
Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
123.20 (d, 50-C), 126.14 (d, 20-C), 127.52 (s, 3a0-C), 139.16
(s, 7a0-C), 174.28 (s, COOH); HRFAB-MS m/z: 283.0092
[M]þ, calcd for C11H12O2N2Br79: 283.0082 [M]. (S)-14:
[a]2D7¼þ8.228 (c¼0.73, acetone); HRFAB-MS m/z:
325.0152 [MþH]þ, calcd for C13H14O3N2Br79: 325.0188
[MþH]. Rf and 1H NMR data coincided with that of (RS)-14.
(2170 U/mg, 100 mg) in phosphate buffer solution (pH 7.41,
8 ml) and CoCl2·6H2O (0.2 mg) was added to a solution of
(RS)-14 (100 mg, 0.309 mmol) in phosphate buffer solution
(15 ml). The solution was shaken for 24 h at 378C. The
reaction mixture was adjusted to pH 5 with 10% HCl,
filtered through celite pad. The filtrate was washed with
AcOEt (30 ml£2). Thewater layer was purified by column
chromatography (SEPABEADS SP207, 150 ml of H2O,
followed by 200 ml of MeOH). Concentration of eluate of
MeOH afforded (S)-2 (39 mg, 45%) as white plates. The
organic layer was washed with saturated aqueous NaCl
(10 ml), dried over Na2SO4, concentrated in vacuo to give
(R)-14 (31 mg, 46%) as a white powder. (S)-2: mp: 125–
1278C; [a]2D7¼218.578 (c¼0.14, MeOH); HRFAB-MS m/z:
283.0082 [M]þ, calcd for C11H12O2N2Br79: 283.0076 [M].
Rf, 1H NMR data coincided with that of (R)-2. (R)-14: mp:
88–928C; [a]2D7¼212.58 (c¼0.16, acetone); HRFAB-MS
m/z: 324.0107 [M]þ, calcd for C13H13O3N2Br79: 324.0110
[M]. Rf and 1H NMR data were coincided to that of (RS)-14.
4.1.21. 60-Bromo-N-carbobenzyloxy-D-tryptophan ((R)-
15). Cbz-Cl (40.3 ml, 0.282 mmol) in diethyl ether (0.2 ml)
was dropped to a solution of (R)-2 (80.0 mg, 0.282 mmol) in
10% aqueous Na2CO3 (1.6 ml) at 08C, and stirred for 1.5 h.
The reaction mixture was acidified with 10% HCl at 08C to
give precipitates which were filtered, washed with H2O
(0.1 ml£2) to afford (R)-15 (73.3 mg, 62.2%) as yellow-
gray crystals. Rf¼0.34 (CHCl3/MeOH/H2O¼10:2:0.1); mp:
110–1148C (acetone); [a]2D5¼þ6.808 (c¼1.0, MeOH); IR
(KBr): nmax cm21 3390 (indole-NH), 3280 (amide-NH),
1700 (COOH), 1640–1680 (NHCO), 1610 (benzene), 1530
(indole); 1H NMR (300 MHz, acetone-d6) dH 3.22 (1H, dd,
J¼8.0, 14.5 Hz, 3-Ha), 3.38 (1H, dd, J¼5.0, 14.5 Hz, 3-Hb),
4.58 (1H, dt, J¼5.5, 8.0 Hz, 2-H), 5.05 (2H, brs, benzyl-H2),
5.05 (1H, m, 2-NHCO), 7.15 (1H, dd, J¼2.0, 8.3 Hz, 50-H),
7.27 (1H, brs, 20-H), 7.57 (1H, d, J¼8.3 Hz, 400-H), 7.10–
7.44 (5H, m, phenyl), 7.59 (1H, t, J¼1.5 Hz, 7 -H), 10.19
(1H, br, 10-H); 13C NMR (100 MHz, CD3COCD3) dC: 28.08
(t, 3-C), 55.46 (d, 2-C), 66.63 (t, COOCH2), 111.49 (s, 30-C),
114.96 (d, 70-C), 115.26 (d, 60-C), 120.90 (d, 40-C), 122.65
(d, 50-C), 125.38 (d, 20-C), 128.56, 128.89, 129.15 (each d,
arom-C), 127.31 (s, 3a0-C), 138.13 (s, 7a0-C), 146.0 (s,
arom-C), 156.78 (s, NHCOO), 173.42 (s, 1-C); HRFAB-MS
m/z: 416.0378 [MþH]þ, calcd for C19H17N2O4Br79:
416.0372 [MþH].
4.1.24. 60-Bromo-N-carbobenzyloxy-L-tryptophan ((S)-
15). Cbz-Cl (21.1 mg, 0.124 mmol) in diethyl ether (0.2 ml)
was dropped to a solution of (S)-2 (35 mg, 0.124 mmol) in
10% aqueous Na2CO3 (1.0 ml) at 08C, and stirred for 1.5 h.
The reaction mixture was acidified with 10% HCl at 08C to
give precipitates which were filtered, washed with H2O
(1 ml£5) to afford (S)-15 (32 mg, 78.0%) as gray granules.
Mp: 115–1208C (acetone); Rf¼0.34 (CHCl3/MeOH/H2O¼
10:2:0.1); [a]2D7¼28.998 (c¼0.20, acetone); HRFAB-MS
m/z: 415.0321 [M2H]þ, calcd for C19H16O4N279Br 415.0293
[M2H]. Rf and 1H NMR data coincided with that of (R)-15.
4.1.25. 60-Bromo-N-carbobenzyloxy-L-tryptophan (R)-
(1)-1-phenylethylamide (17). (R)-(þ)-1-Phenylethyl-
amine (1.8 mg, 0.015 mmol), EDCI (2.9 mg, 0.015 mmol),
hydroxybenzotriazole (2.0 mg, 0.015 mmol) were added to
a solution of (S)-15 (5 mg, 0.015 mmol) in THF (0.4 ml) and
stirred for 3.6 h at room temperature under argon. The
reaction mixture was concentrated in vacuo, purified by
preparative TLC (hexane/AcOEt¼1:2) to give 17 (5.1 mg,
82%) as a light yellow powder. Rf¼0.38 (hexane/
AcOEt¼1:1); mp: 170–1748C; [a]2D6¼þ4.008 (c¼0.15,
CHCl3); 1H NMR (300 MHz, CDCl3) dH: 1.17 (3H, d,
J¼7.0 Hz, CHCH3), 3.11 (1H, dd, J¼8.0, 14.5 Hz, 3-Ha),
3.33 (1H, dd, J¼5.0, 14.5 Hz, 3-Hb), 4.45 (1H, dt, J¼5.0,
8.0 Hz, 2-H), 4.93 (1H, quintet J¼7.5 Hz, CHCH3), 5.10
(2H, br, benzyl-CH2), 5.41 (1H, brd, J¼8.0 Hz, 2-NHCO),
5.77 (1H, brd, J¼7.0 Hz, 1-CONH), 6.94 (1H, br, 20-H),
7.04 (1H, d, J¼8.5 Hz, 50-H), 7.25 (5H, m, CHPh), 7.34 (5H,
m, benzyl-arom.-H), 7.45 (1H, d, J¼2.0 Hz, 70-H), 7.51 (1H,
brd, J¼8.5 Hz, 40-H), 7.83 (1H, br, 10-H). 13C NMR
(100 MHz, CD3COCD3) dC 21.41 (each q, CHCH3), 28.50
(t, 3-C), 48.95 (d, CHCH3), 55.55 (d, 2-C), 67.11 (t, benzyl-
CH2), 110.98 (s, 60-C), 114.16 (d, 70-C), 116.06 (s, 30-C),
120.19 (d, 40-C), 123.34 (d, phenyl), 123.77 (d, 20-C), 125.98
(d, 50-C), 127.37, 128.15, 1028.30, 128.59 (each d, phenyl),
136.09, 136.93 (each s, 3 a, 7a0-C), 142.58 (s, phenyl),
155.93 (s, NHCOO), 169.90 (s, CONH); HRFAB-MS m/z:
520.1224 [M]þ, calcd for C27H27O3N3Br79: 520.1236 [M].
4.1.22. 60-Bromo-N-carbobenzyloxy-D-tryptophan (R)-
(1)-1-phenylethylamide (16). (þ)-1-Phenylethylamine
(1.6 mg, 0.014 mmol), EDCI (2.6 mg, 0.014 mmol), hydro-
xybenzotriazole (1.8 mg, 0.014 mmol) were added to a
solution of (R)-15 (4.5 mg, 0.014 mmol) in THF (0.4 ml)
and stirred for 3.6 h at room temperature under argon. The
reaction mixture was concentrated in vacuo, purified by
preparative TLC (hexane/AcOEt¼1:2) to give 16 (5.5 mg,
98%) as light yellow crystals. Rf¼0.58 (hexane/
AcOEt¼1:2); mp: 170–1748C; [a]2D5¼21.258 (c¼0.17,
CHCl3); 1H NMR (300 MHz, CDCl3) dH: 1.31 (3H, d,
J¼6.5 Hz, CHCH3), 3.06 (1H, dd, J¼8.5, 14.5 Hz, 3-Ha),
3.25 (1H, dd, J¼5.0, 14.5 Hz, 3-Hb), 4.42 (1H, dt, J¼5.0,
8.0 Hz, 2-H), 4.98 (1H, quintet J¼7.5 Hz, CHCH3), 5.11
(2H, s, benzyl-CH2), 5.52 (1H, brd, J¼8.0 Hz, 2-NHCO),
5.72 (1H, brd, J¼7.5 Hz, 1-CONH), 6.70 (1H, d, J¼2.0 Hz,
20-H), 7.18 (1H, brd, J¼8.5 Hz, 50-H), 7.25 (5H, m, CHPh),
7.34 (5H, m, benzyl-arom-H), 7.45 (1H, d, J¼2.0 Hz, 70-H),
7.51 (1H, brd, J¼8.5 Hz, 40-H), 7.83 (1H, br, 10-H); 13C
NMR (100 MHz, CD3COCD3) dC 21.58 (q, CHCH3), 28.72,
29.69 (each, t, 3-C), 48.88 (d, CHCH3), 55.46 (each d, 2-C),
67.06, 67.07 (each t, benzyl-CH2), 110.70, 110.74 (each, s,
60-C), 114.12 (d, 70-C), 115.98 (s, 030-C), 120.19 (d, 400-C),
123.21 (d, phenyl), 123.86 (d, 2 -C), 126.02 (d, 5 -C),
1207.35, 128.12, 128.28, 128.57 (each d, phenyl), 130.88 (s,
3a -C), 136.88 (s, 7a0-C), 142.59 (s, phenyl), 155.93 (s,
NHCOO), 169.87 (s, CONH); HRFAB-MS m/z: 520.1230
[M]þ, calcd for C27H27N3O3Br79: 520.1236 [M].
4.1.26. N-Acetyl-60-bromo-L-tryptophan (R)-(1)-1-
phenylethylamide ((S)-14-amide). (R)-(þ)-1-Phenylethyl-
4.1.23. 60-Bromo-L-tryptophan ((S)-2). L-Aminoacylase
amine
(16.6 mg,
0.138 mmol),
EDCI
(35.2 mg,

Y. Konda-Yamada et al. / Tetrahedron 58 (2002) 7851–7861
7861
0.184 mmol),
hydroxybenzotriazole
(12.42 mg,
K. Murakami of Touhou University for valuable
suggestions to obtain N-acetyl-D-amino acid and L-amino
acid in enzymatic optical resolution using L-aminoacylase
and thank Amano Enzyme Inc. for supply of D and
L-aminoacylases.
0.092 mmol), diisopropylethylamine (16 ml, 0.138 mmol)
were added to a solution of (S)-14 (30 mg, 0.092 mmol) in
THF (2.5 ml) and stirred for 7 h at room temperature under
argon. The reaction mixture was concentrated in vacuo,
purified by preparative TLC (hexane/AcOEt¼1:5) to give
(S)-14-amide (23 mg, 58%) as a white powder. Rf¼0.31
(hexane/AcOEt¼1:5); mp: 200–2058C; [a]2D4¼þ32.678
(c¼0.3, MeOH); 1H NMR (300 MHz, CD3COCD3) dH:
1.24 (3H, d, J¼7.0 Hz, CHCH3), 1.85 (3H, s, COCH3), 3.12,
3.20 (each 1H, ddd, J¼14.0, 7.0, 0.8 Hz, 3-H2), 4.71 (1H, dt,
J¼8.0, 7.0 Hz, 2-H), 4.97 (1H, quintet J¼7.0 Hz, CHCH3),
7.15 (1H, dd, J¼8.5, 2.0 Hz, 50-H), 7.21 (1H, t, J¼1.2 Hz,
20-H), 7.23–7.30 (6H, m, phenyl, 1-CONH), 7.52 (1H, brd,
J¼8.0 Hz, 2-NHCO), 7.58 (1H, d, J¼2.0 Hz, 70-H), 7.60
(1H, d, J¼8.5 Hz, 40-H), 10.25 (1H, br, 10-H). 13C NMR
(100 MHz, CD3COCD3) dC 22.39, 22.45 (each q, CHCH3),
22.78, 22.82 (each q, COCH3), 28.94 (t, 3-C), 49.12, 49.28
(each d, CHCH3), 54.67, 54.78 (each d, 2-C), 111.95 (s,
60-C), 114.82 (d, 70-C), 115.16 (s, 60-C), 121.018 (d, 40-C),
122.42, 122.47 (d, 50-C), 125.32, 125.23 (d, 2 -C), 126.87,
127.46, 129.03 (each d, phenyl), 138.14 (s, 7a0-C), 145.21
(s, phenyl), 169.89, 171.08 (each s, NHCO£2); HRFAB-MS
m/z: 428.0947 [Mþ1], calcd for C21H23O2N3Br79: 428.0974
[MþH].
4.1.27. N-Acetyl-60-bromo-D-tryptophan (R)-(1)-1-
phenylethylamide ((R)-14-amide). (R)-(þ)-1-Phenylethyl-
amine (8.8 mg, 0.074 mmol), EDCI (28 mg, 0.148 mmol),
hydroxybenzotriazole (9.9 mg, 0.074 mmol), diisopropyl-
ethylamine (19 ml, 0.148 mmol) were added to a solution of
(R)-14 (24 mg, 0.074 mmol) in THF (2.5 ml) and stirred for
24 h at room temperature under argon. The reaction mixture
was concentrated in vacuo, purified by preparative TLC
(hexane/AcOEt¼1:5) to give (R)-14-amide (20 mg, 63.4%)
as a white powder. Rf¼0.22 (hexane/AcOEt¼1:5); mp:
247–2508C; [a]2D5¼þ7.148 (c¼0.28, MeOH); 1H NMR
(300 MHz, CD3COCD3) dH: 1.35 (3H, d, J¼7.0 Hz,
CHCH3), 1.90 (3H, s, COCH3), 3.05, 3.16 (each 1H, ddd,
J¼14.0, 6.5, 0.8 Hz, 3-H2), 4.72 (1H, dt, J¼7.5, 6.5 Hz,
2-H), 5.02 (1H, quintet J¼7.0 Hz, CHCH3), 7.01 (1H, d,
J¼2.5 Hz, 20-H), 7.11 (1H, dd, J¼8.5, 1.7 Hz, 50-H), 7.21
(1H, brd, J¼7.5 Hz, 2-NHCO), 7.23 (5H, phenyl), 7.55 (1H,
d, J¼8.5 Hz, 40-H), 7.57 (1H, d, J¼1.7 Hz, 70-H), 7.58 (1H,
brd, J¼7.0 Hz, 1-CONH), 10.18 (1H, br, 10-NH). 13C NMR
(100 MHz, CD3COCD3) dC 22.42 (q, CHCH3), 22.93 (q,
COCH3), 28.94 (t, 3-C), 49.18 (d, CHCH3), 54.71 (d, 2-C),
111.81 (s, 30-C), 114.085 (d, 70-C), 1150.56 (s, 60-C), 121.20
(d, 40-C), 122.45 (d, 5 -C), 125.41 (d, 2 -C),0126.85, 127.46,
1209.02 (each s, phenyl-H), 127.77 (s, 3a -C), 138.29 (s,
7a -C), 145.05 (s, phenyl), 169.88, 171.17 (NHCO£2);
HRFAB-MS m/z: 428.0990 [Mþ1]þ, calcd for
C21H23O2N3Br79: 428.0974 [MþH].
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The authors greatly thank Dr Yokoyama and Professor Dr