Both enantiomers of N-Boc-indoline-2-carboxylic esters

Article abstract of DOI:10.1246/bcsj.77.1021

An immobilized form of Candida antarctica lipase (Chirazyme L-2) catalyzed enantioselective hydrolysis (E > 1000) of N-Boc-indoline-2-carboxylic acid methyl ester. The reaction proceeded efficiently at 60 °C, a temperature over the melting point of substrate, in the conversion of 49.9% to provide the hydrolyzed product, (S)-carboxylic acid with >99.9% ee and the unreacted (R)-ester with 99.6% ee. A newly developed expeditious route to the racemic substrate (a total of six steps, 60% yield), starting from aniline and ethyl α-methylacetoacetate, established the scalable chemoenzymatic synthesis of the desired compounds in both enantiomerically pure forms.

Full text of DOI:10.1246/bcsj.77.1021

ꢀ 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 1021–1025 (2004) 1021
Both Enantiomers of N-Boc-indoline-2-carboxylic Esters
ꢀ
Masayuki Kurokawa and Takeshi Sugai
Department of Chemistry, Keio University, Hiyoshi, Yokohama 223-8522
Received November 28, 2003; E-mail: sugai@chem.keio.ac.jp
An immobilized form of Candida antarctica lipase (Chirazyme L-2) catalyzed enantioselective hydrolysis
(E > 1000) of N-Boc-indoline-2-carboxylic acid methyl ester. The reaction proceeded efficiently at 60 ꢁC, a temperature
over the melting point of substrate, in the conversion of 49.9% to provide the hydrolyzed product, (S)-carboxylic acid with
>99:9% ee and the unreacted (R)-ester with 99.6% ee. A newly developed expeditious route to the racemic substrate
(a total of six steps, 60% yield), starting from aniline and ethyl ꢀ-methylacetoacetate, established the scalable chemo-
enzymatic synthesis of the desired compounds in both enantiomerically pure forms.
Enantiomerically pure N-protected forms of indoline-2-car-
boxylic esters (1, Fig. 1) are the starting material of diamines,
which are involved in catalytic asymmetric syntheses such as
enantiofacially selective reductions.1 They also play important
roles in medicinal chemistry2 and natural product synthesis.3 So
far, the traditional preferential crystallization of the diastereo-
meric amine salt4 and an enzymatic hydrolysis of a non-N-pro-
tected form, pentyl 2-indolinecarboxylate,5 have been reported
for the enantiomeric resolution of racemates, along with the
asymmetric syntheses.6 Our recent success in the enzyme-cata-
lyzed enantiomeric resolution of the N-protected form of pro-
line esters7 (2, Fig. 1) prompted us to establish a scalable
way to 1, involving expeditious synthesis of the racemic pre-
cursors.
ed as quickly as possible. Between two candidates, Cbz deriv-
ative 3a and Boc form 4a (Fig. 1), the direct analysis of the ee
of the former was successful (ChiralCel OB), but for the latter,
the chromatographic determination of the ee was possible, only
after derivatization to the corresponding alcohol 5.
This situation prompted us to take (ꢂ)-3a as the initial objec-
tive for elaboration of the reaction conditions. Although C. an-
tarctica lipase (Chirazyme L-2, immobilized form) showed an
excellent enantioselectivity (E > 200) on (ꢂ)-3a (Scheme 1),
as inferred from the structurally similar Cbz-proline ester 2,
there was a big difference from 2, namely, the very low reaction
rate. The reason for this was apparently the very low solubility
For establishment of the conditions of kinetic enantiomeric
resolution, the direct determination of the enantiomeric excess
(ee) of the enzyme-catalyzed reaction product and/or the un-
reacted substrate is the most important process so that the enan-
tiomeric ratio (E value)8 and the conversion should be evaluat-
Fig. 1.
Scheme 1.
Published on the web May 6, 2004; DOI 10.1246/bcsj.77.1021

1022 Bull. Chem. Soc. Jpn., 77, No. 5 (2004)
Enantiomers of Indoline-2-carboxylic Esters
ꢁ
due to the crystalline property of (ꢂ)-3a (80.0–80.6 C). The
addition of acetone, a water-miscible solvent,9 in a two-phase
reaction with toluene, was not effective, and only resulted in
low (6–22%) consumption of the initial racemate. The addition
of a detergent, Tween-80, could enhance its conversion to 49%
with the retention of high enantioselectivity (E > 200), howev-
er, the purification of the product from this additive turned out
to be a formidable task.
As this immobilized form of lipase (L-2) has substantial sta-
bility even at high temperature,10 we next tried the hydrolysis
reaction at a temperature of 85 ꢁC, expecting that the en-
zyme-catalyzed hydrolysis would be facilitated on the molten
substrate over the melting point. The reaction proceeded with
the E value of 120, at the conversion of 30% to give the enzy-
matically hydrolyzed product (S)-3b (97.2% ee) and the un-
reacted substrate (R)-3a (41.4% ee).
An alternative candidate, Boc form (ꢂ)-4a, turned out to be
an excellent substrate. As the melting point of the racemic form
(54.1–54.5 ꢁC) is lower than that of 3a (see above), the reaction
proceeded very smoothly at a lower reaction temperature (60
ꢁC). The successful reaction gave the enzymatically hydrolyzed
product (S)-4b (>99:9% ee) and the unreacted substrate (R)-4a
(99.6% ee) with the E value over 1000, and the conversion
reached 49.9% (Scheme 1). An ethyl ester (ꢂ)-4c (Fig. 1),
which is an oil even at room temperature, was expected to be
hydrolyzed at the conventional temperature, however, the reac-
tion was very slow even at 50 ꢁC, to result in conversion of as
low as 28.9%, although the enantioselectivity was still high
(E > 1000). The retardation is probably due to an increased
steric hindrance of the ethyl ester.11
At this juncture, we turned our attention to attempts for an
efficient preparation of the substrate (ꢂ)-4a, which is indispen-
sable to establish a ‘‘chemo-enzymatic’’ synthesis. As the key
intermediate, we selected the corresponding Boc derivative
6a12 (Scheme 2) of indole-2-carboxylic acid.13 Methyl ꢀ-meth-
ylacetoacetate (7a) and aniline were chosen as the starting ma-
terial through Japp–Klingemann azo ester synthesis.14
Toward this end, methyl acetoacetate was methylated,15 and
the resulting 7a that contains 9% of ꢀ,ꢀ-dialkylated by-prod-
uct16 was submitted to the coupling reaction with benzenedi-
azonium salt to give a mixture of an ꢀ-azo ester (8a) and ꢀ-hy-
drazone ester (9a).17 The rather acid-labile 8a was readily con-
verged to 9a, through a retro-Claisen condensation, by treat-
ment with aqueous acetic acid (total 59% from 7a). Fischer
indole cyclization of 9a in 30% HBr–acetic acid4a worked well
to give the desired product 6b in 80% yield.
The choice of the ethyl ester in the starting material brought
about some advantages. The commercially available, pure ethyl
ester 7b was derived to a mixture of 8b (63%) and 9b (23%).
Although the mixture of 8b and 9b was directly treated in aque-
ous HCl in ethanol, according to the previous paper,14b the re-
action resulted in a very complex mixture. Then, the azo ester
8b was converted to 9b, and the combined yield of 9b was re-
markably enhanced to as high as 81%, compared with 9a. In the
Fischer indole cyclization with HBr–acetic acid, also an en-
hanced (85%) yield of 6c was also recorded. The product was
treated with a catalytic amount of DBU in methanol to give
the corresponding methyl ester 6b in good yield. The use of
readily available homolog 7c from ethyl propionate via a newly
Scheme 2.
developed Claisen condensation18 was also attempted. The eno-
late formation of this compound with an increased hydropho-
bicity was very slow and the hydrolysis of the ester predominat-
ed under the same conditions used for Japp–Klingemann azo
ester synthesis. The major product under the treatment was a
hydrazone 1019 by way of the decarboxylative hydrazone
formation from the intermediate, azo carboxylic acid.
To route the optimum course from 6b to (ꢂ)-4a, preliminary
experiments provided an important suggestion: the t-butoxy-
carbonylation of indole-2-carboxylic ester 6b was quite faster
(at room temperature, 1 h, 99%) than that of the indoline-2-car-
boxylic ester 11 (at room temperature, 40 h, 69% of 4a; 27%
recovery of 11). The difference is supposed to be due to the in-
creased steric hindrance of the adjacent methoxycarbonyl
group over the lone pair electron of the heterocyclic secondary
amine. The indole derivative 6a became available from 6c in
96% yield in two steps. Accordingly, the remaining task was
the selective hydrogenation on the C-2 and C-3 positions of in-
dole to indoline. Inspired by the successful result on the reduc-
tion of 6b with magnesium in methanol,20 we submitted the
Boc derivative 6a to this reduction. The reaction worked well
and the desired product (ꢂ)-4a was obtained in 92% yield.
The Boc ester 6a was highly susceptible to electron transfer re-

M. Kurokawa et al.
Bull. Chem. Soc. Jpn., 77, No. 5 (2004) 1023
duction, and the use of alkali metal21 only resulted in deprotec-
tion of the Boc group into CO and t-BuOH or resulted in over-
reduction of the methoxycarbonyl group to a hydroxymethyl
group. In the case of the use of magnesium in methanol, the un-
desired reaction via ketene formation could be suppressed due
to the co-existing magnesium methoxide. Moreover, the seven-
membered chelate structure22 involving the magnesium ion sta-
bilized the intermediate to prevent the release of methoxide.
There is obviously an advantage that the feasibility of every
steps in large quantity makes our route scalable, compared with
the previous synthesis of (ꢂ)-4a which started from the metal-
lation of Boc-indole at C-2 position with t-BuLi and the subse-
quent methoxycarbonylation.12a
afford (S)-4a. Then the methyl ester (S)-4a was reduced with
NaBH4 to afford an alcohol (S)-5,6a on which the ee was estimated
to be 99.9% by the HPLC analysis. 1H NMR (270 MHz, CDCl3) ꢁ
1.58 (9H, br), 2.80 (2H, br), 3.34 (1H, dd, J ¼ 10:2, 16.3 Hz), 3.73
(2H, m), 4.60 (1H, br), 6.95 (1H, dd, J ¼ 7:4, 7.4 Hz), 7.12–7.18
(2H, m), 7.55 (1H, br); IR (neat) 3427 (OH), 2976, 2931, 1697
(C=O), 1603, 1485, 1392, 1287, 1255, 1169, 1140, 1041, 1018
cmꢄ1. The HPLC conditions were as follows: column, ChiralCel
OJ; eluent, hexane/i-PrOH = 29/1; flow rate, 0.5 mL/min; reten-
tion time, 26.8 (S) and 31.0 (R) min.
20
(R)-4a: Mp 51.3–52.0 ꢁC (lit.6a 51.0–53.0 ꢁC); ½ꢀꢃD þ72:3 (c
22
1.06, CHCl3) [lit.6a ½ꢀꢃD ꢄ73 (c 0.0088, CHCl3) for (S)-4a];
1H NMR (400 MHz, CDCl3) ꢁ 1.55 (9H, br), 3.11 (1H, dd,
J ¼ 4:4, 16.6 Hz), 3.51 (1H, dd, J ¼ 11:7, 16.1 Hz), 3.75 (3H,
s), 4.87 (1H, br), 6.95 (1H, dd, J ¼ 7:3, 7.3 Hz), 7.11 (1H, d, J ¼
7:3 Hz), 7.20 (1H, dd, J ¼ 7:3, 7.3 Hz), 7.50 (0.3H, br), 7.89 (0.7H,
br); IR (KBr) 2983, 1753 (C=O), 1703 (C=O), 1603, 1487, 1390,
1321, 1284, 1261, 1207, 1169, 1151, 1049 cmꢄ1. The spectral data
were identical with those reported previously.3a Due to the limited
rotation of N-Boc group, the proton NMR signal on C-7 split un-
equally. Found: C, 64.91; H, 6.82; N, 5.03%. Calcd for
C15H19NO4: C, 64.97; H, 6.91; N, 5.05%. The ee was estimated
to be 99.6% by the HPLC analysis of (R)-5 as above.
In conclusion, an expeditious chemo-enzymatic route to both
enantiomers of N-Boc-indoline-2-carboxylic esters, starting
from ethyl ꢀ-methylacetoacetate (7b) and aniline, was estab-
lished.
Experimental
General. No melting points were corrected. Infrared (IR) spec-
tra were recorded on a JASCO FT/IR-410 infrared spectrometer on
KBr pellets or liquid film on NaCl. 1H NMR spectra were recorded
on a JEOL JNM EX-270 (270 MHz) or JEOL JNM GX-400 (400
MHz) spectrometer using CDCl3 or DMSO-d6 as a solvent and
with tetramethylsilane as an internal standard. Analytical and prep-
arative thin-layer chromatography (TLC) were developed on E.
Merck Silica Gel 60 F256 plates (No. 5715; 0.25 mm and
No. 5744; 0.50 mm), respectively. High-performance liquid chro-
matography (HPLC) analyses were performed with a SSC-5410
(Senshu Scientific Co., Ltd.) liquid chromatograph. Column chro-
matography was carried out with silica gel 60 (spherical, 100–210
mm, Kanto Chemical Co.37558-79). Optical rotations were record-
ed with a JASCO DIP-360 polarimeter. Melting points were meas-
ured by Yanaco MP-S3.
Lipase-Catalyzed Enantioselective Hydrolysis of Methyl
(Æ)-1-Benzyloxycarbonyl-indoline-2-carboxylate
[(Æ)-3a].
To an emulsion of (ꢂ)-3a23 (101 mg, 0.324 mmol) and Tween-
80 (18.4 mg) in 0.1 M phosphate buffer (pH 7.0, 4.0 mL) and tol-
uene (1.1 mL) was added Candida antarctica lipase (Chirazyme L-
2, c-f, 202 mg) at 50 ꢁC. This mixture was vigorously stirred at 50
ꢁC for 36 h. A similar workup to that given above afforded (R)-3a
(51 mg, 51%) and (S)-3b (46 mg, 47%). A small portion of (S)-3b
was treated with TMSCHN2 to afford (S)-3a for the HPLC
analysis.
21
(S)-3a: Mp 81.0–81.5 ꢁC; ½ꢀꢃD ꢄ71:4 (c 0.83, CHCl3);
1H NMR (400 MHz, CDCl3) ꢁ 3.10 (1H, dd, J ¼ 4:0, 16.7 Hz),
3.57 (3H, br s), 3.41–3.75 (1H, m), 4.90 (1H, m), 5.07–5.35 (2H,
m), 6.83–7.94 (9H, m); IR (KBr) 2949, 1751 (C=O), 1703
(C=O), 1601, 1487, 1408, 1369, 1317, 1269, 1207, 1182, 1167,
1049 cmꢄ1. The absolute configuration was confirmed by compar-
Lipase-Catalyzed Enantioselective Hydrolysis of Methyl
(Æ)-1-t-Butoxycarbonyl-indoline-2-carboxylate [(Æ)-4a]. To
a suspension of (ꢂ)-4a (1.39 g, 5.01 mmol) in 0.1 M phosphate
buffer solution (pH 7.0, 50 mL) was added Candida antarctica li-
pase (Chirazyme L-2, c-f, 2.50 g) at 60 ꢁC. After having been vig-
21
ing its sign of rotation with that of the authentic (S)-3a [½ꢀꢃD
ꢁ
orously stirred at 60 C for 30 h, the mixture was cooled to room
ꢄ76:6 (c 0.99, CHCl3)], prepared from the commercially available
(S)-indoline-2-carboxylic acid (Aldrich. 34,680-2). The spectral
data were identical with those reported previously.1a Due to the
limited rotation of N-Cbz group, the NMR signals broadened.
Found: C, 69.31; H, 5.66; N, 4.44%. Calcd for C18H17NO4: C,
69.44; H, 5.50; N, 4.50%. The ee of (S)-3a was determined to be
96.9% by the HPLC analysis, and the conditions were as follows:
column, ChiralCel OB; eluent, hexane/i-PrOH = 5/1; flow rate,
0.5 mL/min; retention time, 36.0 (R) and 58.4 (S) min.
temperature and acidified by 4 M hydrochloric acid to pH 2.5.
The mixture was diluted with EtOAc and filtered through a Celite
pad. The filtrate was extracted with EtOAc three times and the
combined organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
silica-gel column chromatography (75 g). Elution with hexane–
EtOAc (14:1) afforded (R)-4a (0.700 g, 50%) as colorless needles,
and the further elution with hexane–EtOAc (1:2) gave (S)-4b
(0.640 g, 49%) as a colorless solid.
20
(R)-3a: Mp 78.1–78.8 ꢁC; ½ꢀꢃD þ69:6 (c 1.10, CHCl3). The ee
20
(S)-4b: Mp 126.0–126.4 ꢁC (lit.1d 124.1–124.8 ꢁC); ½ꢀꢃD
was estimated to be 92.5% by the HPLC analysis as above. Found:
C, 69.06; H, 5.68; N, 4.31%. Calcd for C18H17NO4: C, 69.44; H,
5.50; N, 4.50%.
ꢄ77:5 (c 1.03, CHCl3) [lit.1d ½ꢀꢃD ꢄ77:3 (c 1.00, CHCl3)];
20
1H NMR (400 MHz, DMSO-d6) ꢁ 1.47 (9H, s), 3.01 (1H, d, J ¼
16:4 Hz), 3.51 (1H, dd, J ¼ 12:0, 16.4 Hz), 4.75 (1H, dd,
J ¼ 4:2, 11.5 Hz), 6.92 (1H, dd, J ¼ 7:1, 7.1 Hz), 7.16 (2H, m),
7.38 (0.3H, br), 7.73 (0.7H, br), 12.91 (1H, br); IR (KBr) 3500–
2800 (br), 2978, 2650, 2567, 1711 (C=O), 1603, 1487, 1394,
1321, 1281, 1242, 1169, 1149, 1047 cmꢄ1. The spectral data were
identical with those reported previously.1d Due to the limited rota-
tion of N-Boc group, the signals on C-7 split unequally. Found: C,
63.87; H, 6.67; N, 5.25%. Calcd for C14H17NO4: C, 63.87; H, 6.51;
N, 5.32%. A small portion of (S)-4b was treated with TMSCHN2 to
Ethyl 2-Methyl-2-phenylazoacetoacetate (8b) and Ethyl 2-
(Phenylhydrazono)propionate (9b). According to the reported
procedure,14b to a mixture of aniline (3.73 g, 40.1 mmol), conc.
HCl (10.1 mL), and water (19.0 mL) was added dropwise a solu-
tion of NaNO2 (2.88 g, 41.7 mmol) in water (5.4 mL) with external
cooling in an ice–salt bath (ꢄ5 ꢁC). After the addition, the mixture
ꢁ
was stirred at 0 C for 15 min and then brought to pH 3.5 by the
addition of NaOAc (3.15 g, 38.4 mmol). In another flask separate-
ly, to a solution of ethyl ꢀ-methylacetoacetate (7b, 5.01 g, 34.8

1024 Bull. Chem. Soc. Jpn., 77, No. 5 (2004)
Enantiomers of Indoline-2-carboxylic Esters
mmol) in ethanol (27 mL) was added a solution of KOH (1.95 g,
ꢁ
with EtOAc three times, and the combined organic layer was wash-
ed with sat. aq. NaHCO3 solution and brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by silica-gel
column chromatography (45 g). Elution with hexane–EtOAc
(24:1) afforded 6a (795 mg, 96%) as a colorless solid. Mp 65.0–
65.5 ꢁC (lit.12b 63.0–65.0 ꢁC); 1H NMR (270 MHz, CDCl3) ꢁ
1.60 (9H, s), 3.92 (3H, s), 7.10 (1H, s), 7.25 (1H, dd, J ¼ 7:4,
7.4 Hz), 7.41 (1H, dd, J ¼ 7:4, 7.4 Hz), 7.60 (1H, d, J ¼ 7:4
Hz), 8.09 (1H, d, J ¼ 7:4 Hz). Its NMR spectrum was identical
with that reported previously.12 Found: C, 65.60; H, 6.28; N,
4.99%. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09%.
Methyl (Æ)-1-t-Butoxycarbonylindoline-2-carboxylate [(Æ)-
4a]. To a solution of 6a (338 mg, 1.23 mmol) in MeOH (8 mL)
was added Mg (92.0 mg, 3.78 mmol) at 0 ꢁC. The mixture was stir-
red at 0 ꢁC for 4 h, and then sat. aq. NH4Cl solution was added. The
mixture was extracted with EtOAc three times, and the combined
organic layer was washed with brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by silica-gel column
chromatography (20 g). Elution with hexane–EtOAc (16:1) afford-
34.7 mmol) in water (2.71 mL) at 0 C, followed by the addition
of ice (54.2 g). After stirring at 0–4 ꢁC for 1 h, the benzenediazo-
nium salt prepared above was added in one portion to the enolate
solution. The mixture was then adjusted to pH 6.0; this was stirred
at 0 ꢁC for 3 h, and was further stirred at 4 ꢁC for 12 h. The mixture
was extracted with EtOAc three times and the combined organic
layer was washed with brine, dried over Na2SO4, and concentrated
in vacuo to afford a dark viscous residue (8.2 g). A small portion of
the residue (72.0 mg) was purified by preparative TLC [20 ꢅ 20
cm, two plates, developed with hexane–EtOAc (4:1)] to afford
8b (47.8 mg) as red oil and 9b (15.0 mg) as yellow oil. The yields
of 8b and 9b were estimated to be 63% and 23%, respectively.
8b: 1H NMR (400 MHz, CDCl3) ꢁ 1.30 (3H, t, J ¼ 7:1 Hz), 1.68
(3H, s), 2.35 (3H, s), 4.30 (2H, q, J ¼ 7:1 Hz), 7.50 (3H, m), 7.77
1
(2H, m). 9b: H NMR (270 MHz, CDCl3) ꢁ 1.38 (3H, t, J ¼ 7:1
Hz), 2.07 (3H, s), 4.33 (2H, q, J ¼ 7:1 Hz), 6.92 (1H, t, J ¼ 7:3
Hz), 7.15–7.33 (4H, m), 7.70 (1H, br). Its NMR spectrum was iden-
tical with that reported previously.24
ꢁ
Ethyl 2-(Phenylhydrazono)propionate (9b). A mixture of 8b
and 9b (1.03 g) in AcOH (7.5 mL) and water (1.5 mL) was stirred
at room temperature for 15 h, and the reaction mixture was poured
into ice-cooled sat. aq. NaHCO3. The mixture was extracted with
EtOAc three times, and the combined organic layer was washed
with brine, dried over Na2SO4, and concentrated in vacuo. The res-
idue was purified by silica-gel column chromatography (40 g). Elu-
tion with hexane–EtOAc (7:1) afforded 9b (732 mg, 81%) as yel-
low crystals. Mp 116.0–116.5 ꢁC (lit.24 116.0–117.0 ꢁC). Its NMR
spectrum was identical with the sample above.
Methyl 2-(Phenylhydrazono)propionate (9a). In a similar
manner, methyl ꢀ-methylacetoacetate [7a, containing 9% of
ꢀ,ꢀ-dimethylated by-product:16 ꢁ (CDCl3) 1.36 (6H, s), 2.12
(3H, s)] was converted to 9a. Mp 101.0–101.5 ꢁC (lit.17 93.5
ꢁC); 1H NMR (400 MHz, CDCl3) ꢁ 2.10 (3H, s), 3.85 (3H, s),
6.95 (1H, t, J ¼ 7:3 Hz), 7.15–7.33 (4H, m), 7.72 (1H, br). Its
NMR spectrum was identical with that reported previously.17
Ethyl Indole-2-carboxylate (6c). A suspension of 9b (1.00 g,
4.85 mmol) in 30% HBr solution of acetic acid (5.0 mL, 25.1
mmol) was stirred at room temperature for 2 h. After the reaction
mixture was poured into an ice-cooled 0.1 M phosphate buffer so-
lution (pH 8.0), the mixture was extracted with EtOAc three times.
The combined organic layer was washed with sat. aq. NaHCO3 and
brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by silica-gel column chromatography (46 g). Elution
with hexane–EtOAc (9:1) afforded 6c (0.780 g, 85%) as colorless
needles. Mp 121.4–122.1 ꢁC (lit.25 121.0–124.0 ꢁC); 1H NMR (270
MHz, CDCl3) ꢁ 1.42 (3H, t, J ¼ 7:1 Hz), 4.42 (2H, q, J ¼ 7:1 Hz),
7.12–7.44 (4H, m), 7.69 (1H, d, J ¼ 8:1 Hz), 9.07 (1H, br). Its
NMR spectrum was identical with that reported previously.25
In the same manner, 6b was prepared from 9a in 80% yield.
ed 4a (316 mg, 92%) as colorless needles. Mp 54.1–54.4 C. The
1H NMR and IR data were identical with those of (R)-4a given
before. Found: C, 64.94; H, 6.69; N, 5.03%. Calcd for C15H19NO4:
C, 64.97; H, 6.91; N, 5.05%.
The authors thank Mr. Takeyuki Shindo for his help in dis-
solving the metal-mediated reduction of indole intermediates.
This work was accomplished as part of the 21st Century COE
Program (KEIO LCC) from the Ministry of Education, Culture,
Sports, Science and Technology. This work was also supported
by the collaborated program of ‘‘CREST: Creation of Functions
of New Molecules and Molecular Assemblies’’ of Japan Sci-
ence and Technology Corporation, and we express our sincere
thanks to Professors Keisuke Suzuki and Takashi Matsumoto of
the Tokyo Institute of Technology. Part of this work was sup-
ported by Grant-in-Aid for Scientific Research (No. 14560084).
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ꢁ
ꢁ
1
Mp 150.0–151.3 C (lit.26 147.0–150.0 C); H NMR (270 MHz,
CDCl3) ꢁ 3.95 (3H, s), 7.12–7.44 (4H, m), 7.69 (1H, d, J ¼ 8:1
Hz), 9.00 (1H, br). Its NMR spectrum was identical with that
reported previously.12b
4
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tion mixture was diluted with water. The mixture was extracted
5
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