Synthesis of tricyclic indole-2-caboxylic acids as potent NMDA-glycine antagonists

Article abstract of DOI:10.1021/jo010002h

The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz [cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for affinity to the NMDA-glycine binding site using the radio ligand binding assay with [³H]-5,7-dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the others and that especially substituted anilide (-)-isomer 24 (K_i = 0.8 nM) showed high affinity.

Full text of DOI:10.1021/jo010002h

3474
J . Org. Chem. 2001, 66, 3474-3483
Syn th esis of Tr icyclic In d ole-2-ca boxylic Acid s a s P oten t
NMDA-Glycin e An ta gon ists
Seiji Katayama, Nobuyuki Ae, and Ryu Nagata*
Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98 Kasugadenaka 3-chome, Konohana-ku,
Osaka 554-0022, J apan
rnagata@sumitomopharm.co.jp
Received J anuary 2, 2001
The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocar-
bonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-
glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a
regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, J effery’s Heck-
type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole
C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic
indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and
(2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed.
The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic
indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic
purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the
resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for
affinity to the NMDA-glycine binding site using the radio ligand binding assay with [3H]-5,7-
dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the
others and that especially substituted anilide (-)-isomer 24 (Ki ) 0.8 nM) showed high affinity.
There is increasing evidence that over-excitation of the
of tricyclic quinoxalinediones as a new class of potent
NMDA-glycine antagonists,6 both in in vitro and in vivo,
including SM-18400, which showed extremely high affin-
ity to the glycine site (Ki ) 0.4 nM) and neuroprotective
properties in several animal models.7 We have also
synthesized a series of tricyclic azakynurenic acids using
a novel Stille-type coupling reaction.8 These successful
results led us to devise another tricyclic series based on
indole-2-carboxylic acids. For the purpose of not only
investigating the structure-activity relationship (SAR)
but also extensive pharmacological and toxicological
studies, we required a practical route leading to a large
quantity of the target molecule. In this paper, we report
a practical synthesis of tricyclic indole-2-carboxylic acids
as a new class of potent NMDA-glycine antagonists.
NMDA receptor plays an important role in neuronal cell
death during ischemic or hypoxic conditions such as
stroke.1 Several binding sites on the NMDA receptor
including glutamate, glycine, and channel blocker binding
sites have been identified, and these sites offer a target
for the drug treatment of not only stroke but other
neurodegenerative disorders such as Alzheimer’s and
Hungtington’s diseases.2 However, an antagonist acting
at the glycine binding site will be more promising than
at other sites, since a glycine antagonist appears to have
less adverse side effects.3 Immediately after discovery of
the glycine binding site, several structurally distinct
antagonists of this site were identified, including quin-
oxalinediones such as 6,7-dichloroquinoxalinedione (1a ),
kynurenic acids such as 5,7-dichlorokynurenic acid (2a ),
and indole-2-carboxylic acids such as 4,6-dichloroindole-
2-carboxylic acid (3a ) (Figure 1).3 These antagonists were,
however, found not to penetrate the blood-brain barrier
and thus did not show activities in vivo. Much effort has
been devoted to identifying in vivo active glycine antago-
nists, and a few compounds including ACEA 10214 and
L-701,3245 have satisfied this criteria among a number
of the compounds synthesized so far. On the basis of the
quinoxalinedione structure, we have synthesized a series
(5) For L-701, 324, see: Bristow, L. J .; Hutson, P. H.; Kulagowski,
J . J .; Leeson P. D.; Matheson, S.; Murray, F.; Rathbone, D.; Saywell,
K. L.; Thorn, L.; Watt, A. P.; Tricklebank, M. D. J . Pharmacol. Exp.
Ther. 1996, 279, 492.
(6) (a) Nagata, R.; Tanno, N.; Kodo, T.; Ae, N.; Yamaguchi, H.;
Nishimura, T.; Antoku, F.; Tatsuno, T.; Kato, T.; Tanaka, H.; Naka-
mura, M.; Ogita, K.; Yoneda, Y. J . Med. Chem. 1994, 37, 3956. (b)
Nagata, R.; Ae, N.; Tanno, N. Bioorg. Med. Chem. Lett. 1995, 5, 1527.
(c) Nagata, R.; Kodo, T.; Yamaguchi, H.; Tanno, N. Bioorg. Med. Chem.
Lett. 1995, 5, 1533. (d) Katayama, S.; Ae, N.; Nagata, R. Tetrahedron:
Asymmetry 1998, 9, 4295.
(7) (a) SM-18400: (S)-9-chloro-5-[p-aminomethyl-o-(carboxymeth-
oxy)phenylcarbamoylmethyl]-6,7-dihydro-1H,5H-pyrido[1,2,3-de]quin-
oxaline-2,3-dione hydrochloride. (b) Nagata, R.; Tanno, N.; Yamaguchi,
H.; Kodo, T.; Ae, N.; Tanaka, H.; Nakamura, M.; Ogita, K.; Yoneda, Y.
Abstracts of Papers. 210th Meeting of the American Chemical Society;
Chicago, IL, August 1995; American Chemical Society: Washington,
DC, 1995; Medi 150. (c) Tanaka, H.; Yasuda, H.; Kato, T.; Maruoka,
Y.; Kawabe, A.; Kawashima, C.; Ohtani, K.; Nakamura, M. J . Cereb.
Blood. Flow. Metabol. 1995, 15, Suppl. 1, S431. (d) Ohtani, K.; Tanaka,
H.; Yasuda, H.; Maruoka, Y.; Kawabe, A.; Nakamura, M. Brain Res.
2000, 871, 311.
(1) Review: Rothman, S. M.; Olney, J . W. Trends Neurosci. 1995,
18, 57.
(2) Reviews: (a) Lipton, S. A.; Rosenberg, P. A. N. Engl. J . Med.
1994, 330, 613. (b) Muir, K. W.; Lees, K. R. Stroke 1995, 26, 503.
(3) Reviews: (a) Carter, A. J . Drugs Future 1992, 17, 595. (b) Kemp,
J . A.; Leeson, P. D. Trends Pharmacol. Sci. 1993, 14, 20. (c) Leeson,
P. D.; Iversen, L. L. J . Med. Chem. 1994, 37, 4053. (d) Danysz, W.;
Parsons, C. G. Pharmacol. Rev. 1998, 50, 597.
(4) For ACEA 1021, see: Lufty, K.; Weber, E. Brain Res. 1996, 743,
17.
(8) Hume, W. E.; Nagata, R. Synlett 1997, 5, 473.
10.1021/jo010002h CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/26/2001

Synthesis of Tricyclic Indole-2-caboxylic Acids
J . Org. Chem., Vol. 66, No. 10, 2001 3475
F igu r e 1.
Sch em e 1
Resu lts a n d Discu ssion
able and inexpensive. It was expected that the nitro
group should contribute to the regioselectivity of the
iodination at the C-6 position. Although the desired iodide
4 was formed under typical conditions such as using
iodine-silver sulfate in concentrated sulfuric acid11
(Table 1, entries 1 and 2), both the yield and the
regioselectivity were poor and considerable amounts of
undesired iodide 5 and diiodide were formed as byprod-
ucts. After several experiments, we found that addition
of 4-chloro-2-nitrotoluene into premixed N-iodosuccin-
imide (NIS)12 and concentrated sulfuric acid at 0 °C
afforded 4 with acceptable yield and regioselectivity
(Table 1, entry 3). However, NIS was too expensive to be
used in a large-scale synthesis. As an alternative, treat-
ing sodium iodate with a mixture of 4-chloro-2-nitro-
toluene and iodine in concentrated sulfuric acid13 at 5-10
According to the knowledge gained from our previous
study on tricyclic quinoxalinediones,6 we expected that
a series of 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-
tetrahydrobenz[cd]indole-2-carboxylic acids (tricyclic in-
dole-2-carboxylic acids) should also be potent NMDA-
glycine antagonists. To synthesize tricyclic indole-2-
carboxylic acid derivatives containing various aromatic
moieties on the C-3 side chain and examine their
pharmacological and toxicological profiles, we required
a large quantity of the desired tricyclic indole 16. As
outlined in Scheme 1, we planned to synthesize 16 by
an intramolecular cyclization of precursor 12, which could
be derived from 7 by installing a C5-unit at the C-4
position. Preparation of 7 was intended to be accom-
plished by a regioselective iodination of the readily
available 4-chloro-2-nitrotoluene followed by a Reissert
indole synthesis.9
(10) For a review of the synthesis of iodoaromatic compounds, see:
Merkushev, E. B. Synthesis 1988, 923.
(11) For an example of iodination using iodine-silver sulfate in
concentrated sulfuric acid, see: Derbyshire, D. H., Waters, W. A. J .
Chem. Soc. 1951, 3694.
Our route began with regioselective iodination10 of
4-chloro-2-nitrotoluene, which was commercially avail-
(12) For iodination using NIS in triflic acid, see: Olah, G. A.; Wang,
Q.; Sandford, G.; Prakash, G. K. S. J . Org. Chem. 1993, 58, 3194.
(9) Reissert, A.; Heller, H. Chem. Ber. 1904, 37, 4364.

3476 J . Org. Chem., Vol. 66, No. 10, 2001
Ta ble 1. Iod in a tion of 4-Ch lor o-2-n itr otolu en e
Katayama et al.
entry
reagents (molar equiv)
T (°C)
time (h)
yielda (%)
ratiob CNTc/4/5/diiodided
e
e
1
2
3
4
I2 (1.2), Ag2SO4 (1.2), H2SO4
I2 (1.2), Ag2SO4 (1.2), H2SO4
85
120
0
5
3
1
6
40
24
63
59
39:40:16:5
0:31:26:43
10:66:17:7
9:64:17:10
e
NIS (1.8), H2SO4
e
I2 (0.4), NaIO3 (0.4), H2SO4
5-10
a
b
Determined by HPLC analysis of crude products. Determined by 1H NMR of crude products, and values indicate the molar ratio.
c 4-Chloro-2-nitrotoluene. The structure was not determined. e H2SO4 was used as both an activator and a solvent.
d
Sch em e 2
six-membered ring product such as 8b was detected.
Quantitative conversion of 9 into the desired 7 was
effected by aqueous titanium trichloride. A more useful
modified Reissert indole synthesis has thus been discov-
ered. Treatment of the crude ketoester 6 with tin(II)
chloride dihydrate in DME at ambient temperature and
succesive addition of aqueous titanium trichloride to the
mixture produced crude 7 as a solid that was purified by
a simple washing with acetonitrile to give 7 with suf-
ficient purity (93 wt % purity, as determined by HPLC)
and the overall yield from 4-chloro-2-nitrotoluene was
51%.
As shown in Scheme 3, one-step formylethylation of 7
at the C-4 position was achieved by J effery’s Heck-type
reaction using allyl alcohol.15 More practically, cheap and
readily available benzyltriethylammonium chloride was
employed as a phase-transfer catalyst (PTC) instead of
tetrabutylammonium chloride, which had been used in
the original paper. Treatment of 7 with palladium
acetate, sodium hydrogen carbonate, PTC, and allyl
alcohol in DMF at 50 °C afforded aldehyde 10 in 90%
yield. Wittig-Horner-Emmons reaction of 10 with ethyl
diethylphosphonoacetate in THF in the presence of
potassium tert-butoxide afforded 11a , which underwent
iodination at the C-3 position with sodium iodide-N-
chlorosuccinimide (NCS)16 in DMF at ambient temper-
ature to give 12a in 94% yield from 10.
F igu r e 2.
°C also gave 4, although the yield was slightly lower than
that in the case of the NIS iodination (Table 1, entry 4).
The crude product 4 obtained under these conditions was
subjected to the next procedure without further purifica-
tion (Scheme 2).
4-Iodoindole 7 was prepared from 4 in accordance with
a modified Reissert procedure9 as shown in Scheme 2.
Treatment of 4 with dimethyl oxalate and potassium
methoxide in a mixed solvent of toluene/methanol at
ambient temperature quantitatively afforded 6, which
was used for the next step without further purification.
Reductive cyclization of 6 to 7 using standard reagents
such as iron powder, zinc powder, or aqueous titanium
trichloride always resulted in unsatisfactory yields. The
major reason for this was the accompanied formation of
3-hydroxyquinolin-2-one 8a (Figure 2). Using zinc powder
as a reducing reagent, significant deiodination was also
observed. The formation of 8a could be suppressed to less
than 20% when the reduction was carried out using iron
powder in a mixed solvent of toluene and acetic acid at
110 °C. An important discovery was made when tin(II)
chloride dihydrate14 was used as a reductant. Treatment
of 6 with tin(II) chloride dihydrate in dimethoxyethane
at room temperature did not yield 7 but N-hydroxyindole
9, exclusively (Figure 2), and importantly, none of the
We next examined the intramolecular radical cycliza-
tion of 12a to 13a . Many successful examples in similar
ω-halo-R,â-unsaturated ester systems have been re-
(15) For J effery’s Heck-type reaction, see: J effery, T. J . Chem. Soc.,
Chem. Commun. 1984, 1287.
(16) For in situ preparation of NIS using sodium iodide-N-chloro-
succinimide, see: (a) Vankar, Y. D.; Kumaravel, G. Tetrahedron Lett.
1984, 25, 233. For an example of bromination of indole at C-3 position
using N-bromosuccinimide (NBS) in DMF, see: (b) Tani, M.; Ikegami,
H.; Tashiro, M.; Hiura, T.; Tsukioka, H.; Kaneko, C.; Notoya, T.;
Shimizu, M.; Uchida, M.; Alda, Y.; Yokoyama, Y.; Murakami, Y.
Heterocycles 1992, 34 (12), 2349.
(13) For an example of iodination using a combination of iodine and
sodium iodate in concentrated sulfuric acid, see: Abderhalden, E Chem.
Ber. 1909, 44, 3411.
(14) For the reduction of aromatic nitro compounds with tin(II)
chloride, see: Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839.

Synthesis of Tricyclic Indole-2-caboxylic Acids
J . Org. Chem., Vol. 66, No. 10, 2001 3477
Sch em e 3
conditions, the reaction was sluggish, and deiodination19
occurred significantly although a small amount of desired
14a was formed. To overcome these problems, we inten-
sively investigated suitable conditions using highly puri-
fied substrate and selected examples are listed in Table
2.
Sch em e 4
To the palladium(II) acetate-triphenylphosphine sys-
tem in DMF, addition of both silver(I) phosphate20 and
an appropriate amount of triethylamine cooperatively
improved the yield (Table 2, entries 1-4). Silver(I)
phosphate afforded a better yield than other silver(I) salts
such as carbonate and sulfate (Table 2, entries 4-6).
Replacement of triethylamine with PTC such as tetra-
butylammonium hydrogensulfate was also effective, and
interestingly addition of water to the conditions signifi-
cantly increased conversion of 12a into 14a (Table 2,
entries 7, 8).21 Moreover, tetrakis(triphenylphosphine)-
palladium(0) (Pd(PPh3)4) was found to be a catalyst more
suitable for our system than others.22 In this case, the
reaction proceeded smoothly with excellent yield regard-
less of the presence of PTC (Table 2, entries 9, 10),
although anhydrous conditions resulted in the retarda-
tion of the reaction (Table 2, entry 11). It is noteworthy
that water enhanced the rate of the reaction even without
PTC. Heck cyclization of 12a was performed on a large
scale under the optimized conditions using Pd(PPh3)4,
silver(I) phosphate, and water in DMF (e.g., Table 2,
entry 10) followed by purification by washing the crude
ported.17 Substrate 12a was treated with tributyltin
hydride in the presence of AIBN in monochlorobenzene
(MCB) to give the desired cyclized product 13a as a major
product together with a considerable amount of deiodi-
nated byproduct 11a (e.g., 13a /11a ) ca. 7:3 at 100 °C,
0.2 M). To suppress the formation of 11a , we optimized
this procedure with respect to both concentration and
temperature and found that both lower concentration and
higher temperature were more preferable. Slow addition
of tributyltin hydride was ineffective. Simply heating a
0.05 M solution of the substrate and AIBN in MCB at
132 °C gave the most satisfactory result (Scheme 4).
Under these conditions, 13a was obtained in 80% yield
as determined by HPLC together with ca. 10% of 11a
and a small amount of impurity derived from the tin
reagent, although almost all the impurity was removed
by washing the acetonitrile solution of the crude reaction
mixture with hexane. The product was then used for the
next step without further purification.
Although radical cyclization could conveniently afford
the desired cyclized product, use of tributyltin hydride
should be avoided in a large-scale synthesis because of
its toxicity. Furthermore, the high dilution conditions
required were unfavorable for scaling-up. Next, we
examined an intramolecular Heck reaction. The resulting
R,â-unsaturated ester could be converted to the desired
saturated product by an appropriate 1,4-reduction. Ex-
amples of the construction of cyclic systems using the
Heck reaction have been reported.18 Among them, we
employed at first the standard conditions using palla-
dium(II) acetate, triphenylphosphine, and triethylamine
for 12a and soon encountered two problems. Under the
(18) For reviews of Heck cyclization, see: (a) De Meijere, A.; Meyer,
F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (b) J effery, T. Adv.
Met.-Org. Chem. 1996, 5, 153. (c) Gibson, S. E.; Middleton, R. J .
Contemp. Org. Synth. 1996, 3(6), 447. (d) Shibasaki, M.; Boden, C. D.
J .; Kojima, A. Tetrahedron 1997, 53(22), 7371. (e) Link, J . T.; Overman,
L. E. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J ., Eds.; Wiley-VCH Verlag GmbH: Weinheim, Germany,
1998; pp 231-69. (f) Brass, S.; De Meijere, A. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH Verlag
GmbH: Weinheim, Germany, 1998; pp 99-166. (g) Link, J . T.;
Overman, L. E. CHEMTECH 1998, 28 (8), 19.
(19) For an example of debromination of 3-bromoindole, see: Tani,
M.; Goto, M.; Shimizu, M.; Mochimaru, Y.; Amemiya, J .; Mizuno, N.;
Sato, R.; Murakami, Y. Synlett 1996, 931.
(20) For examples of Heck reaction using silver(I) salt effectively
and examples using AgNO3, see: (a) Karabelas, K.; Westerlund, C.;
Hallberg, A. J . Org. Chem. 1985, 50, 3896. (b) Abelman, M. M.; Oh,
T.; Overman, L. E. J . Org. Chem. 1987, 52, 4130. For an example using
Ag2CO3, see: (c) Abelman, M. M.; Overman, L. E.; Tran, V. D. J . Am.
Chem. Soc. 1990, 112, 6959. For examples using Ag3PO4, see: (d)
Madin, A.; Overman, L. E. Tetrahedron Lett. 1992, 33, 4859. (e) Sato,
Y.; Honda, T.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2593.
(21) For examples of the Heck reaction in aqueous medium, see: (a)
Genet, J . P.; Blart, E.; Savignac, M. Synlett 1992, 715. (b) J effery, T.
Tetrahedron Lett. 1994, 35, 3051.
(17) For reviews of radical cyclization, see: (a) Giese, B. Radicals
in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon
Press Oxford. 1986. (b) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J .;
Thoma, G.; Kulicke, K. J .; Trach, F. Org. React. 1996, 48, 301.
(22) For an excellent example of Heck cyclization using Pd(PPh3)4,
see: McClure, K. F.; Danishefsky, S. J . J . Am. Chem. Soc. 1993, 115,
6094.

3478 J . Org. Chem., Vol. 66, No. 10, 2001
Ta ble 2. Op tim iza tion of Con d ition s for In tr a m olecu la r Heck Rea ction a
Katayama et al.
entry
catalystb
additives (molar equiv)
Ag3PO4 (2.0)
time (h)
yieldc (%)
ratiod 12a :14a :11a
1
2
3
4
5
6
7
8
9
A
A
A
A
A
A
A
A
B
B
B
7
7
7
7
7
0
24
35
80 (73)
63
42
70
87 (82)
95
96 (90)
95
Et3N (3.0)
Ag3PO4 (2.0), Et3N (2.5)
Ag3PO4 (2.0), Et3N (0.5)
Ag2CO3 (2.0), Et3N (0.5)
Ag2SO4 (2.0), Et3N (0.5)
Ag3PO4 (2.0), nBu4NHSO4 (1.0)
Ag3PO4 (2.0), nBu4NHSO4 (1.0), H2Oe
Ag3PO4 (0.8), nBu4NHSO4 (0.2), H2Oe
Ag3PO4 (0.8), H2Oe
39:40:21
10:83:7
17:68:15
41:53:6
24:73:3
3:93:4
1:97:2
1:97:2
5:94:1
7
13
12
6
5
10
10
11
Ag3PO4 (0.8)
a
b
Reaction conditions: 100 mg of substrate, 1.0 mL of DMF, 80 °C; other reagents and times were described in table. Catalyst: (A)
4 mol % of Pd(OAc)2, 0.08 equiv of Ph3P; (B) 2 mol % of Pd(Ph3P)4. c Determined by HPLC analysis of crude product, and values in
d
parentheses were isolated yields. In isolation of product, the reaction scale was 10-fold as large as that described in footote a. Determined
by HPLC analysis of crude product, and values were area ratio. e Water (0.1 mL) was added to DMF (1.0 mL).
Sch em e 5
F igu r e 3.
Sch em e 6
product with toluene to afford 14a in 81% isolated yield
nickel chloride24 in a mixed solvent of THF and methanol
at 10 °C was also effective in reducing 14a to 13a in a
practical yield (85%, as determined by HPLC).
(Scheme 5).
Unfortunately, 1,4-reduction of 14a by hydrogenation
using the typical heterogeneous catalysts such as pal-
ladium or palladium hydroxide on carbon and platinum
dioxide did not proceed, even at elevated temperatures
and pressures. Although the use of Wilkinson’s catalyst,
under 60 kg/cm2 of hydrogen, afforded the saturated
product, dechlorination was significant. Next, we inves-
tigated various electron-transfer reductions and found
that the combination of samarium and iodine23 was
promising, while the use of magnesium afforded a
complex mixture of products. In the literature,23 sa-
marium reduction of R,â-unsaturated esters was per-
formed in alcoholic solvent such as methanol or 2-pro-
panol. Under the conditions using methanol, however,
our substrate 14a significantly afforded the transesteri-
fied product and 14a did not dissolve well in 2-propanol,
which might have avoided the transesterification. A
simple solution of the problem was to use THF as a
solvent and add a small amount of methanol as a
hydrogen donor. Under these conditions, the substrate
was completely consumed and the desired product 13a
was formed in high yield (87%, as determined by HPLC)
with concomitant formation of indoline 15a (Figure 3,
5%). We found that 15a could be converted into 13a by
adding some base such as triethylamine or potassium
tert-butoxide. Under the optimum conditions with sa-
marium, iodine, and methanol in THF at 0 °C followed
by in situ treatment with triethylamine, 14a was con-
verted into 13a in 92% yield (as determined by HPLC)
(Scheme 5), which was used for the next step without
purification. A combination of sodium borohydride and
At this stage, both an ethyl and a methyl ester were
present in the same molecule and it was necessary to
hydrolyze selectively the ethyl ester to obtain the mono-
carboxylic acid 16. Fortunately, hydrolysis of 13a with
aqueous 12 N HCl in acetic acid at 80 °C afforded 16
exclusively. As the reaction proceeded, we observed that
16 gradually precipitated out. Such precipitate formation
from the reaction media might avoid further hydrolysis
to the dicarboxylic acid. Crude 16 could be purified by
washing with acetonitrile to sufficient purity (95 wt %
purity, as determined by HPLC). Using crude 13a
obtained via radical cyclization, 16 was formed in 56%
overall yield from 12a (Scheme 6). Upon using crude 13a
obtained via the sequence of Heck cyclization and sa-
marium reduction, the yield of 16 was slightly enhanced
to 60% from 12a (Scheme 6). It is noteworthy from the
standpoint of the large-scale synthesis that any chro-
matographic purifications were not required through the
entire sequence from 4-chloro-2-nitrotoluene to 16 which-
ever cyclization method was employed.
The optical resolution of racemate 16 was achieved by
using (+)- and (-)-norephedrine as a resolving agent, in
2-propanol (Scheme 7). The simplified protocol of succes-
sive resolution, purification, and desalination afforded
(-)-isomer 17 ([R]25D -105.7°, c 1.0, MeOH) in 39% yield
using (-)-norephedrine.25 In a similar manner, (+)-
norephedrine gave (+)-isomer 18 ([R]25 +106.2°, c 1.0,
D
MeOH) in 40% yield. The optical purity of 17 and 18 was
(24) For 1,4-reduction using sodium borohydride and nickel chloride,
see: Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19, 9
(4), 817.
(23) For 1,4-reduction using samarium and iodine in alcohol, see:
Yanada, R.; Bessho, K.; Yanada, K. Synlett 1995, 443.

Synthesis of Tricyclic Indole-2-caboxylic Acids
J . Org. Chem., Vol. 66, No. 10, 2001 3479
Sch em e 7
Sch em e 8
Ta ble 3. Affin ity for th e Glycin e Bin d in g Sitea
compd
Ki (nM) vs [3H]DCKAb
19
19
23 [(-)- isomer]
24 [(-)-isomer]
25 [(+)-isomer]
MDL29951c (3b)
SM-18400
1.5
0.8
24
13
0.4
F igu r e 4.
determined to be 98.5% ee and 98.6% ee, respectively,
by HPLC using a chiral stationary column.
a
b
See ref 27. DCKA: 5,7-dichlorokynurenic acid. c See ref 28.
Scheme 8 illustrates the synthesis of selected tricyclic
indole-2-carboxylic acids which were subsequently evalu-
ated for their biological activities. Hydrolysis of 16 with
aqueous 2 N LiOH in a mixed solvent of methanol and
THF provided the corresponding dicarboxylic acid 19 in
94% yield. Condensation of 16 with aniline, using a
combination of 1-(3-(dimethylamino)propyl)-3-ethylcarbo-
diimide hydrochloride (WSC) and 1-hydroxybenzotriazole
(HOBT) in DMF, followed by saponification gave anilide
20 in 92% yield. Introduction of the anilide moiety, which
is identical to that in SM-184007 the most potent glycine
antagonist in a series of our tricyclic quinoxalinediones,
to 16 by using aniline 2126 followed by deprotection
afforded substituted anilide 22 in 84% yield. (-)-Isomers
23, 24, and (+)-isomer 25 were prepared starting from
(-)-isomer 17 and (+)-isomer 18, respectively, without
loss of optical purity according to the procedure described
for the corresponding racemic compounds as shown in
Scheme 8.
The affinity of the compounds was measured by the
radio ligand binding assay using [3H]-5,7-dichloro-
kynurenic acid27 and listed as their Ki values in Table 3.
As expected, this series of tricyclic indole-2-carboxylic
acids had appreciable affinity. The affinity of racemic
dicarboxylic acid 19 (Ki ) 19 nM) was comparable to that
of MDL29951 (3b)28 (Ki ) 13 nM), which is a standard
indole-2-carboxylic acid-based glycine antagonist. Fur-
thermore, the affinity of anilide (-)-isomer, 23 (Ki ) 1.5
nM), was much higher than that of 3b. Remarkably, the
affinity of substituted anilide (-)-isomer, 24 (Ki ) 0.8
nM), was not only superior to that of 3b but also
comparable to that of SM-18400 (Ki ) 0.4 nM). In
contrast, the affinity of anilide (+)-isomer 25 (Ki ) 24
nM) was 30-fold weaker than that of (-)-isomer 24.
(25) The absolute configuration of (-)-isomer 17 which led to active
compounds 23 and 24 was confirmed by a single X-ray crystallography
to be S, and that was consistent with our previous results (ref 6a).
The details will be published elsewhere.
(26) For the practical synthesis of SM-18400 aromatic fragment 21,
see: (a) Kodo, T.; Nishihara, T.; Nagata, R. Abstracts of Papers. 219th
Meeting of the American Chemical Society, San Francisco, March 2000;
American Chemical Society: Washington, DC, 2000; Orgn 610. For
the preparation of 21 and initial synthetic routes of tricyclic indole-
2-carboxylic acids, also see: (b) Nagata, R.; Tanno, N.; Ae, N. US Patent
5,496,843.
(27) For the binding assay using [3H]-5,7-dichlorokynurenic acid,
see: Yoneda, Y.; Suzuki, T.; Ogita, K.; Han, D. J . Neurochem. 1993,
60, 634.
(28) For MDL29951, see: Baron, B. M.; Harrison, B. L.; McDonald,
I. A.; Meldrum, B. S.; Palfreyman, M. G.; Salituro, F. G.; Siegel, B.
W.; Slone, A. L.; Turner, J . P.; White, H. S. J . Pharmacol. Exp. Ther.
1992, 262, 947.

3480 J . Org. Chem., Vol. 66, No. 10, 2001
Katayama et al.
separated and the aqueous layer was extracted with 2:1 ethyl
acetate/toluene (750 mL). The organic layers were combined
and concentrated to give crude 6 (935 g) as a brown oil. This
product was used in the following reaction without further
purification. The purity of crude 6 was 41 wt % determined
by HPLC. HPLC conditions: column, SUMIPAX ODS A-212;
mobile phase, acetonitrile/0.1% aqueous H3PO4 (60:40); flow
rate, 1.0 mL/min; UV detection, 254 nm; tR for 6, 10.1 min; 4,
20.7 min. A pure sample of 6 was obtained as a white solid
after purification by silica gel column chromatography with
20:1 hexane/ethyl acetate: mp 101-103 °C; 1H NMR (270
MHz, CDCl3) δ 3.95 (s, 3H), 4.70 (s, 2H), 8.01 (d, 1H, J ) 2.0
Hz), 8.15 (d, 1H, J ) 2.0 Hz); 13C NMR (75 MHz, CDCl3) δ
48.28, 53.42, 104.71, 125.32, 130.51, 134.99, 143.57, 149.18,
Con clu sion
Thus, we successfully generated a novel series of
tricyclic indole-2-carboxylic acids as potent NMDA-gly-
cine antagonists based on our tricyclic strategy by using
a practical synthetic route. In particular, the anilide (-)-
isomer 24 (Ki ) 0.8 nM) represents a class of compounds
with the highest affinity for the NMDA-glycine binding
site known to date. Further modification of these mol-
ecules to improve the in vivo activities and the pharma-
cological evaluation are in progress.29 The results will be
published elsewhere.
160.18, 187.25; HRMS (EI) (m/z) calcd for
C10H7NO5ClI
Exp er im en ta l Section
382.9057, found 382.9017. Anal. (C10H7NO5ClI): C, H, N.
Meth yl 4-Iod o-6-ch lor oin d ole-2-ca r boxyla te (7). A solu-
tion of crude 6 (880 g) obtained above in dimethoxyethane (1.65
L) was added dropwise to a solution of SnCl2‚2H2O (1.16 kg,
5.15 mol) in dimethoxyethane (1.65 L) at room temperature
while the temperature was maintained below 30 °C. The
mixture was stirred for 1 h at room temperature. 20% Aqueous
TiCl3 solution (2.65 kg, 3.43 mol) was then added dropwise to
the mixture under cooling with an ice bath while the temper-
ature was kept below 10 °C. The resulting mixture was stirred
at 0-10 °C for a further 1 h. Aqueous 6 N HCl (5.6 L) and 2:1
ethyl acetate/toluene (9.6 L) were added to the reaction
mixture. The organic layer was separated, washed with
aqueous 1 N HCl (5.6 L), and concentrated to give the crude
product (632 g). This product was suspended in acetonitrile
(6.3 L), heated at reflux for 30 min, and then allowed to cool
to room temperature. The precipitate produced was collected
by filtration, washed with ice-cooled acetonitrile (600 mL ×
2), and dried in vacuo to give 7 (295 g, 51% overall yield from
4-chloro-2-nitrotoluene) as a white solid. The purity of 7 was
93 wt % determined by HPLC. HPLC conditions: column,
SUMIPAX ODS A-212; mobile phase, acetonitrile/0.1% aque-
ous H3PO4 (55:45); flow rate, 1.0 mL/min; UV detection, 254
nm; tR for 6, 13.7 min; intermediate 9, 19.1 min; 7, 27.8 min.
Compound 7 could be further purified by recrystallization from
acetone/water to give the analytically pure sample as a white
Gen er a l P r oced u r e. All reactions were carried out in oven-
dried glassware under an atmosphere of N2. All reagents and
solvents were obtained commercially and used without puri-
fication. Melting points were uncorrected. Elemental analyses
and high-resolution mass spectra were obtained from Sumi-
tomo Analytical Center, Inc. Thin-layer chromatography and
flash column chromatography were performed on silica gel
glass-backed plates (5719, Merck & Co.), and silica gel 60
(230-400 or 70-230 mesh, Merck & Co.), respectively. Optical
purity was determined by HPLC with chiral stationary
columns (CHIRALPAK AD, Daicel; SUMICHIRAL OA-4400,
OA-2500, Sumitomo Analytical Center).
2-Iod o-4-ch lor o-6-n itr otolu en e (4). To an ice-cooled mix-
ture of 4-chloro-2-nitrotoluene (343 g, 2.00 mol), iodine (204
g, 0.800 mol), and concentrated sulfuric acid (1.96 kg, 20.0 mol)
was added portionwise sodium iodate (158 g, 0.800 mol) while
the temperature was maintained below 10 °C. The mixture
was then stirred at 5-10 °C for 6 h. The reaction mixture was
poured slowly into 1:1 ice/water (2 L) with stirring while
cooling in an ice bath, and the mixture was extracted with
toluene (2.5 L). The organic layer was treated with aqueous
10% sodium thiosulfate solution (1 L × 2), washed with water
(1 L × 2) and aqueous 1 N NaOH (1 L × 2) successively, dried
over sodium sulfate, and concentrated to give crude 4 (548 g)
as a yellow oil. This crude product was used in the following
reaction without further purification. The purity of crude 4 at
this stage was 62 wt % determined by HPLC. HPLC condi-
tions: column, SUMIPAX ODS A-212; mobile phase, acetoni-
trile/0.1% aqueous H3PO4 (60:40); flow rate, 1.0 mL/min; UV
detection, 254 nm; tR for 4-chloro-2-nitrotoluene, 10.5 min;
3-iodo-4-chloro-6-nitrotoluene 5, 17.8 min; 2-iodo-4-chloro-6-
nitrotoluene 4, 20.7 min; diiodide, 30.7 min. The crude product
can be further purified by silica gel column chromatography
with hexane to give the analytically pure sample as a white
solid: mp 42-44 °C; 1H NMR (270 MHz, CDCl3) δ 2.56 (s, 3H),
7.74 (d, 1H, J ) 2.0 Hz), 8.06 (d, 1H, J ) 2.0 Hz); 13C NMR
(75 MHz, CDCl3) δ 24.48, 103.47, 124.04, 132.76, 133.63,
142.33, 149.86; HRMS (EI) (m/z) calcd for C7H5NO2ClI 296.9053,
found 296.9064. Anal. (C7H5NO2ClI): C, H, N.
1
solid: mp 216-218 °C; H NMR (270 MHz, DMSO-d6) δ 3.89
(s, 3H), 6.91 (s, 1H), 7.48 (m, 1H), 7.56 (d, 1H, J ) 2.0 Hz),
12.5 (bs, 1H); 13C NMR (75 MHz, DMSO-d6) δ 52.15, 89.80,
110.24, 112.18, 128.46, 129.02, 129.40, 130.07, 135.84, 161.07;
HRMS (EI) (m/z) calcd for C10H7NO2ClI 334.9209, found
334.9185. Anal. (C10H7NO2ClI): C, H, N.
8a : 1H NMR (270 MHz, DMSO-d6) δ 7.12 (s, 1H), 7.31 (d,
1H, J ) 1.8 Hz), 7.71 (d, 1H, J ) 1.8 Hz), 10.21 (s, 1H), 12.20
(bs, 1H); HRMS (FAB) (m/z) calcd for C9H6NO2ClI (MH+)
321.9131, found 321.9117.
9: 1H NMR (270 MHz, CDCl3) δ 4.02 (s, 3H), 6.90 (d, 1H, J
) 0.7 Hz), 7.53-7.55 (m, 2H); LC-MS (ESI) (m/e) calcd for
C
10H7NO3ClI (MH+) 351.9, found 352.1.
Met h yl 4-(2-F or m ylet h yl)-6-ch lor oin d ole-2-ca r b oxyl-
5: 1H NMR (270 MHz, CDCl3) δ 2.54 (s, 3H), 7.89 (s, 1H),
8.04 (s, 1H).
a te (10). To a solution of 7 (280 g, 835 mmol) in DMF (1.4 L)
were added sodium hydrogen carbonate (140 g, 1.67 mol),
benzyltriethylammonium chloride (190 g, 835 mmol), palla-
dium(II) acetate (3.74 g, 16.7 mmol), and allyl alcohol (97.0 g,
1.67 mol). The mixture was stirred at 50 °C for 4 h and then
allowed to cool to room temperature. A solution of sodium
thiosulfate pentahydrate (8.32 g, 33.5 mmol) in water (58 mL)
was added, and the resulting mixture was stirred vigorously
at room temperature for 20 min. Activated charcoal (14 g) was
added and the mixture stirred for 15 min. The mixture was
filtered, and the solid collected on the filter was washed with
DMF (180 mL). Water (4.8 L) was added slowly to the
combined filtrate under cooling with an ice bath while the
temperature was maintained below 10 °C. The mixture was
allowed to warm to room temperature and stirred for 30 min.
The precipitate produced was collected by filtration and
washed with water (960 mL × 2) and dried in vacuo to give
10 (200 g, 90% yield) as a white solid. The purity of 10 was 83
wt % determined by HPLC. HPLC conditions: column, SUMI-
PAX ODS A-212; mobile phase, acetonitrile/0.1% aqueous TFA
Diiodide: 1H NMR (270 MHz, CDCl3) δ 2.40 (s, 3H), 8.00
(s, 1H).
Meth yl (2-Iod o-4-ch lor o-6-n itr op h en yl)p yr u va te (6).
Toluene (700 mL) and dimethyl oxalate (795 g, 6.73 mol) were
added to a solution of potassium methoxide (470 g, 6.70 mol)
in methanol (1.4 L). The mixture was stirred at room temper-
ature for 20 min, and a solution of crude 4 (500 g) obtained
above in toluene (700 mL) was added dropwise. The resulting
mixture was stirred at room temperature for 4 h. The reaction
mixture, being occasionally diluted with methanol (total 600
mL), was poured slowly into aqueous 5 N HCl (1.5 L) with
stirring while cooling in an ice bath. After ethyl acetate (2.5
L) and water (1.5 L) were added, the organic layer was
(29) Katayama, S.; Ae, N.; Tanaka, H.; Nagata, R. Abstracts of
Papers. 220th Meeting of the American Chemical Society, Washington,
DC, August 2000; American Chemical Society: Washington, DC, 2000;
Medi 215.

Synthesis of Tricyclic Indole-2-caboxylic Acids
J . Org. Chem., Vol. 66, No. 10, 2001 3481
(60:40); flow rate, 1.0 mL/min; UV detection, 254 nm; tR for
10, 6.2 min; 7, 17.8 min. Compound 10 could be further
purified by recrystallization from toluene/ethyl acetate to give
the analytically pure sample as a white solid: mp 167-169
°C; 1H NMR (270 MHz, CDCl3) δ 2.90 (t, 2H, J ) 7.4 Hz), 3.20
(t, 2H, J ) 7.4 Hz), 3.96 (s, 3H), 6.96 (d, 1H, J ) 1.7 Hz), 7.22
(d, 1H, J ) 1.7 Hz), 7.29 (d, 1H, J ) 1.3 Hz), 9.06 (bs, 1H),
9.86 (t, 1H, J ) 1.0 Hz); 13C NMR (75 MHz, DMSO-d6) δ 24.76,
43.30, 51.86, 106.44, 110.00, 119.69, 125.02, 127.54, 129.31,
136.61, 137.50, 161.46, 202.50; Anal. (C13H12NO3Cl.1/8H2O): C,
H, N.
Meth yl 4-(4-Eth oxycar bon yl-3-bu ten yl)-6-ch lor oin dole-
2-ca r boxyla te (11a ). To a suspension of potassium tert-
butoxide (87.8 g, 792 mmol) in THF (1.1 L) was added dropwise
triethyl phosphonoacetate (176 g, 792 mmol), and the mixture
was stirred for 30 min at room temperature. A solution of 10
(189 g, 713 mmol) in THF (1.9 L) was added dropwise followed
by stirring for 1.5 h at room temperature. Water (2.0 L) was
added, and the resulting mixture was extracted with 1:1 ethyl
acetate/toluene (4.0 L). The organic layer was washed with
water (2.0 L × 2) and concentrated in vacuo to give 11a (237
g, 99% yield) as a white solid. The purity of 11a was 83 wt %
determined by HPLC. HPLC conditions: column, SUMIPAX
ODS A-212; mobile phase, acetonitrile/0.1% aqueous H3PO4
(66:33); flow rate, 1.0 mL/min; UV detection, 254 nm; tR for
10, 5.9 min; 11a , 10.8 min. Compound 11a could be further
purified by recrystallization from toluene to give the analyti-
cally pure sample as a white solid: mp 134-137 °C; 1H NMR
(270 MHz, CDCl3) δ 1.29 (t, 3H, J ) 7.2 Hz), 2.63 (m, 2H),
3.02 (m, 2H), 3.96 (s, 3H), 4.19 (q, 2H, J ) 7.2 Hz), 5.87 (d,
1H, J ) 15.8 Hz), 6.95 (d, 1H, J ) 1.65 Hz), 7.02 (dt, 1H, J )
15.8, 6.9 Hz), 7.21 (t, 1H, J ) 1.0 Hz), 7.29 (s, 1H), 9.02 (bs,
1H); 13C NMR (75 MHz, DMSO-d6) δ 14.09, 30.59, 32.12, 51.81,
59.68, 106.57, 109.99, 119.68, 121.44, 125.17, 127.52, 129.32,
136.73, 137.55, 148.47, 161.49, 165.61. Anal. (C17H18NO4Cl):
C, H, N.
Meth yl3-Iod o-4-(4-eth oxyca r bon yl-3-bu ten yl)-6-ch lor o-
in d ole-2-ca r boxyla te (12a ). To DMF (880 mL) with stirring
in a water bath was added portionwise sodium iodide (118 g,
785 mmol), a solution of N-chlorosuccinimide (105 g, 785 mmol)
in DMF (880 mL) was added slowly, and the mixture was
stirred at room temperature for 1 h. A solution of 11a (220 g,
655 mmol) obtained above in DMF (880 mL) was added slowly
followed by stirring at room temperature for 2 h. To the
reaction mixture were added dropwise aqueous 10% sodium
thiosulfate solution (1.3 L) and water (4.9 L), and the resulting
mixture was stirred at room temperature for 2 h. The
precipitate produced was collected by filtration, washed with
water (1 L × 3), and dried in vacuo to give 12a (286 g, 95%
yield) as a white solid. The purity of 12a was 87 wt %
determined by HPLC. HPLC conditions: column, SUMIPAX
ODS A-212; mobile phase, acetonitrile/0.1% aqueous H3PO4
(66:33); flow rate, 1.0 mL/min; UV detection, 254 nm; tR for
12a , 17.6 min; 11a , 11.0 min. Compound 12a could be further
purified by recrystallization from toluene to give the analyti-
cally pure sample as a white solid: mp 188-190 °C; 1H NMR
(270 MHz, CDCl3) δ 1.31 (t, 3H, J ) 7.2 Hz), 2.61 (m, 2H),
3.44 (m, 2H), 3.99 (s, 3H), 4.21 (q, 2H, J ) 7.2 Hz), 5.94 (d,
1H, J ) 15.8 Hz), 6.94 (d, 1H, J ) 1.7 Hz), 7.10 (dt, 1H, J )
15.8, 6.9 Hz), 7.32 (d, 1H, J ) 1.7 Hz), 9.35 (bs, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 14.14, 29.19, 34.33, 51.92, 59.76, 61.56,
110.83, 121.47, 122.10, 124.57, 127.72, 129.42, 137.58, 137.91,
147.91, 160.55, 165.61; HRMS (EI) (m/z) calcd for C17H17NO4-
ClI 460.9890, found 460.9880. Anal. (C17H17NO4ClI): C, H, N.
Ra d ica l Cycliza tion of 12a . Meth yl 7-Ch lor o-3-eth oxy-
ca r bon ylm eth yl-1,3,4,5-tetr a h yd r oben z[cd ]in d ole-2-ca r -
boxyla te (13a ). To a solution of 12a (160 g, 347 mmol) in
monochlorobenzene (6.4 L), heated at reflux was added drop-
wise a solution of tributyltin hydride (121 g, 415 mmol) and
azobisisobutyronitrile (14.2 g, 86.6 mmol) in monochloro-
benzene (710 mL). The mixture was heated at reflux for 1 h.
The reaction mixture was allowed to cool to room temperature,
and the solvent was removed in vacuo. Acetonitrile (1 L),
hexane (1 L), and activated charcoal (16 g) were added to the
residue, and the mixture was stirred rapidly at room temper-
ature for 30 min and filtered. The acetonitrile layer was
separated, and the hexane layer was extracted with acetoni-
trile (360 mL). The combined acetonitrile layers were washed
with hexane (1 L × 3) and concentrated in vacuo to give crude
13a (111 g). This product was used in the following reaction
without further purification. The purity of 13a was 73 wt %
determined by HPLC. HPLC conditions: column, SUMIPAX
ODS A-212; mobile phase, acetonitrile/H2O (66:33); flow rate,
1.0 mL/min; UV detection, 254 nm; tR for 11a , 11.4 min; 13a ,
13.2 min; 12a , 17.7 min. Compound 13a could be further
purified by recrystallization from hexane/toluene to give the
analytically pure sample as a white solid: mp 127-129 °C;
1H NMR (270 MHz, CDCl3) δ 1.28 (t, 3H, J ) 7.3 Hz), 2.01
(m, 1H), 2.17 (m, 1H), 2.48 (dd, 1H, J ) 14.9, 10.5 Hz), 2.73
(dd, 1H, J ) 14.9, 4.0 Hz), 2.82 (m, 1H), 3.00 (m, 1H), 3.92 (m,
1H), 3.95 (s, 3H), 4.18 (q, 2H, J ) 7.3 Hz), 6.88 (s, 1H), 7.17
(s, 1H), 8.70 (bs, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.07,
22.18, 27.68, 28.92, 38.04, 51.61, 59.87, 108.97, 116.76, 121.44,
123.22, 124.39, 130.43, 134.64, 134.77, 161.59, 171.54. Anal.
(C17H18NO4Cl): C, H, N.
Meth yl 7-Ch lor o-3-ca r boxym eth yl-1,3,4,5-tetr a h yd r o-
ben z[cd ]in d ole-2-ca r boxyla te (16). Crude 13a (110 g) ob-
tained above was dissolved in acetic acid (660 mL) at 80 °C.
Aqueous 12 N HCl (220 mL) was added, and the mixture was
stirred at 80 °C for 3.5 h and then cooled to room temperature.
Water (1.2 L) was added, and the mixture was extracted with
1:3 THF/ethyl acetate (4.8 L). The organic layer was washed
with water (1.2 L × 2), treated with activated charcoal (6.5
g), filtered, and concentrated in vacuo to give crude product
(108 g). This product was suspended in acetonitrile (500 mL),
heated at reflux for 1 h, and allowed to cool to room temper-
ature. The precipitated crystals were collected by filtration,
washed with acetonitrile (60 mL × 3), and dried in vacuo to
give 16 (59.5 g, 56% yield from 12a ) as white crystals. The
purity of 16 was 95 wt % determined by HPLC. HPLC
conditions: column, SUMIPAX ODS A-212; mobile phase,
acetonitrile/0.1% aqueous H3PO4 (66:33); flow rate, 1.0 mL/
min; UV detection, 254 nm; tR for 16, 4.95 min; 13a , 13.0 min.
Compound 16 could be recrystallized from 2-propanol: mp 235
°C dec; 1H NMR (270 MHz, DMSO-d6) δ 1.88 (m, 1H), 2.11
(md, 1H, J ) 12.5 Hz), 2.37 (dd, 1H, J ) 15.2, 10.6 Hz), 2.56
(dd, 1H, J ) 15.2, 4.3 Hz), 2.80 (md, 1H, J ) 17.2 Hz), 2.94
(mt, 1H, J ) 13.9 Hz), 3.77 (m, 1H), 3.88 (s, 3H), 6.84 (s, 1H),
7.17 (s, 1H), 11.60 (s, 1H), 12.17 (bs, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 22.20, 27.57, 28.77, 38.10, 51.57, 108.93, 116.69,
121.35, 123.58, 124.45, 130.42, 134.65, 134.85, 161.65, 173.20.
Anal. (C15H14NO4Cl.1/10H2O): C, H, N.
In tr am olecu lar Heck Reaction of 12a. Meth yl 7-Ch lor o-
3-et h oxyca r b on ylm et h ylid en e-1,3,4,5-t et r a h yd r ob en z-
[cd ]in d ole-2-ca r boxyla te (14a ). To a solution of 12a (240
g, 520 mmol) and tetrakis(triphenylphosphine)palladium(0)
(12.0 g, 10.4 mmol) in DMF (2.4 L) were added silver(I)
phosphate (174 g, 416 mmol) and water (480 mL) at room
temperature, and the mixture was stirred at 90 °C for 4 h and
then allowed to cool to room temperature. The reaction mixture
was treated with activated charcoal (12 g) at room temperature
for 15 min and filtered. The solid collected on the filter was
washed with 1:1 ethyl acetate/toluene (1 L × 2). To the
combined filtrates were added water (2 L) and 1:1 ethyl
acetate/toluene (2 L). The organic layer was separated, washed
with water (1.2 L × 2), treated with activated charcoal (12 g),
dried over magnesium sulfate, and concentrated in vacuo to
give the crude product (187 g). The product was triturated in
toluene (380 mL), filtered, washed with toluene (19 mL × 2),
and dried in vacuo to give 14a (140 g, 81% yield) as a yellow
solid. The purity of 14a was 88 wt % determined by HPLC.
HPLC conditions: column, SUMIPAX ODS A-212; mobile
phase, acetonitrile/H2O (60:40); flow rate, 1.0 mL/min; UV
detection, 254 nm; tR for 14a , 19.6 min; 12a , 22.1 min.
Compound 14a could be further purified by recrystallization
from hexane/tert-butyl methyl ether to give the analytically
pure sample as a pale yellow solid: mp 180-181 °C; 1H NMR
(270 MHz, CDCl3) δ 1.34 (t, 3H, J ) 7.2 Hz), 3.06 (t, 2H, J )
6.5 Hz), 3.48 (t, 2H, J ) 6.5 Hz), 3.99 (s, 3H), 4.24 (q, 2H, J )
7.2 Hz), 6.96 (d, 1H, J ) 1.3 Hz), 7.20 (d, 1H, J ) 1.3 Hz),

3482 J . Org. Chem., Vol. 66, No. 10, 2001
Katayama et al.
7.26 (s, 1H), 9.01 (bs, 1H); 13C NMR (75 MHz, DMSO-d6) δ
14.07, 30.58, 32.10, 51.79, 59.66, 106.54, 109.97, 119.66,
121.42, 125.15, 127.50, 129.30, 136.71, 137.53, 148.44, 161.47,
165.59; HRMS (EI) (m/z) calcd for C17H16NO4Cl 333.0768,
found 333.0770. Anal. (C17H16NO4Cl): C, H, N.
Meth yl (+)-7-Ch lor o-3-ca r boxym eth yl-1,3,4,5-tetr a h y-
d r oben z[cd ]in d ole-2-ca r boxyla te (18). A procedure similar
to that described in synthesis of 17 was carried out with 16
(60.0 g, 195 mmol) using (1S,2R)-(+)-norephedrine instead of
(1R,2S)-(-)-norephedrine to give the title compound (23.8 g,
98.6% ee, 40% yield from 16): mp 200-201 °C; [R]25D ) +106.2°
(c 1.00, MeOH). The spectral properties of the title compound
were identical with those of the racemate.
7-Ch lor o-3-ca r boxym eth yl-1,3,4,5-tetr a h yd r oben z[cd ]-
in d ole-2-ca r boxylic Acid (19). To a solution of 16 (1.00 g,
3.25 mmol) in 1:1 THF/methanol (20 mL) was added aqueous
2 N LiOH (10 mL, 20 mmol) The mixture was stirred at room
temperature for 20 h, acidified with aqueous 1 N HCl, and
extracted with ethyl acetate. The organic layer was washed
successively with water and brine, dried over magnesium
sulfate, and concentrated. The residual solid was rinsed with
1:1 hexane/2-propanol, collected by filtration, and dried in
vacuo to give 19 (900 mg, 94% yield) as a white solid: mp 245-
247 °C dec; 1H NMR (270 MHz, DMSO-d6) δ 1.87 (m, 1H), 2.08
(md, 1H, J ) 12.2 Hz), 2.35 (dd, 1H, J ) 15.5, 11.5 Hz), 2.64
(dd, 1H, J ) 15.3, 3.0 Hz), 2.78 (md, 1H, J ) 15.8 Hz), 2.93
(mt, 1H, J ) 12.7 Hz), 3.76 (m, 1H), 6.83 (s, 1H), 7.14 (s, 1H),
11.45 (s, 1H), 12.58 (bs, 2H); 13C NMR (75 MHz, DMSO-d6) δ
22.28, 27.34, 28.66, 37.98, 108.90, 116.53, 122.54, 122.94,
1,4-Red u ction of 14a . Meth yl 7-Ch lor o-3-eth yoxyca r -
bon ylm eth yl-1,3,4,5-tetr a h yd r oben z[cd ]in d ole-2-ca r box-
yla te (13a ). To a mixture of 14a (135 g, 405 mmol), methanol
(54.1 mL, 1.33 mol), and metallic samarium (134 g, 890 mmol)
in THF (1.0 L) was added slowly a solution of iodine (103 g,
405 mmol) in THF (350 mL) at 0-5 °C, and the mixture was
stirred for 2 h at the same temperature. Triethylamine (113
mL, 809 mmol) was added, and the resulting mixture was
allowed to warm to room temperature and stirred for 3 h. After
the reaction mixture was cooled to 0 °C again, aqueous 1 N
HCl (2.4 L) was added slowly while the temperature was
maintained below 5 °C. Ethyl acetate (2.4 L) was then added,
and the mixture was stirred vigorously at room temperature
for 30 min. The organic layer was separated, washed with
aqueous 1 N HCl (1.2 L × 2), aqueous 10% sodium thiosulfate
solution (1.2 L × 2), and brine (800 mL) successively, treated
with activated charcoal (6.7 g), dried over magnesium sulfate,
and concentrated in vacuo to give crude 13a (132 g). This
product was used in the following reaction without further
purification. The purity of 13a was 83 wt % determined by
HPLC. HPLC conditions: column, SUMIPAX ODS A-212;
mobile phase, acetonitrile/H2O (60:40); flow rate, 1.0 mL/min;
UV detection, 254 nm; tR for indoline 15a , 11.2 min; 13a , 15.7
min; 14a , 19.9 min. The physical data of 13a was described
above.
15a : 1H NMR (270 MHz, CDCl3) δ 1.26 (t, 3H, J ) 7.3 Hz),
2.44-2.54 (m, 2H), 2.92-2.68 (m, 2H), 3.32 (s, 2H), 3.75 (s,
3H), 4.18 (q, 2H, J ) 7.3 Hz), 5.02 (s, 1H), 6.55 (m, 2H); GC-
EIMS m/z 335 (M+).
Meth yl 7-Ch lor o-3-ca r boxym eth yl-1,3,4,5-tetr a h yd r o-
ben z[cd ]in d ole-2-ca r boxyla te (16). A procedure similar to
that described in synthesis of 16 from crude 13a obtained via
radical cyclization was carried out with crude 13a (130 g)
obtained above (via Heck reaction) to give the title compound
(91.2 g, 60% yield from 12a ). The purity of 16 was 95 wt %
determined by HPLC. The physical data of 16 were described
above.
Meth yl (-)-7-Ch lor o-3-ca r boxym eth yl-1,3,4,5-tetr a h y-
d r oben z[cd ]in d ole-2-ca r boxyla te (17). Compound 16 (126
g, 409 mmol) was dissolved in boiling 2-propanol (6.3 L), and
a solution of (1R,2S)-(-)-norephedrine (61.8 g, 409 mmol) in
2-propanol (1.2 L) was added. The mixture was stirred at reflux
for 10 min, cooled gradually to 50 °C, followed by maintenance
of the temperature at 50 °C for 5 h, and then allowed to cool
to room temperature and stirred for 20 h. The crystals
precipitated were collected by filtration, washed with ice-cooled
2-propanol (300 mL × 2), and dried in vacuo to give (1R,2S)-
(-)-norephedrine salt of 17 (88.8 g, 79.7% ee). A suspension
of the above crystals in 2-propanol (1.78 L) was stirred at reflux
for 4 h. The mixture was then cooled gradually to room
temperature and stirred for 20 h. The crystals precipitated
were collected by filtration, washed with ice-cooled 2-propanol
(180 mL × 2), and dried in vacuo to give the (1R,2S)-(-)-
norephedrine salt of 17 (75.8 g, 98.6% ee), which was dissolved
in a mixture of aqueous 1 N HCl (600 mL), ethyl acetate (1.8
L), and THF (600 mL). The organic layer was separated,
washed with water (600 mL × 2), treated with activated
charcoal (3.8 g), dried over magnesium sulfate, and concen-
trated in vacuo to give the solid material (51 g), which was
suspended in acetonitrile (250 mL), filtered, washed with
acetonitrile (12 mL × 2), and dried in vacuo to give 17 (49.5 g,
98.5% ee, 39% yield from 16) as white crystals. Chiral HPLC
conditions: column, CHIRALPAK AD; mobile phase, 0.1%
AcOH in EtOH/hexane (60:40); flow rate, 0.5 mL/min; UV
detection, 254 nm; tR for (-)-isomer 17, 9.2 min; (+)-isomer
18, 13.1 min. Both 17 and 18 could be recrystallized from
2-propanol: mp 200-201 °C; [R]25D ) -105.7° (c 1.05, MeOH);
The spectral properties of the title compound were identical
with those of the racemate.
124.72, 130.06, 134.46, 134.83, 162.82, 173.29. Anal. (C14H12
-
NO4Cl.1/8H2O): C, H, N.
7-Ch lor o-3-ph en ylam in ocar bon ylm eth yl-1,3,4,5-tetr ah y-
d r ob en z[cd ]in d ole-2-ca r b oxylic a cid (20). Met h yl 7-
Ch lor o-3-p h en yla m in oca r b on ylm et h yl-1,3,4,5-t et r a h y-
d r oben z[cd ]in d ole-2-ca r boxyla te. To a solution of 16 (1.00
g, 3.25 mmol) and aniline (333 mg, 3.58 mmol) in DMF (15
mL) were added 1-hydroxybenzotriazole (483 mg, 3.58 mmol)
and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydro-
chloride (685 mg, 3.58 mmol) at 0 °C. The mixture was stirred
at room temperature for 20 h, acidified with aqueous 5%
KHSO4, and extracted with 1:1 toluene/ethyl acetate. The
organic layer was washed successively with aqueous 5%
KHSO4, water, aqueous 5% NaHCO3, and brine, dried over
magnesium sulfate, and concentrated. The residual solid was
rinsed with 2-propanol, collected by filtration, and dried in
vacuo to give the title compound (1.20 g, 96% yield) as an
amorphous solid: 1H NMR (270 MHz, DMSO-d6) δ 1.88 (m,
1H), 2.08 (md, 1H, J ) 13.2 Hz), 2.53 (m, 1H), 2.61 (dd, 1H, J
) 14.1, 5.1 Hz), 2.80 (md, 1H, J ) 16.5 Hz), 3.05 (mt, 1H, J )
13.2 Hz), 3.77 (s, 3H), 3.90 (m, 1H), 6.86 (s, 1H), 7.03 (t, 1H,
J ) 7.3 Hz), 7.19 (s, 1H), 7.29 (t, 2H, J ) 7.9 Hz), 7.61 (d, 2H,
J ) 8.1 Hz), 9.85 (s, 1H), 11.59 (s, 1H), 11.70 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 22.33, 27.75, 29.19, 40.83, 51.59, 108.94,
116.66, 119.12 (2C), 121.37, 123.07, 123.90, 124.53, 128.64
(2C), 130.39, 134.78, 134.98, 139.23, 161.74, 169.68; HRMS
(FAB) (m/z) calcd for C21H20N2O3Cl (MH+) 383.1162, found
383.1153.
7-Ch lor o-3-ph en ylam in ocar bon ylm eth yl-1,3,4,5-tetr ah y-
d r oben z[cd ]in d ole-2-ca r boxylic Acid (20). To a solution of
methyl 7-chloro-3-phenylaminocarbonylmethyl-1,3,4,5-tetrahy-
drobenz[cd]indole-2-carboxylate (1.20 g, 3.13 mmol) in 2:1
THF/methanol (45 mL) was added aqueous 2 N LiOH (15 mL,
30 mmol). The mixture was stirred at room temperature for
24 h, acidified with aqueous 1 N HCl, and extracted with 1:1
THF/ethyl acetate. The organic layer was washed successively
with water and brine, dried over magnesium sulfate, and
concentrated. The residual solid was rinsed with 1:1 hexane/
2-propanol, collected by filtration, and dried in vacuo to give
20 (1.10 g, 95% yield) as a white solid: mp 268 °C dec; 1H
NMR (270 MHz, DMSO-d6) δ 1.85 (m, 1H), 2.06 (md, 1H, J )
12.2 Hz), 2.50 (m, 1H), 2.68 (dd, 1H, J ) 14.2, 4.3 Hz), 2.79
(md, 1H, J ) 16.8 Hz), 3.06 (mt, 1H, J ) 12.6 Hz), 3.89 (m,
1H), 6.85 (s, 1H), 7.03 (t, 1H, J ) 7.3 Hz), 7.16 (s, 1H), 7.30 (t,
2H, J ) 7.3 Hz), 7.60 (d, 2H, J ) 7.3 Hz), 9.86 (s, 1H), 11.44
(s, 1H), 12.92 (bs, 1H); 13C NMR (75 MHz, DMSO-d6) δ 22.37,
27.26, 28.90, 40.42, 108.88, 116.44, 119.21 (2C), 122.42, 123.11,
123.36, 124.75, 128.69 (2C), 130.02, 134.53, 134.90, 139.19,
162.83, 169.72. Anal. (C20H17N2O3Cl.1/4H2O): C, H, N.
(-)-7-Ch lor o-3-p h en yla m in oca r b on ylm et h yl-1,3,4,5-
tetr a h yd r oben z[cd ]in d ole-2-ca r boxylic Acid (23). The

Synthesis of Tricyclic Indole-2-caboxylic Acids
J . Org. Chem., Vol. 66, No. 10, 2001 3483
title compound was prepared starting with 17 as described for
20. The optical purity of the product was determined by chiral
HPLC to be 98.6% ee. Chiral HPLC conditions: column,
SUMICHIRAL OA-4400; mobile phase, hexane/2-propanol/
MeOH/TFA (75:15:10:0.2); flow rate, 1.0 mL/min; UV detection,
254 nm; tR for (-)-isomer 23, 13.9 min; (+)-isomer, 11.1 min:
7-Ch lor o-3-(4-am in om eth yl-2-(car boxym eth oxy)ph en yl)-
a m in oca r bon ylm eth yl-1,3,4,5-tetr a h yd r oben z[cd ]in d ole-
2-ca r boxylic Acid Hyd r och lor id e (22). To a solution of
methyl 7-chloro-3-(4-tert-butoxycarbonylaminomethyl-2-(car-
boxymethoxy)phenyl)aminocarbonylmethyl-1,3,4,5-tetrahy-
drobenz[cd]indole-2-carboxylic acid (950 mg, 1.66 mmol) in a
mixture of 1,4-dioxane (8 mL) and acetic acid (16 mL) was
added 4 N HCl in 1,4-dioxane (8 mL). The mixture was stirred
at room temperature for 24 h and concentrated. The residual
solid was rinsed with 1:1 diethyl ether/dichloromethane,
collected by filtration, and dried in vacuo to give 22 (830 mg,
98% yield) as a white solid: mp 232-236 °C dec; 1H NMR (270
MHz, DMSO-d6) δ 1.85 (m, 1H), 2.08 (m, 1H), 2.69 (m, 2H),
2.78 (m, 1H), 3.09 (m, 1H), 3.90-3.95 (m, 3H), 4.74 (s, 2H),
6.84 (s, 1H), 7.06 (d, 1H, J ) 8.3 Hz), 7.16 (s, 1H), 7.20
(s, 1H), 8.04 (d, 1H, J ) 8.3 Hz), 8.30 (bs, 3H), 9.24 (s, 1H),
11.45 (s, 1H), 13.05 (bs, 2H); 13C NMR (75 MHz, DMSO-d6)
δ 22.39, 27.15, 29.16, 40.39, 42.04, 66.13, 108.84, 114.06,
116.41, 121.75, 121.87, 122.51, 123.24, 124.77, 128.16, 129.76,
129.96, 134.47, 135.02, 148.18, 162.86, 170.00, 170.21. Anal.
(C23H23N3O6Cl2‚H2O): C, H, N.
mp 268-270 °C dec; [R]25 ) -112.4° (c 0.53, DMF). The
D
spectral properties of the title compound were identical with
those of the racemate.
7-Ch lor o-3-(4-am in om eth yl-2-(car boxym eth oxy)ph en yl)-
a m in o c a r b o n y lm e t h y l-1,3,4,5-t e t r a h y d r o b e n z[cd ]-
in d ole-2-ca r boxylic Acid Hyd r och lor id e (22). Meth yl
7-Ch lor o-3-(4-ter t-b u t oxyca r b on yla m in om et h yl-2-(ter t-
b u t oxyca r b on ylm et h oxy)p h en yl)a m in oca r b on ylm et h -
yl-1,3,4,5-tetr a h yd r oben z[cd ]in d ole-2-ca r boxyla te. To a
solution of 16 (1.00 g, 3.25 mmol) and 4-tert-butoxycarbonyl-
aminomethyl-2-tert-butoxymethoxyaniline 21 (1.20 g, 3.41
mmol) in DMF (7 mL) were added 1-hydroxybenzotriazole (597
mg, 3.90 mmol) and 1-(3-(dimethylamino)propyl)-3-ethylcarbo-
diimide hydrochloride (748 mg, 3.90 mmol) at 0 °C. The
mixture was stirred at room temperature for 22 h, acidified
with aqueous 5% KHSO4, and extracted with 1:1 toluene/ethyl
acetate. The organic layer was washed successively with
aqueous 5% KHSO4, water, aqueous 5% NaHCO3, and brine,
dried over magnesium sulfate, and concentrated. The residue
was purified by silica gel column chromatography with 2:1
hexane/ethyl acetate to give the title compound (1.83 g, 88%
yield) as an amorphous solid: 1H NMR (270 MHz, DMSO-d6)
δ 1.39 (s, 9H), 1.42 (s, 9H), 1.86 (m, 1H), 2.12 (md, 1H, J )
12.7 Hz), 2.63-2.71 (m, 2H), 2.79 (md, 1H, J ) 16.9 Hz), 3.08
(mt, 1H, J ) 13.6 Hz), 3.79 (s, 3H), 3.88 (m, 1H), 4.06 (d, 2H,
J ) 5.5 Hz), 4.65 (s, 2H), 6.80-6.85 (m, 3H), 7.17 (s, 1H), 7.30
(t, 1H, J ) 5.5 Hz), 7.93 (d, 1H, J ) 7.9 Hz), 9.04 (s, 1H), 11.58
(s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 22.34, 27.64 (4C), 28.21
(3C), 29.36, 40.56, 43.18, 51.57, 66.15, 77.74, 81.64, 108.89,
111.46, 116.62, 119.63, 121.35, 121.87, 123.98, 124.57, 126.49,
130.36, 134.74, 135.16, 136.19, 148.13, 155.73, 161.75, 167.90,
169.70; HRMS (FAB) (m/z) calcd for C33H41N3O8Cl (MH+)
642.2582, found 642.2585.
7-Ch lor o-3-(4-ter t-bu toxyca r bon yla m in om eth yl-2-(ca r -
boxym eth oxy)p h en yl)a m in oca r bon ylm eth yl-1,3,4,5-tet-
r a h yd r oben z[cd ]in d ole-2-ca r boxylic Acid . To a solution
of methyl 7-chloro-3-(4-tert-butoxycarbonylaminomethyl-2-
(tert-butoxycarbonylmethoxy)phenyl)aminocarbonylmethyl-
1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (1.28 g, 2.00
mmol) in 1:1 THF/methanol (20 mL) was added aqueous 2 N
LiOH (6 mL, 12 mmol) The mixture was stirred at room
temperature for 24 h, acidified with aqueous 5% KHSO4, and
extracted with ethyl acetate. The organic layer was washed
successively with water and brine, dried over magnesium
sulfate, and concentrated. The residual solid was rinsed with
diethyl ether, collected by filtration, and dried in vacuo to give
the title compound (1.10 g, 97% yield) as an amorphous solid:
1H NMR (270 MHz, DMSO-d6) δ 1.39 (s, 9H), 1.83 (m, 1H),
2.08 (md, 1H, J ) 11.7 Hz), 2.58-2.66 (m, 2H), 2.78 (md, 1H,
J ) 17.4 Hz), 3.08 (mt, 1H, J ) 13.2 Hz), 3.87 (m, 1H), 4.05
(d, 2H, J ) 6.0 Hz), 4.67 (s, 2H), 6.82 (d, 1H, J ) 7.9 Hz), 6.84
(s, 2H), 7.14 (s, 1H), 7.34 (t, 1H, J ) 6.0 Hz), 7.89 (d, 1H, J )
7.9 Hz), 9.15 (s, 1H), 11.44 (s, 1H), 13.04 (bs, 2H); 13C NMR
(75 MHz, DMSO-d6) δ 22.40, 27.16, 28.26 (3C), 29.15, 40.34,
43.19, 65.99, 77.82, 108.81, 111.93, 116.42, 119.68, 122.05,
122.43, 123.40, 124.79, 126.58, 130.01, 134.51, 135.08, 136.36,
148.41, 155.78, 162.85, 169.74, 170.41; HRMS (FAB) (m/z)
calcd for C28H31N3O8Cl (MH+) 572.1800, found 572.1807.
(-)-7-Ch lor o-3-(4-a m in om et h yl-2-(ca r b oxym et h oxy)-
p h en yl)a m in oca r b on ylm et h yl-1,3,4,5-t et r a h yd r ob en z-
[cd ]in d ole-2-ca r boxylic Acid Hyd r och lor id e (24). The title
compound was prepared starting with 17 as described for 22.
The optical purity of the product was determined by chiral
HPLC to be > 99% ee. Chiral HPLC conditions: column,
SUMICHIRAL OA-2500; mobile phase, acetonitrile/5 mM
aqueous 1-heptanesulfonic acid, sodium salt (adjusted to pH
2.5 with H3PO4) (27:73); flow rate, 1.0 mL/min; UV detection,
240 nm; tR for (-)-isomer 24, 25.0 min; (+)-isomer 25, 28.7
min: mp 195-200 °C, dec; [R]25 ) -44.1° (c 0.23, MeOH).
D
The spectral properties of the title compound were identical
with those of the racemate.
(+)-7-Ch lor o-3-(4-a m in om et h yl-2-(ca r b oxym et h oxy)-
p h en yl)a m in oca r b on ylm et h yl-1,3,4,5-t et r a h yd r ob en z-
[cd ]in d ole-2-ca r boxylic Acid Hyd r och lor id e (25). The title
compound was prepared starting with 18 as described for 22.
The optical purity of the product was determined by chiral
HPLC to be > 99% ee. Chiral HPLC conditions were the same
as described for 24: mp 195-200 °C dec; [R]25 ) +44.0° (c
D
0.24, MeOH). The spectral properties of the title compound
were identical with those of the racemate.
Ack n ow led gm en t. We are grateful to Prof. Y.
Yoneda of Kanazawa University for evaluation of the
biological activities. We are indebted to Mr. S. Horai of
Sumitomo Chemical Co. Ltd. for X-ray crystallography
determinations. We thank Mr. T. Kodo, T. Toyoda, and
T. Umezome for their synthetic contributions. We ap-
preciate Dr. M. Nakamura and Mr. H. Tanaka for their
discussions of the pharmacology. We also express our
appreciation to Prof. B. M. Trost for his generous
discussions.
Su p p or tin g In for m a tion Ava ila ble: Elemental analyti-
cal data for products 4-7, 10, 11a -14a , 16, 19, 20, and 22.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O010002H