Synthesis of caulersin and its isomers by reaction of indole-2,3-dicarboxylic anhydrides with methyl indoleacetates

Article abstract of DOI:10.1016/j.tetlet.2006.04.157

1-Benzenesulfonylindole-2,3-dicarboxylic anhydride was reacted with methyl 1-benzenesulfonylindole-2-acetate to give the corresponding 2-acylindole-3-carboxylic acid as the sole product in high yield, which could be converted to caulersin in four steps. I

Full text of DOI:10.1016/j.tetlet.2006.04.157

Tetrahedron Letters 47 (2006) 5215–5218
Synthesis of caulersin and its isomers by reaction
of indole-2,3-dicarboxylic anhydrides with methyl indoleacetates
Yasuyoshi Miki,* Yosiyuki Aoki, Hideaki Miyatake,
Toshie Minematsu and Hajime Hibino
Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Received 20 March 2006; revised 20 April 2006; accepted 28 April 2006
Abstract—1-Benzenesulfonylindole-2,3-dicarboxylic anhydride was reacted with methyl 1-benzenesulfonylindole-2-acetate to give
the corresponding 2-acylindole-3-carboxylic acid as the sole product in high yield, which could be converted to caulersin in four
steps. In a similar manner, three isomers A, B, and C were synthesized by reaction of indole-2,3-dicarboxylic anhydrides with methyl
indoleacetates.
Ó 2006 Elsevier Ltd. All rights reserved.
Staurosporine,1 rebeccamycin,2 and arcyriaflavins,3
a
products, murrayaquinone-A,8 ellipticine,9 and oliva-
cine,10 2-acylindoles,11 and cyclopent[3,4-b]indol-3-
ones.12 In this letter, we report the efficacy of the anhy-
drides 1 and its application to a simple and useful syn-
thesis of caulersin and its isomer A, B, and C by
reaction of 1 with methyl indoleacetates to confirm the
structure of caulersin.
family of bisindole natural products, have an extra six-
membered cyclic ring between the two indole rings and
show a variety of important biological activities. Cauler-
sin4 and caulerpin5 are also members of bisindole alka-
loid, which have an extra seven- and eight-membered
cyclic ring between the two indole rings, which are incor-
porated directly with the carbonyl group. Caulersin, was
isolated in 1997 from the alga Caulerpa serrulata,4 but its
biological activity was not reported. Caulersin was syn-
thesized by Molina6 and Bergman.7 However, the struc-
ture of natural caulersin is not clear because Bergman
reported that the structure of synthetic caulersin was
confirmed by X-ray diffraction study, but 13C NMR
spectral data of natural caulersin4 was not the same as
that of natural caulersin. Three isomers A, B, and C,
are thought by structural analysis of the structure of nat-
ural possible caulersin considering the binding pattern of
one cycloheptatriene ring and two indole rings.
Reaction of 1-benzenesulfonylindole-2,3-dicarboxylic
anhydride 1a with methyl 1-benzenesulfonylindole-2-
acetate 2 in dichloromethane in presence of titanium(IV)
chloride to afford 2-acylindole-3-carboxylic acid 3 in
quantitative yield. Treatment of the 3-carboxylic acid 3
with oxalyl chloride, followed by tetrabutyltin hydride
in the presence of Pd(PPh3)4 (rt, in toluene) led to the
aldehyde 4 in 77% yield. Cyclization of 4 to N,N0-di-
benzenesulfonylcaulersin 5 was performed by NaH treat-
ment in THF at rt in 67% yield. Debenzenesulfonylation
of 5 with tetrabutylammonium fluoride13 in THF gave
caulersin14 in 91% yield. We found that caulersin synthe-
sized by us is the same as the compound synthesized
by Bergman and not the same as natural caulersin by
Recently, we showed that indole-2,3-dicarboxylic anhy-
drides 1 were useful synthons in the synthesis of natural
H
O
O
COOMe
N
COOMe
H
N
N
H
N
N
N
N
N
COOMe
H
H
H
H
O
O
H
COOMe
isomer A
caulersin
isomer B
isomer C
*
Corresponding author. E-mail: y_miki@phar.kindai.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.157

5216
Y. Miki et al. / Tetrahedron Letters 47 (2006) 5215–5218
1
comparison the H NMR and 13C NMR spectral data
followed by tetrabutyltin hydride in the presence of
Pd(PPh3)4 (rt, in toluene) led to the aldehyde 7 in 58%
yield. Cyclization of 7 to 8 was performed by treatment
with NaH in THF at rt in 43% yield. Debenzenesulf-
onylation of 8 with tetrabutylammonium fluoride in
THF gave 9 (77%), followed by treatment of 9 with alu-
minum(III) chloride in 1,3-dimethoxybenzene (DMB) to
provide caulersin isomer A16 in 70% yield. However, the
1H NMR and 13C NMR spectral of isomer A was not
the same as those of natural caulersin (Scheme 2).
among the three compounds (Scheme 1).
Next, we would like to synthesize isomer A because we
encountered a Hayashi rearrangement in the synthesis
of acid chloride.15 1-(p-Methoxybenzyl)indole-2,3-dicar-
boxylic anhydride 1b was reacted with 2 in dichloro-
methane in the presence of titanium(IV) chloride to
afford 3-acylindole-2-carboxylic acid 6 in 30% yield.
Treatment of the carboxylic acid 6 with oxalyl chloride,
SO2Ph
COOMe
COOMe
SO2Ph
N
N
MeOOC
O
SO2Ph
OHC
N
HOOC
N
2
1) (COCl)2
O
2) n-Bu3SnH
Pd(PPh3)4
N
TiCl4
N
O
O
O
SO2Ph
SO2Ph
SO2Ph
1a
4
3
COOMe
SO2Ph
N
COOMe
H
TBAF
NaH
N
N
N
H
O
O
SO2Ph
caulersin
5
Scheme 1. Synthetic route to caulersin.
O
O
O
1) (COCl)2
NaH
2
O
2) n-Bu3SnH
Pd(PPh3)4
TiCl4
N
N
N
N
N
CHO
COOH
O
SO2Ph
COOMe
SO2Ph
COOMe
PMB
PMB
PMB
1b
7
6
PMB = p-Methoxybenzyl
O
O
O
TBAF
AlCl3
DMB
N
N
H
N
H
SO2Ph
N
N
N
H
COOMe
PMB
PMB
COOMe
COOMe
8
9
isomer A
Scheme 2. Synthetic route to isomer A.
COOMe
N
COOMe
COOMe
HOOC
1) KOH
BnBr
H
1a
2) MeOH
H2SO4
K2CO3
TiCl4
N
N
N
N
H
H
H
O
O
SO2Ph
10
11
COOMe
COOMe
N
OHC
COOMe
POCl3
DMF
1) NaH
2) AlCl3
Anisole
N
Bn
N
N
N
H
N
O
O
O
Bn
Bn
Bn
H
isomer B
13
12
Scheme 3. Synthetic route to isomer B.

Y. Miki et al. / Tetrahedron Letters 47 (2006) 5215–5218
5217
SO2Ph
N
SO2Ph
N
COOH
1) n-Bu4NBH4
2) Dess-Martin
1) (COCl)2
COOH
COOMe
1b
2) TiCl4
3) SiO2
CHO
LHMDS
N
N
COOMe
OH
PMB
14
PMB
15
SO2Ph
H
O
N
O
N
AlCl3
Toluene
N
N
COOMe
COOMe
H
PMB
isomer C
16
Scheme 4. Synthetic route to isomer C.
Isomers B and C were synthesized as follows. Reaction
of the anhydride 1a with methyl indole-3-acetate in
dichloromethane in the presence of titanium(IV) chlo-
ride gave 3-acylindole-2-carboxylic acid 10 in 85% yield.
Treatment of the carboxylic acid 10 with hot aqueous
potassium hydroxide solution, followed by dry metha-
nol in the presence of sulfuric acid led to the ketone
11 in 41% yield. Benzylation of 11 with benzyl bromide
in the presence of potassium carbonate in hot acetoni-
trile afforded 12 (quant.), which was formylated by
DMF and POCl3 to provide the corresponding aldehyde
13 in 59% yield. Cyclization of 13 with NaH in THF
gave a N,N0-dibenzyl derivative (64%), which was trea-
ted with tetrabutylammonium fluoride in THF to give
isomer B17 in 69% yield (Scheme 3).
Table 1. 1H NMR and 13C NMR spectral data of caulersin, isomers A,
B, and C
Natural
caulersin4
Synthetic
caulersin
Isomer A
Isomer B
Isomer C
1H NMR spectral data
13.14 s
12.40 s
9.16 s
12.95 s
12.26 s
9.15 s
9.07 d
8.35 d
7.94 d
7.79 d
7.58 t
7.51 t
7.44 t
7.40 t
4.11 s
12.71 s
12.17 s
9.11 s
9.02 d
8.63 s
7.90 d
7.69 d
7.55 t
7.48 t
7.40 t
7.36 t
4.08 s
12.79 s
12.79 s
8.42 s
8.34 d
7.80 d
7.79 d
7.75 d
7.59 t
7.55 t
7.38 t
7.31 t
4.08 s
12.83 s
12.62 s
8.92 d
7.77 d
7.71 d
7.70 s
7.69 d
7.54 t
7.50 t
7.41 t
7.30 t
4.08 s
9.08 m
8.39 d
7.98 m
7.79 d
7.58 m
7.52 m
7.44 m
7.40 m
4.09 s
Reduction of 1b with tetra-n-butylammonium borohy-
dride in THF (86%), followed by Dess–Martin oxida-
tion gave 2-formylindole-3-carboxylic acid 14 in 97%
yield. The aldehyde 14 was reacted with methyl 1-benz-
enesulfonylindole-3-acetate in the presence of lithium
hexamethyl-disilazane (LHMDS) in THF to provide
the b-hydroxy ester 15 (50%), which could be converted
by treatment of oxalyl chloride, then titanium(IV) chlo-
ride and silica gel to afford the cyclization compound
1618 in 35% yield. Finally, deprotection of 16 with alu-
minum(III) chloride in toluene was performed to give
isomer C19 in 56% yield (Scheme 4).
13C NMR spectral data
172.1
167.5
146.7
140.6
138.3
138.3
136.6
129.4
126.6
126.5
125.8
125.5
123.2
121.7
121.5
120.1
172.4
168.0
179.8
167.5
170.6
167.8
172.9
170.0
141.0
138.6
136.9
136.4
129.6
126.9
126.6
126.2
125.7
123.5
121.9
121.6
120.2
119.4
114.7
114.4
113.2
112.2
52.93
137.9
136.5
135.8
134.5
127.1
126.9
126.8
126.2
125.8
124.5
124.1
122.3
122.1
121.8
121.5
120.4
112.5
111.9
53.57
138.2
138.0
137.9
137.2
127.8
127.2
126.2
125.8
123.8
122.6
121.4
121.4
120.9
119.8
119.3
116.8
113.2
113.0
53.05
140.5
137.4
136.9
130.7
126.6
126.5
126.4
126.3
124.3
123.8
122.1
122.1
121.4
118.7
115.5
113.4
112.2
111.7
53.31
1
We compared the H NMR and 13C NMR spectra of
natural caulersin, synthetic caulersin, isomers A, B,
and C. The spectra of natural caulersin are quite differ-
ent from those of isomers A, B, and C, but are the same
as that of synthetic caulersin except two peaks (d 136.9
and 119.4) of the 13C NMR spectra. However, we could
show the real structure of caulersin is the proposed
structure reported by Su4 from the synthesis of caulersin
and three isomers, A, B, and C by using indole-2,3-
dicarboxylic anhydrides (Table 1).
References and notes
114.3
114.1
112.9
112.1
52.9
1. Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya,
J.; Tsuchiya, H.; Takahashi, Y.; Masuma, R. J. Antibiot.
1977, 30, 275–282; Funato, N.; Takayanagi, H.; Konda,
Y.; Toda, Y.; Harigaya, Y.; Imai, Y.; Omura, S. Tetra-
hedron Lett. 1994, 35, 1251–1254.
d in DMSO-d6.

5218
Y. Miki et al. / Tetrahedron Letters 47 (2006) 5215–5218
15. Miki, Y.; Tsuzaki, Y.; Matsukida, H. Heterocycles 2002,
2. Nettleton, D. E.; Doyle, T. W.; Krishnan, B.; Matsumoto,
G. K.; Clardy, J. Tetrahedron Lett. 1985, 26, 4011–
4014; Pearce, C. J.; Doyle, T. W.; Forenza, S.; Lam,
K. S.; Schroeder, D. R. J. Nat. Prod. 1988, 51, 937–
940.
57, 1645–1651.
16. Isomer A: mp >250 °C (n-hexane–THF). IR (CHCl3)
cmꢀ1: 3333, 1698, 1617. H NMR (DMSO-d6, 270 MHz):
1
d 4.08 (3H, s, COOMe), 7.36 (1H, ddd, J = 8.3, 7.1,
1.0 Hz), 7.40 (1H, ddd, J = 8.3, 7.1, 1.0 Hz), 7.48 (1H,
ddd, J = 8.3, 7.1, 1.0 Hz), 7.55 (1H, ddd, J = 8.3, 7.1,
1.0 Hz), 8.63 (1H, s, H-9), 9.02 (1H, d, J = 8.3 Hz), 9.11
(1H, d, J = 8.3 Hz), 12.17 (1H, br s, H-1, NH), 12.72 (1H,
br s, H-1, NH). 13C NMR (DMSO-d6) d: 178.8, 167.5,
137.9, 136.5, 135.8, 134.5, 127.1, 126.9, 126.8, 126.2, 125.8,
124.5, 124.1, 122.3, 122.1, 121.8, 121.5, 120.4, 112.5, 111.9,
53.57. MS m/z: 342. HRMS m/z: calcd for C21H14N2O3:
342.1004. Found: 342.1001.
3. Steglich, W.; Steffan, B.; Kopanski, L.; Eckhardt, G.
Angew. Chem., Int. Ed. Engl. 1980, 19, 459–460.
4. Su, J.-Y.; Zhu, Y.; Zeng, L.-M.; Xu, X.-H. J. Nat. Prod.
1997, 60, 1043–1044.
5. Schwede, J. G.; Cardellina, J. H., II; Grode, S. H.; James,
T. R., Jr.; Blackman, A. J. Phytochemistry 1987, 26, 155–
158, and references cited therein.
6. Fresneda, P. M.; Molina, P.; Saez, M. A. Synlett 1999,
1651–1653.
7. Wahlstroem, N.; Stensland, B.; Bergman, J. Tetrahedron
2004, 60, 2147–2153.
17. Isomer B: mp >260 °C (MeOH). IR (CHCl3) cmꢀ1: 3433,
1
1721. H NMR (DMSO-d6) d: 4.08 (3H, s, OCH3), 7.31
8. Miki, Y.; Hachiken, H. Synlett 1993, 333–334.
9. Miki, Y.; Tada, Y.; Yanase, N.; Hachiken, H.; Matsu-
shita, K. Tetrahedron Lett. 1996, 37, 7753–7754.
10. Miki, Y.; Tsuzaki, Y.; Hibino, H.; Aoki, Y. Synlett 2004,
2206–2208.
11. Miki, Y.; Hachiken, H.; Yoshikawa, I. Heterocycles 1997,
45, 1143–1150.
12. Miki, Y.; Hachiken, H.; Sugimoto, Y.; Yanase, N.
Heterocycles 1997, 45, 1759–1766.
(1H, t, J = 8.2 Hz), 7.38 (1H, t, J = 7.7 Hz), 7.55 (1H, t,
J = 8.0 Hz), 7.59 (1H, t, J = 8.0 Hz), 7.75 (1H, d, J =
8.2 Hz), 7.79 (1H, d, J = 7.2 Hz), 7.80 (1H, d, J = 7.2 Hz),
8.34 (1H, s), 8.42 (1H, d, J = 8.0 Hz), 12.79 (2H, br s, H-1
and H-10). 13C NMR d: 170.6, 167.8, 138.2, 138.0, 137.9,
137.2, 127.8, 127.2, 126.2, 125.8, 123.8, 122.6, 121.4, 121.4,
120.9, 119.8, 119.3, 116.8, 113.2, 113.0, 53.05. MS m/z:
342. HRMS m/z: calcd for C21H14N2O3: 342.1005. Found:
342.0997.
13. Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39,
595–596.
18. Compound 16: mp 221–223 °C (EtOAc). IR (Nujol) cmꢀ1
:
1724, 1618. 1H NMR (CDCl3) d: 3.74 (3H, s, OCH3), 3.95
(3H, s, OCH3), 5.59 (2H, s, CH2), 6.81 (2H, d, J = 8.5 Hz),
7.02 (2H, d, J = 8.5 Hz), 7.32–7.72 (9H, m), 7.88 (1H, s),
8.35–8.44 (3H, m), 8.74–8.81 (1H, m).
14. Caulersin: mp >250 °C (MeOH) (lit.,4 mp 269–270 °C,
lit.,6 mp 273–274 °C, lit.,7 mp 352–355 °C). IR (Nujol)
1
cmꢀ1: 3346, 3238, 1670. H NMR (DMSO-d6, 270 MHz):
d: 4.11 (3H, s, COOMe), 7.40 (1H, ddd, J = 8.1, 7.1,
1.0 Hz), 7.44 (1H, ddd, J = 8.1, 7.1, 1.0 Hz), 7.51 (1H,
ddd, J = 8.1, 7.1, 1.0 Hz), 7.58 (1H, ddd, J = 8.1, 7.1,
1.0 Hz), 7.79 (1H, d, J = 8.1 Hz), 7.94 (1H, d, J = 8.1 Hz),
8.35 (1H, d, J = 8.1 Hz), 9.07 (1H, d, J = 8.1 Hz), 9.15
(1H, s, H-9), 12.26 (1H, br s, NH), 12.95 (1H, br s, NH).
13C NMR (DMSO-d6) d: 172.4, 168.0, 141.0, 138.6, 136.9,
136.4, 129.6, 126.9, 126.6, 126.2, 125.7, 123.5, 121.9, 121.6,
120.2, 119.4, 114.7, 114.4, 113.2, 112.2, 52.9. MS m/z: 342.
HRMS m/z: calcd for C21H14N2O3: 342.1004. Found:
342.1011.
19. Isomer C: mp >260 °C (MeOH). IR (Nujol) cmꢀ1: 3367,
3308, 1708, 1621. 1H NMR (DMSO-d6) d: 4.08 (3H, s,
OCH3), 7.30 (1H, t, J = 8.2 Hz), 7.41 (1H, t, J = 8.2 Hz),
7.50 (1H, t, J = 8.2 Hz), 7.54 (1H, t, J = 8.2 Hz), 7.69 (1H,
d, J = 8.2 Hz), 7.70 (1H, s), 7.71 (1H, d, J = 8.2 Hz), 7.77
(1H, d, J = 8.2 Hz,), 8.92 (1H, d, J = 8.2 Hz), 12.62 (1H,
br s, NH), 12.83 (1H, br s, NH). 13C NMR (DMSO-d6) d:
172.9, 170.0, 140.5, 137.4, 136.9, 130.7, 126.6, 126.5, 126.4,
126.3, 124.3, 123.8, 122.1, 121.4, 118.7, 115.5, 113.4, 112.2,
111.7, 53.31. MS m/z: 342. HRMS m/z: calcd for
C21H14O3N2: 342.1005. Found: 342.1008.