A concise synthesis of indolic enamides: coscinamide A, coscinamide B, and igzamide

Article abstract of DOI:10.1016/j.tetlet.2009.05.030

A concise synthesis of indolic enamides coscinamide A, coscinamide B, and the brominated tryptamine derivative igzamide is described. Both E- and Z-isomers of these natural compounds were obtained during the thermally assisted dehydration reaction and wer

Full text of DOI:10.1016/j.tetlet.2009.05.030

Tetrahedron Letters 50 (2009) 4343–4345
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Tetrahedron Letters
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A concise synthesis of indolic enamides: coscinamide A, coscinamide B,
and igzamide
Yuelong Ma, Kenichi Yakushijin, Fumiko Miyake, David Horne *
Department of Molecular Medicine, Beckman Research Institute and Graduate School of Biological Sciences at City of Hope, Duarte, CA 91010, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of indolic enamides coscinamide A, coscinamide B, and the brominated tryptamine
derivative igzamide is described. Both E- and Z-isomers of these natural compounds were obtained dur-
ing the thermally assisted dehydration reaction and were tested for antitumor activity. Coscinamide B
Received 10 April 2009
Accepted 12 May 2009
Available online 19 May 2009
was found to possess antitumor activity against DU145 with an IC50 of 7.6 lg/mL.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indolic enamide
Coscinamide A
Coscinamide B
Igzamide
Dehydration reaction
The 3-substituted indolic enamide moiety is found in a myriad
of marine compounds isolated over the past 20 years. Both E- and
Z-indolic enamides are found in nature. Representative examples
Conversion of amino alcohols 5 and 8 to their corresponding
1
7
bis-3-indoleglyoxamides 9 and 10 was achieved in good yields
with 3-indoleglyoxylyl chloride (Scheme 2). With these precursors
in hand, their transformation to E- and Z-indolic enamides under
thermal dehydration conditions was investigated.
1
of the former include coscinamides A, B, and C, chondriamides A
2
3
4
and B, aspergillamide B, while others such as igzamide , terpep-
5
3
6
tin, aspergillamide A , and halocyamines A and B comprise the
latter. Coscinamides A and B were isolated from the marine
sponge, Coscinoderma sp. and show partial cytoprotection against
Using xylene as the solvent, dehydration of hydroxyl amide 9
took place at 130 °C giving both E- and Z-isomers of coscinamide
B. From the crude reaction mixture, a 5:3 E:Z ratio of coscinamide
1
18
HIV in the NCI assay. Igzamide was isolated from another marine
B (2) and its Z-isomer (11) was determined by NMR. Efforts to
sponge, Plocamissa igzo and displays weak cytotoxicity against the
optimize the Z-isomer by shortening the reaction time were unsuc-
cessful due to incomplete reaction. The combined yield for both
isomers after chromatography was 69% in addition to 5% of recov-
ered starting amide 9 (Scheme 3).
4
L1210 murine leukemia cell line. Several methods for construction
7
–
of these and other indolic enamides have been recently reported.
1
2
All methods require the use of protection either on the indole
ring or elsewhere. Herein, we report a concise synthesis of indolic
enamides coscinamide A, coscinamide B, and igzamide that is void
of protecting groups (Fig. 1).
6
When (Z)-coscinamide B was maintained in DMSO-d at 45 °C
for 2 d, 80% of the Z-isomer was converted to the natural E-config-
uration. This observation prompted us to investigate the use of a
polar aprotic solvent for the dehydration in order to obtain a higher
E/Z ratio. When hydroxyl amide 9 was heated at 130 °C in DMF, a
5:1 E:Z ratio of 2 and 11 was obtained in a combined yield of 90%.
The synthesis begins with the preparation and reduction of in-
dole-3-carbonyl nitrile 413 (Scheme 1). Depending on the mode of
1
4
reduction, either amino alcohol 5 or the amino ketone 6 can be
15
obtained in excellent yields. The use of LiAlH
4
produces the ami-
no alcohol and hydrogenolysis affords the amino ketone. The direct
introduction of the 6-bromo substituent was achieved by bromin-
ation of oxotryptamine 6 using molecular bromine. This resulted in
a regioisomeric mixture of 5- and 6-brominated oxotryptamine
derivatives from which 7 was obtained in pure form after flash
O
HN
NH
O
O
HN
R
Br
NH2
N
H
N
H
1
4
O
4
chromatography. Reduction of 7 with NaBH provided amino
1
6
alcohol 8.
1
2
R = Br coscinamide A
R = H coscinamide B
3 igzamide
*
Corresponding author. Tel.: +1 626 471 7310; fax: +1 626 930 5410.
E-mail address: dhorne@coh.org (D. Horne).
Figure 1. Structure of coscinamides A and B and igzamide.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.030

4
344
Y. Ma et al. / Tetrahedron Letters 50 (2009) 4343–4345
O
HO
O
CN
HO HN
LiAlH4
THF
60%
NH2
OMe
xylene
ClCOCO Me
2
O
8
N
H
4
N
H
5
Br
130 ºC
21%
3
NEt , 76%
N
H
13
H2
AcOH
O
Pd/C 90%
MeOH/NH3
HN
igzamide (3)
O
Br
O
OMe 0 ºC, quant.
N
H
4
O
Br2
AcOH
NH2
NH2
Br
1
N
H
N
H
HCO H
2
Scheme 4. Synthesis of igzamide.
2
1%
6
7
NaBH
4
methyl chlorooxoacetate with Et
3
N in THF produced amide 1320
MeOH
9%
8
in 76% yield. Heating this compound in xylene at 130 °C yielded
a separable mixture of Z and E enamides of 14 in a 3:2 ratio, respec-
HO
21
tively. Quantitative transformation of purified intermediate 14 to
NH2
7,22
igzamide was achieved with saturated ammonia methanol.
Br
Derivatives 9–14 and natural products 1–3 were evaluated for
cytotoxicity (MTS assay) against DU145, a human prostate cancer
cell line. Only coscinamide B (2) was found to possess in vitro anti-
N
H
8
tumor activity with an IC50 of 7.6
reported active against L1210 murine leukemia cell line, was inac-
tive against DU145 at 9.2 g/mL.
lg/mL. Igzamide (3), which was
Scheme 1. Synthesis of amino alcohols 5 and 8.
l
In conclusion, a concise synthesis of coscinamides A and B, and
igzamide has been accomplished from readily available starting
materials. Noteworthy is the absence of protecting groups which
simplifies the procedure. Further application of this methodology
to the synthesis of related indolic enamides and evaluation of their
biological properties are in progress.
O
Cl
O
O
HO HN
NH
N
H
O
5
or 8
R
Et N
N
H
3
Acknowledgments
9
1
R = H (80%)
0 R = Br (83%)
Financial support from Chugai Pharmaceutical Co is gratefully
acknowledged. We thank Dr. Sangkil Nam for assistance with bio-
logical testing and the Graduate School of Biological Sciences at
City of Hope for a Merit Fellowship to Y.M.
Scheme 2. Synthesis of amides 9 and 10.
O
References and notes
HN
NH
1
.
Bokesch, H. R.; Pannell, L. K.; McKee, T. C.; Boyd, M. R. Tetrahedron Lett. 2000,
1, 6305–6308.
Palermo, J. A.; Flower, P. B.; Seldes, A. M. Tetrahedron Lett. 1992, 33, 3097–3100.
4
H O
2.
R
xylene
30 ºC
3. Toske, S. G.; Jensen, P. R.; Kauffman, C. A.; Fenical, W. Tetrahedron 1998, 54,
N
H
9
or 10
13459–13466.
4
5
.
.
Dumdei, E.; Andersen, R. J. Nat. Prod. 1993, 56, 792–794.
Kagamizono, T.; Sakai, N.; Arai, K.; Kobinata, K.; Osada, H. Tetrahedron Lett.
1
coscinamide B (2)
(Z)-coscinamide B (11)
1997, 38, 1223–1226.
R = H (49%)
R = H (20%)
6.
7.
8.
9.
Azumi, K.; Yokosawa, H.; Ishii, S. Biochemistry 1990, 29, 159–165.
Kuramochi, K.; Osada, Y.; Kitahara, T. Tetrahedron 2003, 59, 9447–9454.
Chakrabarty, M.; Basak, R.; Harigaya, Y. Synthesis 2003, 13, 2011–2014.
Rivas, L.; Quintero, L.; Fourrey, J.; Benhida, R. Tetrahedron Lett. 2002, 43, 7639–
coscinamide A (1)
(Z)-coscinamide A (12)
R = Br (43%)
R = Br (17%)
7
641.
Scheme 3. Synthesis of coscinamides A and B and Z-isomers.
1
1
1
0. Su, S.; Kakeya, H.; Osada, H.; Porco, J. A., Jr. Tetrahedron 2003, 59, 8931–8946.
1. Beck, B.; Hess, S.; Dömling, A. Bioorg. Med. Chem. Lett. 2000, 10, 1701–1705.
2. Yang, L.; Deng, G.; Wang, D.; Huang, Z.; Zhu, J.; Wang, M. Org. Lett. 2007, 9,
1
387–1390.
13. Hogan, I. T.; Sainsbury, M. Tetrahedron 1984, 40, 681–682.
4. Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2, 3185–3187.
15. Burger, A.; Hornbaker, E. D. J. Am. Chem. Soc. 1952, 74, 5514.
Similar results were seen with 10. The thermally assisted dehy-
dration of 10 in xylene yielded coscinamide A (1) along with its Z-
1
1
9
isomer 12 (Scheme 3) in a 5:3 ratio, respectively. The combined
yield for both isomers after chromatography is approximately 70%.
The corresponding reaction in DMF also provided similar results to
that previously seen with coscinamide B. The E:Z ratio was approx-
imately 5:1. These results indicate better selectivity for E-indolic
enamides in DMF while the amount of Z-enamide isomers can be
increased using a non-polar solvent such as xylene.
À1
1
6. Compound 8: IR (KBr)
m
max 3415, 3359, 3286, 1435, 1331, 1049, 894, 803 cm
;
1
H NMR (DMSO-d , 300 MHz) d 11.02 (br s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.51 (d,
6
J = 1.8 Hz, 1H), 7.22 (br s, 1H), 7.08 (dd, J = 8.5, 1.8 Hz, 1H), 5.00 (br s, 1H), 4.96
dd, J = 7.1, 5.0 Hz, 1H), 2.81 (dd, J = 12.8, 5.0 Hz, 1H), 2.76 (dd, J = 12.8, 7.1 Hz,
(
1
1
H), 1.89 (br s, 2H); 13C NMR (DMSO-d
21.95, 118.9, 114.8, 114.5, 69.8, 49.7; HRFABMS m/z calcd for C10
, 300 MHz) d 138.1, 125.8, 124.0, 122.0,
6
79
H
2
11 Br N O
+
M : 254.00548; found: 254.00486.
7. Compound 9: IR (KBr)
DMSO-d
À1
1
m
max 3375, 3251, 1657, 1601, 1499, 1430 cm ; 1H NMR
(
6
, 300 MHz) d 12.22 (br s, 1H), 10.92 (br s, 1H), 8.80 (d, J = 3.1 Hz, 1H),
.57 (t, J = 5.8 Hz, 1H), 8.24 (m, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.53 (m, 1H), 7.36
(d, J = 8.0 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.26 (m, 2H), 7.08 (td, J = 7.1, 1.0 Hz,
Based on the above observation, the synthesis of the Z-indolic
enamide, igzamide was pursued (Scheme 4). Treatment of 8 and
8

Y. Ma et al. / Tetrahedron Letters 50 (2009) 4343–4345
4345
1
1
1
1
H), 6.99 (td, J = 7.4, 1.0 Hz, 1H), 5.32 (d, J = 4.8 Hz, 1H), 5.08 (m, 1H), 3.71 (m,
H), 3.53 (m, 1H); 13C NMR (DMSO-d
, 300 MHz) d 182.7, 164.2, 139.5, 137.3,
37.1, 127.1, 126.7, 124.3, 123.4, 123.1, 122.2, 121.9, 120.1, 119.3, 117.8, 113.4,
1H), 7.29 (m, 2H), 7.25 (dd, J = 1.7, 8.5 Hz, 1H), 6.83 (d, J = 14.7 Hz, 1H); 13C
NMR (DMSO-d , 300 MHz) d 181.5, 160.9, 139.1, 138.2, 136.8, 126.7, 125.6,
6
6
124.3, 124.0, 123.1, 122.7, 121.8, 121.2, 119.8, 114.9, 114.7, 113.1, 112.7, 112.4,
+
79
+
13.0, 112.3, 66.4, 46.6; HRFABMS m/z calcd for C20
max 3372, 3251, 1660, 1600, 1492,
, 300 MHz) d 12.22 (br s, 1H), 11.07
br s, 1H), 8.75 (d, J = 3.2 Hz, 1H), 8.58 (t, J = 5.8 Hz, 1H), 8.21 (m, 1H), 7.65 (d,
J = 8.5 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.52 (m, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.25
H
N
17 3
O
3
M : 347.1270;
109.7; HRFABMS m/z calcd for C20
Compound 12: IR (KBr)
H
14 BrN
3
O
2
M : 407.0269; found: 407.0258.
À1
found: 347.1280. Compound 10: IR (KBr)
m
6
m
max 3311, 1668, 1621, 1600, 1531, 1483, 1436 cm
H NMR (DMSO-d , 300 MHz) d 12.39 (br s, 1H), 11.58 (br s, 1H), 9.70 (d,
6
;
À1
1
1
1
440, 1436, 1064 cm
;
H NMR (DMSO-d
(
J = 10.8 Hz, 1H), 8.92 (s, 1H), 8.25 (m, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.65 (d,
J = 1.8 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.57 (m, 1H), 7.30 (m, 2H), 7.21 (dd,
(
(
1
1
m, 2H), 7.11 (dd, J = 8.5, 1.8 Hz, 1H), 5.37 (d, J = 4.9 Hz, 1H), 5.04 (m, 1H), 3.63
J = 8.5, 1.7 Hz, 1H), 6.84 (dd, J = 10.8, 9.2 Hz, 1H), 6.21 (d, J = 9.2 Hz, 1H); 13
C
1
3
m, 1H), 3.49 (m, 1H); C NMR (DMSO-d
6
, 300 MHz) d 182.3, 163.8, 139.1,
37.7, 136.7, 126.7, 125.4, 123.9, 123.8, 123.0, 121.7 Â 2, 121.5, 117.7, 114.5,
14.3, 113.0, 112.6, 65.7, 46.2.
max 3436, 3227, 1650, 1597, 1542, 1490, 1442,
, 300 MHz) d 12.30 (br s, 1H), 11.21 (br s, 1H), 10.83
d, J = 10.1 Hz, 1H), 8.84 (d, J = 3.1 Hz, 1H), 8.28 (m, 1H), 7.69 (br d, J = 6.9 Hz,
H), 7.55 (m, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.42 (dd, J = 14.8, 10.1 Hz, 1H), 7.39
NMR (DMSO-d
6
, 400 MHz) d 180.3, 160.5, 139.7, 137.1, 136.8, 126.7, 125.9,
125.2, 124.2, 123.3, 122.7, 121.8, 120.8, 118.5, 115.2, 114.8, 113.2, 112.4, 110.4,
79
+
105.8; HRFABMS m/z calcd for C20
20. Compound 13: IR (KBr) max 3415, 3311, 1741, 1686, 1212 cm
(acetone-d , 300 MHz) d 10.32 (br s, 1H), 8.10 (br s, 1H), 7.70 (d, J = 8.5 Hz, 1H),
H14 BrN O M : 407.0269; found: 407.0273.
3 2
À1
1
1
8. Coscinamide B 2: IR (KBr)
m
m
; H NMR
À1
1
cm
(
;
H NMR (DMSO-d
6
6
7.62 (dd, J = 1.8 Hz, 0.5 Hz, 1H), 7.38 (dd, J = 2.5, 0.8 Hz, 1H), 7.18 (dd, J = 8.5,
1
(
1.8 Hz, 1H), 5.20 (m, 1H), 4.55 (d, J = 4.4 Hz, 1H), 3.82 (s, 3H), 3.79 (m, 1H), 3.60
br d, J = 6.8 Hz, 1H), 7.28 (m, 2H), 7.12 (m, 2H), 6.85 (d, J = 14.8 Hz, 1H); 13
C
13
6
(m, 1H); C NMR (acetone-d , 300 MHz) d 161.2, 156.6, 137.8, 125.1, 123.1,
NMR (DMSO-d
6
, 300 MHz) d 182.0, 161.2, 139.5, 137.8, 137.2, 127.1, 125.7,
121.8, 121.0, 117.4, 114.5, 114.2, 66.2, 52.4, 46.3; HRFABMS m/z calcd for
79 +
1
1
25.2, 124.4, 123.5, 122.5, 122.2, 120.3, 119.9, 119.5, 113.5, 113.2, 112.8, 112.5,
10.9; HRFABMS m/z calcd for C20
C
13
H
13 BrN
21. Compound 14: IR (KBr)
(acetone-d , 300 MHz) d 10.74 (br s, 1H), 9.20 (d, J = 11.9 Hz, 1H), 7.70 (d,
J = 1.7 Hz, 1H), 7.63 (m, 2H), 7.27 (dd, J = 8.5, J = 1.8 Hz, 1H), 6.85 (dd, J = 11.1,
2
O
4
M : 340.0059; found: 340.0044.
+
max 3303, 1751, 1697, 1533, 1285 cm ; 1H NMR
À1
H
15
N
3
O
2
M : 329.1164; found: 329.1158.
m
Compound 11: IR (KBr)
m
max 3304, 3051, 1672, 1610, 1535, 1483, 1433,
H NMR (DMSO-d , 300 MHz) d 12.37 (br s, 1H), 11.45 (br s, 1H),
.69 (d, J = 11.1 Hz, 1H), 8.93 (br s, 1H), 8.24 (m, 1H), 7.66 (br s, 1H), 7.64 (br d,
6
À1
1
7
9
42 cm
;
6
13
9.2 Hz, 1H), 6.22 (d, J = 9.2 Hz, 1H), 3.88 (s, 3H);
6
C NMR (acetone-d ,
J = 8.1 Hz, 1H), 7.56 (m, 1H), 7.45 (br d, J = 8.0, 1H), 7.28 (m, 2H), 7.17 (bt,
J = 7.5 Hz, 1H), 7.08 (bt, J = 7.4 Hz, 1H), 6.82 (dd, J = 11.1, 9.2 Hz, 1H), 6.23 (d,
300 MHz) d 160.8, 153.4, 137.1, 125.7, 124.1, 122.8, 120.3, 118.4, 115.4, 114.5,
79
+
110.5, 105.3, 52.9; HRFABMS m/z calcd for C13
H
2
11 BrN O
3
M : 321.9953;
J = 9.2 Hz, 1H); 13C NMR (DMSO-d
found: 321.9960.
6
, 300 MHz) d 180.6, 160.7, 140.1, 137.2,
max 3391, 3372, 3329, 3233, 1662, 1528, 1040, cm ; 1
À1
H
1
1
36.7, 127.3, 127.1, 124.6 Â 2, 123.7, 122.8, 122.2, 120.3, 119.3, 118.2, 113.6,
22. Igzamide 3: IR (KBr)
NMR (DMSO-d
m
+
12.8, 112.6, 110.5, 106.8; HRFABMS m/z calcd for C20
H
15
3
N O
2
M : 329.1164;
6
, 300 MHz) d 11.56 (br s, 1H), 9.48 (d, J = 11.5 Hz, 1H), 8. 39 (br
found: 329.1168.
s, 1H), 8.09 (br s, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.57 (d, J = 8.9, 1H), 7.56 (br s, 1H),
À1
1
9. Coscinamide A 1: IR (KBr)
m
max 3354, 1664, 1617, 1539, 1488, 1423, 1109 cm
;
7.20 (dd, J = 8.6, J = 1.7 Hz, 1H), 6.70 (dd, J = 11.3, 9.4 Hz, 1H), 6.17 (d, J = 9.1 Hz,
1
13
H NMR (DMSO-d
6
, 300 MHz) d 12.32 (br s, 1H), 11.35 (br s, 1H), 10.87 (d,
6
1H); C NMR (DMSO-d , 400 MHz) d 161.9, 157.7, 137.1, 125.8, 124.9, 122.8,
J = 10.1 Hz, 1H), 8.84 (s, 1H), 8.29 (m, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.59 (d,
J = 1.2 Hz, 1H), 7.57 (m, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.41 (dd, J = 14.7, 10.1 Hz,
120.8, 118.5, 115.2, 114.8, 110.3, 105.8; HRFABMS m/z calcd for
C H10 BrN O M : 306.9956; found: 306.9944.
12 3 2
79 +