Total synthesis of styelsamine C, a cytotoxic fused tetracyclic aromatic alkaloid

Article abstract of DOI:10.3987/COM-03-9827

A cytotoxic fused tetracyclic aromatic alkaloid, styelsamine C (3) from the ascidian Eusynstyela latericius, was synthesized utilizing biaryl cross-coupling reaction.

Full text of DOI:10.3987/COM-03-9827

HETEROCYCLES, Vol. 60, No. 9, 2003, pp. 2017 - 2018
Received, 17th June, 2003, Accepted, 1st August, 2003, Published online, 18th August, 2003
TOTAL SYNTHESIS OF STYELSAMINE C, A CYTOTOXIC FUSED
TETRACYCLIC AROMATIC ALKALOID
Shinsuke Nakahara* and Akinori Kubo
Meiji Pharmaceutical University
2-552-1, Noshio, Kiyose, Tokyo 204-8588, J apan
Abstract - A cytotoxic fused tetracyclic aromatic alkaloid, styelsamine C
(3) from the ascidian Eusynstyela latericius, was synthesized utilizing
biaryl cross-coupling reaction.
A series of structurally fascinating and biologically active fused polycyclic aromatic
alkaloids containing pyrido[2,3,4-kl]acridine subunit have been isolated from marine
sources during the last twenty years.1 Styelsamines A~D (1)~(4) , structurally the most
simple compound in the group and mild cytotoxicity toward the human colon tumor cell
line HCT-116, was obtained in 1998 from the marine ascidian Eusynstyela latericius.2
Previously we have achieved the synthesis of pantherinine, pyridoacridine ring system
alkaloid.3 We report herein the first total synthesis of 3 utilizing biaryl cross-coupling
reaction.4
NO2
NO2
NO2
O
Br
Me
Me
Me
HN
N
H
N
R
R
OMe
OMe
OMe
9
8
5 R = NO2
6 R = NH2
+
N
-O2CCF3
H
O
OH
NH
7 R =
O
O
O
OH
O
+
NH3
-O2CCF3
1 R =
2 R =
H
N
O
HN
NO2
NO2
(free base)
3 R =
4 R =
H
OHC
OHC
+
NH3
R
-O2CCF3
N
N
N
R
OMe
OMe
12
13 R = OMe
3 R = OH
10 R = Me
11 R =
Me
Me
N

5
Selective transfer hydrogenation of 5-methoxy-2,4-dinitrotoluene (5) with 10% Pd-C
catalyst and cyclohexene in EtOH at 90℃ for 15 min gave 4-amino compound (6) and
2-amino-4-nitro compound in 60% and 7% yield, respectively. 6 was treated with
5-methoxymethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione6 under reflux for 2 h to give the
enaminone (7) in 94% yield. The cyclization of 7 in refluxing diphenyl ether for 15 min
afforded the 4-quinolinone (8) via unstable aminoketene in 83% yield. Treatment of 8 with
POBr3 at 70℃ for 1.5 h afforded the 4-bromoquinoline (9) in 78% yield. Suzuki reaction
between 9 and phenylboronic acid in EtOH/toluene containing K2CO3 and catalytic
amounts of tetrakis(triphenylphosphine) palladium (0) at 95 ℃ for 3 h gave the
4-phenylquinoline (10) in 94% yield. Treatment of 10 and N,N-dimethylformamide at 170℃
for 4 d afforded the aminoalkene (11) in 91% yield. Oxidation7 of 11 was accomplished with
NaIO4 in THF/H2O at room temperature for 2 h to provide the aldehyde (12) in 90% yield.
The intramoleculer nitrene insertion reaction8 of 12 with (EtO)3P at 180℃ for 2 h gave the
tetracyclic compound (13) in 65% yield. Finally, demethylation of 13 with BBr3 in CH2Cl2 at
room temperature for 2 h furnished styelsamine C (3)9 in 86% yield. The spectral data of 3
obtained in the same solvent condition were identical with those of the natural product.2
The synthesis of styelsamines A, B and D is currently in progress.
REFERENCES AND NOTES
1 (a) T. Ozturk, “The Alkaloid”, Vol. 49, ed. by G. A. Cordell, Academic Press Inc., New
York, 1997, pp. 79-220. (b) D. Skyler and C. H. Heathcock, J . Nat. Prod., 2002, 65,
1573.
2 B. R. Copp, J . J ompa, A. Tahir, and C. M. Ireland, J . Org. Chem., 1998, 63, 8024.
3 S. Nakahara, J . Matsui, and A. Kubo, Tetrahedron Lett., 1998, 39, 5521.
4 N. Miyaura and A. Suzuki, Synth. Commun., 1981, 11, 513.
5 S. S. Gitis and V. I. Trunov-Krasovskii, Zhur. Obshchet. Khim., 1959, 29, 2648.
6 R. Cassis, R. Tapia, and J . A. Valderrama, Synth. Commun., 1985, 15, 125.
7 E. C. Riesgo, X. J in, and R. P. Thummel, J . Org. Chem., 1996, 61, 3017.
8 R. J . Sundberg, B. P. Dass, and R. H. Smith, J r., J . Amer. Chem. Soc., 1969, 91, 658.
9 Styelsamine C (3): orange solid, mp 270-272℃(CHCl3). HRFABMS(glycerol, MH+) calcd
for C16H11N2O2 263.0821, found 263.0826. MS(FAB, glycerol) m/z(%) 263(100, MH+).
IR(KBｒ)ν
3296, 1648, 1620, 1514, 1248 cm-1. NMR: δ (500 MHz, DMSO-d6)
m a x
H
7.26(m, 1H), 7.34(s, 1H), 7.58(m, 2H), 7.91(d, 1H, J = 5.2 Hz), 8.30(d, 1H, J = 8.2 Hz),
8.81(d, 1H, J = 5.2 Hz), 9.91(s, 1H), 12.02(br s); δ (125 MHz, DMSO-d6) 108.25, 109.32,
C
113.09; 116.77, 117.71, 117.78, 122.94, 124.27, 132.46, 134.79, 137.06, 140.42, 143.14,
143.92, 152.16, 191.76.