Alkaloids from marine organisms. Part 7: Synthesis of bisdemethylaaptamine and bisdemethyloxyaaptamine - A biomimetic approach to the aaptamines?

Article abstract of DOI:10.1016/S0040-4020(01)00101-6

Aaptamines are marine alkaloids with a unique 1H-benzo[d,e][1,6]naphthyridine structure and interesting biological properties. Bisdemethylaaptamine and bisdemethyloxyaaptamine were synthesized in four steps on a Bischler-Napieralski route including an oxi

Full text of DOI:10.1016/S0040-4020(01)00101-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2331±2335
Alkaloids from marine organisms. Part 7:q Synthesis of
bisdemethylaaptamine and bisdemethyloxyaaptamineÐa
biomimetic approach to the aaptamines?
Franz von Nussbaum,a Susanne Schumannb,² and Wolfgang Steglichb,p
aBayer AG, Central Research, Life Science, Q18, D-51368 Leverkusen, Germany
È È È
Department Chemie, Universitat Munchen, Butenandtstr. 5-13, D-81377 Munchen, Germany
b
Received 9 January 2001; accepted 19 January 2001
AbstractÐAaptamines are marine alkaloids with a unique 1H-benzo[d,e][1,6]naphthyridine structure and interesting biological properties.
Bisdemethylaaptamine and bisdemethyloxyaaptamine were synthesized in four steps on a Bischler±Napieralski route including an oxidative
formation of the crucial C9a±N1-bond. This synthetic approach may serve as a model for an oxidative Pictet±Spengler biosynthesis of the
aaptamines. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
A patent claims the inhibition of protein kinase C by iso-
aaptamine derivatives.7 The ®rst aaptamines 1±3 were
isolated by Nakamura et al.8 from the marine sponge Aaptos
aaptos.9 Later on it was shown that the presence of these
alkaloids is not limited to the genus Aaptos. Besides the
O-methyl compounds 1±3, the new N-methylaaptamine 4
(isoaaptamine) was isolated from sponges of the genus
Suberites.6
The aaptamines form a small group of 1H-benzo[d,e][1,6]-
naphthyridine alkaloids2 with interesting biological
activities (Scheme 1). Due to their antagonistic effects on
a-adrenergic receptors,
a cardiac activity has been
described for aaptamine (1).3 Also antitumor activity has
been reported for aaptamines.4,5 The inhibition of Ehrlich
tumor cell growth seems to be the strongest for those
compounds with a free phenolic group at C-9 (2 and 4).6
So far eight synthetic approaches to these unique alkaloids
have been published.10,11 However, none of these efforts was
designed to mimic a possible biosynthesis of the aaptamine
system. In this paper we report on a concise four-step
synthesis of bisdemethylaaptamine (8) based on bio-
synthetic considerations.12 As shown in Scheme 2, the
aaptamine skeleton can be assumed to be derived from
l-dopa (5) and a biosynthetic equivalent of b-alanine alde-
hyde (6).13 A biochemical Pictet±Spengler condensation
followed by oxidative closure of the piperidine ring C
should yield the perhydro derivative 7.14 Decarboxylation
and dehydrogenation of 7 would then afford bisdemethyl-
aaptamine 8, from which the natural aaptamine alkaloids
could be formed by methylation. Interestingly, the hypo-
thetical precursor 915 of the sponge alkaloid halitulin
appears to originate from the same two building blocks 5
and 6, which points to a common biosynthetic origin of
these compounds.
Scheme 1. Natural 1H-benzo[d,e][1,6]naphthyridine alkaloids.
q For Part 6, see Ref. 1.
2. Results
Keywords: marine metabolites; biomimetic reactions; Bischler±Napieralski
reaction; oxidative C±N bond formation.
According to our hypothesis bisdemethylaaptamine (8) was
synthesized from homoveratrylamine (10) and N-tri¯uoro-
acetyl-b-alanine (11) (Scheme 3). Coupling of the two
p
Corresponding author. Tel.: 149-89-2180-7757; fax: 149-89-2180-
7756; e-mail: wos@cup.uni-muenchen.de
X-Ray crystallography.
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00101-6

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F. von Nussbaum et al. / Tetrahedron 57 (2001) 2331±2335
Scheme 2. Proposed biosynthesis of the aaptamine alkaloids and the halitulin precursor 9.
components followed by Bischler±Napieralski cyclization
of the resulting amide 12 afforded the dihydroisoquinoline
13 in high yield, whose structure was con®rmed by X-ray
crystallography (Scheme 4). On treatment with aqueous
hydrobromic acid, 13 underwent cleavage of the methyl
ether and tri¯uoroacetamido groups and afforded the cate-
cholamine 14 in form of its stable and analytically pure
bishydrobromide. As 14 precipitated from the reaction
mixture, no cumbersome puri®cation had to be carried out
with this air-sensitive, amphoteric compound.
the instability of the free base, 8 was puri®ed as tri¯uoro-
acetate 15 or hydrochloride 16 by gel chromatography (20%
overall yield).
Experiments, to convert the dihydroxy compound 8 or its
salts into the natural products 1±4 by selective methylation
were as yet unsuccessful.
3. Conclusions
At this point, the envisaged biomimetic key step had to be
carried out. In fact, oxidative cyclization of 14 in 1%
aqueous KOH with potassium peroxodisulfate or air yielded
bisdemethylaaptamine (8) besides minor amounts of its
oxidation product bisdemethyloxyaaptamine (17). Due to
Our synthesis illustrates that bisdemethylaaptamine (8) can
be obtained in one step from the simple catecholamine 14.
The mild conditions of this oxidative ring closure support
the idea that the biosynthesis of the aaptamines may follow
a similar course (Scheme 2).14
Scheme 3. Synthesis of the bisdemethylaaptaminium salts 15, 16, and bisdemethyloxyaaptamine (17).

F. von Nussbaum et al. / Tetrahedron 57 (2001) 2331±2335
2333
and brine (150 mL), dried (MgSO4), ®ltered and concen-
trated under reduced pressure. Recrystallization from
EtOAc±hexanes provided 12 as a colorless solid (58.5 g,
63%): mp 148±1498C; UV/Vis (MeOH) lmax (log e)ˆ228
(3.94), 278 nm (3.46); IR (KBr) 3304 (m, br), 3105 (m),
2941 (s), 1698 (s, nCvO), 1644 (s, nCvO), 1591 (w), 1552
(m), 1519 (m), 1459 (m), 1332 (m), 1263 (m), 1239 (m),
1185 (s), 1160 (w), 1026 (s), 938 (w), 877 (w), 804 (w), 766
1
(w), 729 cm21 (m); H NMR (300 MHz, CDCl3) d 2.41 (t,
Jˆ5.7 Hz, 2H), 2.76 (t, Jˆ6.9 Hz, 2H), 3.51 (`q', Jˆ6.9 Hz,
2H), 3.61 (`q', Jˆ5.7 Hz, 2H), 3.84 (s, 3H, OCH3), 3.86 (s,
3H, OCH3), 5.54 (s, 1H, NH), 6.70 (s, 1H, ArH), 6.72 (d,
Jˆ8.6 Hz, 1H, ArH), 6.81 (d, Jˆ8.6 Hz, 1H, ArH), 7.61 (s,
1H, NH); 13C NMR (75 MHz, CDCl3, TMS) d 34.11, 35.11,
35.93, 40.78 (each 1 C, C-2, a-CH2, b-CH2, C-3), 55.90
(OCH3), 55.94 (OCH3), 111.50 (C-50), 111.89 (C-20),
1
,116 (q, JCF<290 Hz, CF3), 120.66 (C-60), 130.98
2
(C-10), 147.87 (C-40), 149.17 (C-30), 157.32 (q, JCFˆ
36.9 Hz, COCF3), 171.03 (C-1); EI-MS m/z (%)ˆ348 (14)
[M1], 164 (100) [M12C5H6F3N2O2], 151 (25)
[M12C6H8F3N2O2]; HR-EI-MS calcd for C15H19F3N2O4
348.1297, found 348.1290. Anal. Calcd C, 51.72, H, 5.50,
N, 8.04, found C, 51.95, H, 5.60, N, 8.04.
Scheme 4. Crystal structure of dihydroisoquinoline 13 (Ortep plot).16
4. Experimental
4.1. General
4.1.2. 6,7-Dimethoxy-1-[2-(tri¯uoroacetylamino)ethyl]-
3,4-dihydroisoquinoline (13). POCl3 (150 mL, 1.6 mmol)
was added dropwise (30 min) to a stirred suspension of 12
(50.58 g, 145.2 mmol) in CH3CN (300 mL, dried over
Ê
molecular sieves 3 A), and the stirring was continued for
Silica gel 60 230±400 mesh (Merck), MN Polyamide SC
6-AC (Macherey and Nagel, Germany) and Sephadex LH-
20 (Pharmacia) were used for chromatography. Rf values
were determined on silica gel 60 F254 TLC plates
1 h at room temperature. The resulting mixture was re¯uxed
for approximately 8 h until all the starting material had been
consumed (TLC monitoring). After removal of the solvent
in vacuo, the residue was poured into ice water and neutra-
lized with saturated aq. NaHCO3. The aqueous layer was
extracted with EtOAc (3£200 mL). The combined organic
extracts were washed with saturated aq. NaHCO3
(2£200 mL) and brine (100 mL), dried (MgSO4), and
®ltered. Evaporation of the solvent provided isoquinoline
13 as a yellow solid (45.2 g, 94%): mp 144.0±146.88C; Rf
0.80 (1:1 CHCl3±MeOH); UV/Vis (CH3CN) lmax
(log e)ˆ225 (4.36), 270 (3.89), 304 (3.80), 356 nm (2.25);
IR (KBr) 3349 (br, NH), 3256 (m, br), 2934 (s), 1712 (s,
1
(Merck). H and 13C NMR spectra were recorded on a
1
Bruker ARX 300 instrument. H and 13C chemical shifts
are given with respect to TMS or the solvent as internal
standard. If there was no certain assignment possible #, ³
and § indicate an interchangeable assignment of NMR
signals. IR spectra were measured on a Perkin±Elmer FT
1000. C, H, N and Br analyses were performed by the micro-
analytical laboratory of our institute. The X-ray diffraction
analyses were carried out on a Enraf±Nonius CAD4
Ê
diffractometer at 296 (2) K using MoKa (lˆ0.71069 A)
radiation.16 The structure was solved with shelxs 86 and
re®ned by shelxl 93 program.17 The full data of the X-ray
crystal structure have been deposited at the Cambridge
Crystallographic Data Center.16 Mass spectra were
measured with a Finnigan MAT 95Q sector mass
spectrometer using EI at 70 eV.
n
CvO), 1643 (s), 1628 (m), 1591 (w), 1563 (s), 1519 (s),
1472 (m), 1449 (m), 1261 (m), 1246 (m), 1209 (m), 1197
(m), 1157 (m), 1026 (m, CO), 850 (m), 810 (m), 768 (w),
460 cm21 (w); 1H NMR (300 MHz, CDCl3, TMS) d 2.64 (t,
Jˆ7.7 Hz, 2H), 2.92 (t, Jˆ5.5 Hz, 2H), 3.66 (t, Jˆ7.7 Hz,
2H), 3.78 (`q', Jˆ5.5 Hz, 2H), 3.90 (s, 3H, OCH3), 3.92 (s,
3H, OCH3), 6.70 (s, 1H, ArH), 6.94 (s, 1H, ArH), 8.17 (s,
1H, NHCOCF3); 13C NMR (75 MHz, CDCl3, TMS) d 25.62
4.1.1.
N-[2-(3,4-Dimethoxyphenyl)ethyl]-3-(tri¯uoro-
#
³
³
(C-4#), 33.98 (C-10 ), 36.38 (C-3 ), 46.62 (C-20 ), 56.02
acetylamino)propionamide (12). To a stirred, ice-cold
solution of 10 (48.54 g, 267.8 mmol), 11 (49.0 g,
264.7 mmol), N-ethylmorpholine (33.3 mL, 263.1 mmol),
and N-hydroxybenzotriazole (HOBt) (27.03 g, 200 mmol)
in THF (400 mL) was added dropwise within 1 h to a 1 M
solution of dicyclohexylcarbodiimide (DCC) (60.4 g,
292.7 mmol) in THF. The reaction mixture was warmed
to room temperature and stirred for additional 6 h. After
cooling to 08C, the dicyclohexylurea was ®ltered off. The
®ltrate was concentrated, the residue dissolved in EtOAc
(500 mL) and stirred for 12 h. After ®ltration, the organic
layer was washed with saturated aq. NaHCO3 (3£200 mL),
2N citric acid (200 mL), saturated aq. NaHCO3 (100 mL),
(OCH3), 56.31 (OCH3), 108.25 (C-8), 110.50 (C-5),
1
116.11 (q, JCFˆ287.7 Hz, CF3), 121.68 (C-8a), 131.23
2
(C-3a), 147.76 (C-7§), 151.34 (C-6§), 156.91 (q, JCFˆ
36.6 Hz, COCF3), 164.74 (C-1); EI-MS m/z (%)ˆ330 (35)
[M1], 261 (30) [M12CF3], 233 (39) [M12C2F3O], 217
(100)
[M12C2H2F3NO];
HR-EI-MS
calcd
for
C15H17F3N2O3 330.1191, found 330.1188. Anal. Calcd C,
54.54, H, 5.19, N, 8.48, found C, 54.59, H, 5.19, N, 8.46.
4.1.3. 1-(2-Aminoethyl)-6,7-dihydroxy-3,4-dihydroiso-
quinoline dihydrobromide (14). A suspension of 13
(24.34 g, 73.7 mmol) in 48% aqueous HBr (210 mL) was

2334
F. von Nussbaum et al. / Tetrahedron 57 (2001) 2331±2335
re¯uxed (1458C) until the TLC showed no more starting
material (approximately 4±8 h). The reaction mixture was
cooled to 58C and stirred at this temperature for additional
12 h. The resulting yellow precipitate was ®ltered under
argon, immediately washed with Et2O (3£30 mL) under
argon and then dried in vacuo. 14 was obtained as a hygro-
scopic, bright yellow solid (18.9 g, 70%, analytically pure):
mp 2008C (dec); Rf 0.20 (95:5 MeOH±NH4OH); UV/Vis
(MeOH) lmax (log e)ˆ251 (4.06), 313 (3.93), 371 nm
(3.83); IR (KBr) 3421 (m, br, NH), 3158 (m, br), 3086
(m, br), 2959 (m, br), 1648 (m), 1614 (m), 1579 (s), 1491
(m), 1468 (m), 1390 (m), 1335 (m), 1305 (s), 1266 (m),
1204 (m), 1161 (m), 1079 (w), 1035 (w), 462 cm21 (w);
1H NMR (300 MHz, CDCl3) d 2.98 (t, Jˆ8.1 Hz, 2H),
3.37 (m, 4H), 3.78 (t, Jˆ8.1 Hz, 2H), 6.87 (s, 1H, ArH),
7.33 (s, 1H, ArH); 13C NMR (75 MHz, CDCl3) d 24.66
(m), 723 cm21 (w); 1H NMR (300 MHz, d6-DMSO) d 6.23
(d, Jˆ7.0 Hz, 1H, 3-H), 6.67 (d, Jˆ7.3 Hz, 1H, 6-H), 6.82
(s, 1H, 7-H), 7.13 (dd, Jˆ7.0, 5.0 Hz, 1H, 5-H), 7.69 (`t',
Jˆ6.6 Hz, 1H, 2-H), 9.84 (s, br, 1H, OH), 11.31 (s, br, 1H,
OH), 11.89 (d, Jˆ5.3 Hz, 1H, HN1), 12.43 (d, Jˆ3.9 Hz,
1H, HN4); 13C NMR (75 MHz, d6-DMSO) d 97.46 (C-3),
104.30 (C-7), 112.45 (C-6), 116.14 (C-9b), 116.98 (q,
1JCFˆ297.6 Hz, CF3), 127.82 (C-5), 128.27 (C), 129.28
(C), 130.02 (C), 141.84 (C-2), 150.04 (C), 151.39 (C),
2
158.54 (q, JCFˆ32.3 Hz, COCF3); EI-MS m/z (%)ˆ200
(100) [M1], 171 (19) [M12H±CO], 143 (5) [M122CO±
H]; HR-EI-MS calcd for C11H8N2O2 200.0586, found
200.0576; Anal. Calcd for C13H9F3N2O4´2H2O: C, 44.58,
H, 3.74, N, 8.00, found C, 44.84, H, 3.61, N, 8.53.
4.3.2. 8,9-Dihydroxy-1H-benzo[d,e][1,6]naphthyridin-
4-ium chloride (16, bisdemethylaaptamin-4-ium chlo-
ride). 14 (925 mg, 2.51 mmol) was oxidized according to
the general procedure A. Immediately, a 1 M aqueous solu-
tion of BaCl2 (4.16 g, 20.0 mmol) was added dropwise to
the violet reaction mixture. After removal of the precipitate
by ®ltration over a G3 glass frit, the ®ltrate was acidi®ed
(pH 3±4) with conc. HCl and diluted with degassed H2O
(100 mL). The yellow aqueous phase was extracted under
argon with EtOAc (400 mL) in a liquid±liquid extractor for
12 h. After phase separation, the organic layer was concen-
trated in vacuo to afford crude 16 as a brown solid. Ion
exchange chromatography [Dowex 50 WX8; H2O
(500 mL)!4N HCl (500 mL)] followed by gel chromato-
graphy (2£, Sephadex LH-20; 1:0.00075 MeOH-conc. HCl)
provided 16 as a brown solid (288 mg, 49%; 129 mg, 22%
after rechromatography): mp.2728C (dec); Rf 0.86 (95:5
MeOH±NH4OH); UV/Vis (MeOH) lmax (log e)ˆ248
(4.26), 270 (4.20), 315 (3.52), 362 (3.57), 410 nm (3.46);
IR (KBr): 3401 (m, br), 3131 (s), 1657 (s), 1626 (s), 1610
(s), 1575 (m), 1437 (m), 1393 (m), 1339 (s), 1227 (m), 1179
#
(C-4), 30.87 (C-10), 37.43 (C-3#), 41.80 (C-20 ), 116.0
³
³
(C-8 ), 116.38 (C-5 ), 117.25 (C-8a), 134.72 (C-4a),
144.16 (C-7§), 154.62 (C-6§), 173.29 (C-1); FAB-MS m/z
(%)ˆ207 (100) [M11H]; Anal. Calcd for C11H16Br2N2O2:
C, 35.90, H, 4.38, N, 7.61, Br, 43.42, found C, 36.20, H,
4.50, N, 7.64, Br, 43.04.
4.2. General procedure A
Solid 14 (1 mmol) was dissolved in degassed 1% aq. KOH
(150 mL) under argon. A 0.05 M solution of potassium
peroxodisulfate (2.1 mmol) in degassed 0.5% aq. KOH
was added via a syringe pump within 2 h, and the resulting
deep violet reaction mixture was immediately worked up as
indicated below.
4.3. General procedure B
A solution of 14 (1 mmol) in 1% aq. KOH (250 mL) was
stirred vigorously in an open Erlenmeyer ¯ask (1000 mL) at
room temperature. After approximately 4±5 h, the solution,
yellow in color originally, turned deep violet and was
immediately worked up as discussed in the following
paragraphs.
1
(w), 1091 (w), 1080 (w), 939 (w), 847 cm21 (w); H NMR
(300 MHz, d6-DMSO) d 6.29 (d, Jˆ6.5 Hz, 1H, 3-H), 6.68
(d, Jˆ7.0 Hz, 1H, 6-H), 6.86 (s, 1H, 7-H), 7.13 (dd, Jˆ7.1,
5.0 Hz, 1H, 5-H), 7.70 (`t', Jˆ6.5 Hz, 1H, 2-H), 9.86 (s, br,
1H, OH), 11.12 (s, br, 1H, OH), 11.89 (d, Jˆ6.2 Hz, 1H,
HN1), 12.43 (s, br, 1H, HN4); 13C NMR (75 MHz, d6-
DMSO) d 97.39 (C-3), 104.50 (C-7), 112.37 (C-6), 116.10
(C-9b), 127.63 (C-5), 128.19 (C), 129.19 (C), 129.91 (C),
141.69 (C-2), 149.94 (C), 151.18 (C); EI-MS m/z (%)ˆ200
(100) [M1], 171 (27) [M12H±CO], 154 (12), 143 (8)
[M122CO±H]; HR-EI-MS calcd for C11H8N2O2
200.0586, found 200.0576.
4.3.1. 8,9-Dihydroxy-1H-benzo[d,e][1,6]naphthyridin-4-
ium monotri¯uoroacetate (15, bisdemethylaaptamin-4-
ium monotri¯uoroacetate). 14 (368 mg, 1.0 mmol) was
oxidized according to the general procedure A. The reaction
mixture was acidi®ed (pH 3±4) with TFA and diluted with
degassed H2O (100 mL). The green aqueous phase was
extracted under argon with EtOAc (400 mL) in a liquid-
liquid extractor for 12 h. After phase separation, the organic
layer was concentrated in vacuo to afford crude 15 (160 mg,
51%) as a brown solid. Adsorption chromatography (MN
Polyamide SC 6-AC; hexanes!EtOAc!1:1:0.001 EtOAc±
MeOH±TFA) followed by gel chromatography (Sephadex
LH-20; 1:0.001 MeOH±TFA) provided 15 as a brown solid
(104 mg, 28%): mp 2478C (dec from 1488C); Rf 0.86 (95:5
MeOH±NH4OH); UV/Vis (MeOH) lmax (log e)ˆ206
(4.31), 246 (4.43), 271 (4.19), 315 (3.63), 363 (3.67),
409 nm (3.58); (1% aq. KOH) lmax (log e)ˆ231 nm
(4.25), 268 (4.29), 364 (3.56), 548 (br, 3.47); (6N HCl):
lmax (log e)ˆ243 nm (4.32), ,270 (sh, 4.06), 311 (3.59),
359 (3.54), 397 (3.56); IR (KBr) 3430 (s), 3137 (m), 1679
(m), 1657 (s), 1627 (s), 1611 (s), 1576 (m), 1437 (m), 1394
(w), 1339 (s), 1227 (m), 1204 (s), 1181 (s), 1138 (m), 1080
4.3.3. Bisdesmethyloxyaaptamine (17, 8-hydroxy-
benzo[d,e][1,6]naphthyridin-9-one). 14 (250 mg, 0.68
mmol) was oxidized according to the general procedures
A or B and worked up as described above for compound
16. Minor amounts of crude 17 (30 mg, 22%) were obtained
as a second fraction. Further gel chromatography (Sephadex
LH-20; MeOH) yielded 17 as a green solid (8 mg, 6%): mp
.2508C (dec); Rf 0.40 (5:1, Chloroform±MeOH); UV/Vis
(MeOH) lmaxˆ210 (s), 230 (s), 295 (m), 360 (m), 375 (m),
410±430 nm (w, sh); IR (KBr) 3436 (s, br), 1630 (s), 1486
(w), 1385 (w), 1285 (s), 1195 (m), 1090 cm21 (m); 1H NMR
(300 MHz, d6-DMSO) d 6.97 (s, 1H), 7.63 (d, Jˆ4.5 Hz,
1H), 8.19 (d, Jˆ5.6 Hz, 1H), 9.05 (d, Jˆ4.5 Hz, 1H), 9.07
(d, Jˆ5.6 Hz, 1H); (300 MHz, CDCl3, TMS) d 6.91 (s, 1H,

F. von Nussbaum et al. / Tetrahedron 57 (2001) 2331±2335
2335
10. For a review see: Sugino, E.; Choshi, T.; Hibino, S. Hetero-
cycles 1999, 50, 543±559.
7-H), 7.50 (d, Jˆ4.4 Hz, 1H, 6-H), 8.22 (d, Jˆ5.5 Hz, 1H,
2-H), 9.12 (d, Jˆ4.4 Hz, 1H, 5-H), 9.22 (d, Jˆ5.5 Hz, 1H,
3-H); EI-MS: m/z (%)ˆ200 (100) [MH21], 199 (14)
[M11H], 198 (12) [M1], 170 (47), 160 (31), 142 (26).
11. (a) Pelletier, J. C.; Cava, M. P. Tetrahedron Lett. 1985, 26,
1259±1260. (b) Pelletier, J. C.; Cava, M. P. J. Org. Chem.
1987, 52, 616±622. (c) Bassoli, A.; Maddinelli, G.; Rindone,
B.; Tollari, S.; Chioccara, F. J. Chem. Soc., Chem. Commun.
1987, 150±151. (d) Sakamoto, T.; Miura, N.; Kondo, Y.;
Yamanaka, H. Chem. Pharm. Bull. 1986, 34, 2760±2765.
(e) Kelly, T. R.; Maguire, M. P. Tetrahedron 1985, 41,
3033±3036. (f) Andrew, R. G.; Raphael, R. A. Tetrahedron
1987, 43, 4803±4816. (g) Hibino, S.; Sugino, E.; Choshi, T.;
Sato, K. J. Chem. Soc., Perkin Trans. 1 1988, 2429±2432.
(h) Balczewski, P.; Mallon, M. K. J.; Street, J. D.; Joule,
J. A. Tetrahedron Lett. 1990, 31, 569±572. (i) Molina, P.;
Vidal, A.; Barquero, I. Synthesis 1996, 1199±1202.
Acknowledgements
This investigation was supported by the Deutsche
Forschungsgemeinschaft (SFB 369). We thank Edward
Htun and Thomas StuÈhler for their collaborative efforts as
well as Kirsten Zeitler for valuable help with the X-ray
crystallography.
È
12. (a) Fugmann, B. PhD Thesis, Universitat Bonn, 1985. (b) von
È
È
Nussbaum, F. PhD Thesis, Universitat Munchen, 1998.
13. b-Alanine aldehyde (6) is the formal Michael addition product
of acrolein and ammonia, both precursors in Baldwin's
hypothesis for the biosynthesis of manzamine alkaloids
(Baldwin, J. E.; Claridge, T. D. W.; Cushaw, A. J.; Heupel,
F. A.; Lee, V.; Spring, D. R.; Whitehead, R. C.; Bought¯ower,
R. J.; Mutton, I. M.; Upton, R. J. Angew. Chem., Int. Ed. Engl.
1998, 37, 2661±2663). Alternatively, aminoaldehyde 6 could
be derived from aspartic acid by a decarboxylation/reduction
sequence.
References
1. Peschko, C.; Steglich, W. Tetrahedron Lett. 2000, 41, 9477±
9481.
2. Fungal alkaloids with a related 1H-benzo[de,h][1,6]naphthy-
ridine system are the necatorones: (a) Fugmann, B.; Steffan,
B.; Steglich, W. Tetrahedron Lett. 1984, 25, 3575±3578.
(b) Klamann, J.-D.; Fugmann, B.; Steglich, W. Phytochemistry
1989, 28, 3519±3522.
3. Ohizumi, Y.; Kajiwara, A.; Nakamura, H.; Kobayashi, J.
J. Pharm. Pharmacol. 1984, 36, 785±786.
14. In the biosynthesis of necatorone2 an analogous biosynthetic
pathway, starting from 2-aminobenzaldehyde and tyrosine is
4. Longley, R. E.; McConnell, O. J.; Essich, E.; Harmody, D.
J. Nat. Prod. 1993, 56, 915±920.
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followed: von Nussbaum, F.; Eizenhofer, T.; Klamann, J.-D.;
Spiteller, P.; Heinrich, M.; Steglich, W. Unpublished results.
15. 3-(7,8-Dihydroxyquinolin-5-yl)pyruvic acid (10) has been
proposed by Kashman as a biosynthetic precursor of halitulin:
Kashman, Y.; Koren-Goldshlager, G.; Garcia Gravalos, M. D.;
Schleyer, M. Tetrahedron Lett. 1999, 40, 997±1000.
16. Further details of the X-ray analysis (CCDC 154819) are
available on request from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK
(deposit@ccdc.cam.ac.uk).
5. Shen, Y.-C.; Lin, T.-T.; Sheu, J.-H.; Duh, C.-Y. J. Nat. Prod.
1999, 62, 1264±1267.
6. Fedoreev, S. A.; Prokof'eva, N. G.; Denisenko, V. A.; Reba-
chuk, N. M. Pharm. Chem. J. (USSR) 1988, 22, 615±618.
7. SmithKline Beecham Corp. USA WO 9,505,824 A1 950302;
Chem. Abstr. 1995, 122, 282233.
8. (a) Nakamura, H.; Kobayashi, J.; Ohizumi, Y.; Hirata, Y.
Tetrahedron Lett. 1982, 23, 5555±5558. (b) Nakamura, H.;
Kobayashi, J.; Ohizumi, Y. J. Chem. Soc., Perkin Trans. 1
1987, 173±176.
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17. (a) Sheldrick, G. M.; shelxs 86; Universitat Gottingen, 1986.
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(b) Sheldrick, G. M. shelxs 93; Universitat Gottingen, 1993.
(c) Sheldrick, G. M., shelxl-93, Program for Re®nement of
È È
Crystal Structures, Universitat Gottingen, 1993.
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9. For alkaloids with an rearranged skeleton see (a) Rudi, A.;
Kashman, Y. Tetrahedron Lett. 1993, 34, 4683±4684. (b)
Tinto, W. F. Heterocycles 1998, 48, 2089±2093.