Total synthesis of ascididemin-type alkaloids using alkyne building blocks

Article abstract of DOI:10.1021/jo501927e

A common approach to ascididemin-type alkaloids, including ascididemin, bromoleptoclinidinone, neocalliactine acetate, and 11-hydroxyascididemin, based on a Bronsted acid-promoted tandem annulation has been developed. Alkyne building blocks were first des

Full text of DOI:10.1021/jo501927e

Article
pubs.acs.org/joc
Total Synthesis of Ascididemin-Type Alkaloids Using Alkyne Building
Blocks
Hao Yin, Naiyu Shan, Shaozhong Wang,* and Zhu-Jun Yao
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210093, P. R. China
S
* Supporting Information
ABSTRACT: A common approach to ascididemin-type alkaloids,
including ascididemin, bromoleptoclinidinone, neocalliactine acetate,
and 11-hydroxyascididemin, based on a Brønsted acid-promoted
tandem annulation has been developed. Alkyne building blocks were
first designed and then employed in alkaloid synthesis; these
building blocks can be accessed by a Sonogashira coupling reaction
on a multigram scale.
rapidly access diverse ascididemin-type alkaloids and their
analogues by means of chemical synthesis.
INTRODUCTION
■
Ascididemin-type alkaloids, consisting of ascididemin,1 bromo-
leptoclinidinone,2 neocalliactine,3 and 11-hydroxyascididemin,4
belong to a subclass of pyridoacridine alkaloids that were
isolated from marine tunicates and sponges.5 These pentacyclic
alkaloids share a common 6H-pyrido[2,3,4-kl]acridin-6-one
skeleton and differ in substituent pattern and distribution
(Scheme 1). Because of their significant cytotoxic properties,
Among the known strategies to synthesize ascididemin-type
alkaloids, the classic methodology of Bracher starting from o-
aminoacetophenone (I) proved applicable (Scheme 2). This
approach consists of an oxidative amination followed by
stepwise construction of rings B and E of ascididemin.8 To
implement biomimetic synthesis as well as to improve Bracher’s
protocol with “pot economy”, Kashman9 and Echavarren10
independently synthesized N-trifluoroacetamidokynuramine
(II) and cinnamaldehyde-N,N-dimethylhydrazone (III) as
surrogates for I. Although aminoquinone precursors derived
from building blocks II and III introduce all of the requisite
atoms for the assembly of the final ascididemin alkaloid,
inherent limitations such as reaction efficiency and substituent
flexibility still remain. Following our continuing studies on
aminoquinones,11 as well as aiming at developing a more
common and efficient approach to ascididemin-type alkaloids,
we designed IV, a new type of alkyne building block. As
outlined in Scheme 3, aminoquinones V derived from alkyne
building blocks IV were envisioned to be transformed to
ascididemin alkaloids through a tandem [(6 + 0) + (4 + 2)]
annulation, in which two six-membered nitrogen-containing
rings might be constructed in a one-pot manner.
Scheme 1. Ascididemin-Type Alkaloids
RESULTS AND DISCUSSION
■
Alkyne building blocks IV were prepared from N-Boc-protected
propargylamine and a variety of 2-iodoanilines by a Sonogashira
coupling reaction. As shown in Table 1, the reaction gave
excellent results in terms of yield and functional group
tolerance. Both bromine and hydroxy groups on the benzene
moiety were kept intact. Furthermore, the synthesis of alkyne
IV-1 could be scaled to decagram quantities without any loss of
yield.
especially in vitro antitumor activity, the ascididemin-type
alkaloids have attracted considerable attention as potential drug
candidates for the treatment of cancers.6 Recent studies of
structure−activity relationships have revealed that some
ascididemin analogues even display stronger cytotoxity than
natural ascididemin alkaloid.7 Consequently, for further screen-
ing and biological evaluation, it still remains an urgent need to
Received: August 20, 2014
Published: September 19, 2014
© 2014 American Chemical Society
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Scheme 2. Different Building Blocks
Ph3PAuNTf2 was employed, a messy reaction mixture was
obtained at 100 °C using acetic acid as the solvent. Only a trace
amount of the anticipated product ascididemin (VI-1) was
detected (Table 3, entry 1). When acidic additives such as
H2SO4, p-toluenesulfonic acid (p-TSA), and (+)-camphor-10-
sulfonic acid [(+)-CSA] were used, a moderate yield was
observed in the case of concentrated H2SO4 (Table 3, entries
2−4). It was demonstrated that H2SO4 is superior to the two
sulfonic acids. A control experiment excluding the gold(I)
catalyst gave ascididemin in a comparable yield (Table 3, entry
5), which led us to recognize that Brønsted acids play a crucial
role in the domino cyclization. Attempts to increase the amount
of H2SO4 from 10 to 50 equiv resulted in a slight improvement
in the yield (Table 3, entry 6). Further screening revealed that a
mixture of H2SO4 and HOAc in a 1:1 (v/v) ratio improved the
transformation, and the yield was enhanced to 66% (Table 3,
entry 7). To accelerate the transient aromatization process,
copper(II) and iron(III) salts containing acetate and sulfate
counteranions were employed. The experimental results
demonstrated that iron(III) sulfate is more advantageous than
copper(II) acetate (Table 3, entries 8 and 9). Accordingly, the
optimized conditions were defined as a combination of
iron(III) sulfate and H2SO4 (Table 3, entry 9).
As well as aminoquinone V-1, brominated aminoquinone V-
2 underwent the domino cyclization to afford alkaloid
bromoleptoclinidinone (VI-2) in good yield (Table 4, entries
1 and 2). For ease of isolation, neocalliactine derived from V-3
was converted to its acetate derivative by in situ acetylation, and
neocalliactine acetate (VI-3) was isolated in 44% yield over two
steps (Table 4, entry 3). The solubility of neocalliactine methyl
ether (VI-4) is different from that of neocalliactine, and it could
be prepared straightforwardly from aminoquinone V-4 in a very
high yield (Table 4, entry 4). However, aminoquinone V-5
containing a chlorine atom located at the para position of the
pyridine ring was converted to 11-chloroascididemin (VI-5) in
Scheme 3. Our Synthetic Plan
With significant amounts of the alkyne building blocks in
hand, we next attempted to perform the oxidative amination
between IV and quinones (Table 2). Because of the relatively
low nucleophilicity of the aniline functionality, metallic Lewis
acids such as CeCl3·7H2O,10 NaAuCl4·2H2O,11a and Cu-
12
(OAc)2 were employed as promoters for the transformation.
After careful experimental comparisons, we eventually fixed the
conditions by using a catalytic amount of the cerium salt in
combination with alcoholic solvent. According to the optimized
conditions, the oxidative amination of quinoline-5,8-dione and
IV-1−4 proceeded smoothly to afford aminoquinones V-1−4
in yields ranging from 65% to 75%. However, in the case of 4-
chloroquinoline-5,8-dione, the yield of aminoquinone V-5
dropped to 50%, even though it was isolated as a major
product. Additionally, as a precursor of deazaascididemin
alkaloid, aminoquinone V-6 could be accessed smoothly from
naphthalene-1,4-dione and alkyne building block IV-1.
To test the feasibility of the postulated tandem [(6 + 0) + (4
+ 2)] annulation, aminoquinone V-1 was initially chosen as a
model substrate (Table 3). At the beginning, a gold(I) catalyst
with benign carbophilicity was regarded as an ideal catalyst,13
since its selective activation of the triple bond was expected to
induce an intramolecular attack by the aminoquinone
functionality that in turn would trigger the whole domino
process. However, to our disappointment, when 5 mol %
a
Table 1. Preparation of Alkyne Building Blocks via Sonogashira Reaction
a
b
Unless otherwise mentioned, the reaction was performed on a 10 mmol scale. The yield was calculated when the scale of the reaction was
increased to 50 mmol.
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a b
,
Table 2. Preparation of Aminoquinones via Oxidative Amination
a
Reaction conditions: a mixture of quinone (5.0 mmol), IV (5.0 mmol), CeCl3·7H2O (180 mg), and 50 mL of MeOH was stirred at rt for 24 h
b
under an oxygen atmosphere. Isolated yields after column chromatography are shown.
11-hydroxyascididemin were in agreement with the reported
ones.1,2,4
Table 3. Optimization of the Tandem Annulation
CONCLUSION
■
An array of ascididemin-type alkaloids were successively
prepared by means of a Brønsted acid-promoted tandem
annulation. A new class of alkyne building blocks that can be
generated on a multigram scale were first designed and
employed. Further details on the tandem annulation as well as
applications of the alkyne building blocks in alkaloid synthesis
will be pursued in the future.
yield
b
a
entry
conditions
(%)
1
2
5 mol % Ph3PAuNTf2, HOAc, 100 °C, 1 h
5 mol % Ph3PAuNTf2, 10 equiv of H2SO4, HOAc, 100 °C,
1 h
<5
40
EXPERIMENTAL SECTION
■
3
4
5 mol % Ph3PAuNTf2, 10 equiv of p-TSA, HOAc, 100 °C,
1 h
<5
<5
General Information. All melting points were determined without
1
correction. H NMR spectra were obtained at 300, 400, or 600 MHz,
and 13C NMR spectra were obtained at 75, 100, or 125 MHz. Spectra
were recorded in CDCl3, CD3COD, DMSO-d6, or CF3CO2D solution
using the residual protonated solvent as the internal standard; J values
are given in hertz. High-resolution mass spectrometry measurements
were carried out on a Q-TOF micromass apparatus.
5 mol % Ph3PAuNTf2, 10 equiv of (+)-CSA, HOAc, 100
°C, 1 h
10 equiv H2SO4, HOAc, 100 °C, 1 h
50 equiv of H2SO4, HOAc, 100 °C, 1 h
H2SO4/HOAc (1:1 v/v), 100 °C, 2 h
10 mol % Cu(OAc)2, H2SO4/HOAc (1:1 v/v), 100 °C, 2 h
10 mol % Fe2(SO4)3, H2SO4/HOAc (1:1 v/v), 100 °C, 2 h
5
6
7
8
9
45
50
66
51
75
General Procedure for the Preparation of Alkyne Building
Blocks IV by a Sonogashira Coupling Reaction. Under the
protection of nitrogen, triethylamine (40 mL) was added to a flask
containing substituted 2-iodoaniline (10.0 mmol), tert-butyl prop-2-
ynylcarbamate (1.55 g, 10 mmol), trans-dichlorobis-
(triphenylphosphine)palladium(II) (70.4 mg, 0.1 mmol), and copper-
(I) iodide (38.1 mg, 0.2 mmol). The mixture was stirred overnight at
room temperature (monitored by TLC). After completion of the
reaction, the solvent was removed under vacuum. The obtained
residue was treated with a mixture of chloroform (60 mL) and water
(60 mL). The separated organic layer was washed with brine (60 mL)
and dried with anhydrous MgSO4. After filtration, the filtrate was
concentrated. The residue was purified by column chromatography on
silica gel (EtOAc/PE = 1:4 for IV-1, IV-2, and IV-4; EtOAc/PE = 1:2
for IV-3) to give alkyne building block IV.
a
The reaction was performed under an oxygen atmosphere; the
concentration of V-1 was 0.1 M. Isolated yields after column
chromatography.
b
an inferior yield (Table 4, entry 5). The chorine atom in VI-5
can be further replaced by a hydroxyl group, delivering 11-
hydroxyascididemin in 82% yield (Scheme 4). Under identical
conditions, the synthesis of VI-6, an isomer of deazaascidide-
min, was achieved in 80% yield from aminoquinone V-6 in a
similar manner (Table 4, entry 6). The NMR spectral data for
the synthetic alkaloids ascididemin, bromoleptoclinidinone, and
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a b
,
Table 4. Synthesis of Ascididemin-Type Alkaloids via Tandem Annulation
a
Reaction conditions: a mixture of aminoquinone (0.3 mmol), Fe2(SO4)3 (0.03 mmol), 1.5 mL of H2SO4 (c) and 1.5 mL of HOAc was stirred at
b
c
100 °C for 2 h under an oxygen atmosphere. Isolated yields after column chromatography are shown. 2.0 equiv of Ac2O was used to acylate the
free phenol group.
tert-Butyl [3-(2-Amino-5-hydroxyphenyl)prop-2-yn-1-yl]-
Scheme 4. Synthesis of 11-Hydroxyascididemin
carbamate (IV-3). Brown solid, 2.10 g, 80% yield; mp 144−147 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.36 (t, J = 5.2 Hz,
1H), 6.56−6.49 (m, 3H), 4.76 (s, 2H), 3.96 (d, J = 5.2 Hz, 2H), 1.40
(s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 155.4, 147.6, 142.7, 117.6,
116.6, 115.1, 106.3, 91.4, 79.4, 78.3, 30.5, 28.2; IR (KBr) νmax 3420,
3385, 3291, 2971, 1699, 1509, 1456, 1283, 1155, 852, 783 cm−1;
HRMS (ESI) m/z calcd for C14H18N2NaO3 285.1215 [M + Na]+,
found 285.1212.
tert-Butyl [3-(2-Amino-5-methoxyphenyl)prop-2-yn-1-yl]-
carbamate (IV-4). Brown oil, 2.32 g, 84% yield; 1H NMR (400
MHz, CDCl3) δ 6.80 (d, J = 2.8 Hz, 1H), 6.75 (dd, J1 = 8.8 Hz, J2 =
2.8 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 4.18 (d, J = 5.2 Hz, 2H), 3.94 (s,
2H), 3.72 (s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.3, 151.6, 142.3, 117.2, 115.9, 115.8, 107.9, 90.7, 79.9, 79.7, 55.7,
31.2, 28.3; IR (KBr) νmax 3358, 2977, 2223, 1670, 1503, 1367, 1170,
1039, 856 cm−1; HRMS (ESI) m/z calcd for C15H20N2NaO3 299.1372
[M + Na]+, found 299.1370.
tert-Butyl [3-(2-Aminophenyl)prop-2-yn-1-yl]carbamate (IV-1).
White solid, 2.24 g, 91% yield; mp 95−97 °C; H NMR (400 MHz,
1
CDCl3) δ 7.24 (dd, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.13−7.09 (m, 1H),
6.68−6.63 (m, 2H), 4.83 (s, 1H), 4.22 (s, 2H), 4.18 (d, J = 5.4 Hz,
2H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.4, 148.1,
132.0, 129.6, 117.7, 114.2, 107.1, 90.8, 79.9, 79.7, 31.3, 28.3; IR (KBr)
νmax 3451, 3367, 1681, 1517, 1449, 1249, 1167, 865, 745 cm−1; HRMS
(ESI) m/z calcd for C14H18N2NaO2 269.1266 [M + Na]+, found
269.1263.
General Procedure for the Oxidative Amination of
Quinones and Alkyne Building Blocks IV. A solution of
quinoline-5,8-dione or naphthoquinone (5.0 mmol), alkyne building
block IV (5.0 mmol), cerium chloride heptahydrate (CeCl3·7H2O,
180.0 mg), and methanol (50 mL) was stirred under an oxygen
atmosphere at room temperature for 24 h. The solvent was
evaporated, and the residue was purified by column chromatography
on silica gel (EtOAc/PE = 1:1 for V-1−5; EtOAc/PE = 1:4 for V-6) to
give aminoquinone V.
tert-Butyl [3-(2-Amino-4-bromophenyl)prop-2-yn-1-yl]-
carbamate (IV-2). Light-yellow solid, 2.78 g, 86% yield; mp 109−
111 °C; 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 7.8 Hz, 1H), 6.83
(d, J = 1.6 Hz, 1H), 6.76 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 4.85 (s,
1H), 4.31 (s, 2H), 4.15 (d, J = 5.6 Hz, 2H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 155.4, 149.2, 133.1, 123.4, 120.5, 116.8, 106.1,
91.8, 80.1, 78.9, 31.3, 28.3; IR (KBr) νmax 3451, 3361, 1667, 1504,
1366, 1247, 1164, 882, 792 cm−1; HRMS (ESI) m/z calcd for
C14H17BrN2NaO2 347.0371 [M + Na]+, found 347.0367.
tert-Butyl [3-(2-((5,8-Dioxo-5,8-dihydroquinolin-6-yl)amino)-
phenyl)prop-2-yn-1-yl]carbamate (V-1). Red needle solid, 1.51 g,
1
75% yield; mp 147−149 °C (EA); H NMR (300 MHz, CDCl3) δ
9.06 (dd, J1 = 4.6 Hz, J2 = 1.4 Hz, 1H), 8.45 (dd, J1 = 7.8 Hz, J2 = 1.4
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Hz, 1H), 8.23 (s, 1H), 7.64 (dd, J1 = 7.9 Hz, J2 = 4.7 Hz, 1H), 7.48 (t,
J = 8.0 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.14 (t, J = 7.0 Hz, 1H), 6.73
(s, 1H), 4.95 (s, 1H), 4.26 (d, J = 5.1 Hz, 2H), 1.47 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 182.1, 181.6, 155.2, 148.6, 143.0, 138.4, 134.4,
132.9, 129.5, 127.3, 126.5, 124.6, 119.9, 115.8, 105.2, 94.1, 80.0, 78.0,
31.2, 28.3; IR (KBr) νmax 3329, 3301, 1711, 1615, 1571, 1307, 751
cm−1; HRMS (ESI) m/z calcd for C23H21N3NaO4 426.1430 [M +
Na]+, found 426.1430.
tert-Butyl [3-(4-Bromo-2-((5,8-dioxo-5,8-dihydroquinolin-6-yl)-
amino)phenyl)prop-2-yn-1-yl]carbamate (V-2). Red needle solid,
1.68 g, 70% yield; mp 109−111 °C (EA); 1H NMR (300 MHz,
CDCl3) δ 9.07 (dd, J1 = 4.7 Hz, J2 = 1.7 Hz, 1H), 8.45 (dd, J1 = 7.9 Hz,
J2 = 1.7 Hz, 1H), 8.25 (s, 1H), 7.66 (dd, J1 = 7.9 Hz, J2 = 4.7 Hz, 1H),
7.60 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.26 (dd, J1 = 8.1
Hz, J2 = 1.5 Hz, 1H), 6.75 (s, 1H), 4.96 (s, 1H), 4.26 (d, J = 5.4 Hz,
2H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 182.2, 181.4, 155.4,
148.4, 142.4, 139.6, 134.5, 133.7, 127.6, 127.2, 126.7, 123.4, 122.3,
114.4, 106.0, 95.4, 80.2, 77.2, 31.3, 28.4; IR (KBr) νmax 3347, 3280,
1713, 1682, 1615, 1565, 1325, 795 cm−1; HRMS (ESI) m/z calcd for
C23H20BrN3NaO4 504.0535 [M + Na]+, found 504.0532.
mmol) and aminoquinone V (0.3 mmol) were added successively to a
flask containing sulfuric acid (1.5 mL) and acetic acid (1.5 mL). The
reaction mixture was heated at 100 °C for 2 h and then cooled to 0 °C.
After the pH was adjusted to 9.0 with saturated Na2CO3 solution (30
mL), chloroform (60 mL) was added. The separated organic layer was
washed with brine (30 mL) and water (30 mL) and dried with
anhydrous MgSO4. After filtration, the filtrate was concentrated. The
residue was purified by column chromatography on silica gel (CHCl3/
PE = 3:1 for VI-1 and VI-5; CHCl3/MeOH = 100:1 for VI-2−4 and
VI-6) to give ascididemin alkaloid VI.
Ascididemin (VI-1). Yellow solid, 63.6 mg, 75% yield; mp >300 °C
1
(CHCl3); H NMR (300 MHz, CDCl3) δ 9.27 (d, J = 5.6 Hz, 1H),
9.17 (d, J = 3.2 Hz, 1H), 8.79 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 8.0 Hz,
1H), 8.62 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 5.7 Hz, 1H), 8.01 (t, J = 7.1
Hz, 1H), 7.94 (t, J = 7.7 Hz, 1H), 7.67 (dd, J1 = 7.5 Hz, J2 = 4.6 Hz,
1H); 13C NMR (75 MHz, CF3CO2D) δ 175.6, 154.7, 151.4, 148.2,
147.3, 147.1, 144.9, 141.4, 139.5, 138.7, 138.1, 132.7, 131.4, 128.9,
127.6, 127.5, 123.3; IR (KBr) νmax 3061, 2973, 1674, 1579, 1411, 1266,
767, 738, 725 cm−1; HRMS (ESI) m/z calcd for C18H9N3NaO
306.0643 [M + Na]+, found 306.0640.
Bromoleptoclinidinone (VI-2). Yellow solid, 85.6 mg, 79% yield;
mp >300 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.27 (d, J = 5.7
Hz, 1H), 9.17 (dd, J1 = 4.6 Hz, J2 = 1.7 Hz, 1H), 8.79−8.76 (m, 2H),
8.52 (d, J = 8.8 Hz, 1H), 8.48 (d, J = 5.7 Hz, 1H), 8.01 (dd, J1 = 8.8
Hz, J2 = 2.0 Hz, 1H), 7.68 (dd, J1 = 7.9 Hz, J2 = 4.6 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 181.2, 155.6, 152.0, 150.1, 149.8, 146.7,
146.2, 137.6, 136.6, 135.2, 134.0, 128.8, 126.1, 125.7, 124.2, 122.1,
117.8, 116.5; IR (KBr) νmax 3070, 2954, 1678, 1598, 1580, 1409, 1263,
950, 738 cm−1; HRMS (ESI) m/z calcd for C18H8BrN3O 360.9851
[M]+, found 360.9850.
Neocalliactine Acetate (VI-3). Yellow solid, 45.0 mg, 44% yield; mp
>300 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.26 (d, J = 5.5 Hz,
1H), 9.17 (d, J = 3.3 Hz, 1H), 8.70 (d, J = 7.7 Hz, 1H), 8.62 (d, J = 9.0
Hz, 1H), 8.43−8.41 (m, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.67 (dd, J1 =
7.4 Hz, J2 = 4.7 Hz, 1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3/
CD3OD) δ 181.3, 169.0, 155.1, 152.1, 151.7, 149.3, 149.2, 145.1,
143.0, 137.5, 136.4, 133.8, 128.7, 126.6, 125.7, 124.4, 117.6, 117.1,
115.0, 20.7; IR (KBr) νmax 2961, 2928, 1759, 1717, 1701, 1580, 1511,
1209, 807, 739 cm−1; HRMS (ESI) m/z calcd for C20H11N3NaO3
364.0698 [M + Na]+, found 364.0699.
5-Methoxyascididemin (VI-4). Yellow solid, 80.8 mg, 86% yield;
mp >300 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.23 (d, J = 5.7
Hz, 1H), 9.16 (dd, J1 = 4.6 Hz, J2 = 1.7 Hz, 1H), 8.80 (dd, J1 = 7.9 Hz,
J2 = 1.8 Hz, 1H), 8.50 (d, J = 9.2 Hz, 1H), 8.44 (d, J = 5.7 Hz, 1H),
7.92 (d, J = 2.6 Hz, 1H), 7.67 (dd, J1 = 7.9 Hz, J2 = 4.6 Hz, 1H), 7.59
(dd, J1 = 9.2 Hz, J2 = 2.7 Hz, 1H), 4.09 (s, 3H); 13C NMR (75 MHz,
CF3CO2D) δ 175.0, 169.3, 154.4, 150.7, 148.4, 147.2, 146.3, 142.4,
136.0, 133.6, 132.6, 132.4, 131.6, 131.4, 129.0, 123.4, 107.9, 58.9; IR
(KBr) νmax 2973, 1666, 1611, 1400, 1243, 852, 743 cm−1; HRMS
(ESI) m/z calcd for C19H11N3NaO2 336.0749 [M + Na]+, found
336.0745.
tert-Butyl [3-(2-((5,8-Dioxo-5,8-dihydroquinolin-6-yl)amino)-5-
hydroxyphenyl)prop-2-yn-1-yl]carbamate (V-3). Red needle solid,
1
1.36 g, 65% yield; mp 192−194 °C (CHCl3/MeOH); H NMR (300
MHz, CD3OD) δ 8.92 (dd, J1 = 4.8 Hz, J2 = 1.6 Hz, 1H), 8.48 (dd, J1
= 7.9 Hz, J2 = 1.6 Hz, 1H), 7.75 (dd, J1 = 7.9 Hz, J2 = 4.8 Hz, 1H), 7.23
(d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.7 Hz, 1H), 6.88 (dd, J1 = 8.6 Hz, J2 =
2.8 Hz, 1H), 5.98 (s, 1H), 4.00 (s, 2H), 1.37 (s, 9H); 13C NMR (75
MHz, CD3OD) δ 183.5, 182.4, 157.5, 156.5, 150.1, 148.5, 136.0, 131.4,
129.3, 128.4, 127.3, 123.5, 121.8, 120.4, 118.1, 103.8, 93.8, 80.7, 79.0,
31.5, 28.8; IR (KBr) νmax 3326, 3272, 1723, 1697, 1603, 1570, 1536,
1302, 987 cm−1; HRMS (ESI) m/z calcd for C23H21N3NaO5 442.1379
[M + Na]+, found 442.1382.
tert-Butyl [3-(2-((5,8-Dioxo-5,8-dihydroquinolin-6-yl)amino)-5-
methoxyphenyl)prop-2-yn-1-yl]carbamate (V-4). Red needle solid,
1.51 g, 70% yield; mp 188−190 °C (EA/cyclohexane); 1H NMR (300
MHz, CDCl3) δ 9.04 (dd, J1 = 4.7 Hz, J2 = 1.7 Hz, 1H), 8.43 (dd, J1 =
7.9 Hz, J2 = 1.7 Hz, 1H), 7.96 (s, 1H), 7.62 (dd, J1 = 7.8 Hz, J2 = 4.7
Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.01 (d, J = 2.9 Hz, 1H), 6.93 (dd,
J1 = 8.9 Hz, J2 = 2.9 Hz, 1H), 6.54 (s, 1H), 4.92 (s, 1H), 4.22 (d, J =
5.5 Hz, 2H), 3.81 (s, 3H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 182.0, 181.7, 156.6, 155.2, 148.8, 143.7, 134.3, 131.4, 127.3, 126.4,
122.4, 117.8, 117.5, 115.7, 104.1, 93.7, 80.0, 78.1, 55.6, 31.1, 28.3; IR
(KBr) νmax 3403, 3247, 1720, 1618, 1577, 1495, 1309, 722 cm−1;
HRMS (ESI) m/z calcd for C24H23N3NaO5 456.1535 [M + Na]+,
found 456.1535.
tert-Butyl [3-(2-((4-Chloro-5,8-dioxo-5,8-dihydroquinolin-6-yl)-
amino)phenyl)prop-2-yn-1-yl]carbamate (V-5). Red needle solid,
1.09 g, 50% yield; mp 161−162 °C (EA); 1H NMR (300 MHz,
CDCl3) δ 8.87 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 7.64 (d, J = 5.2 Hz,
1H), 7.50 (d, J = 7.7 Hz, 1H), 7.45−7.36 (m, 2H), 7.15 (t, J = 6.9 Hz,
1H), 6.71 (s, 1H), 4.99 (s, 1H), 4.27 (d, J = 2H, 1H), 1.46 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 180.4, 179.7, 155.2, 154.0, 150.6, 145.0,
11-Chloroascididemin (VI-5). Yellow solid, 42.8 mg, 45% yield; mp
>300 °C (CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.27 (d, J = 5.5 Hz,
1H), 8.96 (d, J = 5.0 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 8.0
Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.00 (t, J = 7.1 Hz, 1H), 7.92 (t, J =
7.5 Hz, 1H), 7.69 (d, J = 5.1 Hz, 1H); 13C NMR (75 MHz,
CF3CO2D) δ 174.7, 159.8, 152.4, 150.5, 149.1, 146.9, 146.1, 142.0,
139.9, 137.8, 135.6, 128.3, 128.0, 127.6, 123.8, 118.3; IR (KBr) νmax
2955, 1682, 1600, 1558, 1419, 1287, 762 cm−1; HRMS (ESI) m/z
calcd for C18H8ClN3NaO 340.0254 [M + Na]+, found 340.0252.
9H-Benzo[b]pyrido[4,3,2-mn]acridin-9-one (VI-6). Yellow solid,
143.7, 138.2, 132.9, 129.5, 124.9, 124.1, 120.2, 116.1, 104.1, 94.2, 80.2,
78.0, 31.2, 28.3; IR (KBr) νmax 3385, 1715, 1627, 1555, 1506, 1301,
750 cm−1; HRMS (ESI) m/z calcd for C23H20ClN3NaO4 460.1040 [M
+ Na]+, found 460.1043.
tert-Butyl [3-(2-((1,4-Dioxo-1,4-dihydronaphthalen-2-yl)amino)-
phenyl)prop-2-yn-1-yl]carbamate (V-6). Red needle solid, 1.60 g,
1
80% yield; mp 148−150 °C (EA); H NMR (300 MHz, CDCl3) δ
8.30 (s, 1H), 8.12 (d, J = 6.5 Hz, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.68 (t,
J = 7.6 Hz, 1H), 7.49−7.35 (m, 3H), 7.10 (t, J = 7.5 Hz, 1H), 6.55 (s,
1H), 5.04 (s, 1H), 4.27 (d, J = 5.4 Hz, 2H), 1.47 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 183.9, 181.8, 143.2, 139.0, 134.8, 133.0, 132.7,
132.4, 130.2, 129.4, 126.5, 126.1, 124.1, 119.4, 115.5, 104.4, 94.0, 79.9,
78.2, 31.2, 28.3; IR (KBr) νmax 3358, 3284, 1687, 1670, 1613, 1521,
1295, 1268, 720 cm−1; HRMS (ESI) m/z calcd for C24H22N2NaO4
425.1477 [M + Na]+, found 425.1478.
1
67.6 mg, 80% yield; mp >300 °C (CHCl3); H NMR (300 MHz,
CDCl3) δ 9.03 (d, J = 5.7 Hz, 1H), 8.85 (dd, J1 = 8.0 Hz, J2 = 0.9 Hz,
1H), 8.62−8.58 (m, 2H), 8.48 (dd, J1 = 7.8 Hz, J2 = 1.1 Hz, 1H), 8.36
(d, J = 5.7 Hz, 1H), 7.99−7.94 (m, 1H), 7.90−7.80 (m, 2H), 7.68 (td,
J1 = 7.7 Hz, J2 = 1.3 Hz, 1H); 13C NMR (75 MHz, CF3CO2D) δ
177.5, 153.6, 148.1, 144.6, 143.6, 141.1, 140.6, 140.0, 137.9, 134.1,
132.9, 129.2, 128.8, 128.5, 128.3, 127.2, 122.2; IR (KBr) νmax 2986,
1676, 1593, 1572, 1412, 1262, 735 cm−1; HRMS (ESI) m/z calcd for
C19H10N2NaO 305.0691 [M + Na]+, found 305.0687.
General Procedure for the Preparation of Ascididemin-Type
Alkaloids through Brønsted Acid-Promoted Domino Cycliza-
tion. Under an oxygen atmosphere, ferric sulfate (12.0 mg, 0.03
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dx.doi.org/10.1021/jo501927e | J. Org. Chem. 2014, 79, 9748−9753

The Journal of Organic Chemistry
Article
11-Hydroxyascididemin. A mixture of VI-5 (104 mg, 0.33
mmol), acetic acid (6.8 mL), and sodium acetate (340 mg) was heated
at 90 °C for 1.5 h. The reaction mixture was cooled and diluted with
water. The precipitated solid was filtered, washed with water (10 mL),
and dried to give 11-hydroxyascididemin. Yellow solid, 73.6 mg, 82%
yield; mp >260 °C (MeOH); 1H NMR (600 MHz, CDCl3) δ 13.06 (s,
1H), 9.31 (d, J = 5.6 Hz, 1H), 8.89 (d, J = 5.5 Hz, 1H), 8.73 (d, J = 7.8
Hz, 1H), 8.64 (dd, J1 = 8.2 Hz, J2 = 0.7 Hz, 1H), 8.58 (d, J = 5.6 Hz,
1H), 8.06 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 8.00 (td, J1 = 7.6 Hz, J2 =
1.1 Hz, 1H), 7.16 (d, J = 6.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
187.3, 169.4, 156.6, 154.0, 150.0, 149.2, 145.7, 145.6, 137.8, 133.3,
132.1, 131.4, 123.7, 123.0, 117.7, 117.1, 115.5, 114.8; IR (KBr) νmax
3486, 1668, 1604, 1561, 1494, 1179, 842, 773 cm−1; HRMS (ESI) m/z
calcd for C18H9N3NaO2 322.0592 [M + Na]+, found 322.0589.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangsz@nju.edu.cn. Phone: +86 25 83593732. Fax:
+86 25 83317761.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financially supported by the 863 Program
(2013AA092903), the National Natural Science Foundation of
China (20802034 and 21032002), and the Natural Science
Foundation of Jiangsu Province (BK 20141313).
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