Total synthesis of makaluvamine A/D, damirone B, batzelline C, makaluvone, and isobatzelline C featuring one-pot benzyne-mediated cyclization- functionalization

Article abstract of DOI:10.1016/j.tet.2012.09.034

Total synthesis of pyrroloquinoline alkaloids, such as makaluvamine A/D, damirone B, batzelline C, makaluvone, and isobatzelline C, was achieved featuring a one-pot benzyne-mediated cyclization-functionalization reaction. The synthetic utility was demonstrated by the construction of the common pyrrolo[4,3,2-de]quinoline skeleton.

Full text of DOI:10.1016/j.tet.2012.09.034

Tetrahedron 68 (2012) 9376e9383
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Tetrahedron
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Total synthesis of makaluvamine A/D, damirone B, batzelline C, makaluvone,
and isobatzelline C featuring one-pot benzyne-mediated
cyclizationefunctionalization
*
Takashi Oshiyama, Takahito Satoh, Kentaro Okano, Hidetoshi Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2012
Received in revised form 4 September 2012
Accepted 5 September 2012
Available online 12 September 2012
Total synthesis of pyrroloquinoline alkaloids, such as makaluvamine A/D, damirone B, batzelline C,
makaluvone, and isobatzelline C, was achieved featuring
a one-pot benzyne-mediated cycliza-
tionefunctionalization reaction. The synthetic utility was demonstrated by the construction of the
common pyrrolo[4,3,2-de]quinoline skeleton.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Benzyne
Cyclization
One-pot reaction
Pyrroloquinoline
1. Introduction
(5c)7 featuring a facile construction of pyrrolo[4,3,2-de]quinolines
via a benzyne-mediated cyclization that was developed during the
Marine alkaloids, such as makaluvamines,1 damirones,1c,2 bat-
zellines,3 makaluvone,1a and isobatzellines3b,4 are of great impor-
tance owing to their potent pharmacological activities (Fig. 1).
Makaluvamine A exhibits potent in vitro cytotoxicity with an IC50
total synthesis of dictyodendrins.8 In this paper we describe full
details of the sequential reaction and its application to the total
synthesis of makaluvamine A (1a), D (1c), damirone B (2b), bat-
zelline C (3c), makaluvone (4), and isobatzelline C (5c).
value of 1.3 mM against human colon tumor cell line HCT116 and
inhibitory activity against topoisomerase II.1a Damirone A and B
also displays in vitro antimalarial activity with IC50 values of
0.36 mM and 3.8 mM against chloroquine-resistant (Dd2) Plasmo-
dium falciparum, respectively.5 Batzellines and isobatzellines, iso-
lated from the marine sponge Batzella sp., show cytotoxic activity
based on the inhibition of topoisomerase II and, in particular, the
latter compound has been found to inhibit HIV-1 envelope-medi-
ated cell fusion with an IC50 value of 200 nM.3b In addition to the
significant biological activities, these compounds commonly share
a characteristic tricyclic pyrrolo[4,3,2-de]quinoline, which has
attracted a great deal of attention in the synthetic community.
While syntheses of these pyrroloquinolines have been extensively
investigated,6 development of a general and efficient synthetic
methodology for these molecules is still needed. Recently we have
developed total synthesis of batzelline C (3c) and isobatzelline C
* Corresponding author. Tel.: þ81 22 795 6887; fax: þ81 22 795 6877; e-mail
address: tokuyama@mail.pharm.tohoku.ac.jp (H. Tokuyama).
Fig. 1. Structure of pyrroloquinone alkaloids.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.034

T. Oshiyama et al. / Tetrahedron 68 (2012) 9376e9383
9377
The retrosynthetic sequence in Scheme 1 demonstrates a di-
vergent synthesis of pyrroloquinoline alkaloids using the pivotal
intermediate 6. Makaluvamine A (1a), D (1c), and damirone B (2b)
would be synthesized from tricyclic compound 7a via oxidation to
para-iminoquinone/ortho-quinone and functional group manipu-
lations. Key intermediate 7a would be prepared by cyclization of
benzyne 8 from the indoline 6 followed by subsequent protonation
of the generated aryl anion species 9. On the other hand, cyclization
of benzyne 8 followed by trapping of the generated aryl anion
species 9 with a chlorine/bromine atom should allow the regiose-
lective halogenation to give 7b, which is required for the synthesis
of batzelline C (3c), makaluvone (4), and isobatzelline C (5c).
Scheme 2. Reagents and conditions; (i) KCN, CH3CN/H2O, reflux; (ii) LAH, AlCl3, Et2O,
0
ꢁC; (iii) Boc2O, Et3N, CH2Cl2, rt; (iv) ClCO2Et, NaI, acetone, reflux.
With 4-iodoindoline derivative 14 in hand, we then examined
several amide bases for the benzyne-mediated construction of the
pyrrolo[4,3,2-de]quinoline skeleton10 (Table 1). Disappointingly,
Mg(TMP)2$2LiBr,11 an optimal base in our synthesis of dictyoden-
drins, resulted in slow consumption of the starting material (entry
1). The use of Mg(TMP)2$2LiCl,12 also provided the desired com-
pound 15 in low yield (entry 2). Best results were obtained when
LiTMP13 was added at ꢀ78 ꢁC (entry 3). The use of i-Bu3Al(TMP)Li14
also provided 15 in moderate yield (entry 4). Related bases, such as
Me2Zn(TMP)Li15 and MeCu(TMP)CNLi2,16 did not give the desired
product at all with recovery of the starting material (entries 5
and 6).
Table 1
Exploration of bases for benzyne generationecyclization cascade
Entry
Base (5 equiv)
Temperature
Yield (%)
1
2
3
4
5
6
Mg(TMP)2$2LiBr
Mg(TMP)2$2LiCl
LiTMP
i-Bu3Al(TMP)Li
Me2Zn(TMP)Li
MeCu(TMP)CNLi2
ꢀ78 ꢁC to rt
ꢀ78 to 0 ꢁC
ꢀ78 ꢁC
13
19
80
52
0
ꢀ78 to 0 ꢁC
ꢀ78 ꢁC to rt
ꢀ78 to 0 ꢁC
0
Having established the benzyne-mediated cyclization for the
construction of the tricyclic pyrrolo[4,3,2-de]quinoline skeleton, we
then pursued further transformations to synthesize makaluvamine
A (1a), D (1c), and damirone B (2b) (Scheme 3). First, indoline 15
was smoothly converted to indole 16 using DDQ. Then, Boc and
ethoxycarbonyl groups were removed in a stepwise manner to give
known compound 18.6l Selective methylation of the indole nitrogen
of 18 provided 19, which was converted to makaluvamine A (1a) in
two steps according to Iwao’s report.6l Makaluvamine D (1c) was
also synthesized via oxidation of 18 using Fremy’s salt.6h On the
other hand, damirone B (2b) has the methyl group at the quinoline
nitrogen, requiring an alternative method for the N-methylation.
Considering that the imine nitrogen should have stronger nucleo-
philicity than pyrrole nitrogen under neutral conditions, we ex-
amined electrophilic methylating conditions. To this end,
a combination of MeI and KI proved to be effective for the selective
methylation of imine nitrogen and, gratifyingly, subsequent cleav-
age of the methyl ether smoothly took place to give damirone B (2b)
in one pot.
Scheme 1. Retrosynthetic analysis based on a benzyne-mediated reaction.
2. Results/discussion
The synthesis commenced with the preparation of the known
indoline 10 from m-anisidine derivative 11 according to the
procedure by Buchwald and co-workers (Scheme 2).9 The iodo-
methyl group at the 3-position of indoline 10 was homologated
by treatment with potassium cyanide to provide 12, which was
then subjected to AlH3 reduction followed by Boc protection to
give carbamate 13. The allyl group was then switched to the
ethoxycarbonyl group by treatment with ethyl chloroformate
and sodium iodide to provide the substrate 14 for the key
reaction.

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T. Oshiyama et al. / Tetrahedron 68 (2012) 9376e9383
makaluvone (4), and isobatzelline C (5c) (Scheme 4). Com-
pounds 21a/21b were converted to the unprotected dihy-
dropyrroloquinoline 24a/24b for the oxidation to construct
iminoquinone. Thus, the Fremy’s salt oxidation of indoles 22 or
23 resulted in slower conversion, associated with a substantial
amount of unidentified side products, possibly due to the in-
sufficient electron density of the aromatic rings. Methylation of
the pyrrole nitrogen followed by acidic cleavage of the methyl
ether and spontaneous isomerization led to batzelline C (3c)
and makaluvone (4). We found that bromides 25b/26b were
quite unstable, which resulted in lower yields in the final stage
of the synthesis. Total synthesis of isobatzelline C (5c) was
achieved by treatment of iminoquinone 26a with NH4Cl/EtOH in
53% yield in over two steps.
Scheme 3. Reagents and conditions; (i) DDQ, toluene, 0 ꢁC; (ii) TMSOTf, CH2Cl2, 0 ꢁC;
(iii) NaOH aq, MeOH, reflux; (iv) MeI, NaH, DMF/THF, rt; (v) O2, salcomine, DMF, rt; (vi)
NH4Cl, MeOH, rt; (vii) Fremy’s salt, acetone/pH 6.86 buffer, 0 ꢁC to rt; (viii) tyramine,
MeOH, reflux; (ix) MeI, KI, acetone, reflux.
For the total synthesis of batzelline C (3c), makaluvone (4),
and isobatzelline C (5c) having a chlorine/bromine atom on the
aromatic ring, we then turned our efforts toward the one-pot
cyclizationefunctionalization sequence, namely, construction
of the piperidine ring followed by chlorination/bromination
(Table 2). We found that the choice of chlorinating agent was
important for the high-yielding process. Thus, the use of NCS or
TfCl resulted in low yield of the desired product 21a, and
Cl(CCl2)2Cl drastically improved the yield up to 64% (entries
1e3). Similarly, trapping of the generated aryl anion species
with Br(CCl2)2Br gave the corresponding bromide 21b in 70%
yield (entry 4).
Scheme 4. Reagents and conditions; (i) DDQ, toluene, rt; (ii) TMSOTf, CH2Cl2, 0 ꢁC; (iii)
NaOH aq, MeOH, reflux; (iv) Fremy’s salt, acetone/pH 6.86 buffer, 0 ꢁC; (v) MeI, K2CO3,
DMF, rt; (vi) BBr3, CH2Cl2, ꢀ40 ꢁC; (vii) BBr3, CH2Cl2, ꢀ78 ꢁC; (viii) NH4Cl, EtOH, reflux.
With the chlorinated/brominated compounds 21a/21b in
3. Conclusion
hand, we focused on total synthesis of batzelline
C (3c),
In summary, we have accomplished divergent synthesis of
functionalized pyrrolo[4,3,2-de]quinolines by the benzyne-
mediated cyclizationefunctionalization sequence. The presented
synthetic strategy enabled us to access a variety of pyrroloqui-
nolines from the common substrate. Thus, after construction of
a piperidine ring, trapping the resulting aryl anion species with
an electrophile rapidly provided substituted tricyclic compounds
by simply switching an electrophile. The utility of this method is
fully demonstrated by the total synthesis of a series of pyrrolo-
quinoline natural products, makaluvamines A (1a), D (1c), dam-
irone B (2b), batzelline C (3c), makaluvone (4), and isobatzelline C
(5c). The one-pot cyclizationefunctionalization strategy de-
veloped in this work would be a powerful synthetic tool for
highly substituted nitrogen-containing natural products, as well
as polycyclic compounds found in drug candidates and functional
molecules.
Table 2
Benzyne-mediated double functionalization
Entry
Electrophile (5 equiv)
E
Yield (%)
1
2
3
4
NCS
TfCl
Cl(CCl2)2Cl
Br(CCl2)2Br
Cl
Cl
Cl
Br
5
Trace
64
70

T. Oshiyama et al. / Tetrahedron 68 (2012) 9376e9383
9379
4. Experimental section
4.1. General remarks
1607, 1565, 1476, 1337, 1292, 1207, 1174, 1106, 1038, 924, 817; 1H
NMR (400 MHz, CDCl3)
d
6.51 (d, 1H, J¼2.0 Hz), 5.97 (d, 1H,
J¼2.0 Hz), 5.87e5.76 (m, 1H), 5.26e5.15 (m, 2H), 3.75e3.67 (m, 1H),
3.70 (s, 3H), 3.53 (dd, 1H, J¼15.4, 5.8 Hz), 3.38e3.28 (m, 2H),
3.11e3.03 (m, 1H), 2.79e2.73 (m, 2H), 1.85e1.69 (m, 2H), 1.16 (br,
All reactions were performed in oven-dried glassware, sealed
with a rubber septum under a slight positive pressure of argon
unless otherwise noted. Anhydrous THF, Et2O, DMF, and dichloro-
methane were purchased from Kanto Chemical Co. Inc. 2,2,6,6-
Tetramethylpiperidine was distilled from CaH2. Unless otherwise
mentioned, materials were obtained from commercial suppliers
and were used without further purification. Chromatography was
carried out using Kanto silica gel 60 (230e400 mesh) or
ChromatorexÒ (FUJI SILYSIA, NH, 100e200 mesh). Preparative TLC
was performed with precoated silica gel 60 F254 plates (Merck). IR
spectra were measured on a JASCO FTIR 4100 spectrometer. NMR
spectra were measured on a JEOL AL 400 spectrometer and a JEOL
ECA600 spectrometer. For 1H NMR spectra, chemical shifts are
expressed in parts per million downfield from internal tetrame-
2H); 13C NMR (100 MHz, CDCl3)
d 160.4, 152.2, 133.0, 129.5, 117.3,
110.4, 94.4, 91.8, 57.1, 55.3, 50.9, 40.9, 39.7, 36.4; HRMS (EIþ) calcd
for C14H19IN2O (Mþ), 358.0542; found 358.0533. A 300-mL round-
bottomed flask equipped with a magnetic stirring bar was charged
with the crude amine, triethylamine (4.71 mL, 33.8 mmol), and dry
dichloroethane (100 mL). To the solution was added Boc2O (7.38 g,
33.8 mmol). The reaction mixture was stirred for 10 h, after which
time TLC (hexanes/ethyl acetate¼3:1) indicated complete con-
sumption of starting material. The reaction mixture was treated
with H2O, and the mixture was extracted with dichloromethane
three times. The organic extracts were dried over anhydrous so-
dium sulfate, and filtered. The organic solvents were removed un-
der reduced pressure to give a crude material, which was purified
by column chromatography on silica gel (hexanes/ethyl
acetate¼9:1 to 5:1) to provide the title compound 13 (6.55 g,
14.3 mmol, 85%) as a colorless oil; Rf (hexanes/ethyl acetate¼3:1)
0.25; IR (neat, cmꢀ1) 3362, 2975, 2931, 2834, 1698, 1608, 1567, 1507,
thylsilane (
or CHD2OD (
expressed in ppm downfield from relative internal CDCl3
DMSO-d6 39.7), or CD3OD (
d
0) or relative internal CHCl3 (
d
d
7.26), DMSO-d5 (
d
2.49),
3.30). For 13C NMR spectra, chemical shifts are
(
d
77.0),
(d
d
49.0). Coupling constants are in
hertz. Mass spectra were recorded on a JEOL JMSeDXe303 or
a JMSe700 spectrometer.
1476, 1364, 1277, 1249, 1207; 1H NMR (400 MHz, CDCl3)
d 6.53 (d,
1H, J¼2.0 Hz), 6.00 (d, 1H, J¼2.0 Hz), 5.88e5.78 (m, 1H), 5.28e5.16
(m, 2H), 4.68 (br, 1H), 3.77e3.70 (m, 1H), 3.73 (s, 3H), 3.58e3.51 (m,
1H), 3.42e3.32 (m, 2H), 3.22e3.12 (m, 2H), 3.12e3.06 (m, 1H),
4.2. 2-(1-Allyl-4-iodo-6-methoxyindolin-3-yl)acetonitrile (12)
1.86e1.77 (m, 2H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 160.7,
A 300-mL round-bottomed flask equipped with a magnetic
stirring bar was charged with 10 (11.2 g, 24.7 mmol), KCN (19.2 g,
296 mmol), CH3CN (90 mL), and H2O (30 mL). The resulting mixture
was heated at reflux for 4 h, after which time TLC (hexanes/ethyl
acetate¼3:1) indicated complete consumption of 10. The reaction
mixture was treated with aqueous NaOH and was extracted with
ethyl acetate three times. The organic extracts were washed with
aqueous NaOH and brine, dried over anhydrous sodium sulfate, and
filtered. The organic solvents were removed under reduced pres-
sure to give a crude material, which was purified by column
chromatography on silica gel (hexanes/ethyl acetate¼9:1 to 5:1) to
provide 12 (5.97 g,16.9 mmol, 68%) as a pale yellow oil; Rf (hexanes/
ethyl acetate¼3:1) 0.28; IR (neat, cmꢀ1) 3080, 3003, 2935, 2835,
2246, 1609, 1566, 1479, 1339, 1296, 1209, 1173, 1107, 1038, 927, 819;
155.9, 152.5, 133.0, 129.2, 117.7, 110.8, 94.8, 92.0, 78.9, 57.2, 55.5,
51.2, 40.9, 38.1, 32.7, 28.4; HRMS (EIþ) calcd for C19H27IN2O3 (Mþ),
458.1066; found 458.1060.
4.4. Ethyl 3-(2-(tert-butoxycarbonylamino)ethyl)-4-iodo-6-
methoxyindoline-1-carboxylate (14)
A 300-mL round-bottomed flask equipped with a reflux con-
denser and a magnetic stirring bar was charged with 13 (6.55 g,
14.3 mmol), ethyl chloroformate (6.84 mL, 71.5 mmol), NaI (10.7 g,
71.5 mmol), and acetone (70 mL). The resulting mixture was heated
at reflux for 5 h, after which time TLC (hexanes/ethyl acetate¼3:1)
indicated complete consumption of 13. The reaction mixture was
treated with H2O, and the mixture was extracted with ethyl acetate
three times. The organic extracts were dried over anhydrous so-
dium sulfate, and filtered. The organic solvents were removed un-
der reduced pressure to give a crude material, which was purified
by column chromatography on silica gel (hexanes/ethyl
acetate¼5:1 to 2:1) to provide the ethyl carbamate 14 (6.14 g,
12.5 mmol, 88%) as a colorless amorphous solid; Rf (hexanes/ethyl
acetate¼3:1) 0.19; IR (neat, cmꢀ1) 3370, 2977, 2933, 1707, 1601,
1571, 1519, 1474, 1446, 1312, 1220, 1173, 1141, 1053, 914; 1H NMR
1H NMR (400 MHz, CDCl3)
d
6.54 (d, 1H, J¼2.0 Hz), 6.02 (d, 1H,
J¼2.0 Hz), 5.89e5.77 (m, 1H), 5.31e5.20 (m, 2H), 3.79e3.72 (m, 1H),
3.72 (s, 3H), 3.63e3.55 (m,1H), 3.51 (d, 2H, J¼4.4 Hz), 3.39e3.32 (m,
1H), 2.77 (dd, 1H, J¼16.8, 3.4 Hz), 2.51 (dd, 1H, J¼16.8, 10.4 Hz); 13C
NMR (100 MHz, CDCl3) d 161.5, 152.2, 132.4, 125.8, 118.3, 118.1, 111.2,
95.0, 92.1, 56.8, 55.5, 50.8, 40.7, 20.6; HRMS (EIþ) calcd for
C14H15IN2O (Mþ), 354.0229; found 354.0223.
4.3. tert-Butyl 2-(1-allyl-4-iodo-6-methoxyindolin-3-yl)eth-
ylcarbamate (13)
(400 MHz, CDCl3)
d
7.52 (br, 1H), 6.90 (d, 1H, J¼2.0 Hz), 4.56 (br, 1H),
4.27 (q, 2H, J¼6.8 Hz), 3.97 (d, 2H, J¼5.6 Hz), 3.77 (s, 3H), 3.27e3.06
(m, 3H), 2.01e1.90 (m, 1H), 1.72e1.59 (m, 1H), 1.45 (s, 9H) 1.36 (t,
A 500-mL round-bottomed flask equipped with a magnetic
stirring bar was charged with AlCl3 (6.76 g, 16.9 mmol), and dry
Et2O (160 mL). The solution was cooled to 0 ꢁC. To the solution was
added LAH (2.50 g, 65.9 mmol) at 0 ꢁC and stirred for 10 min. To the
mixture was added the solution of 12 (5.97 g, 16.9 mmol) in dry
Et2O (40 mL) at 0 ꢁC and the resulting mixture was stirred for
10 min, after which time TLC (dichloromethane/methanol¼4:1)
indicated complete consumption of 12. The reaction was quenched
with H2O followed by concd H2SO4. The mixture was basified with
aqueous NaOH and extracted with Et2O three times. The combined
organic extracts were dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated under reduced pressure to
give amine as a pale yellow oil, which was used for the next re-
action without further purification; IR (neat, cmꢀ1) 2931, 2834,
3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
d 160.1,155.9,153.2, 143.2,
129.3, 117.9, 101.0, 91.6, 79.0, 61.6, 55.5, 52.8, 40.0, 37.9, 34.0, 28.3,
14.4; HRMS (EIþ) calcd for C19H27IN2O5 (Mþ), 490.0965; found
490.0984.
4.5. 5-tert-Butyl 1-ethyl 7-methoxy-2,2a,3,4-tetrahydropyr
rolo[4,3,2-de]quinoline-1,5-dicarboxylate (15)
A flame-dried 100-mL Schlenk tube equipped with a magnetic
stirrer bar and an inlet adapter with three-way stopcock was
charged with 2,2,6,6-tetramethylpiperidine (1.70 mL, 10.1 mmol)
and dry THF (5 mL) under argon atmosphere. To the solution was
added n-BuLi (1.60 M in n-hexane, 5.96 mL, 10.1 mmol) at ꢀ78 ꢁC.
The resulting solution was warmed to 0 ꢁC over 25 min. The

9380
T. Oshiyama et al. / Tetrahedron 68 (2012) 9376e9383
resulting pale yellow solution was added to the solution of 14
(1.01 g, 2.01 mmol) in THF (15 mL) at ꢀ78 ꢁC dropwise. The reaction
mixture was stirred for 5 min, after which time TLC (hexanes/ethyl
acetate¼3:1) indicated complete consumption of 14. The reaction
mixture was treated with aqueous NH4Cl, and the mixture was
extracted with ethyl acetate three times. The organic extracts were
washed with brine, dried over anhydrous sodium sulfate, and fil-
tered. The organic solvents were removed under reduced pressure
to give a crude material, which was purified by column chroma-
tography on silica gel (hexanes/ethyl acetate¼8:1) to provide the
title compound 15 (582 mg, 1.61 mmol, 80%) as a pale yellow
amorphous solid; Rf (hexanes/ethyl acetate¼3:1) 0.28; IR (neat,
cmꢀ1) 2978, 2935, 2879, 1708, 1613, 1496, 1472, 1450, 1410, 1379,
2H, J¼5.6 Hz), 1.45 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d
160.1, 151.5, 141.2, 134.8, 115.4, 114.7, 113.6, 94.0, 90.2, 62.6, 55.6,
42.7, 22.6, 14.3; HRMS (EIþ) calcd for C14H16N2O3 (Mþ), 260.1161;
found 260.1160.
4.8. 7-Methoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline
(18)
A 20-mL round-bottomed flask equipped with a reflux con-
denser and a magnetic stirring bar was charged with 17 (105 mg,
405 mmol), 5 M aqueous NaOH (810 mL), and methanol (6 mL). The
resulting mixture was heated at reflux for 30 min, after which time
TLC (hexanes/ethyl acetate¼3:1) indicated complete consumption
of 17. The solvent was removed under reduced pressure, and the
residue was treated with aqueous NH4Cl and diluted with ethyl
acetate, and filtered. The organic solvents were removed under
1339, 1300, 1201, 1160, 1132; 1H NMR (400 MHz, CDCl3)
d 7.42e7.20
(m, 1.5H), 7.20e7.00 (m, 0.3H), 6.82e6.64 (m, 0.2H), 4.40e4.21 (m,
3H), 4.10 (ddd, 1H, J¼13.2, 4.8, 2.0 Hz), 3.79 (s, 3H), 3.51 (dd, 1H,
J¼10.8, 10.0 Hz), 3.42 (ddd, 1H, J¼13.2, 13.2, 4.4 Hz), 3.28e3.17 (m,
1H), 2.31e2.23 (m, 1H), 1.70e1.58 (m, 1H), 1.57 (s, 9H), 1.58e1.28
reduced pressure to give 18 (52.6 mg, 279 mmol, 69%) as a pale
yellow liquid, which was pure enough without further purification;
Rf (hexanes/ethyl acetate¼3:1) 0.27; IR (neat, cmꢀ1) 3380, 2936,
2906, 2837, 1620, 1550, 1511, 1305, 1194, 1149, 1026, 806; 1H NMR
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 160.7,153.4, 153.0, 141.7,135.7,
114.1, 101.0, 96.0, 81.1, 61.2, 55.5, 55.0, 45.6, 34.1, 28.2, 27.6, 14.5;
HRMS (EIþ) calcd for C19H26N2O5 (Mþ), 362.1842; found 362.1851.
(400 MHz, CDCl3)
d 7.69 (br, 1H), 6.58 (s, 1H), 6.22 (s, 1H), 5.94 (s,
1H), 4.04 (br, 1H), 3.78 (s, 3H), 3.44 (t, 2H, J¼5.8 Hz), 2.97 (t, 2H,
4.6. 5-tert-Butyl 1-ethyl 7-methoxy-3,4-dihydropyrrolo[4,3,2-
de]quinoline-1,5-dicarboxylate (16)
J¼5.8 Hz); 13C NMR (100 MHz, CDCl3)
d 158.9, 141.4, 134.6, 113.8,
112.7, 110.3, 90.8, 85.0, 55.7, 43.5, 23.0; HRMS (ESIþ) calcd for
C11H12N2O (Mþ), 188.0950; found 188.0941.
A 30-mL round-bottomed flask equipped with a magnetic stir-
ring bar was charged with 15 (212 mg, 591
(7 mL). To the solution was added DDQ (134 mg, 591
m
mol) and toluene
4.9. Makaluvamine A (1a)
m
mol) at 0 ꢁC.
The reaction mixture was stirred for 20 min, after which time TLC
(hexanes/ethyl acetate¼3:1) indicated complete consumption of
15. The reaction mixture was treated with aqueous NaOH, and the
mixture was extracted with ethyl acetate three times. The organic
extracts were washed with aqueous NaHCO3 and brine and dried
over anhydrous sodium sulfate, and filtered. The organic solvents
were removed under reduced pressure to give a crude material,
which was purified by column chromatography on silica gel (hex-
anes/ethyl acetate¼9:1 to 2:1) to provide the title compound 16
A 10-mL round-bottomed flask equipped with a magnetic
stirring bar was charged with 18 (51.0 mg, 271
DMF (5:1, 2.4 mL) under argon atmosphere. To the solution were
added NaH (13.0 mg, 325 mol) and MeI (25.3 L, 406 mol) at
ꢁC. The reaction mixture was stirred for 1 h, after which time
mmol) and THF/
m
m
m
0
TLC (hexanes/ethyl acetate¼3:1) indicated complete consump-
tion of 18. The reaction mixture was treated with H2O, and the
mixture was extracted with ethyl acetate three times. The organic
extracts were washed with H2O three times and brine, dried over
anhydrous sodium sulfate, and filtered. The organic solvents were
removed under reduced pressure to give a crude 19, which was
used for the next reaction without further purification. A 10-mL
round-bottomed flask equipped with a magnetic stirring bar
(196 mg, 544
mmol, 92%) as a white solid; Rf (hexanes/ethyl
acetate¼3:1) 0.34; IR (neat, cmꢀ1) 2977, 2939, 1735, 1700, 1377,
1357, 1260, 1239, 1134; 1H NMR (400 MHz, CDCl3)
d 7.36e7.18 (m,
2H), 7.18e7.09 (m, 1H), 4.46 (q, 2H, J¼7.2 Hz), 4.01 (t, 2H, J¼5.6 Hz),
3.86 (s, 3H), 2.89 (t, 2H, J¼5.6 Hz), 1.59 (s, 9H), 1.45 (t, 3H, J¼7.2 Hz);
was charged with a crude 19, salcomine (17.6 mg, 54.2 mmol), and
13C NMR (100 MHz, CDCl3)
d
159.0, 153.3, 151.2, 134.3, 133.4, 116.5,
DMF (0.5 mL). The reaction mixture was stirred for 1 h under
oxygen atmosphere, after which time TLC (hexanes/ethyl
acetate¼3:1) indicated complete consumption of 19. The organic
solvents were removed under reduced pressure to give a crude
material, which was purified by column chromatography on silica
gel (ethyl acetate, then dichloromethane/methanol¼7:1) to pro-
116.1, 115.2, 103.2, 95.2, 81.3, 62.8, 55.8, 44.7, 28.2, 22.4, 14.2; HRMS
(EIþ) calcd for C19H24N2O5 (Mþ), 360.1685; found 360.1685.
4.7. Ethyl 7-methoxy-4,5-dihydropyrrolo[4,3,2-de]quinoline-
1(3H)-carboxylate (17)
vide the pyrroloiminoquinone compound.
A 20-mL round-
A 30-mL round-bottomed flask equipped with a magnetic stir-
bottomed flask equipped with a magnetic stirring bar was
charged with the pyrroloiminoquinone compound, NH4Cl
(145 mg, 2.71 mmol) and MeOH (7 mL) under argon atmosphere.
The resulting mixture was stirred for 13 h, after which time TLC
(dichloromethane/methanol¼4:1) indicated complete consump-
tion of starting material. The mixture was directly purified by
column chromatography on silica gel (ethyl acetate, then
dichloromethane/methanol¼9:1 to 4:1) to provide makaluv-
ring bar was charged with 16 (195 mg, 541
methane (10 mL) under argon atmosphere. To the solution was
added TMSOTf (187
L, 1.08 mmol) at 0 ꢁC. The reaction mixture
was stirred for h, after which time TLC (hexanes/ethyl
mmol) and dichloro-
m
1
acetate¼3:1) indicated complete consumption of the 16. The re-
action mixture was treated with aqueous NaHCO3, and the mixture
was extracted with dichloromethane three times. The organic ex-
tracts were dried over anhydrous sodium sulfate, and filtered. The
organic solvents were removed under reduced pressure to give
a crude 17, which was purified by column chromatography on silica
gel (hexanes/ethyl acetate¼4:1 to 2:1) to provide the title com-
amine A (1a) (24.9 mg, 124 mmol, 46% from 18) as a brown solid;
Rf (dichloromethane/methanol¼4:1) 0.42; IR (neat, cmꢀ1) 3233,
3033, 2925, 2854, 1698, 1610, 1541, 1522, 1436, 1393, 1354, 1323,
845; 1H NMR (400 MHz, TFA salt, DMSO-d6)
d 10.43 (br, 1H), 9.10
pound 17 (115 mg, 441
m
mol, 82%) as a white solid; Rf (hexanes/
(br, 1H), 8.40 (br, 1H), 7.31 (s, 1H), 5.61 (s, 1H), 3.90 (s, 3H), 3.76
ethyl acetate¼3:1) 0.16; IR (neat, cmꢀ1) 3381, 2938, 2837, 1730,
(td, 2H, J¼7.6, 2.8 Hz), 2.84 (t, 2H, J¼7.6 Hz); 13C NMR (100 MHz,
1624, 1415, 1309, 1253, 1165, 1128, 1029; 1H NMR (400 MHz, CDCl3)
TFA salt, DMSO-d6) d 168.2, 156.8, 156.0, 131.0, 123.0, 122.4, 117.9,
d
7.03 (br, 1H), 6.96 (br, 1H), 6.07 (d, 1H, J¼1.6 Hz), 4.45 (q, 2H,
86.5, 42.0, 35.8, 18.0; HRMS (EIþ) calcd for C11H12N3O (MþHþ),
J¼7.2 Hz), 4.07 (br, 1H), 3.83 (s, 3H), 3.43 (t, 2H, J¼5.6 Hz), 2.91 (t,
202.0977; found 202.0980.

T. Oshiyama et al. / Tetrahedron 68 (2012) 9376e9383
9381
4.10. 7-Methoxy-3,4-dihydropyrrolo[4,3,2-de]quinolin-8(1H)-
one (20)
170.4, 153.5, 124.9, 124.5, 124.1, 116.4, 92.4, 51.2, 37.7, 19.8; HRMS
(FABþ) calcd for C11H11N2O2 (MþHþ), 203.0821; found 203.0820.
A 200-mL round-bottomed flask equipped with a magnetic
stirring bar was charged with Fremy’s salt (1.25 g, 4.68 mmol) and
pH 6.86 buffer solution (60 mL). To the solution was added 18
4.13. 5-tert-Butyl 1-ethyl 6-chloro-7-methoxy-2,2a,3,4-
tetrahydropyrrolo[4,3,2-de]quinoline-1,5-dicarboxylate (21a)
(22.0 mg, 117 mmol) in acetone (30 mL) dropwise over 10 min at
A flame-dried 50-mL Schlenk tube equipped with a magnetic
stirrer bar and an inlet adapter with three-way stopcock was
charged with 2,2,6,6-tetramethylpiperidine (1.70 mL, 10.0 mmol)
and dry THF (20 mL) under argon atmosphere. To the solution was
added n-BuLi (1.60 M in n-hexane, 6.14 mL,10 mmol) at ꢀ78 ꢁC. The
resulting solution was warmed to 0 ꢁC over 25 min. The resulting
pale yellow solution was added to the solution of 14 (980 mg,
2.00 mmol) in THF (20 mL) at ꢀ78 ꢁC dropwise over 5 min. The
reaction mixture was stirred for 10 min, after which time TLC
(hexanes/ethyl acetate¼3:1) indicated complete consumption of
14. To the reaction mixture was added 1,1,1,2,2,2-hexachloroethane
(2.37 g, 10 mmol) at ꢀ78 ꢁC. The resulting suspension was warmed
to 0 ꢁC for 30 min. The reaction mixture was treated with saturated
aqueous NH4Cl, and the mixture was extracted with ethyl acetate
three times. The organic extracts were dried over anhydrous so-
dium sulfate, and filtered. The organic solvents were removed un-
der reduced pressure to give a crude material, which was purified
by column chromatography on silica gel (hexanes/ethyl
acetate¼8:1 to 3:1) to provide the title compound 21a (506 mg,
1.27 mmol, 64%) as a pale yellow amorphous solid; Rf (hexanes/
ethyl acetate¼3:1) 0.17; IR (neat, cmꢀ1) 2979, 2936, 1704, 1608,
1487, 1450, 1409, 1378, 1330, 1303, 1169, 1138, 760; 1H NMR
0 ꢁC. The resulting solution was warmed to room temperature over
10 min. After which time TLC (ethyl acetate) indicated complete
consumption of 18. The reaction mixture was treated with brine,
and the mixture was extracted with ethyl acetate eight times. The
organic extracts were dried over anhydrous sodium sulfate, and
filtered. The organic solvents were removed under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (hexanes/ethyl acetate¼1:1, then ethyl acetate/methanol¼1:0
to 4:1) to afford 20 (14.6 mg, 72.2 mmol, 62%) as a yellow solid; Rf
(ethyl acetate/methanol¼4:1) 0.24; IR (neat, cmꢀ1) 3065, 3011,
2927, 2837, 2752, 1654, 1624, 1566,1395, 1238, 1074, 1008, 792, 733;
1H NMR (600 MHz, CDCl3)
d 9.69 (br, 1H), 6.90 (s, 1H), 6.14 (s, 1H),
4.20 (t, 2H, J¼5.2 Hz), 3.86 (s, 3H), 2.80 (t, 2H, J¼5.2 Hz); 13C NMR
(150 MHz, CDCl3) d 171.1,158.4,156.5,123.9,122.4,121.3,117.1,106.6,
56.4, 51.0, 18.2; HRMS (EIþ) calcd for C11H10N2O2 (Mþ), 202.0742;
found 202.0738.
4.11. Makaluvamine D (1c)
A 10-mL round-bottomed flask equipped with a reflux con-
denser and a magnetic stirring bar was charged with 20 (7.8 mg,
39 mmol), tyramine (5.3 mg, 39 mmol) and MeOH (0.5 mL) under
(400 MHz, CDCl3)
d 7.40e7.25 (m, 0.8H), 7.06e6.87 (m, 0.2H), 4.38
(dd, 1H, J¼1.0, 1.0 Hz), 4.35e4.18 (m, 2H), 4.07e3.92 (m, 1H), 3.91 (s,
3H), 3.60 (dd, 1H, J¼11.2, 8.4 Hz), 3.45e3.28 (m, 1H), 3.26e3.14 (m,
1H), 2.54e2.40 (m, 1H), 1.56e1.44 (m, 1H), 1.49 (s, 9H), 1.44e1.26
argon atmosphere. The resulting mixture was heated at reflux for
30 min. Then additional tyramine (1 mg) was added, and the
resulting mixture was heated at reflux for 1 h, after which time TLC
(ethyl acetate/methanol¼4:1) indicated complete consumption of
20. The reaction mixture was treated with H2O, and the mixture
was extracted with dichloromethane/MeOH ten times. The organic
extracts were dried over anhydrous sodium sulfate, and filtered.
The organic solvents were removed under reduced pressure to give
a crude makaluvamine D, which was purified by preparative TLC
(NH silica gel, acetone); to afford makaluvamine D (1c) (8.5 mg,
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 156.3, 153.5, 152.9, 139.6,
134.5, 121.2, 111.3, 97.0, 81.2, 61.4, 56.7, 55.4, 44.3, 32.8, 31.2, 27.9,
14.5; HRMS (EIþ) calcd for C19H25ClN2O5 (Mþ), 396.1452; found
396.1436.
4.14. 5-tert-Butyl 1-ethyl 6-bromo-7-methoxy-2,2a,3,4-
tetrahydropyrrolo[4,3,2-de]quinoline-1,5-dicarboxylate (21b)
28 mmol, 72%) as a brown solid; Rf (NH silica gel, acetone) 0.09; IR
(neat, cmꢀ1) 2923, 2844, 1653, 1558, 1542, 1496, 1457, 1387, 1246,
Compound 21b was obtained starting from 14 by the same
procedure for the preparation of 21a in 70% yield as a pale yellow
amorphous solid; Rf (hexanes/ethyl acetate¼3:1) 0.27; IR (neat,
cmꢀ1) 2979, 2935, 1704, 1605, 1450, 1407, 1329, 1301, 1167, 1139; 1H
1224, 1033, 1011, 826, 729; 1H NMR (400 MHz, TFA salt, DMSO-d6)
d
12.95 (br, 1H), 10.32 (br, 1H), 8.86 (t, 1H, J¼6.2 Hz), 7.19 (d, 1H,
J¼2.0 Hz), 6.91 (d, 2H, J¼8.4 Hz), 6.56 (d, 2H, J¼8.4 Hz), 5.33 (s, 1H),
3.67 (td, 2H, J¼7.6, 2.0 Hz), 3.39e3.28 (m, 2H), 2.74 (t, 2H, J¼7.6 Hz),
2.66 (t, 2H, J¼7.6 Hz); 13C NMR (150 MHz, TFA salt, DMSO-d6)
NMR (400 MHz, CDCl3) d 7.38e7.25 (m, 0.8H), 6.86e6.97 (m, 0.2H),
4.39 (t, 2H, J¼1.0 Hz), 4.35e4.20 (m, 2H), 4.20e4.00 (m, 1H), 3.90 (s,
3H), 3.60 (dd, 1H, J¼10.8, 8.4 Hz), 3.33e3.16 (m, 2H), 2.58e2.44 (m,
1H), 1.49 (s, 9H), 1.44e1.31 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
167.5, 157.1, 156.0, 153.1, 129.6, 128.2, 127.0, 123.8, 122.6, 118.7,
115.3, 84.1, 45.1, 42.5, 32.4, 18.2; HRMS (FABþ) calcd for C18H18N3O2
(MþHþ), 308.1394; found 308.1397.
d
157.1, 153.3, 152.9, 140.6, 136.3, 121.9, 101.5, 97.0, 81.1, 61.4, 56.7,
55.6, 44.0, 32.6, 31.1, 27.9, 14.4; HRMS (EIþ) calcd for C19H25BrN2O5
(Mþ), 440.0947; found 440.0961.
4.12. Damirone B (2b)
A sealed tube equipped with a magnetic stirring bar was
4.15. 5-tert-Butyl 1-ethyl 6-chloro-7-methoxy-3,4-
charged with 20 (12.4 mg, 61.3
acetone (4 mL). The resulting mixture was heated at 60 ꢁC for
30 min. Then KI (102 mg, 613 mol) was added, and the resulting
m
mol), MeI (38.2
m
L, 613
m
mol) and
dihydropyrrolo[4,3,2-de]quinoline-1,5-dicarboxylate (22a)
m
Compound 22a was obtained from 21a in quantitative yield as
a white solid according to the same procedure for the preparation
of 16; Rf (hexanes/ethyl acetate¼3:1) 0.27; IR (neat, cmꢀ1) 3125,
2980, 2937, 1739, 1713, 1615, 1576, 1473, 1408, 1371, 1343, 1256,
mixture was heated at 70 ꢁC for 7 h. The reaction mixture was
passed through silica gel to remove salt. The organic solvents were
removed under reduced pressure to give a crude damirone B, which
was purified by preparative TLC (ethyl acetate/methanol¼3:1) to
1159, 1126, 887, 822, 761; 1H NMR (400 MHz, CDCl3)
d 7.46 (br, 1H),
afford damirone B (2b) (6.2 mg, 31
m
mol, 50%) as a purple solid; Rf
7.16 (br, 1H), 4.45 (q, 2H, J¼6.8 Hz), 3.96 (s, 3H), 4.10e3.85 (m, 2H),
(dichloromethane/methanol¼4:1) 0.73; IR (neat, cmꢀ1) 3111, 2917,
2.86e2.80 (m, 2H), 1.50 (s, 9H), 1.45 (t, 3H, J¼6.8 Hz); 13C NMR
2849, 1661, 1586, 1539, 1419, 1321; 1H NMR (600 MHz, DMSO-d6)
(100 MHz, CDCl3) d 154.6, 153.4, 151.1, 131.9, 131.8, 118.6, 117.9, 115.3,
d
12.44 (br, 1H), 7.08 (s, 1H), 5.11 (s, 1H), 3.59 (t, 2H, J¼6.9 Hz), 3.03
112.8, 96.6, 81.6, 63.1, 56.9, 46.6, 28.0, 22.5, 14.3; HRMS (EIþ) calcd
for C19H23ClN2O5 (Mþ), 394.1295; found 394.1292.
(s, 3H), 2.81 (t, 2H, J¼6.9 Hz); 13C NMR (150 MHz, DMSO-d6)
d 178.6,

9382
T. Oshiyama et al. / Tetrahedron 68 (2012) 9376e9383
4.16. 5-tert-Butyl 1-ethyl 6-bromo-7-methoxy-3,4-
dihydropyrrolo[4,3,2-de]quinoline-1,5-dicarboxylate (22b)
4.21. 6-Chloro-7-methoxy-3,4-dihydropyrrolo[4,3,2-de]qui-
nolin-8(1H)-one (25a)
Compound 22b was obtained from 21b in 93% yield as
a white solid according to the same procedure for the prepa-
ration of 16; Rf (hexanes/ethyl acetate¼3:1) 0.42; IR (neat,
cmꢀ1) 2979, 2938, 1737, 1706, 1471, 1440, 1408, 1370, 1342, 1314,
Compound 25a was obtained from 24a by the same procedure
for the preparation of 20 in 42% yield as a yellow solid; Rf (NH silica
gel, hexanes/ethyl acetate¼1:1) 0.19; IR (neat, cmꢀ1) 3065, 3002,
2926, 2908, 2841, 2767, 1738, 1657, 1615, 1260, 1067, 1006, 890, 801;
1254, 1157, 1125, 733; 1H NMR (400 MHz, CDCl3)
d
7.47 (br, 1H),
1H NMR (400 MHz, DMSO-d6)
d
12.31 (br, 1H), 7.08 (d, 1H, J¼1.6 Hz),
7.19 (br, 1H), 4.47 (q, 2H, J¼6.8 Hz), 4.30e3.65 (m, 2H), 3.96 (s,
4.13 (t, 2H, J¼8.0 Hz), 3.89 (s, 3H), 2.69 (t, 2H, J¼8.0 Hz); 13C NMR
3H), 2.90e2.79 (m, 2H), 1.49 (s, 9H), 1.46 (t, 3H, J¼6.8 Hz); 13C
(100 MHz, DMSO-d6) d 169.4, 154.9, 152.6, 127.8, 123.7, 122.9, 119.9,
NMR (100 MHz, CDCl3)
d
155.1, 153.1, 150.9, 133.6, 132.6, 119.0,
116.6, 60.8, 50.9, 17.8; HRMS (EIþ) calcd for C11H9ClN2O2 (Mþ),
236.0353; found 236.0358.
117.7, 115.1, 103.3, 96.4, 81.4, 63.0, 56.9, 46.8, 27.9, 22.3, 14.2;
HRMS (EIþ) calcd for C19H23BrN2O5 (Mþ), 438.0790; found
438.0778.
4.22. 6-Bromo-7-methoxy-3,4-dihydropyrrolo[4,3,2-de]qui-
nolin-8(1H)-one (25b)
4.17. Ethyl 6-chloro-7-methoxy-4,5-dihydropyrrolo[4,3,2-de]-
quinoline-1(3H)-carboxylate (23a)
Compound 25b was obtained from 24b by the same procedure
for the preparation of 20 in 29% yield from 23b as a yellow solid; Rf
(NH silica gel, hexanes/ethyl acetate¼1:1) 0.10; IR (neat, cmꢀ1
)
Compound 23a was obtained from 22a by the same procedure
for the preparation of 17, which was used for the next reaction
without further purification; Rf (hexanes/ethyl acetate¼3:1) 0.29;
IR (neat, cmꢀ1) 3410, 3388, 3119, 2973, 2938, 2908, 2844, 1735,
1627, 1575, 1475, 1412, 1312, 1252, 1217, 1128, 1085, 1021, 817, 759;
3064, 2998, 2925, 2844, 1657, 1613, 1253; 1H NMR (400 MHz,
DMSO-d6)
d
12.33 (br, 1H), 7.09 (s, 1H), 4.16 (t, 2H, J¼7.8 Hz), 3.90 (s,
3H), 2.70 (t, 2H, J¼7.8 Hz); 13C NMR (100 MHz, DMSO-d6)
d 169.0,
156.8, 152.9, 123.6, 123.1, 121.1, 120.3, 116.7, 60.6, 51.1, 17.7; HRMS
(FABþ) calcd for C11H10BrN2O2 (MþHþ), 280.9926; found 280.9916.
1H NMR (400 MHz, CDCl3)
d 7.10e7.00 (m, 2H), 4.46 (br,1H), 4.45 (q,
2H, J¼7.2 Hz), 3.93 (s, 3H), 3.50 (t, 2H, J¼5.0 Hz), 2.93 (t, 2H,
4.23. Batzelline C (3c)
J¼5.0 Hz), 1.45 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d 154.5,
151.4, 137.6, 132.5, 115.4, 114.8, 113.5, 99.7, 89.6, 62.9, 56.5, 42.6,
22.3, 14.3; HRMS (EIþ) calcd for C14H15ClN2O3 (Mþ), 294.0771;
found 294.0764.
A 10-mL round-bottomed flask equipped with a magnetic stir-
ring bar was charged with 25a (23.3 mg, 98.4
(27.2 mg, 197 mol), and DMF (1 mL) under argon atmosphere. To
the solution was added MeI (9.2 L, 0.15 mmol). The reaction
mmol), K2CO3
m
m
4.18. Ethyl 6-bromo-7-methoxy-4,5-dihydropyrrolo[4,3,2-de]-
quinoline-1(3H)-carboxylate (23b)
mixture was stirred for 10 min, after which time TLC (NH silica gel,
hexanes/ethyl acetate¼1:1) indicated complete consumption of
25a. The reaction mixture was treated with H2O, and the mixture
was extracted with ethyl acetate three times. The organic extracts
were washed with H2O three times and brine, dried over anhydrous
sodium sulfate, and filtered. The organic solvents were removed
under reduced pressure to give a crude 26a, which was used for the
Compound 23b was obtained from 22b by the same procedure
for the preparation of 17 in 93% yield as a white solid; Rf (hexanes/
ethyl acetate¼3:1) 0.46; IR (neat, cmꢀ1) 3381, 2978, 2940, 2838,
1731, 1626, 1469, 1439, 1410, 1311, 1249, 1218, 1145, 1121; 1H NMR
(400 MHz, CDCl3)
d
7.16e6.96 (m, 2H), 4.51 (br, 1H), 4.45 (q, 2H,
next reaction without further purification.
A 20-mL round-
J¼7.2 Hz), 3.93 (s, 3H), 3.50 (t, 2H, J¼6.0 Hz), 2.92 (td, 2H, J¼6.0,
bottomed flask equipped with magnetic stirring bar was
charged with a crude 26a and dichloromethane (5 mL) under argon
atmosphere. To the solution was added BBr3 (1.0 M in dichloro-
a
1.6 Hz), 1.45 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d
154.9,
151.1,138.9,133.0,115.0,114.6,113.5, 89.4, 89.4, 62.7, 56.3, 42.6, 22.2,
14.2; HRMS (EIþ) calcd for C14H15BrN2O3 (Mþ), 338.0266; found
338.0265.
methane, 246
m
L, 0.25 mmol) at ꢀ40 ꢁC. The reaction mixture was
stirred for 10 min, after which time TLC (ethyl acetate) indicated
complete consumption of 26a. The reaction mixture was treated
with methanol, and concentrated under reduced pressure to give
a crude batzelline C, which was purified by column chromatogra-
phy on silica gel (ethyl acetate/methanol¼1:0 to 9:1, then
4.19. 6-Chloro-7-methoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-de]-
quinoline (24a)
dichloromethane/methanol¼4:1) to afford batzelline
C (3c)
Compound 24a was obtained from 23a by the same procedure
for the preparation of 18 in 93% yield from 22a as a white solid; Rf
(hexanes/ethyl acetate¼3:1) 0.17; IR (neat, cmꢀ1) 3433, 3375,
3355, 2909, 2842, 1617, 1510, 1090, 763; 1H NMR (400 MHz, CDCl3)
(14.1 mg, 59.6 mmol, 61% from 25a) as a purple solid; Rf (dichloro-
methane/methanol¼9:1) 0.49; IR (neat, cmꢀ1) 3216, 3117, 2923,
2852, 1645, 1574, 1508, 1421, 1329, 833, 725; 1H NMR (400 MHz,
DMSO-d6)
d
8.34 (s, 1H), 7.17 (s, 1H), 3.82 (s, 3H), 3.57 (td, 2H, J¼7.2,
d
7.71 (br, 1H), 6.65 (s, 1H), 6.33 (s, 1H), 4.47 (br, 1H), 3.88 (s, 3H),
2.4 Hz), 2.74 (t, 2H, J¼7.2 Hz); 13C NMR (100 MHz, DMSO-d6)
d 171.4,
3.53 (t, 2H, J¼5.8 Hz), 2.99 (t, 2H, J¼5.8 Hz); 13C NMR (100 MHz,
169.1, 149.0, 129.6, 123.4, 123.0, 116.8, 96.8, 41.7, 35.5, 18.9; HRMS
CDCl3) d 153.3, 137.7, 132.1, 114.5, 112.5, 110.0, 96.3, 85.0, 56.5, 43.2,
(EIþ) calcd for C11H9ClN2O2 (Mþ), 236.0353; found 236.0358.
22.6; HRMS (EIþ) calcd for C11H11ClN2O (Mþ), 222.0555; found
222.0560.
4.24. Makaluvone (4)
4.20. 6-Bromo-7-methoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-de]-
A 10-mL round-bottomed flask equipped with a magnetic stir-
quinoline (24b)
ring bar was charged with 25b (35.2 mg, 125
(34.5 mg, 250 mol), and DMF (1 mL) under argon atmosphere. To
the solution was added MeI (11.7 L, 188 mol). The reaction mix-
ture was stirred for 15 min, after which time TLC (NH silica gel,
hexanes/ethyl acetate¼1:1) indicated complete consumption of
25b. The reaction mixture was treated with H2O, and the mixture
mmol), K2CO3
m
Compound 24b was obtained from 23b by the same
procedure for the preparation of 18. 24b was highly unstable
and immediately used to the next step. Rf (hexanes/ethyl
acetate¼3:1) 0.31.
m
m

T. Oshiyama et al. / Tetrahedron 68 (2012) 9376e9383
9383
was extracted with ethyl acetate three times. The organic extracts
were washed with H2O three times and brine, dried over anhydrous
sodium sulfate, and filtered. The organic solvents were removed
under reduced pressure to give a crude 26b, which was used for the
Education, Culture, Sports, Science, and Technology, Japan, the
KAKENHI, Young Scientists (Start-up; 19890014, B; 21790006 and
23790004), Tohoku University Global COE program ‘International
Center of Research and Education for Molecular Complex Chemis-
try’, Nagase Science and Technology Foundation, Suntory Institute
for Bioorganic Research (Sanbor Grant), Astellas Foundation for
Research on Metabolic Disorders, and Banyu Life Science Founda-
tion International.
next reaction without further purification.
A 30-mL round-
bottomed flask equipped with magnetic stirring bar was
a
charged with a crude 26b and dichloromethane (10 mL) under ar-
gon atmosphere. To the solution was added BBr3 (1.0 M in
dichloromethane, 313
m
L, 0.31 mmol) at ꢀ78 ꢁC. The reaction
mixture was stirred for 20 min, after which time TLC (NH silica gel,
hexanes/ethyl acetate¼1:1) indicated complete consumption of
26b. The reaction mixture was treated with methanol, and con-
centrated under reduced pressure to give a crude makaluvone,
which was purified by preparative TLC (ethyl acetate/meth-
References and notes
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ꢀ
Faulkner, D. J. J. Nat. Prod. 1995, 58, 1861; (d) Venables, D. A.; Concepcion, G. P.;
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Hamann, M. T. J. Nat. Prod. 2002, 65, 476; (g) For a recent review, see: Hu, J.-F.;
Fan, H.; Xiong, J.; Wu, S.-B. Chem. Rev. 2011, 111, 5465.
anol¼4:1) to afford makaluvone (4) (3.0 mg, 11
mmol, 8.5% from
25b) as a purple solid; Rf (ethyl acetate/methanol¼4:1) 0.17; IR
(neat, cmꢀ1) 3332, 2921, 2851, 1655, 1636, 1588, 1561, 1533, 1417,
1403, 1351, 1201, 1123; 1H NMR (400 MHz, DMSO-d6)
d
8.15 (br, 1H),
7.16 (s, 1H), 3.83 (s, 3H), 3.58 (t, 2H, J¼7.2 Hz), 2.74 (t, 2H, J¼7.2 Hz);
2. Stierle, D. B.; Faulkner, D. J. J. Nat. Prod. 1991, 54, 1131.
13C NMR (100 MHz, DMSO-d6)
d 171.6, 168.8, 150.4, 129.4, 123.6,
3. (a) Sakemi, S.; Sun, H. H.; Jefford, C. W.; Bernardinelli, G. Tetrahedron Lett. 1989,
30, 2517; (b) Chang, L. C.; Otero-Quintero, S.; Hooper, J. N. A.; Bewley, C. A. J. Nat.
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Quinn, R. J. J. Med. Chem. 2012, 55, 5851.
123.6, 116.7, 87.5, 42.1, 35.5, 18.9; HRMS (EIþ) calcd for C11H9BrN2O2
(Mþ), 279.9847; found 279.9851.
4.25. Isobatzelline C (5c)
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A 10-mL round-bottomed flask equipped with a magnetic stir-
ring bar was charged with 25a (20.4 mg, 86.2
(23.8 mg, 172 mol), and DMF (1 mL) under argon atmosphere. To
the solution was added MeI (8.1 L, 0.13 mmol). The reaction
mmol), K2CO3
m
m
mixture was stirred for 10 min, after which time TLC (NH silica gel,
hexanes/ethyl acetate¼1:1) indicated complete consumption of
25a. The reaction mixture was treated with H2O, and the mixture
was extracted with ethyl acetate three times. The organic extracts
were washed with H2O three times and brine, dried over anhydrous
sodium sulfate, and filtered. The organic solvents were removed
under reduced pressure to give a crude 26a, which was used for the
7. Oshiyama, T.; Satoh, T.; Okano, K.; Tokuyama, H. RSC Adv. 2012, 2, 5147.
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Fukuyama, T. Chem.dAsian J. 2011, 6, 560.
next reaction without further purification.
A 20-mL round-
bottomed flask equipped with a reflux condenser and a magnetic
stirring bar was charged with a crude 26a, NH4Cl (23.0 mg,
431 mmol) and EtOH (1 mL) under argon atmosphere. The resulting
9. Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797.
10. (a) Iwao and co-workers reported a benzyne-mediated approach for maka-
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reported double functionalization of benzyne with a nitrogen nucleophile,
a strong base, such as s-BuLi10b or intramolecular trapping10cef of the generated
anion species with an electrophile was utilized. Recently, Yoshida and co-
workers reported on a three component reaction of benzyne, amine, and car-
bon dioxide to provide anthranilic acid.10g (b) Sielecki, T. M.; Meyers, A. I. J. Org.
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indolyne and its application to synthesis of indolactam V: Bronner, S. M.; Goetz,
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mixture was heated at reflux for 20 min, after which time TLC (ethyl
acetate) indicated complete consumption of 26a. The reaction
mixture was concentrated under reduced pressure to give a crude
isobatzelline C, which was purified by preparative TLC (ethyl ace-
tate/methanol¼1:0 to 20:1, then dichloromethane/methanol¼4:1)
to afford isobatzelline C (5c) (10.8 mg, 45.8 mmol, 53% from 25a) as
a brown solid; Rf (dichloromethane/methanol¼4:1) 0.22; IR (neat,
cmꢀ1) 3010, 2919, 2851, 1670, 1604, 1520, 1406, 1348, 1324, 1256,
1204, 1144, 975; 1H NMR (400 MHz, CDCl3/CD3OD¼1:1)
d 7.10 (s,
1H), 3.98 (s, 3H), 3.94 (t, 2H, J¼7.6 Hz), 2.99 (t, 2H, J¼7.6 Hz); 13C
NMR (100 MHz, CDCl3/CD3OD¼1:1)
d 166.4, 154.6, 152.7, 131.9,
123.7, 122.6, 119.9, 94.0, 43.9, 36.6, 19.1; HRMS (EIþ) calcd for
C11H10ClN3O (Mþ), 235.0512; found 235.0518.
Acknowledgements
This work was financially supported by the Cabinet Office,
Government of Japan through its ‘Funding Program for Next Gen-
eration World-Leading Researchers’ (LS008), the Ministry of
16. Usui, S.; Hashimoto, Y.; Morey, J. V.; Wheatley, A. E. H.; Uchiyama, M. J. Am.
Chem. Soc. 2007, 129, 15102.