Short and flexible route to 3,4-diarylpyrrole marine alkaloids: Syntheses of permethyl storniamide A, ningalin B, and lamellarin G trimethyl ether

Article abstract of DOI:10.1016/S0040-4039(03)01031-1

A highly efficient route to 3,4-diarylpyrrole marine alkaloids has been developed using Hinsberg-type pyrrole synthesis and palladium-catalyzed Suzuki cross-coupling of the 3,4-dihydroxypyrrole bis-triflate derivatives as key reactions. Based on this approach, formal syntheses of permethyl storniamide A and ningalin B, and a total synthesis of lamellarin G trimethyl ether have been achieved.

Full text of DOI:10.1016/S0040-4039(03)01031-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4443–4446
Short and flexible route to 3,4-diarylpyrrole marine alkaloids:
syntheses of permethyl storniamide A, ningalin B, and
lamellarin G trimethyl ether
Masatomo Iwao,a,* Toshiro Takeuchi,a Naotaka Fujikawa,a Tsutomu Fukudaa and
Fumito Ishibashib
aDepartment of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan
bDivision of Marine Life Science and Biochemistry, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan
Received 2 April 2003; accepted 21 April 2003
Abstract—A highly efficient route to 3,4-diarylpyrrole marine alkaloids has been developed using Hinsberg-type pyrrole synthesis
and palladium-catalyzed Suzuki cross-coupling of the 3,4-dihydroxypyrrole bis-triflate derivatives as key reactions. Based on this
approach, formal syntheses of permethyl storniamide A and ningalin B, and a total synthesis of lamellarin G trimethyl ether have
been achieved. © 2003 Elsevier Science Ltd. All rights reserved.
The natural products possessing
a common 3,4-
highly efficient synthesis of this class of natural prod-
ucts using two key reactions: (1) Hinsberg-type
condensation9 of the iminodiacetates 9 with methyl
oxalate to produce 3,4-dihydroxypyrrole-2,5-dicarboxyl-
ates 10, and (2) palladium-catalyzed Suzuki cross-
coupling10 of the bis-triflate derivatives 11 with aryl-
boronic acids.
diarylpyrrole unit have been isolated from a marine
prosoblanch mollusk, ascidians, and sponges. These
include lamellarins A–b,1 lukianols A–B,2 storniamides
A–D,3 ningalins A–D,4 polycitones A–B,5 and
polycitrins A–B.5 Many of these natural products and
their derivatives exhibit unique and highly useful bio-
logical activities. For examples, lamellarin K (1) dis-
played potent cytotoxic activity against multidrug-
resistant (MDR) tumor cell lines, while at non-toxic
doses lamellarin I (2) effectively increased the cytotoxic-
ity of approved anticancer agents on MDR cell lines by
inhibition of P-glycoprotein-mediated drug efflux.6 Per-
methyl storniamide A (4), permethyl ningalin B (6), and
much simpler 3,4-diarylpyrrole derivatives also exhib-
ited similar MDR reversal activity at non-toxic concen-
trations.7 Lamellarin a 20-sulfate (7) showed inhibition
of HIV-1 integrase.1h The sulfate 7 is active against live
HIV-1 virus at non-toxic concentrations.1h These results
suggested that this type of marine natural products are
highly promising leads for new cancer and HIV
chemotherapeutic agents (Fig. 1).
Due to such promising biological activities and their
unique structures, a variety of synthetic approaches
have been developed.7,8 Herein, we report a new and
* Corresponding author. Tel.: +81-95-819-2681; e-mail: iwao@
net.nagasaki-u.ac.jp
Figure 1. 3,4-Diarylpyrrole marine alkaloids.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01031-1

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M. Iwao et al. / Tetrahedron Letters 44 (2003) 4443–4446
The synthesis of bis-triflates 11a,b is shown in Scheme
1. 2-Arylethylamines 8a,b were alkylated with 2.2 equiv.
of methyl bromoacetate in acetonitrile in the presence
of NaHCO3 to give the iminodiacetates 9a,b in over
90% yields. Condensation of 9a,b with dimethyl oxalate
using NaOMe as a base afforded 3,4-dihydroxypyrrole-
2,5-dicarboxylates 10a,b in modest yields. These
pyrroles were converted to the bis-triflates 11a,b in
good yields by the standard procedure.
completed within 5 h to give the 3,4-diarylpyrrole 14a
in 99% yield after chromatographic purification (entry
1). On the other hand, reactions with 2-methoxy, 3,4-
dimethoxy, and 3,4,5-trimethoxyphenylboronic acids
(12b–d) were somewhat slow under similar conditions
to give the mixtures of mono-arylated 13b–d and di-
arylated 14a–d (entries 2–4). However, when the reac-
tion time was elongated to 20 h using 3.0 equiv. of the
boronic acids, the di-arylated products were obtained in
excellent yields (entries 5–7). The 3,4-diarylpyrrole 14d
(R1=H, R2=R3=R4=OMe) thus prepared has previ-
ously been converted to permethyl storniamide A (4) in
three steps by Boger et al.7a Synthesis of mono-arylated
pyrroles as the major products may be possible using
1:1 stoichiometries of the triflates and the boronic acids.
In fact, the reaction of 11a with 1.0 equiv. of 12a in the
presence of 4 or 2 mol% of Pd(PPh3)4 gave the mono-
substituted 13a in good yields (entries 8 and 9).
Next, we carried out palladium-catalyzed cross-cou-
pling of the bis-triflate 11a with a range of methoxy-
substituted phenylboronic acids 12a–d11 (Table 1). A
mixture of 11a (1 mmol), an appropriate amount of a
boronic acid 12, Pd(PPh3)4 (0.04 mmol), aqueous
Na2CO3 (6.6 mmol in 2 mL of H2O) and THF (20 mL)
was heated under reflux.12 The reaction with 2.2 equiv.
of 4-methoxyphenylboronic acid (12a) was essentially
Scheme 1. Reagents and conditions: (a) BrCH2CO2Me (2.2 equiv.), NaHCO3, CH3CN, reflux, 2.5 h; (b) (CO2Me)2 (1.0 equiv.),
MeONa, MeOH, reflux, 18 h; (c) (CF3SO2)2O (2.2 equiv.), pyridine, 0°C, 2 h.
Table 1. Palladium-catalyzed cross-coupling of bis-triflate 11a with arylboronic acids 12a–d
Entry
12
R1
R2
R3
R4
Equiv.
Time (h)
13 (%)a
14 (%)a
1
2
3
4
5
6
7
8
9
12a
12b
12c
12d
12b
12c
12d
12a
12a
H
OMe
H
H
OMe
H
H
H
H
H
H
OMe
H
OMe
OMe
H
OMe
OMe
OMe
OMe
H
H
H
OMe
H
H
OMe
H
2.2
2.2
2.2
2.2
3.0
3.0
3.0
1.0
1.0b
5
5
5
1
66
45
44
1
0
0
77
78
99
34
54
55
99
100
100
9
OMe
OMe
H
OMe
OMe
H
5
20
20
20
3
H
H
4
8
a Isolated yields after column chromatography.
b 2 mol% of Pd(PPh4) was used.

M. Iwao et al. / Tetrahedron Letters 44 (2003) 4443–4446
4445
An efficient synthesis of 3,4-diarylpyrroles being estab-
lished, we planned to develop a new and general route
to pentacyclic lamellarins,8a–j,13 structurally most com-
plex and biologically most significant natural products
in the 3,4-diarylpyrole alkaloids family. We selected
lamellarin G trimethyl ether (20) as a model compound
and executed its total synthesis (Scheme 2). The bistri-
flate 11b was coupled with 1.0 equiv. of 3,4-
dimethoxyphenyboronic acid (12c)11 under standard
conditions described above to give the mono-arylated
15 in 78% yield, accompanied by 11% yield of the
di-arylated product. The second cross-coupling of 15
to lamellarin G trimethyl ether (20) was cleanly effected
by application of Kita’s oxidative biaryl coupling
conditions14 [phenyliodine bis(trifluoroacetate) (PIFA)/
BF3·Et2O] in 86% yield. The spectroscopic data of 20
were identical with those reported previously.8a
Finally, we examined a more straightforward ring clo-
sure of 19 to 20. Steglich has reported an interesting
Pd(0)-mediated decarboxylative cyclization of the
bromo-acid 21 to 20.8a,e We envisioned that a similar
ring closure could be feasible if Pd(II) salt was applied
to the acid 19. In fact, when 19 was heated with 1.1
equiv. of Pd(OAc)2 in acetonitrile under reflux for 12 h,
20 was obtained in 65% yield, accompanied by 12% of
the decarboxylated product 6. The ring closure was
found to be regioselective at C-6 of the pendant aro-
matic ring. This novel cyclization may proceed via
initial decarboxylative palladation15 of the pyrrole ring,
followed by electrophilic palladation of the electron-
rich aromatic ring and reductive elimination of Pd(0).
with
4,5-dimethoxy-2-methoxymethoyphenylboronic
acid (16)11 was found to be somewhat inefficient due to
rapid decomposition of the boronic acid 16 under the
coupling conditions. However, when the reaction was
carried out using excess (2.0 equiv.) of 16 and 8 mol%
of Pd(PPh3)4, the coupling product 17 and its lactone
18 were obtained in 58 and 12% yields, respectively.
The compound 17 was converted to 18 by treatment
with hydrochloric acid in methanol in 90% yield. Alka-
line hydrolysis of 18 followed by heating with p-TsOH
in refluxing toluene produced the acid 19 in 76% yield.8e
Cu2O-mediated decarboxylation of 19 in hot quinoline
afforded permethyl ningalin B (6) in 93% yield.7b This
compound has previously been converted to ningalin B
(5) by exhaustive demethylation.7b The ring closure of 6
In conclusion, we have developed a highly efficient
route to 3,4-diarylpyrrole marine alkaloids, including
pentacyclic lamellarins. We believe this route is flexible
enough to be applied to the syntheses of diverse natural
products and their analogues. Studies along this line are
in progress in our laboratories.
Scheme 2. Reagents and conditions: (a) 12c (1.0 equiv.), Pd(PPh3)4 (2 mol%), aq. Na2CO3, THF, reflux, 4 h (78%); (b) 16 (2.0
equiv.), Pd(PPh3)4 (8 mol%), aq. Na2CO3, THF, reflux, 20 h (17: 58%, 18: 12%); (c) conc. HCl, MeOH, reflux, 1 h (90%); (d) (i)
40% aq. KOH, reflux, 3 h, (ii) cat. p-TsOH, toluene, reflux, 30 min (76%); (e) Cu2O, quinoline, 220°C, 7 min (93%); (f)
PhI(OCOCF3)2, BF3·OEt2, CH2Cl2, −40°C, 1.5 h (86%); (g) Pd(OAc)2 (1.1 equiv.), CH3CN, reflux, 12 h (20: 65%, 6: 12%).

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M. Iwao et al. / Tetrahedron Letters 44 (2003) 4443–4446
(f) Ruchirawat, S.; Mutarapat, T. Tetrahedron Lett. 2001,
Acknowledgements
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