Total synthesis of lamellarins D, H, and R and ningalin B

Article abstract of DOI:10.1021/ol1027877

A concise total synthesis of lamellarins D (7 steps), H (7 steps), and R (5 steps) and ningalin B (5 steps) is achieved starting from the corresponding aldehydes and amines. The synthesis features three oxidative reactions as key steps in a biomimetic manner, involving an AgOAc-mediated oxidative coupling reaction to construct the pyrrole core, a Pb(OAc)₄-induced oxidative cyclization to form the lactone, and Kita's oxidation reaction to form the pyrrole-arene C-C bond.

Full text of DOI:10.1021/ol1027877

ORGANIC
LETTERS
2011
Vol. 13, No. 2
312-315
Total Synthesis of Lamellarins D, H, and
R and Ningalin B
Qingjiang Li,† Jingqian Jiang,† Aili Fan,† Yuxin Cui,† and Yanxing Jia*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking UniVersity, 38 Xueyuan Road, Beijing 100191, China, and State Key
Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy
of Sciences, Shanghai 201203, China
yxjia@bjmu.edu.cn
Received November 17, 2010
ABSTRACT
A concise total synthesis of lamellarins D (7 steps), H (7 steps), and R (5 steps) and ningalin B (5 steps) is achieved starting from the
corresponding aldehydes and amines. The synthesis features three oxidative reactions as key steps in a biomimetic manner, involving an
AgOAc-mediated oxidative coupling reaction to construct the pyrrole core, a Pb(OAc)4-induced oxidative cyclization to form the lactone, and
Kita’s oxidation reaction to form the pyrrole-arene C-C bond.
Since the first isolation of lamellarins A-D (Figure 1) by
Faulkner and co-workers in 1985,1 more than 70 different
lamellarins and related naturally occurring pyrrole-derived
alkaloids have been isolated from diverse marine organisms
such as mollusks, ascidians, and sponges. The lamellarins
and related pyrrole-derived alkaloids have shown promising
biological activities such as antitumor activity, reversal of
multidrug resistance (MDR), and HIV-1 integrase inhibition
activity.2 In light of their fascinating novel structures,
intriguing biological properties, and the difficulty in obtaining
Figure 1
.
The structures of lamellarins D, H, and R and ningalin B.
large quantities from natural sources, the lamellarins and
related alkaloids have attracted considerable attention from
organic and medicinal chemists. Several research groups,
notably those of Steglich,3 Banwell,4 Iwao,5 Boger,6 Ruchira-
wat,7 Faulkner,8 Gupton,9 Handy,10 and Alvarez, have
reported the total synthesis of lamellarins and related pyrrole-
derived alkaloids.12 These syntheses can be divided into two
11
´
† Peking University.
‡ State Key Laboratory of Drug Research.
(1) Andersen, R. J.; Faulkner, D. J.; He, C.; Van Duyne, G. D.; Clardy,
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J. 2000, 6, 1147–1152. (c) Kreipl, A. T.; Reid, C.; Steglich, W. Org. Lett.
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Steglich, W. Synthesis 2007, 608–612.
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ReV. 2008, 108, 264–287. (b) Pla, D.; Albericio, F.; Alvarez, M. Anti-Cancer
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10.1021/ol1027877  2011 American Chemical Society
Published on Web 12/17/2010

broad categories: one is the formation of the pyrrole core as
the key step, and the other is the functionalization of the
pre-existing pyrrole.
Scheme 1. Retrosynthesis of Lamellarins D and H
Recently, we developed a simple and efficient method for
the synthesis of 1,3,4-trisubstituted or 3,4-disubstituted
pyrroles, especially 3,4-diaryl-substituted derivatives, from
simple, readily available aldehydes and amines (anilines) by
using an AgOAc-mediated oxidative coupling reaction in a
one-pot manner.13 Herein, we reported a concise total
synthesis of lamellarins D, H, and R and ningalin B by using
this novel pyrrole synthesis approach as the key step in a
biomimetic manner.
From the biosynthesis point of view, the pentacyclic forms
of lamellarin D and its siblings are generated from their
simpler counterparts (analogues to 7 or 6) through two
consecutive oxidative cyclizations that lead to the formation
of bonds A and B as indicated in structure 1 (Scheme 1).3,4d
(4) (a) Banwell, M.; Flynn, B.; Hockless, D. Chem. Commun. 1997,
2259–2260. (b) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C. R.
Chem. Commun. 1997, 207–208. (c) Banwell, M. G.; Flynn, B. L.; Hockless,
D. C. R.; Longmore, R. W.; Rae, A. D. Aust. J. Chem. 1999, 52, 755–765.
(d) Axford, L. C.; Holden, K. E.; Hasse, K.; Banwell, M. G.; Steglich, W.;
Wagler, J.; Willis, A. G. Aust. J. Chem. 2008, 61, 80–93. (e) Hasse, K.;
Willis, A. C.; Banwell, M. G. Aust. J. Chem. 2009, 62, 683–691.
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T.; Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron Lett. 2006, 47, 3755–
3757. (d) Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi,
F.; Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796–3807. (e) Fukuda,
T.; Sudo, E.; Shimokawa, K.; Iwao, M. Tetrahedron 2008, 64, 328–338.
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8143–8153.
Also, the simpler conterparts are generated from DOPA (2-
amino-3-(3′,4′-dihydroxyphenyl)propionic acid) metabolic
products by oxidative coupling (formation of bond C).3,14
Therefore, biosynthetically, the skeleton of the lamellarins
is formed mainly through oxidative coupling reactions, and
the lamellarins proper represent higher oxidation states.
Inspired by the lamellarin biosynthesis pathway, our ret-
rosynthetic analysis of 1 and 2 is outlined in Scheme 1.
Lamellarins D (1) and H (2) could be synthesized from 5
by using PIFA oxidation according to Iwao’s work.5b Lactone
5 was envisioned by Pb(OAc)4-mediated oxidative lacton-
ization of acid 6.3a,b The acid 6 could be formed by the
Vilsmeier-Haack reaction of 7, followed by Lindgren
oxidation of the corresponding aldehyde.15 The key inter-
mediate pyrrole 7 could be obtained from an AgOAc-
mediated oxidative coupling reaction from aldehyde 8 and
amine 9.
The synthesis of aldehyde 8 and amine 9 is shown in
Scheme 2. Isopropyl protection of the hydroxyl group of the
commercially available vanillin afforded 10 in 97% yield.
Wittig reaction of O-isopropylvanillin (10) with the ylide
generated from (methoxymethyl)triphenylphosphonium chlo-
ride and t-BuOK afforded the enol ether 11 in 82% yield as
an E/Z mixture. Acid-catalyzed hydrolysis of 11 provided
crude aldehyde 8, which was used for the pyrrole synthetic
step without further purification due to its instability. Amine
9 was prepared from commercially available isovanillin
following literature procedures.3b,5b
(6) (a) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin,
Q. J. Am. Chem. Soc. 1999, 121, 54–62. (b) Boger, D. L.; Soenen, D. R.;
Boyce, C. W.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479–2483.
(c) Hamasaki, A.; Zimpleman, J. M.; Hwang, I.; Boger, D. L. J. Am. Chem.
Soc. 2005, 127, 10767–10770.
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1208. (b) Ploypradith, P.; Jinaglueng, W.; Pavaro, C.; Ruchirawat, S.
Tetrahedron Lett. 2003, 44, 1363–1366. (c) Ploypradith, P.; Mahidol, C.;
Sahakitpichan, P.; Wongbundit, S.; Ruchirawat, S. Angew. Chem., Int. Ed.
2004, 43, 866–868. (d) Ploypradith, P.; Kagan, R. K.; Ruchirawat, S. J.
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Sahakitpichan, P.; Litvinas, N. D.; Ruchirawat, S. J. Org. Chem. 2006, 71,
9440–9448.
(8) Ridley, C. P.; Reddy, M. V. R.; Rocha, G.; Bushman, F. D.; Faulkner,
D. J. Bioorg. Med. Chem. 2002, 10, 3285–3290.
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Shuford, J. S.; Sikorski, J. A. Tetrahedron 1999, 55, 14515–14522. (b)
Gupton, J. T.; Banner, E. J.; Sartin, M. D.; Coppock, M. B.; Hempel, J. E.;
Kharlamova, A.; Fisher, D. C.; Giglio, B. C.; Smith, K. L.; Keough, M. J.;
Smith, T. M.; Kanters, R. P. F.; Dominey, R. N.; Sikorski, J. A. Tetrahedron
2008, 64, 5246–5253.
(10) Handy, S. T.; Zhang, Y. N.; Bregman, H. J. Org. Chem. 2004, 69,
2362–2366.
´
(11) (a) Cironi, P.; Manzanares, I.; Albericio, F.; Alvarez, M. Org. Lett.
2003, 5, 2959–2962. (b) Pla, D.; Marchal, A.; Olsen, C. A.; Albericio, F.;
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Alvarez, M. J. Org. Chem. 2005, 70, 8231–8234. (c) Pla, D.; Marchal, A.;
´
Olsen, C. A.; Francesch, A.; Cuevas, C.; Albericio, F.; Alvarez, M. J. Med.
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(12) For miscellaneous approaches, see: (a) Diaz, M.; Guitian, E.;
Castedo, L. Synlett 2001, 7, 1164–1166. (b) Barun, O.; Chakrabarti, S.;
Junjappa, I. H. H. J. Org. Chem. 2001, 66, 4457–4461. (c) Kim, S.; Son,
S.; Kang, H. Bull. Korean Chem. Soc. 2001, 22, 1403–1406. (d) Bullington,
J. L.; Wolff, R. R.; Jackson, P. F. J. Org. Chem. 2002, 67, 9439–9442. (e)
Nyerges, M.; Toke, L. Tetrahedron Lett. 2005, 46, 7531–7534. (f) Su, S.;
Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 7744–7745. (g) Liermann,
J. C.; Opatz, T. J. Org. Chem. 2008, 73, 4526–4531. (h) Korotaev, V. Y.;
Sosnovskikh, V. Y.; Kutyashev, I. B.; Barkov, A. Y.; Shklyaev, Y. V.
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Redd, B. V. S.; Prasad, A. R. Synlett 2009, 43–46.
With aldehyde 8 and amine 9 in hand, they were subjected
to the crucial AgOAc-mediated oxidative coupling reaction,
(14) Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254–3262
.
(15) For a discussion of the Lindgren/Pinnick oxidation nomenclature,
see: Hayashida, J.; Rawal, V. H. Angew. Chem., Int. Ed. 2008, 47, 4373–
4376.
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Org. Lett., Vol. 13, No. 2, 2011
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Scheme 2
.
Synthesis of Aldehyde 8 and Amine 9
Scheme 3. Synthesis of Lamellarins D and H and Ningalin B
which afforded the desired key intermediate, pyrrole 7, in
41% yield (two steps from enol ether 11) (Scheme 3).
Vilsmeier-Haack formylation of pyrrole 7 under traditional
heating conditions did not yield the desired formylpyrrole
12, resulting in either no reaction (60 °C) or decomposition
of the starting material (at reflux). Gratifyingly, the microwave-
accelerated Vilsmeier-Haack reaction provided 12 in 83%
yield.9b
The stage was now set for the oxidation of the formyl
group to the carboxylic group. We soon realized that it was
a difficult reaction. After many attempts, we found that
Lindgren oxidation could give the desired carboxylic acid 6
in low conversion. Thus, a variety of reaction conditions
(mainly the cosolvent and temperature) were examined, and
some of the representative results are shown in Table 1. The
solvent played an important role in the reaction. When
DMSO/H2O was used as the solvent, no reaction occurred
(Table 1, entry 1). When THF/t-BuOH/H2O (4:1:4) was used,
the desired carboxylic acid 6 was obtained in 21% yield (29%
conversion), accompanied by a substantial amount of 5-chlo-
rinated side product 15 (Table 1, entry 2). We reasoned that
the 5-chlorinated product 15 was produced due to the
hypochlorite, which was formed in the reaction and was not
completely removed by the scavenger 2-methylbut-2-ene
from the reaction mixture. Reducing the reaction temperature
might decrease the formation of the byproduct 15 (Table 1,
entry 3). As anticipated, when the reaction was run at 10
°C, it provided acid 6 as the sole product (Table 1, entry 4)
although the conversion was still low. Further optimization
of the reaction indicated that the ratio of the cosolvent
dramatically affected the conversion of 12. When THF/t-
BuOH/H2O (3:3:1) was used, 12 was completely consummed
and converted to the desired carboxylic acid 6 in 87% yield
(Table 1, entry 5).
5 under Kita’s conditions,5b,16 DDQ oxidation, and selective
deprotection of the isopropyl group of 14 with BCl3.
Cleavage of both methyl and isopropyl groups in 14 with
BBr3 afforded lamellarin H (2) in 95% yield.8 Alternatively,
treatment of 5 with BBr3 produced ningalin B (3) in 87%
yield.3e,4e,6b,12d
To further demonstrate the utility of this new strategy, we
planned to perform the total synthesis of the natural product
lamellarin R (4), which belonged to a group of simple and
nonfused 3,4-diarylpyrrole marine alkaloids. Lamellarin R
was first isolated from the southern Australian sponge
Dendrilla cactos by Capon and co-workers in 1995.17 Up
Subsequent reaction of the carboxylic acid 6 with
Pb(OAc)4 in refluxing EtOAc furnished the known lactone
5 in 68% yield,3a,b which was the key intermediate in Iwao’s
total synthesis of lamellarin D. According to the protocol
reported by Iwao, compound 5 was readily converted to
lamellarin D via intramolecular oxidative biaryl coupling of
(16) (a) Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma,
H.; Kita, Y. J. Org. Chem. 1998, 63, 7698–7706. (b) Tohma, H.; Morioka,
H.; Takizawa, S.; Arisawa, M.; Kita, Y. Tetrahedron 2001, 57, 345–352.
(c) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. Chem.sEur. J.
2002, 8, 5377–5383
.
(17) Urban, S.; Hobbs, L.; Hooper, J. N. A.; Capon, R. J. Aust. J. Chem.
1995, 48, 1491–1494.
314
Org. Lett., Vol. 13, No. 2, 2011

Table 1. Optimization of Lindgren Oxidation of 12a
entry
solvent
DMSO/H2O
THF:t-BuOH:H2O (4:1:4)
THF:t-BuOH:H2O (4:1:4)
THF:t-BuOH:H2O (4:1:4)
THF:t-BuOH:H2O (3:3:1)
temp (°C)
convn (%)
ratio (6:15)b
yield % (6 + 15)c
1d
2
0 to 25
25
25 to 10
10
0
29
60
45
100
0
21
44
35
87
3:1
8:1
100:0
3e
4
5
10
100:0
a General reaction conditions: concentration 0.02 M in solvent, 3.0 equiv of NaClO2, 3.0 equiv of NaH2PO4, 8.0 equiv of 2-methylbut-2-ene. b The ratio
of 6 and 15 based on 400 MHz H NMR. c Isolated yield. d 3.0 equiv of NaClO2, 1.0 equiv of NaH2PO4, no 2-methylbut-2-ene was added. e According to
1
entry 2, 25 °C for 24 h, followed by the addition of 3.0 equiv of NaClO2, 3.0 equiv of NaH2PO4, 8.0 equiv of 2-methylbut-2-ene at 10 °C for 24 h.
to now, only one group has reported the total synthesis of
lamellarin R.5e
Our total synthesis of lamellarin R commenced with
aldehyde 16 and amine 17 (Scheme 4). The oxidative
dissolving in CDCl3 for a short period of time. In addition,
when Lindgren oxidation was run in THF:t-BuOH:H2O (4:
1:4) at 25 °C, aldehyde 19 was completely consumed and
converted to 20 and 5-chlorinated 20 in quantative yield with
a ratio of 3 to 1. Treatment of 20 with TMSCHN2 gave
methyl ester 21 in 99% yield. Final demethylation of 21 with
BBr3 at room temperature afforded lamellarin R (4) in 82%
yield.
Scheme 4. Synthesis of Lamellarin R
In summary, we have successfully achieved the total
synthesis of lamellarins D (7 steps), H (7 steps), and R (5
steps), and ningalin B (5 steps) from the corresponding
aldehydes and amines in a biomimetic manner. The synthesis
features three oxidative coupling reactions, involving an
AgOAc-mediated oxidative coupling reaction to form the
1,3,4-trisubstituted pyrrole, a Pb(OAc)4-induced oxidative
cyclization to form the lactone, and Kita’s oxidation reaction
to form the pyrrole-arene C-C bond. The evaluation of
the biological activity of these important lamellarins and
related compounds and their derivatives is in progress in our
laboratory and will be reported in due course.
Acknowledgment. This research was supported by the
National Basic Research Program of China (973 Program,
No. 2010CB833200), the State Key Laboratory of Drug
Research, the National Natural Science Foundation of China
(Nos. 20972007, 20802005, and 30930109), and NCET.
coupling reaction smoothly afforded the pyrrole 18 in 77%
yield. Interestingly, unlike compound 7, traditional Vils-
meier-Haack reaction of 18 smoothly produced formylpyr-
role 19 in 91% yield. Lindgren oxidation of 19 under the
optimized conditions afforded acid 20 in 93% yield, which
was unexpectedly labile and decarboxylated to 18 even upon
Supporting Information Available: Full experimental
procedures, and 1H and 13C NMR spectra of compounds 1-7,
9-14, 18, 19, and 21. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1027877
Org. Lett., Vol. 13, No. 2, 2011
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