Modular total synthesis of lamellarin G trimethyl ether

Article abstract of DOI:10.1055/s-0028-1087387

A modular synthesis of the lamellarin G trimethyl ether has been developed based on the application of several reaction sequences which include Friedel-Crafts acylation, esterification, haloarylation, and oxidative cyclization. The formation of pyrrolo [2

Full text of DOI:10.1055/s-0028-1087387

LETTER
43
Modular Total Synthesis of Lamellarin G Trimethyl Ether
Synthesis
h
of
L
amellarin
i
G Tri
l
methyl
l
E
ther u S. Yadav,* Kamakolanu Uma Gayathri, Basi V. Subba Reddy, Attaluri R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 17 April 2008
HO
Abstract: A modular synthesis of the lamellarin G trimethyl ether
O
has been developed based on the application of several reaction
sequences which include Friedel–Crafts acylation, esterification,
N
OMe
MeO
HO
O
X
MeO
haloarylation, and oxidative cyclization. The formation of pyrrolo
[2,1-a]isoquinoline core, the key step for the successful completion
of lamellarin G trimethyl ether synthesis, is comfortably accom-
plished through the haloarylation of 3-bromo-4-(3,4-dimethoxy-
benzoyl)-6,7-dimethoxy-chroman-2-one which has resulted in ex-
clusive endo product.
O
N
MeO
MeO
O
OH
MeO
OMe
lamellarin L
OMe
RO
MeO
Key words: lamellarins, Friedel–Crafts acylation, esterification,
bromoarylation, oxidative cyclization
Y
OMe
X = OH: lamellarin A
X = H: lamellarin C
O
N
MeO
MeO
O
MeO
O
Lamellarin G belongs to a group of marine natural prod-
ucts that contain 5-oxa-6b-aza-dibenzo[a,i]fluoren-6-one
skeleton. Lamellarins were isolated from the prosobranch
mollusk Lamellaria sp. and the ascidians.1 The first four
lamellarins were isolated by Faulkner et al. in 1985 and
were named lamellarins A, B, C, and D (Figure 1).
N
MeO
MeO
O
OH
HO
OMe
Y and R = H: lamellarin D
Y = OH: R = Me: lamellarin M
OMe
MeO
OMe
lamellarin G trimethyl ether
The structure of lamellarin A was determined by X ray
crystallographic analysis and the structures of the remain-
ing compounds were derived from spectroscopic data.2 At
present 35 lamellarins have so far been isolated and iden-
tified.2,3 Interestingly, some of these lamellarins have
been found to exhibit potent biological activities,4 such as
cytotoxicity to a wide range of cancer cell lines, cell divi-
sion inhibition, immunomodulatory activity, and a recent-
ly discovered multidrug resistant (MDR) reversal5 and
HIV-1 integrase inhibition.6
Figure 1 Members of the lamellarin family of natural products
Heck reaction.9a Simpler members of the lamellarins (O,
P) have also been prepared independently by Banwell and
Wong using Stille and Suzuki cross-coupling methods.9b
Recently, lamellarin G trimethyl ether has been prepared
by Iwao and coworkers,10 Handy et al.,11 and Ruchirawat
et al.12a More recently, large number of methods for the to-
tal synthesis of lamellarin G have been reported by em-
ploying various methodologies.12,13
In view of these interesting biological activities and the
difficulty in obtaining large quantities of the lamellarins
from their natural sources, they have garnered a consider-
able amount of synthetic interest. A number of elegant
studies directed towards the total synthesis of lamellarins
have been employed. The notable strategies involve high-
ly functionalized precursors which assembled into the
pyrrole core by means of an intramolecular ylide cycload-
dition,6 an azadiene Diels–Alder cycloaddition,6c or an
oxidative dimerization.7 One unifying feature of all these
syntheses is that they form the key pyrrole core late in the
synthesis,8 due to the difficulty in functionalizing pyrrole
in a regiocontrolled fashion. There have been other strat-
egies starting with an intact pyrrole core as reported by
Banwell and coworkers whose strategy involved func-
tionalization of pyrrole ester by tandem intramolecular
Our approach to the synthesis of lamellarin skeleton is
based on the formation of pyrrole ring in the final step of
the synthesis, which may be extended for the synthesis of
several analogues in a shortest route (see Scheme 1 for the
retrosynthesis). As depicted in Scheme 2, this strategy fo-
cuses on the Friedel–Craft’s acylation, esterification, in-
tramolecular bromoarylation of alkene and oxidative
cyclisation reactions.
Accordingly, 4-(3,4-dimethoxy-phenyl)-4-oxo-but-2-enoic
acid (3), was synthesized from veratrole and maleic anhy-
dride under Friedel–Crafts conditions.14,15 Compound 3
on esterification with 4 resulted in 4-(3,4-dimethoxy-phe-
nyl)-4-oxo-but-2-enoic acid-3,4-dimethoxy-phenyl ester
(5) following the previously reported procedure.16,17 The
ester 5 on bromo arylation resulted in 3-bromo-4-(3,4-
dimethoxy-benzoyl)-6,7-dimethoxy-chroman-2-one (6) fol-
lowing the intramolecular haloarylation methodology
used for aryl cinnamates.18,19 Upon coupling of 6 with 6,7-
SYNLETT 2009, No. 1, pp 0043–0046
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087387; Art ID: D12408ST
© Georg Thieme Verlag Stuttgart · New York

44
J. S. Yadav et al.
LETTER
MeO
MeO
O
O
O
O
MeO
MeO
OH
N
MeO
MeO
O
MeO
MeO
O
O
OMe
MeO
MeO
OMe
Scheme 1 Retrosynthesis of lamellarin G trimethyl ether
O
O
MeO
MeO
OH
MeO
O
O
O
MeO
MeO
OH
MeO
MeO
MeO
MeO
O
4
AlCl3, C2H4Cl2
60 °C, 85%
O
DCC, DMAP, DMF
20 °C, 89%
O
MeO
5
2
3
MeO
O
O
MeO
MeO
MeO
NH⋅HCl
O
N
MeO
MeO
Br
NBS, Sm(OTf)3
7
MeO
MeO
O
MeCN,
20 °C, 93%
K2CO3, MeCN, air, reflux
O
63%
MeO
OMe
MeO
OMe
lamellarin G trimethyl ether (1)
6
Scheme 2 Synthesis of lamellarin G trimethyl ether
dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride
(7) in the presence of K2CO3 in acetonitrile gave the ex-
pected final product lamellarin G trimethyl ether 1 in 63%
yield (Scheme 2).20,21 The spectral data and the melting
point were consistent with those reported in the litera-
ture.7a,10–12
Acknowledgment
KUG thanks CSIR, New Delhi for the award of fellowship.
References and Notes
(1) Davidson, B. S. Chem. Rev. 1993, 93, 1771.
(2) Anderson, R. J.; Faulkner, D. J.; Cun-Heng, H.; Van Duyne,
G. D.; Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492.
(3) Davis, R. H.; Carroll, A. R.; Pierens, G. K.; Quinn, R. J.
J. Nat. Prod. 1999, 62, 419.
(4) (a) Carroll, A. R.; Bowden, B. F.; Coll, J. C. Aust. J. Chem.
1993, 46, 489. (b) Reddy, R. M. V.; Faulkner, D. J.;
Venkateswarlu, Y.; Rao, M. R. Tetrahedron 1997, 53, 3457.
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Rubins, K.; Bushman, F. D.; Venkateswarlu, Y.; Faulkner,
D. J. J. Med. Chem. 1999, 42, 1901.
Mechanistically, the reaction proceeds via N-alkylation of
isoquinoline (7) with the bromo derivative (6) to give N-
alkylated product A. Then compound A undergoes in-
tramolecular aldol-type condensation to give dihydro-
derivative B, which sequentially undergoes aromatization
under air or atmospheric oxygen to furnish the desired
molecule 1. On the other hand, isoquinoline can also react
with ketone to give enamine (X), which upon intramolec-
ular C-alkylation followed by aromatization would expect
the formation of undesired product (Y). However, no for-
mation of Y was observed under the reaction conditions.
The possible reaction mechanism is depicted in Scheme 3.
(6) (a) Quesada, A. R.; Garcia Gravalos, M. D.;
Fernandez Puentes, J. L. Br. J. Cancer 1996, 74, 677.
(b) Quesada, A. R.; Garcia Gravalos, M. D.;
Fernandez Puentes, J. L. WO 9701336 A1 970116, 2006;
Chem. Abstr. 1996, 126, 166474. (c) Boger, D. L.; Boyce,
C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem.
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C. W.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479.
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Ed. Engl. 1997, 36, 155. (b) Peschko, C.; Winklhofer, C.;
Steglich, W. Chem. Eur. J. 2000, 6, 1147.
In conclusion, we have completed a short synthesis of the
lamellarin skeleton that employs four sequential steps in-
volving Friedel–Crafts acylation, esterification, haloary-
lation, and oxidative cyclization. This route accesses the
complete structure of lamellarin G trimethyl ether in four
steps with 44% overall yields. Future efforts will focus on
the use of various arenes in the first step to obtain other
lamellarin cores. These efforts will be reported in due
course.
(8) Gupton, J. T.; Clough, S. C.; Miller, R. B.; Lukens, J. R.;
Henry, C. A.; Kanters, R. P. F.; Sikorski, J. A. Tetrahedron
2003, 59, 207.
Synlett 2009, No. 1, 43–46 © Thieme Stuttgart · New York

LETTER
Synthesis of Lamellarin G Trimethyl Ether
45
MeO
O
MeO
O
O
N
••
MeO
O
–
MeO
MeO
MeO
MeO
Br
K2CO3, MeCN
reflux
O
+
NH⋅HCl
O
OMe
MeO
OMe
MeO
OMe
A
K2CO3, MeCN
OMe
reflux
MeCN
MeO
MeO
MeO
OMe
O
H
N
N
••
MeO
MeO
O
Br
H
OMe
MeO
O
O
OMe
OMe
OMe
B
X
air [O]
OMe
MeO
MeO
OMe
MeO
O
N
N
MeO
MeO
O
O
O
OMe
OMe
OMe
MeO
Y
1
OMe
Scheme 3 A plausible reaction mechanism
(9) (a) Banwell, M. G.; Hockless, D. C. R.; Flynn, B. L.;
Longmore, R. W.; Rae, D. Aust. J. Chem. 1999, 52, 755.
(b) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless,
D. C. R. Chem. Commun. 1997, 207. (c) Liu, J.-H.; Yang,
Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 2000,
65, 3587.
(10) Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi,
F. Tetrahedron Lett. 2003, 44, 4443.
(11) Handy, S. T.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004,
Manzanares, I.; Cuevas, C.; Bailly, C. Bioorg. Med. Chem.
2004, 12, 1697. (f) Zhang, Y.; Handy, S. T.; Bregman, H.
American Chemical Society 228th National Meeting (August
2004, Philadelphia, PA). (g) Nyerges, M.; Toke, L.
Tetrahedron Lett. 2005, 46, 7531. (h) Ploypradith, P.;
Kagan, R. K.; Ruchirawat, S. J. Org. Chem. 2005, 70, 5119.
(i) Schroter, S.; Bach, T. Synlett 2005, 1957. (j) Yang, G.;
Wang, A. L.; Chen, H. L.; You, Y. C. Chin. J. Org. Chem.
2005, 25, 641. (k) Fujikawa, N.; Ohta, T.; Yamaguchi, T.;
Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron 2006, 62,
594. (l) Fürstner, A.; Domostoj, M. M.; Scheiper, B. J. Am.
Chem. Soc. 2006, 128, 8087. (m) Peschko, C.; Winklhofer,
C.; Terpin, A.; Steglich, W. Synthesis 2006, 3048.
(n) Worayuthakarn, R.; Thasana, N.; Ruchirawat, S. Org.
Lett. 2006, 8, 5845. (o) Thasana, N.; Worayuthakarn, R.;
Kradranrat, P.; Hohn, E.; Young, L. R.; Ruchirawat, S.
J. Org. Chem. 2007, 72, 9379. (p) Toth, J.; Nedves, A.;
Dancso, A.; Blasko, G.; Tőke, L.; Nyerges, M. Synthesis
2007, 1003. (q) Tóth, J.; Varadi, L.; Dancso, A.; Blasko, G.;
Tőke, L.; Nyerges, M. Synlett 2007, 1259.
69, 2362.
(12) (a) Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.;
Litvinas, N. D.; Ruchirawat, S. J. Org. Chem. 2006, 71,
9440. (b) Ruchirawat, S.; Mutarapat, T. Tetrahedron Lett.
2001, 42, 1205. (c) Ploypradith, P.; Jinaglueng, W.; Pavaro,
C.; Ruchirawat, S. Tetrahedron Lett. 2003, 44, 1363.
(13) (a) Ridley, C. P.; Reddy, M. V. R.; Rocha, G.; Bushman,
F. D.; Faulkner, D. J. Bioorg. Med. Chem. 2002, 10, 3285.
(b) Cironi, P.; Manzanares, I.; Albericio, F.; Alvarez, M.
Org. Lett. 2003, 5, 2959. (c) Fernandez, D.; Ahaidar, A.;
Danelon, G.; Cironi, P.; Marfil, M.; Perez, O.; Cuevas, C.;
Albericio, F.; Joule, J. A.; Alvarez, M. Monatsh. Chem.
2004, 135, 615. (d) Marfil, M.; Albericio, F.; Alvrez, M.
Tetrahedron 2004, 60, 8659. (e) Tardy, C.; Facompre,
M. L.; Laine, W.; Baldeyrou, B.; Garcia-Gravalos, D.;
Francesch, A.; Mateo, C.; Pastor, A.; Jimenez, J. A.;
(14) (a) Baddeley, G.; Makar, S. M.; Ivanson, M. G. J. Chem.
Soc. 1953, 3969. (b) Grummitt, O.; Becker, E. I.; Miesse, C.
Org. Synth., Coll. Vol. III 1955, 109.
(15) 4-(3,4-Dimethoxyphenyl)-4-oxobut-2-enoic acid (3)
To a solution of veratrole (0.5 g, 3.6 mmol) and maleic
Synlett 2009, No. 1, 43–46 © Thieme Stuttgart · New York

46
J. S. Yadav et al.
LETTER
anhydride (0.354 g, 3.6 mmol) in anhyd DCE (20 mL) was
added anhyd AlCl3 powder (1.042 g, 7.8 mmol) in two
portions. The reaction mixture was stirred for 1 h under
reflux conditions. The reaction was hydrolyzed by adding
2.08 mL of H2O with vigorous stirring at 0 °C, followed by
neutralization with concd HCl (0.416 mL). The resulting
mixture was extracted with EtOAc and purified by column
chromatography on SiO2 to afford 0.72 g (85%) of an acid as
yellow solid; mp 178–179 °C (lit.13a mp 178 °C, no range
given). 1H NMR (400 MHz, CDCl3): d = 7.80 (dd, J = 12.4,
15.2 Hz, 1 H), 7.48 (m, 2 H), 6.88 (dd, J = 4.1, 8.2 Hz, 1 H),
6.67 (dd, J = 6.2, 15.8 Hz, 1 H), 3.88 (s, 6 H). 13C NMR (50
MHz, CDCl3 + DMSO): d = 186.4, 166.1, 150.4, 144.2,
135.3, 130.7, 127.7, 121.6, 114.4, 114.1, 38.8, 37.9. IR
(neat): 3327, 2925, 2854, 2676, 2361, 1739, 1701, 1654,
1587, 1516, 1461, 1428, 1286, 1169, 1215, 1025, 938, 898,
766, 670, 612, 583 cm–1. ESI-MS: m/z = 261 [M+ + 2 + 23],
232, 218, 146, 124, 105. Anal. Calcd for C12H12O5: C, 61.01;
H, 5.12. Found: C, 61.02; H, 5.14.
(18) Hajra, S.; Maji, B.; Karmkar, A. Tetrahedron Lett. 2005, 46,
8599.
(19) 3-Bromo-4-(3,4-Dimethoxybenzoyl)-6,7-dimethoxy-
chroman-2-one (6)
The ester (0.2 g, 0.53 mmol) was treated with NBS (0.1 g,
0.59 mmol) and Sm(OTf)3 (0.032 g, 0.053 mmol) in MeCN
at 20 °C to produce 0.22 g (93%) of 6, as an exclusively
endo-cyclized product. 1H NMR (200 MHz, CDCl3): d =
7.23 (s, 1 H), 7.18 (s, 1 H), 6.83 (s, 1 H), 6.54 (s, 2 H), 6.05
(s, 1 H), 5.09 (s, 1 H), 3.80 (m, 12 H). 13C NMR (75 MHz,
CDCl3): d = 202.6, 166.5, 149.9, 146.5, 143.7, 135.7, 116.8,
114.9, 106.9, 103.6, 100.6, 99.7, 95.5, 94.6, 56.8, 56.7, 56.5,
56.2, 56.0. IR (neat): 3422, 2925, 2853, 2361, 1713, 1657,
1593, 1507, 1455, 1406, 1204, 1035, 977, 846, 798, 760,
666, 593 cm–1. ESI-MS: m/z = 450 [M+], 490 [M+ + 39], 423,
403, 375, 336, 306, 285, 258, 229, 208, 142. Anal. Calcd for
C20H19BrO7: C, 53.23; H, 4.24. Found: C, 53.26; H, 4.22.
(20) (a) Casagrande, C.; Invernizzi, A.; Ferrini, R.; Ferrari, G. G.
J. Med. Chem. 1968, 11, 765. (b) Alberola, A.; Ortega, A.
G.; Sadaba, M. L.; Sanudo, C. Tetrahedron 1999, 55, 6555.
(21) 13-(3,4-Dimethoxy-phenyl)-2,3,10,11-tetramethoxy-7,8-
dihydro-5-oxa-6b-aza-dibenzo[a,i]fluoren-6-one
(Lamellarin G Trimethyl Ether, 1)
(16) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978,
17, 522.
(17) Experimental Procedure – 4-(3,4-Dimethoxyphenyl)-4-
oxobut-2-enoic Acid 3,4-Dimethoxyphenyl Ester (5)
To a stirred solution of acid 3 (0.3 g, 1.27 mmol) in anhyd
DMF (10 mL) was added DMAP (15.5 mg, 0.127 mmol) and
3,4-dimethoxy phenol (4, 0.19 g, 1.27 mmol). Afterwards,
DCC (0.28 g, 1.37 mmol) was added to the above reaction
mixture at 0 °C and stirred for 5 min at 0 °C and then 3 h at
20 °C. Precipitated urea was filtered off and the filtrate was
washed with 0.5 N HCl, followed by sat. NaHCO3 solution,
and then dried over Na2SO4. The solvent was removed by
evaporation, and the resulting crude reaction mixture was
purified by column chromatography on SiO2 to give 0.42 g
(83%) of ester. 1H NMR (200 MHz, CDCl3): d = 6.62 (d,
J = 8.6 Hz, 3 H), 6.40 (d, J = 2.3 Hz, 3 H), 6.28 (dd, J = 3.1,
8.5 Hz, 2 H), 3.73 (d, J = 7.8 Hz, 12 H). 13C NMR (75 MHz,
CDCl3): d = 193.7, 173.6, 162.9, 156.6, 151.1, 149.7, 147.0,
123.3, 114.2, 114.1, 112.5, 110.1, 109.9, 105.8, 100.7, 99.9,
56.5, 56.0, 55.7, 54.1. IR (neat): 3274, 2933, 2854, 1754,
1690, 1647, 1606, 1512, 1442, 1287, 1223, 1161, 1124,
1026, 953, 834, 803, 763, 720, 626 cm–1. ESI-MS: m/z = 372
[M+]. Anal. Calcd for C20H20O7: C, 64.51; H, 5.41. Found: C,
64.54; H, 5.44.
The bromide 6 (0.05 g, 0.11 mmol) was added to 6,7-
dimethoxy-1,2,3,4-tetrahydro isoquinoline (0.51 g, 2.22
mmol) and K2CO3 (0.10 g, 0.73 mmol) in MeCN (3 mL)
with continuous stirring under aerobic conditions. The
mixture was stirred under reflux for 2 h, and then the
reaction mixture was quenched with H2O and extracted with
EtOAc (3 × 10 mL) and purified by column chromatography
on SiO2 to afford 0.038 g (63%) of lamellarin G trimethyl
ether as white solid; mp 238–239 °C (lit.11 mp 239.1–
240 °C). 1H NMR (300 MHz, CDCl3): d = 7.05 (m, 3 H),
6.88 (s, 1 H), 6.75 (s, 1 H), 6.69 (s, 1 H), 6.64 (s, 1 H), 4.78
(m, 2 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.84 (s,
3 H), 3.46 (s, 3 H), 3.34 (s, 3 H), 3.10 (t, J = 6.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 155.4, 149.7, 148.9, 148.8,
148.6, 147.2, 146.1, 145.5, 135.8, 128.0, 127.9, 126.7,
123.7, 120.1, 114.7, 114.0, 113.6, 111.8, 111.1, 110.2,
108.6, 104.4, 100.3, 56.2, 56.1, 56.0, 55.8, 55.4, 55.0, 42.4,
28.5. IR (neat): 3420, 2930, 1705, 1512, 1488, 1460, 1438,
1415, 1270, 1240, 1214, 1166, 1045, 752 cm–1. ESI-MS:
m/z = 543 [M+]. Anal. Calcd for C31H29NO8: C, 68.50; H,
5.38; N, 2.58. Found: C, 68.48; H, 5.36; N, 2.54.
Synlett 2009, No. 1, 43–46 © Thieme Stuttgart · New York

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