Total synthesis of lamellarins D, L, and N

Article abstract of DOI:10.1016/j.tet.2005.10.014

Total synthesis of cytotoxic marine alkaloids, lamellarins D, L, and N, has been achieved by using Hinsberg-type pyrrole synthesis and palladium-catalyzed Suzuki-Miyaura coupling of the 3,4-dihydroxypyrrole bistriflate 6 as the key reactions. The total yields of lamellarins D, L, and N from the common intermediate 6 are 54, 58, and 50%, respectively.

Full text of DOI:10.1016/j.tet.2005.10.014

Tetrahedron 62 (2006) 594–604
Total synthesis of lamellarins D, L, and N
Naotaka Fujikawa,a Takeshi Ohta,a Tomohiro Yamaguchi,a Tsutomu Fukuda,a
Fumito Ishibashib and Masatomo Iwaoc,
*
aGraduate School of Science and Technology, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
bDivision of Marine Life Science and Biochemistry, Faculty of Fisheries, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan
cDepartment of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 24 August 2005; accepted 6 October 2005
Available online 2 November 2005
Abstract—Total synthesis of cytotoxic marine alkaloids, lamellarins D, L, and N, has been achieved by using Hinsberg-type pyrrole
synthesis and palladium-catalyzed Suzuki–Miyaura coupling of the 3,4-dihydroxypyrrole bistriflate 6 as the key reactions. The total yields of
lamellarins D, L, and N from the common intermediate 6 are 54, 58, and 50%, respectively.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
(SAR) study.5 In this study, we revealed that the hydroxyl
groups at C-8 and C-20 positions (lamellarin numbering2a)
are essential for cytotoxic activity. Recently, Bailly and
co-workers have reported lamellarin D is a potent inhibitor
of DNA topoisomerase I and presented a theoretical model
of lamellarin D bound to the covalent topoisomerase I-DNA
complex.6 The model is in perfect agreement with our SAR
study.5 On the other hand, we have lately reported a more
general synthetic approach to diverse 3,4-diarylpyrrole
marine alkaloids including lamellaris by using Hinsberg-
type pyrrole synthesis and palladium-catalyzed coupling
as the key reactions.4j Herein, we report an efficient total
synthesis of lamellarins D, L, and N using this strategy.
Lamellarin-class marine natural products have received
considerable attention due to their unique structures and
highly useful biological activities.1 In 1985, Faulkner and
co-workers reported the first isolation of novel heterocyclic
marine natural products named lamellarins A–D from a
prosobranch mollusk, Lamellaria sp.2a The combined X-ray
crystallographic and spectroscopic studies revealed that
these natural products possess the unprecedented 14-
phenyl-6H-[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]iso-
quinolin-6-one ring-system. Up to now, over 30 lamellarins
(A–Z and a-g, including acetate and sulfate derivatives)
have been isolated from mollusks, tunicates, and sponges.2
These are different in the number and position of the OH and
OMe substituents on the common structural core. In 1996,
Quesada et al. reported that some lamellarins exhibited
potent cytotoxicity on P-glycoprotein-mediated multidrug-
resistant (MDR) cancer cells as well as their respective
parental cell lines.3 After this important discovery, much
attention has been focused on the chemical synthesis of
lamellarins.4 In 1997, we reported the first total synthesis of
the lamellarin-class natural products, lamellarins D and H,
using N-ylide-mediated cyclization of a benzylisoquinoline
derivative as the key ring-construction procedure.4b By
using this strategy, we have synthesized ten lamellarin D
analogues and carried out a structure–activity relationship
2. Results and discussion
The retrosynthetic analysis of lamellarins D (1), L (2), and N
(3) is shown in Scheme 1. The lamellarin core can be
constructed by intramolecular biaryl coupling of the pyrrole-
lactones (4 and 5), which in turn are obtained by the conse-
cutive palladium-catalyzed cross-coupling (Suzuki–Miyaura
reaction) of the 3,4-dihydroxypyrrole bistriflate 6 with the
arylboronic acids 7 (or 8), and 9, followed by lactonization,
hydrolysis, and decarboxylation. The bistriflate 6 can be
prepared by Hinsberg reaction of the iminodiacate 10 with
dimethyl oxalate followed by triflation.
The synthesis of the bistriflate 6 is shown in Scheme 2.
Henry reaction of O-isopropylisovani[in (11) followed by
lithium aluminum hydride reduction of the resulting
nitrostyrene intermediate produced 2-arylethylamine 12.4e
Keywords: Total synthesis; Lamellarin; Hinsberg reaction; Suzuki–
Miyaura coupling.
*
Corresponding author. Tel./fax: C81 95 819 2681;
e-mail: iwao@net.nagasaki-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.014

N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
595
Scheme 1. Retrosynthetic analysis of lamellarins D (1), L (2), and N (3).
Scheme 2. Synthesis of 3,4-dihydroxypyrrole bistriflate 6. Reagents and conditions: (a) CH3NO2, AcOKNH4C, AcOH, 100 8C, 6 h (74%); (b) LiAlH4,
THF, reflux, 7 h (65%); (c) BrCH2CO2Me, NaHCO3, CH3CN, reflux, 2 h (83%); (d) (CO2Me)2, NaH, THF, reflux, 3 h (87%); (e) (CF3SO2)2O, pyridine,
0 8C, 2 h (91%).
O
Scheme 3. Synthesis of arylboronic acids 7, 8, and 9. Reagents and conditions: (a) NBS, DMF, 0 8C, 0.5 h (86%); (b) i-PrBr, K2CO3, DMSO, 55 8C, 2 h (84%);
(c) (1) t-BuLi, THF, K78 8C, 1 h, (2) B(OMe)3, K78 8C, 1 h, then rt, 1 h (56%); (d) CH3SO2Cl, Et3N, CH2Cl2, 0 8C, 0.5 h (96%); (e) NBS, DMF, rt, 24 h
(96%) (f) LDA, THF, 0 8C, 5 min (91%); (g) (1) n-BuLi, Et2O, K78 8C, 1 h, (2) B(OMe)3, K78 8C, 1 h, then rt, 1 h, (3) 30% H2O2, AcOH, rt, 16 h (91%); (h) i-
PrBr, K2CO3, DMSO, 55 8C, 2 h (96%); (i) (1) t-BuLi, THF, K78 8C, 1 h, (2) B(OMe)3, K78 8C, 1 h, then rt, 1 h (81%); (j) (1) mCPBA, CH2Cl2, 0 8C, 3 h, (2)
K2CO3, MeOH, rt, 1 h (86%); (k) MOMCl, NaH, THF, 0 8C, 2 h, then rt, 1 h (68%); (l) NBS, DMF, 0 8C, 0.5 h, (98%); (m) (1) t-BuLi, THF, K78 8C, 1 h, (2)
B(OMe)3, K78 8C, 1 h, then rt, 1 h (87%).

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N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
The amine was reacted with 2 equiv of methyl bromoacetate
in the presence of sodium hydrogen carbonate in refluxing
acetonitrile to give iminodiacetate 10 in 83% yield.
Hinsberg reaction of 10 with dimethyl oxalate in dry THF
using sodium hydride as a base produced the 3,4-
dihydroxypyrrole 13 in 87% yield. The conventional
conditions using sodium methoxide in methanol4j,7 afforded
13 in much lower yield (w50%). Triflation of 13 with
trifluoromethanesulfonic anhydride in pyridine produced
the stable bistrifalte 6 in excellent yield.
the mesylate 17 with N-bromosuccinimide produced indeed
the 5-brominated compound 18 in excellent yield as a single
isomer. Deprotection of the mesyl group using the protocol of
Carreira9 gave 5-bromoguaiacol (19) in excellent yield.
This compound can also be prepared more conveniently
from commercially available 2,4-dibromoanisole (20) via
regioselective bromine–lithium exchange followed by
boration and oxidation.10 The phenol 19 was converted to
the boronic acid 8 in two steps in a similar manner as
described for 7. Both 7 and 8 are stable crystalline solids and
can be stored for several months without any deterioration.
The synthesis of arylboronic acids 7, 8 and 9 is shown in
Scheme 3. Guaiacol (14) was regioselectively brominated
by N-bromosuccinimide (NBS) to give 15 in 81% yield.
After isopropyl protection of the hydroxyl group, the
resulting 16 was converted to the boronic acid 7 via
bromine–lithium exchange with 2 equiv of tert-butyllithium
followed by a reaction with trimethyl borate.
Another arylboronic acid 9 was prepared in four steps from
O-isopropylisovanillin (11). Baeyer-Villiger oxidation of 11
with m-chloroperbenzoic acid followed by methanolysis
produced phenol 22. After protection of the hydroxyl group
as methoxymethyl ether, the resulting 23 was converted to
rather unstable bromide 24. Bromine–lithium exchange
followed by a reaction with trimethyl borate gave the
boronic acid 9. This compound was used for the subsequent
cross-coupling reactions immediately after preparation due
to its instability.
The regioisomeric arylboronic acid 8 was prepared as
follows. The hydroxyl group of guaiacol (14) was protected
by an electron-withdrawing mesyl group at first in order to
deactivate the electron-donating effect of the hydroxyl
group and alter the most electrophilic site of the aromatic
ring from the 4-position to the 5-position.8 Treatment of
The synthesis of lamellarins D (1), L (2), and N (3) is shown
in Scheme 4. At first, the synthesis of lamellarin D (1) was
Scheme 4. Synthesis of lamellarins D (1), L (2), and N (9). Reagents and conditions: (a) 7 or 8 (1.0 equiv), Pd(PPh3)4 (2 mol%), THF, reflux, 4 h (25: 76%, 26:
77%); (b) (1) 9 (2.0 equiv), Pd(PPh3)4 (8 mol%), THF, reflux, 18 h, (2) concd HCl, MeOH, reflux 1 h (27: 98%, 28: 95%); (c) (1) 40% KOH–EtOH (1/1),
reflux, 3 h, (2) cat. p-TsOH, CH2Cl2, reflux, 1 h (29: 90%, 30: 91%); (d) Cu2O, quinoline, 220 8C, 7 min (4: 94%, 5: 99%); (e) PhI(OCOCF3)2, BF3$OEt2,
CH2Cl2, K40 8C, 1.5 h (31: 88%, 32: 90%); (f) Pd(OAc)2 (1.1 equiv), CH3CN, reflux, 12 h (31: 65%, 4: 14%; 32: 65%, 5: 15%); (g) DDQ (1.5 equiv), toluene,
reflux, 18 h (33: 97%, 34: 96%); (h) BCl3, CH2Cl2, K78 8C, 0.5 h, then rt, 3 h (1: quant., 2: 98%, 3: 88%).

N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
597
executed. Suzuki–Miyaura coupling of the bistriflate 6 with
1.0 equiv of an arylboronic acid 7 under the standard
conditions [Pd(PPh3)4 (2 mol%), aqueous Na2CO3, THF,
reflux, 4 h]4j gave the mono-substituted pyrrole 25 in 76%
yield. The second cross-coupling of 25 with a freshly
prepared boronic acid 9 (2 equiv) using 8 mol% of the same
palladium catalyst, followed by treatment with hydrochloric
acid in methanol afforded the lactone–ester 27 in 98% yield.
Compound 27 was converted to the acid 29 by alkaline
hydrolysis followed by acid-catalyzed relactonization in
90% yield. Decarboxylation of 29 in hot quinoline in the
presence of copper(I) oxide11 produced 4. Intramolecular
oxidative biaryl coupling of 4 under Kita’s conditions12
using phenyliodine bis(trifluoroacetate) (PIFA)–boron tri-
fluoride etherate afforded the cyclized product 31 in good
yield. Pd(II)-mediated decarboxylative ring closure4j of 29
produced 31 directly in 65% yield, accompanied by
simply decarboxylated 4 (14%). Treatment of 31 with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in refluxing
toluene produced 5,6-dehydrogenated compound 33. Final
selective deprotection of the isopropyl group with boron
trichloride13 proceeded cleanly to give lamellarin D (1).
and lithiumdiisopropylamide (LDA) were purchased from
Aldrich Chemical Co., Inc. The alkyllithiums were used
after titration with 2,5-dimethoxybenzyl alcohol. Dry
diethyl ether and THF were distilled from Na–benzophe-
none ketyl under argon immediately before use.
4.2. Synthesis of the bistriflate 6
4.2.1. 2-(3-Isopropoxy-4-methoxyphenyl)ethylamine
(12). Nitromethane (13.3 mL, 246 mmol) was added as a
neat liquid to a solution of 11 (28.0 g, 144 mmol) and
ammonium acetate (33.3 g, 432 mmol) in acetic acid
(240 mL) at room temperature and the solution was heated
at 100 8C for 6 h. The mixture was cooled to room
temperature and then poured into ice-cold water. The
precipitates thus formed were collected by filtration, washed
with water, and dried under reduced pressure. Recrystalliza-
tion from diethyl ether gave (E)-b-nitro-3-isopropoxy-
4-methoxystyrene as yellow prisms (25.3 g, 74%). Mp
115–115.5 8C (lit.4e mp 83 8C); IR (KBr): 3110, 2968, 1625,
1594, 1513, 1493, 1441, 1334, 1262, 1169, 1138, 1113,
1
1026, 1005, 957, 806 cmK1; H NMR (300 MHz, CDCl3):
d 1.40 (d, JZ6.0 Hz, 6H), 3.92 (s, 3H), 4.57 (m, JZ6.0 Hz,
1H), 6.92 (d, JZ8.3 Hz, 1H), 7.05 (d, JZ1.9 Hz, 1H), 7.17
(dd, JZ1.9, 8.3 Hz, 1H), 7.51 (d, JZ13.6 Hz, 1H), 7.95
(d, JZ13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): 21.94,
56.00, 71.77, 111.82, 114.85, 122.54, 124.48, 134.90,
139.25, 147.60, 154.03. EIMS m/z (%): 237 (83), 195
(100), 148 (68), 133 (29). Anal. Calcd for C12H15NO4: C,
60.75; H, 6.37; N, 5.90. Found: C, 60.88; H, 6.42; N, 6.00.
Total synthesis of lamellarin N (3) was also achieved from 6
in an essentially same sequence except for the use of
arylboronic acid 8 at the initial cross-coupling stage.
Selective deprotection of the isopropyl groups of an
intermediate 5,6-dihydrolamellarin 32 produced lamellarin
L (2).
3. Conclusion
Under an argon atmosphere, (E)-b-nitro-3-isopropoxy-
4-methoxystyrene (14.4 g, 60.7 mmol) was added portion-
wise to a suspension of LiAlH4 (7.40 g, 195 mmol) in THF
(600 mL) at 0 8C and the mixture was refluxed for 7 h. The
mixture was cooled to 0 8C and quenched carefully with
water (16 mL) and 10% aqueous NaOH (13 mL). After
removal of white precipitates by filtration, the filtrate was
dried over K2CO3, and evaporated under reduced pressure.
The residue was purified by distillation (94–98 8C/
0.35 mmHg) to give 12 as colorless oil (8.20 g, 65%). IR
(neat): 3364, 2976, 1588, 1515, 1505, 1259, 1234, 1138,
We have achieved the total synthesis of lamellarins D (1), L
(2), and N (3) in relatively short steps. Although the yield of
each step is not fully optimized, the total yields of
lamellarins are quite good (1: 54%, 2: 58%, and 3: 50%,
respectively, from bistriflate 6). Convergence of the strategy
enables the synthesis of a wide range of natural or non-
natural lamellarins by simple structural modification of the
starting bistriflate and arylboronic acids. Hopefully, this will
allow us to produce new antitumor agents based upon the
lamallarin motif.
1
1110, 1029, 989, 807 cmK1; H NMR (300 MHz, CDCl3):
d 1.36 (d, JZ6.0 Hz, 6H), 2.67 (t, JZ6.7 Hz, 2H), 2.93
(t, JZ6.7 Hz, 2H), 3.83 (s, 3H), 4.52 (m, JZ6.0 Hz, 1H),
6.74 (dd, JZ1.7, 8.5 Hz, 1H), 6.75 (d, JZ1.7 Hz, 1H), 6.82
(d, JZ8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): 22.13,
39.48, 43.63, 56.00, 71.41, 112.09, 116.85, 121.21, 132.19,
147.05, 148.80. HREIMS m/z. Calcd for C12H19NO2 (MC):
209.1416. Found: 209.1396.
4. Experimental
4.1. General
Melting points were determined with a Yanagimoto micro
melting points apparatus and are uncorrected. IR spectra
were obtained with a Perkin-Elmer System 2000 instrument.
NMR spectra were recorded on a Varian Gemini-300
instrument (300 MHz for 1H) or a JEOL JNM-AL400
4.2.2. Dimethyl N-[2-(3-isopropoxy-4-methoxyphenyl)-
ethyl]iminodiacatate (10). Methyl bromoacetate
(5.78 mL, 61.1 mmol) was added as a neat liquid to a
suspension of 12 (6.00 g, 28.7 mmol) and NaHCO3 (10.3 g,
123 mmol) in acetonitrile (60 mL) at room temperature and
the mixture was refluxed for 2 h. The mixture was cooled to
room temperature and evaporated under reduced pressure.
The residue was extracted with dichloromethane and the
extract was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by distillation (180 8C/0.6 mmHg) to give 10 as
colorless oil (8.42 g, 83%). IR (neat): 2952, 2838, 1747,
1
instrument (400 MHz for H and 100 MHz for 13C) using
tetramethylsilane as an internal standard. Mass spectra were
recorded on a JEOL JMS-700N spectrometer. Flash
chromatography was conducted on Silica Gel 60N,
40–50 mm (Kanto Chemical Co., Inc.). Column chromato-
graphy was conducted on Silica Gel 60N, 63–210 mm
(Kanto Chemical Co., Inc.) or Chromatorex NH-DM1020
silica gel (Fuji Silysia Chemical Ltd.). tert-Butyllithium was
purchased from Kanto Chemical Co., Inc. n-Butyllithium

598
N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
1732, 1588, 1515, 1505, 1455, 1435, 1372, 1258, 1028,
(90), 137 (100). Anal. Calcd for C22H23F6NO12S2: C, 39.35;
H, 3.45; N, 2.09. Found: C, 39.32; H, 3.19; N, 2.02.
1
808 cmK1; H NMR (300 MHz, CDCl3): d 1.36 (d, JZ
6.3 Hz, 6H), 2.68–2.75 (m, 2H), 2.90–2.97 (m, 2H), 3.60
(s, 4H), 3.71 (s, 6H), 3.82 (s, 3H), 4.51 (m, JZ6.3 Hz, 1H),
6.70–6.81 (m, 3H); 13C NMR (100 MHz, CDCl3): 22.14,
34.24, 51.49, 54.99, 56.01, 56.48, 71.41, 112.05, 116.80,
121.05, 132.09, 147.01, 148.78, 171.45. HREIMS m/z.
Calcd for C18H27NO6 (MC): 353.1838. Found: 353.1848.
4.3. Synthesis of arylboronic acid 7
4.3.1. 4-Bromo-2-methoxyphenol (15). A solution of NBS
(14.3 g, 80.6 mmol) in DMF (50 mL) was added dropwise
to a solution of guaiacol (10.0 g, 80.6 mmol) in DMF
(50 mL) at 0 8C. After being stirred for 30 min, the reaction
mixture was quenched with water at the same temperature
and allowed to warm to room temperature. The products
were extracted with diethyl ether and the extract was
washed with water and brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by column chromatography over Silica Gel 60N
(hexane/ethyl acetateZ3:1) to give 15 as colorless oil
(14.1 g, 86%). Bp 95–110 8C (1.9 mmHg, bulb-to-bulb); IR
(neat): 3521, 2967, 2946, 2842, 1608, 1505, 1445, 1360,
1258, 1224, 1118, 1026, 859, 839, 810, 781 cmK1; 1H NMR
(300 MHz, CDCl3): d 3.89 (s, 3H), 5.54 (s, 1H), 6.80 (d, JZ
8.0 Hz, 1H), 6.97 (d, JZ2.2 Hz, 1H), 6.99 (dd, JZ2.2,
8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): 56.08, 111.43,
114.02, 115.60, 124.01, 144.69, 147.03. HREIMS m/z.
Calcd for C7H7BrO2 (MC): 201.9629. Found: 201.9608.
4.2.3. Dimethyl 3,4-dihydroxy-1-[2-(3-isopropoxy-4-
methoxyphenyl)ethyl]pyrrole-2,5-dicarboxylate (13).
Under an argon atmosphere, a suspension of dimethyl
oxalate (6.68 g, 56.6 mmol) and NaH (60% dispersion in
mineral oil, 4.53 g, ca. 113 mmol, prewashed with hexane)
in THF (50 mL) was heated to reflux. To this suspension
was added dropwise a solution of 10 (10.0 g, 28.3 mmol) in
THF (100 mL) under reflux. After being refluxed for
additional 3 h, the reaction mixture was cooled to room
temperature, quenched with acetic acid (6.7 mL) and
evaporated under reduced pressure. The residue was poured
into ice-cold water and the suspension was adjusted to pH 3
with concd HCl. The precipitates thus formed was collected
by filtration, washed with water, and dried under reduced
pressure to give 13 as colorless powder (10.0 g, 87%).
Recrystallization from diethyl ether–hexane gave colorless
needles. Mp 116.5–117.5 8C; IR (KBr): 3483, 3420, 2994,
2965, 2938, 1724, 1696, 1515, 1467, 1235, 1191, 1146,
4.3.2. 4-Bromo-1-isopropoxy-2-methoxybenzene (16). A
neat liquid of 2-bromopropane (4.86 mL, 51.8 mmol) was
added to a suspension of 15 (7.00 g, 34.5 mmol) and K2CO3
(9.54 g, 69.0 mmol) in DMSO (100 mL) at the room
temperature and the mixture was heated at 55 8C for 2 h.
The reaction mixture was cooled to room temperature and
diluted with water. The mixture was extracted with diethyl
ether and the extract was washed successively with 10%
aqueous NaOH, water, and brine, and dried over Na2SO4.
The solvent was evaporated under reduced pressure and
the residue was purified by bulb-to-bulb distillation
(90 8C/0.5 mmHg) to give 16 as colorless oil (7.07 g,
84%). IR (neat): 2977, 2934, 1585, 1495, 1464, 1445, 1397,
1
1108, 990 cmK1; H NMR (300 MHz, CDCl3): d 1.36 (d,
JZ6.0 Hz, 6H), 2.81 (t, JZ7.4 Hz, 2H), 3.83 (s, 3H), 3.92
(s, 6H), 4.48 (m, JZ6.0 Hz, 1H), 4.68 (t, JZ7.4 Hz, 2H),
6.64 (s, 1H), 6.65 (d, JZ8.8 Hz, 1H), 6.79 (d, JZ8.8 Hz,
1H), 7.51 (br s, 2H); 13C NMR (100 MHz, CDCl3): 22.14,
37.85, 47.75, 51.76, 56.03, 71.60, 110.38, 111.98, 116.90,
121.33, 130.62, 138.57, 147.03, 149.08, 162.32. EIMS m/z
(%): 407 (83), 333 (27), 228 (100), 196 (77). Anal. Calcd for
C20H25NO8: C, 58.96; H, 6.18; N, 3.44. Found: C, 58.76; H,
6.18; N, 3.35.
1383, 1372, 1250, 1224, 1135, 1108, 1031, 836 cmK1
;
4.2.4. Dimethyl 1-[2-(3-isopropoxy-4-methoxyphenyl)-
ethyl]-3,4-bis(trifluoromethanesulfonyloxy)pyrrole-2,5-
dicarboxylate (6). Under an argon atmosphere, trifluoro-
methanesulfonic anhydride (7.76 mL, 46.1 mmol) was
added as a neat liquid to a solution of 13 (8.50 g,
20.9 mmol) in pyridine (35 mL) at 0 8C. After being stirred
for 2 h, the reaction mixture was quenched with water at the
same temperature and allowed to warm to room tempera-
ture. The product was extracted with diethyl ether and the
extract was washed successively with 2 M aqueous HCl,
water, and brine, and dried over Na2SO4. The solvent was
removed by evaporation and the residue was purified by
column chromatography over Silica Gel 60N (hexane/ethyl
acetateZ3:1) to give 6 as colorless solid (12.8 g, 91%).
Recrystallization from dichloromethane–hexane gave color-
less plates. Mp 94–95 8C; IR (KBr): 2967, 1740, 1514,
1H NMR (300 MHz, CDCl3): d 1.35 (d, JZ6.0 Hz, 6H),
3.84 (s, 3H), 4.47 (m, JZ6.0 Hz, 1H), 6.76 (d, JZ9.1 Hz,
1H), 6.99 (d, JZ2.2 Hz, 1H), 6.99 (dd, JZ2.2, 9.1 Hz, 1H);
13C NMR (100 MHz, CDCl3): 21.99, 56.06, 71.80, 113.07,
115.39, 117.27, 123.26, 146.41, 151.16. HREIMS m/z.
Calcd for C10H13BrO2 (MC): 244.0099. Found: 244.0083.
4.3.3. 4-Isopropoxy-3-methoxyphenylboronic acid (7).
Under an argon atmosphere, a pentane solution of tert-
butyllithium (1.38 M, 24.8 mL, 34.2 mmol) was added
dropwise to a solution of 16 (4.00 g, 16.3 mmol) in THF
(60 mL) at K78 8C. After being stirred for 1 h, trimethyl
borate (2.80 mL, 25.1 mmol) was added as a neat liquid and
the mixture was stirred for 1 h at K78 8C. The reaction
mixture was allowed to warm to room temperature and
stirred for an additional 1 h. The mixture was quenched with
saturated aqueous NH4Cl and evaporated under reduced
pressure. To the residue was added 3 M aqueous HCl to
adjust the pH to 3 and then the mixture was extract with
dichloromethane. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure. The
residual solid was washed with hexane, filtered, and dried
under reduced pressure to give 7 as colorless powder
(1.93 g, 56%). This compound was used for the next
1434, 1307, 1245, 1307, 1245, 1131, 987, 973, 812 cmK1
;
1H NMR (300 MHz, CDCl3): d 1.36 (d, JZ6.0 Hz, 6H),
2.97 (t, JZ7.1 Hz, 2H), 3.82 (s, 3H), 3.88 (s, 6H), 4.48 (m,
JZ6.0 Hz, 1H), 5.08 (t, JZ7.1 Hz, 2H), 6.60 (dd, JZ1.9,
8.2 Hz, 1H), 6.66 (d, JZ1.9 Hz, 1H), 6.76 (d, JZ8.2 Hz,
1H); 13C NMR (100 MHz, CDCl3): 22.06, 37.24, 48.65,
52.19, 56.00, 71.39, 112.02, 116.52, 117.13, 118.31 (q, JZ
320 Hz), 121.45, 127.67, 128.98, 147.22, 149.27, 157.97.
EIMS m/z (%): 671 (78), 629 (95), 363 (27), 272 (33), 150

N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
599
reaction without further purification. Mp 100–120 8C; IR
(KBr): 3219, 2979, 2939, 1599, 1361, 1256, 1220, 1136,
(3.98 g, 91%). Recrystallization from diethyl ether–pentane
gave colorless prisms. Mp 64–64.5 8C; IR (KBr): 3399,
2974, 2942, 2841, 1592, 1492, 1436, 1333, 1290, 1260,
1110, 1029, 955, 818, 770, 741, 714 cmK1 1H NMR
;
1
(300 MHz, CDCl3): d 1.44 (d, JZ6.0 Hz, 6H), 3.99 (s, 3H),
4.69 (m, JZ6.0 Hz, 1H), 7.03 (d, JZ8.0 Hz, 1H), 7.70 (d,
JZ1.1 Hz, 1H), 7.82 (dd, JZ1.1, 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): 22.01, 55.99, 70.86, 113.85, 118.20,
129.55, 149.38, 151.29.
1225, 1126, 1025, 856, 799 cmK1; H NMR (300 MHz,
CDCl3): d 3.87 (s, 3H), 5.64 (s, 1H), 6.71 (d, JZ8.5 Hz,
1H), 6.97 (dd, JZ2.5, 8.5 Hz, 1H), 7.07 (d, JZ2.5 Hz, 1H);
13C NMR (100 MHz, CDCl3): 56.02, 111.72, 113.13,
117.70, 122.64, 145.69, 146.32. EIMS m/z (%): 204 (98),
202 (100), 189 (63), 187 (64), 161 (29), 159 (29). Anal.
Calcd for C7H7BrO2: C, 41.41; H, 3.48. Found: C, 41.58;
H, 3.44.
4.4. Synthesis of arylboronic acid 8
4.4.1. 2-Methoxyphenyl methanesulfonate (17). Under an
argon atmosphere, methanesulfonyl chloride (19.5 mL,
252 mmol) was added as a neat liquid to a solution of
guaiacol (25.0 g, 201 mmol) and triethylamine (41.8 mL,
300 mmol) in dichloromethane (200 mL) at 0 8C. After
being stirred for 30 min, the reaction mixture was diluted
with water and the organic layer was separated. The aqueous
layer was extracted with dichloromethane. The combined
extract was washed successively with water and brine, and
dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was purified by distillation
(133 8C/0.4 mmHg) to give 17 as colorless oil (39.0 g,
96%). IR (neat): 3022, 2943, 2843, 1605, 1505, 1360, 1282,
Method 2. Under an argon atmosphere, a hexanes solution of
n-butyllithium (1.19 M, 37.0 mL, 44.0 mmol) was added
dropwise to a solution of 2,4-dibromoanisole (20) (10.6 g,
39.9 mmol) in diethyl ether (200 mL) at K78 8C. After
being stirred for 1 h, trimethyl borate (7.48 mL, 67.1 mmol)
was added as a neat liquid and the mixture was stirred for
1 h at K78 8C. The reaction mixture was allowed to warm
to room temperature and stirred for an additional 1 h. Acetic
acid (7.48 mL, 131 mmol) and 30% aqueous H2O2
(13.6 mL, 133 mmol) were added to the mixture. After
being stirred for 16 h at room temperature, the mixture was
quenched with 10% aqueous Na2SO3. The product was
extracted with diethyl ether and the extract was washed
successively with water and brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by column chromatography over Silica Gel 60N
(toluene) to give 19 as colorless solid (7.36 g, 91%).
1259, 1183, 1155, 1107, 1022, 972, 873, 798, 757 cmK1
;
1H NMR (300 MHz, CDCl3): d 3.17 (s, 3H), 3.88 (s, 3H),
6.92–7.03 (m, 2H), 7.23–7.32 (m, 2H); 13C NMR
(100 MHz, CDCl3): 38.20, 55.91, 112.83, 120.99, 124.39,
128.12, 138.23, 151.25. HREIMS m/z. Calcd for C8H10O4S
(MC): 202.0300. Found: 202.0280.
4.4.4. 4-Bromo-2-isopropoxy-1-methoxybenzene (21).
This compound was prepared in a similar manner as
described for 16 using 19 (16.2 g, 79.8 mmol) as the starting
material. After purification by bulb-to-bulb distillation
(88 8C/0.4 mmHg), 21 was obtained as colorless liquid
(18.7 g, 96%), which on standing solidified. Mp 46–46.5 8C;
IR (KBr): 2976, 2907, 1584, 1500, 1254, 1223, 1130, 1020,
4.4.2. 5-Bromo-2-methoxyphenyl methanesulfonate (18).
A solution of NBS (2.31 g, 13.0 mmol) in DMF (5.0 mL)
was added dropwise to a solution of 17 (2.03 g, 10.0 mmol)
in DMF (5.0 mL) at room temperature. After being stirred
for 24 h, the reaction mixture was quenched with water. The
products were extracted with diethyl ether and the extract
was washed with water and brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was puri-
fied by bulb-to-bulb distillation (150–180 8C/1.1 mmHg) to
give 18 as colorless solid (2.71 g, 96%). Recrystallization
from diethyl ether–hexane gave colorless prisms. Mp
59–59.5 8C; IR (KBr): 3032, 2944, 1497, 1369, 1330,
1
958, 839, 794 cmK1; H NMR (300 MHz, CDCl3): d 1.37
(d, JZ6.0 Hz, 6H), 3.82 (s, 3H), 4.50 (m, JZ6.0 Hz, 1H),
6.73 (d, JZ9.1 Hz, 1H), 7.00 (d, JZ2.2 Hz, 1H), 7.01 (dd,
JZ2.2, 9.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): 21.95,
56.06, 71.75, 112.44, 113.15, 118.72, 123.57, 147.99,
149.51. EIMS m/z (%): 246 (35), 244 (35), 204 (98), 202
(100), 189 (52), 187 (53). Anal. Calcd for C10H13BrO2: C,
49.00; H, 5.35. Found: C, 48.92; H, 5.31.
1299, 1269, 1166, 1125, 1025, 976, 899, 804 cmK1
;
1H NMR (300 MHz, CDCl3): d 3.20 (s, 3H), 3.88 (s, 3H),
6.89 (d, JZ8.8 Hz, 1H), 7.39 (dd, JZ2.2, 8.8 Hz, 1H), 7.45
(d, JZ2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): 38.48,
56.20, 112.18, 114.07, 127.44, 130.90, 138.43, 150.73.
EIMS m/z (%): 282 (59), 280 (57), 203 (97), 201 (100), 94
(98). Anal. Calcd for C8H9BrO4S: C, 34.18; H, 3.23. Found:
C, 34.09; H, 2.98.
4.4.5. 3-Isopropoxy-4-methoxyphenylboronic acid (8).
This compound was prepared in a similar manner as
described for 7 using 21 (7.35 g, 30.0 mmol) as the starting
material. After washing with hexane, 8 was obtained as
colorless powder (5.13 g, 81%). Mp 115–135 8C; IR (KBr):
3220, 2975, 2934, 1596, 1518, 1374, 1268, 1217, 1178,
1
1136, 1112, 1025, 743, 716 cmK1; H NMR (300 MHz,
4.4.3. 5-Bromo-2-methoxyphenol (19). Method 1. Under
an argon atmosphere, a heptane–THF–ethylbenzene
solution of LDA (2.0 M, 16.1 mL, 32.2 mmol) was added
dropwise to a solution of 18 (6.04 g, 21.5 mmol) in THF
(21.5 mL) at 0 8C. After being stirred for 5 min, the mixture
was quenched with 5% aqueous HCl. The product was
extract with diethyl ether and the extract was washed
successively with water and brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by column chromatography over Silica Gel 60N
(hexane/ethyl acetateZ3:1) to give 19 as colorless solid
CDCl3): d 1.45 (d, JZ6.0 Hz, 6H), 3.94 (s, 3H), 4.67 (m,
JZ6.0 Hz, 1H), 7.02 (d, JZ8.0 Hz, 1H), 7.72 (d, JZ
1.4 Hz, 1H), 7.84 (dd, JZ1.4, 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): 22.17, 55.76, 71.63, 111.17, 122.38,
129.94, 146.60, 154.18.
4.5. Synthesis of arylboronic acid 9
4.5.1. 3-Isopropoxy-4-methoxyphenol (22). Under an
argon atmosphere, m-chloroperbenzoic acid (a reagent

600
N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
containing 25% water, 16.0 g, 69.5 mmol) was added
portionwise to a solution of 11 (12.0 g, 61.8 mmol) in
dichloromethane (120 mL) at 0 8C. After being stirred for
3 h, the reaction mixture was quenched with saturated
aqueous NaHCO3. The mixture was diluted with water and
the organic layer was separated. The aqueous layer was
extracted with dichloromethane. The combined extract was
washed with brine, dried over Na2SO4, and evaporated
under reduced pressure. The residue was dissolved in
methanol (240 mL) and K2CO3 (21.0 g, 152 mmol) was
added portionwise to the solution at room temperature.
After being stirred for 1 h, the mixture was evaporated
under reduced pressure. Water was added to the residue and
the product was extracted with diethyl ether. The extract
was washed with brine, dried over Na2SO4, evaporated
under reduced pressure. The residue was purified by column
chromatography over Silica Gel 60N (dichloromethane/
ethyl acetateZ5:1) to give 22 as colorless solid (9.64 g,
86%). Recrystallization from diethyl ether–pentane gave
colorless needles. Mp 121–122 8C; IR (KBr): 3431, 2978,
2934, 1610, 1508, 1459, 1289, 1223, 1129, 1032, 995, 918,
with diethyl ether and the extract was washed with water
and brine, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by column chromato-
graphy over Silica Gel 60N (hexane/ethyl acetateZ3:1) to
give 15 as pale yellow oil (3.31 g, 98%). This compound
was somewhat unstable and used for the next reaction
without further purification. IR (neat): 2977, 2835, 1505,
1374, 1265, 1211, 1152, 1111, 1085, 1017, 977, 921, 845,
1
804 cmK1; H NMR (300 MHz, CDCl3): d 1.36 (d, JZ
6.0 Hz, 6H), 3.54 (s, 3H), 3.81 (s, 3H), 4.49 (m, JZ6.0 Hz,
1H), 5.15 (s, 2H), 6.82 (s, 1H), 7.02 (s, 1H); 13C NMR
(100 MHz, CDCl3): 21.95, 56.32, 56.59, 72.00, 96.23,
103.13, 106.92, 116.51, 146.31, 147.06, 147.74. HREIMS
m/z. Calcd for C12H17BrO4 (MC): 304.0310. Found:
304.0302.
4.5.4. 4-Isopropoxy-5-methoxy-2-methoxymethoxyphenyl-
boronic acid (9). Under an argon atmosphere, a pentane
solution of tert-butyllithium (1.17 M, 24.0 mL, 28.1 mmol)
was added dropwise to a solution of 24 (4.00 g, 13.1 mmol)
in THF (160 mL) at K78 8C. After being stirred for 1 h,
trimethyl borate (2.30 mL, 20.6 mmol) was added as a neat
liquid and the mixture was stirred for 1 h at K78 8C. The
reaction mixture was allowed to warm to room temperature
and stirred for an additional 1 h. The mixture was quenched
with saturated aqueous NH4Cl and evaporated under
reduced pressure. The products were adjusted to pH 3
with acetic acid and the mixture was extract with
dichloromethane. The extract was washed successively
with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, and evaporated under reduced pressure. The
residue was washed with hexane and dried under reduced
pressure to give 9 as pale brown powder (3.09 g, 87%). This
compound was used for the next reaction without further
purification. Mp 83–86 8C; IR (KBr): 3499, 3370, 2987,
2939, 1606, 1509, 1400, 1306, 1261, 1211, 1148, 1103,
1020, 971, 816 cmK1; 1H NMR (300 MHz, CDCl3): d 1.39
(d, JZ6.0 Hz, 6H), 3.51 (s, 3H), 3.86 (s, 3H), 4.59 (m, JZ
6.0 Hz, 1H), 5.23 (s, 2H), 5.82 (s, 2H), 6.79 (s, 1H), 7.30
(s, 1H); 13C NMR (100 MHz, CDCl3): 21.94, 56.30, 56.32,
71.28, 95.39, 102.39, 118.45, 145.15, 150.71, 157.43.
1
856, 803, 772, 719 cmK1; H NMR (300 MHz, CDCl3):
d 1.36 (d, JZ6.0 Hz, 6H), 3.80 (s, 3H), 4.49 (m, JZ6.0 Hz,
1H), 4.66 (br s, 1H), 6.34 (dd, JZ2.8, 8.8 Hz, 1H), 6.48 (d,
JZ2.8 Hz, 1H), 6.74 (d, JZ8.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): 21.94, 56.75, 71.31, 104.08, 106.43,
113.41, 144.05, 147.98, 150.08. EIMS m/z (%): 182 (46),
140 (75), 125 (100). Anal. Calcd for C10H14O3: C, 65.91; H,
7.74. Found: C, 66.19; H, 7.89.
4.5.2. 2-Isopropoxy-1-methoxy-4-methoxymethoxy-
benzene (23). Under an argon atmosphere, a solution of
22 (2.50 g, 13.7 mmol) in THF (20 mL) was added dropwise
to a suspension of NaH (60% dispersion in mineral oil,
2.73 g, 68.3 mmol, prewashed with hexane) in THF
(30 mL) at 0 8C. After being stirred for 30 min, chloro-
methyl methyl ether (1.60 mL, 21.1 mmol) was added as a
neat liquid and the mixture was stirred for 2 h at 0 8C. The
reaction mixture was allowed to warm to room temperature
and stirred for an additional 1 h. The mixture was quenched
with saturated aqueous NH4Cl and the products were extract
with diethyl ether. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography over Silica
Gel 60N (hexane/ethyl acetateZ10:1) to give 23 as
colorless oil (2.10 g, 68%). Bp 135–140 8C (1.9 mmHg,
bulb-to-bulb); IR (neat): 2977, 2902, 2832, 1596, 1505,
4.6. Synthesis of lamellarin D (1)
4.6.1. Dimethyl 3-(4-isopropoxy-3-methoxyphenyl)-1-[2-
(3-isopropoxy-4-methoxyphenyl)ethyl]-4-(trifluoro-
methanesulfonyloxy)pyrrole-2,5-dicarboxylate (25).
Under an argon atmosphere, a degassed solution of
Na2CO3 (1.40 g, 13.2 mmol) in water (4.0 mL) was added
to a solution of 6 (1.34 g, 2.00 mmol), 7 (420 mg,
2.00 mmol) and Pd(PPh3)4 (48.0 mg, 41.5 mmol) in THF
(40 mL) at room temperature and the mixture was refluxed
for 4 h. The mixture was cooled to room temperature and
evaporated under reduced pressure. The products were
extracted with dichloromethane and the extract was washed
successively with water and brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by column chromatography over Silica Gel 60N
(toluene/ethyl acetateZ10:1) to give 25 as colorless solid
(1.05 g, 76%). Recrystallization from dichloromethane–
hexane gave colorless prisms. Mp 90–92 8C; IR (KBr):
2977, 2938, 1728, 1705, 1509, 1425, 1304, 1260, 1174,
1465, 1443, 1259, 1228, 1154, 1077, 1018, 976, 922 cmK1
;
1H NMR (300 MHz, CDCl3): d 1.37 (d, JZ6.0 Hz, 6H),
3.49 (s, 3H), 3.81 (s, 3H), 4.51 (m, JZ6.0 Hz, 1H), 5.11
(s, 2H), 6.59 (dd, JZ2.8, 8.8 Hz, 1H), 6.65 (d, JZ2.8 Hz,
1H), 6.79 (d, JZ8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
22.03, 55.83, 56.55, 71.32, 95.16, 105.79, 107.42, 112.73,
145.50, 147.91, 151.48. HREIMS m/z. Calcd for C12H18O4
(MC): 226.1205. Found: 226.1189.
4.5.3. 1-Bromo-4-isopropoxy-5-methoxy-2-methoxy-
methoxybenzene (24). A solution of NBS (2.05 g,
11.5 mmol) in DMF (15 mL) was added dropwise to a
solution of 23 (2.50 g, 11.0 mmol) in DMF (10 mL) at 0 8C.
After being stirred for 30 min, the reaction mixture was
quenched with water at the same temperature and allowed to
warm to room temperature. The products were extracted
1
1135, 1110, 990, 817 cmK1; H NMR (300 MHz, CDCl3):

N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
601
d 1.36 (d, JZ6.6 Hz, 6H), 1.39 (d, JZ6.3 Hz, 6H), 3.01
(t, JZ7.3 Hz, 2H), 3.58 (s, 3H), 3.83 (s, 6H), 3.91 (s, 3H),
4.45–4.62 (m, 2H), 4.95 (t, JZ7.3 Hz, 2H), 6.69–6.82 (m,
4H), 6.89 (d, JZ8.8 Hz, 1H), 7.18 (d, JZ7.7 Hz, 1H);
13C NMR (100 MHz, CDCl3): 21.98, 22.13, 37.51, 48.68,
51.65, 51.76, 55.96, 56.03, 71.35, 71.42, 112.07, 114.22,
115.23, 116.70, 117.34, 117.90 (q, JZ321 Hz), 121.44,
122.51, 122.67, 122.72, 122.81, 129.98, 135.76, 146.99,
147.19, 149.13, 149.67, 159.05, 160.76. EIMS m/z (%): 687
(100), 603 (20), 554 (13), 470 (25), 438 (27), 411 (19). Anal.
Calcd for C31H36F3NO11S: C, 54.14; H, 5.28; N, 2.04.
Found: C, 53.87; H, 5.25; N, 1.91.
acid monohydrate (40 mg, 0.210 mmol) was added. The
mixture was refluxed for 1 h and evaporated under reduced
pressure. The residue was purified by column chromato-
graphy over Silica Gel 60N (hexane/ethyl acetateZ1:2) to
give 29 as pale brown solid (220 mg, 90%). Recrystalliza-
tion from dichloromethane–hexane gave pale brown
powder. Mp 160–161 8C; IR (KBr): 3232, 2976, 2934,
1720, 1535, 1509, 1438, 1406, 1262, 1138, 1111, 1033,
1012, 943, 921, 853, 769 cmK1 1H NMR (300 MHz,
;
CDCl3): d 1.30–1.44 (m, 18H), 3.08 (t, JZ7.7 Hz, 2H), 3.39
(s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 4.45–4.65 (m, 3H), 5.17
(t, JZ7.7 Hz, 2H), 6.45 (s, 1H), 6.79 (s, 2H), 6.86 (s, 1H),
6.88–6.95 (m, 3H), 7.02 (d, JZ8.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): 21.78, 22.09, 22.22, 37.74, 48.77,
55.35, 56.04, 71.40, 71.42, 71.54, 103.29, 104.83, 109.32,
112.16, 114.15, 115.40, 116.76, 118.40, 121.48, 122.49,
125.71, 126.47, 126.91, 127.70, 130.20, 145.69, 146.64,
147.08, 147.10, 147.38, 149.08, 150.22, 154.94, 163.47.
EIMS m/z (%): 673 (100), 629 (43), 397 (41), 379 (30), 353
(20). Anal. Calcd for C38H43NO10: C, 67.74; H, 6.43; N,
2.08. Found: C, 67.79; H, 6.39; N, 2.05.
4.6.2. Methyl 3,4-dihydro-7-isopropoxy-1-(4-isopropoxy-
3-methoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)-
ethyl]-8-methoxy-4-oxo-[1]benzopyrano[3,4-b]pyrrole-2-
carboxylate (27). Under an argon atmosphere, a degassed
solution of Na2CO3 (2.10 g, 19.8 mmol) in water (6.0 mL)
was added to a solution of 25 (2.06 g, 3.00 mmol), 9 (1.62 g,
6.00 mmol) and Pd(PPh3)4 (288 mg, 249 mmol) in THF
(60 mL) at room temperature and the mixture was refluxed
for 18 h. The mixture was cooled to room temperature and
evaporated under reduced pressure. The residue was
dissolved in methanol (40 mL) and concd HCl (4.0 mL)
was added dropwise to the solution at room temperature.
After being refluxed for 1 h, the mixture was cooled to room
temperature and evaporated under reduced pressure. The
product was extracted with dichloromethane and the extract
was washed successively with water and brine, dried over
Na2SO4, and evaporated under reduced pressure. The residue
was purified by column chromatography over Chromatorex
NH-DM1020 silica gel (hexane/ethyl acetateZ5:1) to give
27 as colorless solid (2.03 g, 98%). Recrystallization from
dichloromethane–hexane gave colorless needles. Mp
149–150 8C; IR (KBr): 2975, 1728, 1702, 1536, 1509,
1438, 1262, 1215, 1158, 1112, 1039, 1012, 940, 859,
4.6.4. 7-Isopropoxy-1-(3-isopropoxy-4-methoxyphenyl)-
3-[2-(3-isopropoxy-4-methoxyphenyl)ethyl]-8-methoxy-
[1]benzopyrano[3,4-b]pyrrol-4(3H)-one (4). Under an
argon atmosphere, a mixture of 29 (337 mg, 0.500 mmol)
and copper(I) oxide (71.4 mg, 0.499 mmol) in quinoline
(15 mL) was heated at 220 8C for 7 min. The mixture was
cooled to room temperature and diluted with water. The
product was extracted with dichloromethane and the extract
was washed succesively with 6 M aqueous HCl and brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography over
Silica Gel 60N (hexane/ethyl acetateZ3:1) to give 4 as
colorless solid (297 mg, 94%). Recrystallization from
dichloromethane–diethyl ether gave colorless powder. Mp
133–134 8C; IR (KBr): 2973, 2931, 1716, 1509, 1466, 1425,
768 cmK1 1H NMR (300 MHz, CDCl3): d 1.32–1.46
;
(m, 18H), 3.08 (t, JZ7.6 Hz, 2H), 3.40 (s, 3H), 3.57
(s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 4.43–4.64 (m, 3H), 5.11
(t, JZ7.6 Hz, 2H), 6.56 (s, 1H), 6.80 (s, 1H), 6.80 (s, 1H),
6.83–6.89 (m, 3H), 6.90 (s, 1H), 6.99 (d, JZ8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): 21.80, 22.13, 22.17, 37.80,
48.63, 51.61, 55.36, 56.03, 71.25, 71.50, 103.32, 104.88,
109.56, 112.00, 114.07, 115.66, 116.57, 117.45, 121.42,
122.45, 124.22, 126.77, 127.21, 129.27, 130.35, 145.72,
146.57, 146.63, 147.16, 147.26, 148.97, 150.12, 155.00,
161.18. EIMS m/z (%): 687 (100), 411 (26), 379 (26). Anal.
Calcd for C39H45NO10: C, 68.11; H, 6.59; N, 2.04. Found: C,
68.18; H, 6.68; N, 1.99.
1388, 1261, 1234, 1211, 1166, 1139, 1108, 1030 cmK1
;
1H NMR (300 MHz, CDCl3): d 1.25 (d, JZ6.3 Hz, 6H),
1.40 (d, JZ6.0 Hz, 6H), 1.41 (d, JZ6.0 Hz, 6H), 3.09
(t, JZ6.9 Hz, 2H), 3.53 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H),
4.39 (m, JZ6.0 Hz, 1H), 4.50–4.64 (m, 2H), 4.64 (t, JZ
6.9 Hz, 2H), 6.61 (d, JZ1.9 Hz, 1H), 6.69 (dd, JZ1.9,
8.0 Hz, 1H), 6.73 (s, 1H), 6.80 (d, JZ8.0 Hz, 1H),
6.86–6.98 (m, 4H), 7.10 (s, 1H); 13C NMR (100 MHz,
CDCl3): 21.83, 22.04, 37.61, 50.98, 55.79, 55.94, 55.95,
71.27, 71.44, 71.67, 103.57, 105.16, 110.49, 112.05, 113.73,
114.75, 116.02, 116.49, 119.07, 121.21, 121.99, 127.09,
127.17, 130.37, 131.67, 145.92, 146.45, 146.55, 147.07,
147.15, 149.02, 150.23, 155.34. EIMS m/z (%): 629 (100),
587 (9), 545 (8), 366 (11), 353 (42). Anal. Calcd for
C37H43NO8: C, 70.57; H, 6.88; N, 2.22. Found: C, 70.68; H,
6.85; N, 2.23.
4.6.3. 3,4-Dihydro-7-isopropoxy-1-(4-isopropoxy-3-
methoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)-
ethyl]-8-methoxy-4-oxo-[1]benzopyrano[3,4-b]pyrrole-
2-carboxylic acid (29). Under an argon atmosphere, a
suspension of 27 (250 mg, 0.363 mmol) in a degassed
mixture of 40% aqueous KOH (15 mL) and ethanol (15 mL)
was refluxed for 3 h. The solution was cooled to room
temperature and concentarted under reduced pressure. The
pH of the solution was adjusted to 2–3 with concd HCl and
the product was extracted with dichloromethane. The
extract was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was dis-
solved in dichloromethane (30 mL) and p-toluenesulfonic
4.6.5. 8,9-Dihydro-3,11-diisopropoxy-14-(4-isopropoxy-
3-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano-
[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (31). Method 1.
Under an argon atmosphere, a solution of PIFA (81.5 mg,
0.190 mmol) and BF3$OEt2 (48 mL, 0.389 mmol) in
dichloromethane (3.8 mL) was added dropwise to a solution
of 4 (100 mg, 0.159 mmol) in dichloromethane (16 mL) at
K40 8C. After being stirred for 1.5 h, the mixture was
quenched with 2 M aqueous NH3 and allowed to warm to

602
N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
room temperature. The product was extracted with
dichloromethane and the extract was washed with brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography over
Silica Gel 60N (hexane/ethyl acetateZ1:1) to give 31 as
colorless solid (87.3 mg, 88%). Recrystallization from
dichloromethane–diethyl ether gave colorless powder. Mp
229.5–230.5 8C; IR (KBr): 2973, 2932, 1699, 1509, 1483,
allowed to warm to room temperature and stirred for an
additional 3 h. The mixture was quenched with saturated
aqueous NaHCO3 and extracted with ethyl acetate. The
extract was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by column chromatography over Silica Gel 60N
(hexane/ethyl acetateZ1:1) to give 1 as pale brown powder
(8.0 mg, quant.). Mp O300 8C (sealed capillary) (lit.4b mp
O300 8C); IR (KBr): 3378, 2925, 1671, 1595, 1546, 1491,
1417, 1271, 1240, 1213, 1162, 1111, 1038, 1015, 939 cmK1
;
1H NMR (300 MHz, CDCl3): d 1.35–1.43 (m, 18H), 3.10
(t, JZ6.7 Hz, 2H), 3.34 (s, 3H), 3.43 (s, 3H), 3.82 (s, 3H),
4.49–4.65 (m, 3H), 4.71–4.90 (m, 2H), 6.67 (s, 1H), 6.74
(s, 1H), 6.77 (s, 1H), 6.92 (s, 1H), 7.02–7.12 (m, 3H);
13C NMR (100 MHz, CDCl3): 21.83, 21.89, 21.94, 22.06,
28.63, 42.43, 55.09, 55.42, 56.12, 71.33, 71.40, 71.77,
103.46, 104.83, 109.12, 110.31, 113.58, 114.56, 114.64,
114.74, 116.90, 120.11, 123.31, 126.25, 128.08, 128.49,
135.81, 145.80, 146.39, 146.81, 146.86, 147.17, 148.51,
151.15, 155.45. EIMS m/z (%): 627 (100), 585 (17), 543 (31),
501 (26). Anal. Calcd for C37H41NO8: C, 70.79; H, 6.58; N,
2.23. Found: C, 70.59; H, 6.61; N, 2.15.
1459, 1433, 1404, 1369, 1276, 1220, 1155, 1041 cmK1
;
1H NMR (400 MHz, DMSO-d6): d 3.38 (s, 3H), 3.39 (s, 3H),
3.77 (s, 3H), 6.71 (s, 1H), 6.87 (s, 1H), 7.01 (dd, JZ2.0,
8.1 Hz, 1H), 7.10 (d, JZ8.1 Hz, 1H), 7.14 (s, 1H), 7.15
(d, JZ2.0 Hz, 1H), 7.19 (s, 1H), 7.21 (d, JZ7.3 Hz, 1H),
9.00 (d, JZ7.3 Hz, 1H), 9.35 (s, 1H), 9.84 (br s, 1H), 9.95
(br s, 1H); 13C NMR (100 MHz, DMSO-d6): d 54.36, 54.89,
55.82, 103.49, 105.13, 105.52, 106.15, 108.10, 110.58,
111.26, 112.14, 114.77, 116.17, 117.31, 121.77, 123.55,
124.41, 125.19, 128.71, 133.81, 144.28, 146.03, 146.52,
147.53, 148.00, 148.20, 148.39, 154.05. HREIMS m/z.
Calcd for C28H21NO8 (MC): 499.1267. Found: 499.1248.
Method 2. Under an argon atmosphere, a mixture of 29
(50.0 mg, 0.0742 mmol) and Pd(OAc)2 (18.3 mg,
0.0816 mmol) in acetonitrile (22 mL) was refluxed for
12 h. The mixture was cooled to room temperature and
evaporated under reduced pressure. The residue was
purified by flash chromatography over Silica Gel 60N
(hexane/ethyl acetateZ2:1) to give 31 (30.2 mg, 65%) and
4 (6.6 mg, 14%).
4.7. Synthesis of lamellarins L (2) and N (3)
4.7.1. Dimethyl 3-(3-isopropoxy-4-methoxyphenyl)-1-
[2-(3-isopropoxy-4-methoxyphenyl)ethyl]-4-(trifluoro-
methanesulfonyloxy)pyrrole-2,5-dicarboxylate (26). This
compound was prepared from 6 (2.69 g, 4.00 mmol) and 8
(840 mg, 4.00 mmol) in a similar manner as described for
25. After chromatographic purification over Silica Gel 60N
(toluene/ethyl acetateZ10:1), 26 was obtained as colorless
solid (2.11 g, 77%). Recrystallization from diethyl ether–
hexane gave colorless prisms. Mp 96.5–98 8C; IR (KBr):
2976, 2952, 1726, 1513, 1438, 1420, 1307, 1263, 1231,
1135, 991, 824 cmK1; 1H NMR (300 MHz, CDCl3): d 1.36
(d, JZ6.0 Hz, 6H), 1.37 (d, JZ6.0 Hz, 6H), 3.01 (t, JZ
7.3 Hz, 2H), 3.58 (s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 3.91
(s, 3H), 4.44–4.56 (m, 2H), 4.94 (t, JZ7.3 Hz, 2H),
6.69–6.75 (m, 2H), 6.77–6.82 (m, 3H), 6.87 (d, JZ8.8 Hz,
1H); 13C NMR (100 MHz, CDCl3): 22.02, 22.13, 37.51,
48.70, 51.74, 51.76, 55.82, 56.03, 71.36, 71.65, 111.02,
112.07, 116.72, 117.29, 117.92 (q, JZ321 Hz), 118.49,
121.43, 122.00, 122.76, 122.80, 123.27, 129.99, 135.77,
146.41, 147.19, 149.13, 150.33, 159.08, 160.75. EIMS m/z
(%): 687 (100), 645 (23), 603 (23), 554 (21), 470 (41), 438
(29), 411 (37). Anal. Calcd for C31H36F3NO11S: C, 54.14;
H, 5.28; N, 2.04. Found: C, 54.18; H, 5.32; N, 1.98.
4.6.6. 3,11-Diisopropoxy-14-(4-isopropoxy-3-methoxy-
phenyl)-2,12-dimethoxy-6H-[1]benzopyrano[40,30:4,5]-
pyrrolo[2,1-a]isoquinolin-6-one (33). A solution of DDQ
(54.2 mg, 0.239 mmol) in toluene (10 mL) was added
dropwise to a solution of 31 (100 mg, 0.159 mmol) in
toluene (10 mL) at room temperature. The mixture was
refluxed for 18 h and evaporated under reduced pressure.
The residue was purified by column chromatography over
Chromatorex NH-DM1020 silica gel (hexane/ethyl
acetateZ3:1) to give 33 as colorless solid (97.0 mg, 97%).
Recrystallization from dichloromethane–diethyl ether gave
pale brown needles. Mp 191–192 8C; IR (KBr): 2975, 2933,
1691, 1509, 1487, 1430, 1266, 1223, 1179, 1111, 1035, 944,
1
855 cmK1; H NMR (300 MHz, CDCl3): d 1.41 (d, JZ
6.3 Hz, 6H), 1.44 (d, JZ6.0 Hz, 12H), 3.44 (s, 3H), 3.45
(s, 3H), 3.84 (s, 3H), 4.53–4.76 (m, 3H), 6.76 (s, 1H), 6.98
(s, 1H), 7.03 (d, JZ7.4 Hz, 1H), 7.11 (s, 1H), 7.13 (s, 1H),
7.17–7.20 (m, 3H), 9.24 (d, JZ7.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): 21.82, 21.83, 21.88, 21.89, 21.91,
21.92, 55.10, 55.41, 56.13, 71.17, 71.44, 71.80, 103.42,
105.44, 105.59, 107.75, 109.88, 110.41, 110.93, 112.19,
114.98, 116.89, 118.92, 123.07, 123.80, 124.59, 128.69,
129.31, 134.27, 146.39, 146.47, 147.04, 147.73, 148.32,
150.04, 151.26, 155.40. EIMS m/z (%): 625 (100), 583 (15),
541 (20), 499 (33). Anal. Calcd for C37H39NO8: C, 71.02;
H, 6.28; N, 2.24. Found: C, 71.24; H, 6.32; N, 2.38.
4.7.2. Methyl 3,4-dihydro-7-isopropoxy-1-(3-isopropoxy-
4-methoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)-
ethyl]-8-methoxy-4-oxo-[1]benzopyrano[3,4-b]pyrrole-2-
carboxylate (28). This compound was prepared from 26
(2.06 g, 3.00 mmol) and 9 (1.62 g, 6.00 mmol) in a similar
manner as described for 27. After chromatographic purifi-
cation over Silica Gel 60N (dichloromethane–dichloro-
methane/ethyl acetateZ5:1), 28 was obtained as colorless
solid (1.95 g, 95%). Recrystallization from dichloromethane–
diethyl ether gave colorless powder. Mp 163–164 8C; IR
(KBr): 2976, 2934, 1711, 1515, 1486, 1439, 1226, 1158,
4.6.7. Lamellarin D (1). Under an argon atmosphere, a
heptane solution of BCl3 (1.0 M, 144 mL, 0.144 mmol) was
added dropwise to a solution of 33 (10.0 mg, 0.0160 mmol)
in dichloromethane (3.0 mL) at K78 8C. After being stirred
for 30 min at this temperature, the reaction mixture was
1109, 1019, 969, 937, 857 cmK1 1H NMR (300 MHz,
;
CDCl3): d 1.32–1.43 (m, 18H), 3.08 (t, JZ7.6 Hz, 2H), 3.40
(s, 3H), 3.59 (s, 3H), 3.83 (s, 3H), 3.91 (s, 3H), 4.47–4.59 (m,
3H), 5.10 (t, JZ7.6 Hz, 2H), 6.52 (s, 1H), 6.80 (s, 1H), 6.80

N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
603
(s, 1H), 6.84–6.92 (m, 4H), 6.98 (d, JZ8.2 Hz, 1H);
13C NMR (100 MHz, CDCl3): 21.79, 21.94, 22.06, 22.12,
37.82, 48.67, 51.70, 55.45, 56.05, 71.27, 71.38, 71.44,
103.26, 104.92, 109.57, 111.58, 111.99, 116.61, 117.44,
117.96, 121.44, 122.87, 124.21, 126.67, 126.86, 129.18,
130.38, 145.74, 146.58, 146.86, 147.17, 147.28, 148.98,
149.90, 155.01, 161.19. EIMS m/z (%): 687 (100), 453 (11),
411 (20), 379 (26). Anal. Calcd for C39H45NO10: C, 68.11; H,
6.59; N, 2.04. Found: C, 67.85; H, 6.68; N, 2.02.
in a similar manner as described for 31 from 4. After
chromatographic purification over Silica Gel 60N (hexane/
ethyl acetateZ1:1), 32 was obtained as colorless solid
(423 mg, 90%). Recrystallization from dichloromethane–
diethyl ether gave colorless powder. Mp 206.5–207.5 8C
(lit.4c mp 174 8C: the sample containing one molecule of
acetone); IR (KBr): 2974, 2933, 1691, 1542, 1509, 1484,
1439, 1417, 1268, 1241, 1211, 1176, 1113, 1042, 940,
1
850 cmK1; H NMR (300 MHz, CDCl3): d 1.30–1.41 (m,
18H), 3.10 (t, JZ6.6 Hz, 2H), 3.34 (s, 3H), 3.43 (s, 3H),
3.92 (s, 3H), 4.47–4.61 (m, 3H), 4.70–4.89 (m, 2H), 6.66 (s,
1H), 6.72 (s, 1H), 6.77 (s, 1H), 6.92 (s, 1H), 7.03–7.09 (m,
3H); 13C NMR (100 MHz, CDCl3): 21.82, 21.91, 21.99,
22.05, 28.63, 42.42, 55.07, 55.46, 56.29, 71.28, 71.36,
103.43, 104.86, 109.10, 110.34, 112.59, 113.55, 114.71,
117.86, 120.14, 123.59, 126.23, 127.89, 128.12, 135.83,
145.83, 146.39, 146.87, 147.16, 147.90, 148.55, 149.92,
155.46. EIMS m/z (%): 627 (100), 585 (13), 543 (32), 501
(14). Anal. Calcd for C37H41NO8: C, 70.79; H, 6.58; N,
2.23. Found: C, 71.03; H, 6.53; N, 2.16.
4.7.3. 3,4-Dihydro-7-isopropoxy-1-(3-isopropoxy-4-
methoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)-
ethyl]-8-methoxy-4-oxo-[1]benzopyrano[3,4-b]pyrrole-
2-carboxylic acid (30). This compound was prepared from
28 (250 mg, 0.363 mmol) in a similar manner as described
for 29. After chromatographic purification over Silica Gel
60N (ethyl acetate), 30 was obtained as colorless solid
(222 mg, 91%). Recrystallization from dichloromethane–
hexane gave colorless powder. Mp 204.5–206.5 8C; IR
(KBr): 3331, 2977, 2934, 1727, 1702, 1509, 1441, 1405,
1
1263, 1238, 1181, 1141, 1112, 1017, 773 cmK1; H NMR
Method 2. This compound was also prepared from 30
(50.0 mg, 0.0742 mmol) in a similar manner as described
for 31 from 29. After chromatographic purification over
Silica Gel 60N (hexane/ethyl acetateZ2:1), 32 (30.5 mg,
65%) and 5 (7.1 mg, 15%) were obtained.
(300 MHz, CDCl3): d 1.31–1.41 (m, 18H), 3.08 (t, JZ
7.7 Hz, 2H), 3.40 (s, 3H), 3.82 (s, 3H), 3.91 (s, 3H),
4.46–4.60 (m, 3H), 5.17 (t, JZ7.7 Hz, 2H), 6.45 (s, 1H),
6.79 (s, 2H), 6.87–6.97 (m, 4H), 7.01 (d, JZ8.2 Hz, 1H);
13C NMR (100 MHz, CDCl3): 21.75, 21.93, 21.98, 22.07,
37.75, 48.80, 55.40, 56.01, 56.03, 71.28, 71.36, 71.45,
103.15, 104.78, 109.28, 111.74, 112.06, 116.68, 117.79,
118.40, 121.44, 122.77, 125.77, 126.13, 126.92, 127.59,
130.18, 145.67, 146.60, 147.06, 147.36, 149.03, 150.11,
154.95, 163.68. EIMS m/z (%): 673 (100), 629 (19), 397
(33), 379 (28). Anal. Calcd for C38H43NO10: C, 67.74; H,
6.43; N, 2.08. Found: C, 68.06; H, 6.39; N, 2.15.
4.7.6. 3,11-Diisopropoxy-14-(3-isopropoxy-4-methoxy-
phenyl)-2,12-dimethoxy-6H-[1]benzopyrano[40,30:4,5]-
pyrrolo[2,1-a]isoquinolin-6-one (34). This compound was
prepared from 32 (100 mg, 0.159 mmol) in a similar manner
as described for 33. After chromatographic purification over
Chromatorex NH-DM1020 silica gel (hexane/ethyl
acetateZ3:1), 34 was obtained as pale yellow solid
(95.6 mg, 96%). Recrystallization from dichloromethane–
diethyl ether gave pale yellow needles. Mp 169–170 8C; IR
(KBr): 2976, 2933, 1702, 1509, 1487, 1420, 1267, 1223,
4.7.4. 7-Isopropoxy-1-(3-isopropoxy-4-methoxyphenyl)-
3-[2-(3-isopropoxy-4-methoxyphenyl)ethyl]-8-methoxy-
[1]benzopyrano[3,4-b]pyrrol-4(3H)-one (5). This com-
pound was prepared from 30 (900 mg, 1.34 mmol) in a
similar manner as described for 4. After chromatographic
purification over Silica Gel 60N (hexane/ethyl acetateZ3:1),
5 was obtained as colorless solid (830 mg, 99%). Recrystalli-
zation from dichloromethane–hexane gave colorless powder.
Mp 113.5–114 8C; IR (KBr): 2978, 2933, 2835, 1710, 1551,
1178, 1111, 1037, 971, 939, 857 cmK1
;
1H NMR
(300 MHz, CDCl3): d 1.35 (dd, JZ1.4, 6.0 Hz, 6H), 1.41
(d, JZ6.0 Hz, 6H), 1.44 (d, JZ6.0 Hz, 6H), 3.44 (s, 3H),
3.45 (s, 3H), 3.96 (s, 3H), 4.47–4.63 (m, 2H), 4.70 (m, JZ
6.0 Hz, 1H), 6.74 (s, 1H), 6.98 (s, 1H), 7.03 (d, JZ7.3 Hz,
1H), 7.10 (s, 1H), 7.13 (d, JZ1.7 Hz, 1H), 7.15–7.20 (m,
3H), 9.23 (d, JZ7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3):
21.80, 21.86, 21.95, 55.08, 55.43, 56.34, 71.09, 71.25,
71.36, 103.32, 105.40, 105.49, 107.66, 109.87, 110.30,
110.90, 112.17, 112.61, 118.07, 118.91, 123.02, 123.97,
124.57, 128.11, 129.31, 134.28, 146.36, 146.46, 147.69,
148.03, 148.28, 150.02, 150.06, 155.38. HREIMS m/z.
Calcd for C37H39NO8 (MC): 625.2676. Found: 625.2671.
1
1509, 1460, 1397, 1258, 1175, 1138, 1112, 1025 cmK1; H
NMR (300 MHz, CDCl3): d 1.27 (d, JZ6.0 Hz, 6H), 1.36 (d,
JZ6.0 Hz, 6H), 1.41 (d, JZ6.0 Hz, 6H), 3.09 (t, JZ6.9 Hz,
2H), 3.54 (s, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 4.41 (m, JZ
6.0 Hz, 1H), 4.47–4.63 (m, 2H), 4.64 (t, JZ6.9 Hz, 2H), 6.65
(d, JZ1.7 Hz, 1H), 6.68(dd, JZ1.7, 8.0 Hz, 1H), 6.74(s, 1H),
6.79 (d, JZ8.0 Hz, 1H), 6.91–6.95 (m, 4H), 7.09 (s, 1H); 13C
NMR (100 MHz, CDCl3): 21.82, 22.03, 22.12, 37.63, 50.94,
55.89, 55.96, 56.06, 71.26, 71.38, 71.42, 103.49, 105.23,
110.48, 111.71, 111.99, 114.73, 116.46, 117.24, 119.02,
121.23, 122.36, 126.55, 127.09, 130.33, 131.60, 145.92,
146.44, 146.99, 147.07, 147.14, 149.01, 149.72, 155.34.
EIMS m/z (%): 629 (100), 587 (9), 545 (13), 408 (11), 395
(12), 353 (38). Anal. Calcd for C37H43NO8: C, 70.57; H, 6.88;
N, 2.22. Found: C, 70.85; H, 6.95; N, 2.16.
4.7.7. Lamellarin L (2). This compound was prepared from
32 (20.0 mg, 0.0319 mmol) in a similar manner as describd
for 1. After chromatographic purification over Silica Gel
60N (ethyl acetate), 2 was obtained as colorless powder
(15.6 mg, 98%). Mp O300 8C (sealed capillary) (lit.4c Mp
301 8C); IR (KBr): 3423, 2934, 1686, 1586, 1484, 1421,
1275, 1248, 1211, 1164, 1044, 1016 cmK1 1H NMR
;
(400 MHz, DMSO-d6): d 3.01 (t, JZ6.7 Hz, 2H), 3.29
(s, 3H), 3.38 (s, 3H), 3.83 (s, 3H), 4.50–4.59 (m, 1H),
4.60–4.69 (m, 1H), 6.67 (s, 1H), 6.68 (s, 1H), 6.75 (s, 1H),
6.80 (s, 1H), 6.89 (s, 1H), 6.90 (dd, JZ2.0, 8.3 Hz, 1H),
7.16 (d, JZ8.3 Hz, 1H), 9.30 (s, 1H), 9.44 (s, 1H), 9.67
4.7.5. 8,9-Dihydro-3,11-diisopropoxy-14-(3-isopropoxy-
4-methoxyphenyl)-2,12-dimethoxy-6H-[1]benzopyrano-
[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one (32). Method 1.
This compound was prepared from 5 (470 mg, 0.746 mmol)

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N. Fujikawa et al. / Tetrahedron 62 (2006) 594–604
(s, 1H); 13C NMR (100 MHz, DMSO-d6): d 27.36, 41.82,
54.53, 54.90, 55.89, 103.37, 104.83, 108.46, 109.05, 112.10,
113.22, 113.69, 115.06, 117.61, 117.76, 121.41, 126.94,
127.12, 127.16, 135.51, 144.17, 145.36, 145.69, 146.53,
146.79, 147.21, 147.35, 153.97. HREIMS m/z. Calcd for
C28H23NO8 (MC): 501.1424. Found: 501.1420.
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4.7.8. Lamellarin N (3). This compound was prepared from
34 (20.0 mg, 0.0320 mmol) in a similar manner as described
for 1. After chromatographic purification over Silica Gel
60N (ethyl acetate), 3 was obtained as pale brown powder
(14.0 mg, 88%). Mp 280–300 8C (dec) (sealed capillary); IR
(KBr): 3430, 2928, 1671, 1558, 1490, 1425, 1276, 1217,
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4443–4446. (k) Ploypradith, P.; Mahidol, C.; Sahakitpichan,
P.; Wongbundit, S.; Ruchirawat, S. Angew. Chem., Int. Ed.
2004, 43, 866–868. (l) Handy, S. T.; Zhang, Y.; Bregman, H.
J. Org. Chem. 2004, 69, 2362–2366.
1
1082, 1042, 955, 863 cmK1; H NMR (400 MHz, DMSO-
d6): d 3.40 (s, 3H), 3.40 (s, 3H), 3.87 (s, 3H), 6.76 (s, 1H),
6.87 (s, 1H), 7.01 (dd, JZ2.0, 8.8 Hz, 1H), 7.01 (d, JZ
2.0 Hz, 1H), 7.17 (s, 1H), 7.19 (s, 1H), 7.20 (d, JZ7.3 Hz,
1H), 7.23 (d, JZ8.8 Hz, 1H), 8.99 (d, JZ7.3 Hz, 1H), 9.41
(s, 1H), 9.86 (s, 1H), 9.97 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): d 54.37, 54.89, 55.96, 103.52, 105.07, 105.46,
106.24, 107.99, 110.23, 111.29, 112.14, 113.40, 117.19,
117.99, 121.78, 121.86, 124.41, 127.12, 128.48, 133.59,
144.28, 146.02, 147.42, 147.52, 147.66, 148.00, 148.23,
154.03. HREIMS m/z. Calcd for C28H21NO8 (MC):
499.1267. Found: 499.1259.
Acknowledgements
5. Ishibashi, F.; Tanabe, S.; Oda, T.; Iwao, M. J. Nat. Prod. 2002,
65, 500–504.
´
6. (a) Facompre, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.;
We thank the Ministry of Education, Science, Sports and
Culture of Japan for financial support; Grant-in-Aid for
Scientific Research (C) (2) (No. 14580612)
Perez, C.; Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res.
2003, 63, 7392–7399. (b) Marco, E.; Laine, W.; Tardy, C.;
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¨
7. Merz, A.; Schropp, R.; Dotterl, E. Synthesis 1995, 795–800.
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