A concise benzotriazolyl-mediated synthesis of 9-methoxycepharanone A

Article abstract of DOI:10.1016/j.tet.2004.10.079

A concise synthesis of 9-methoxycepharanone A is described. The key step is the benzotriazolyl-assisted assemblage of an arylmethyleneisoindolinone ring system comprising the enol ether unit. Radical cyclization followed by deprotections and ultimate formation of the methylenedioxy group complete the total synthesis of the title compound. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.079

Tetrahedron 61 (2005) 665–671
A concise benzotriazolyl-mediated synthesis of
9-methoxycepharanone A
*
Veronique Rys, Axel Couture, Eric Deniau, Stephane Lebrun and Pierre Grandclaudon
´
´
´ ˆ
Laboratoire de Chimie Organique Physique, UMR 8009 ‘Chimie Organique et Macromoleculaire’, Batiment C3(2),
´ ´
Universite des Sciences et Technologie de Lille, F-59655 Villeneuve d’Ascq Cedex, France
Received 22 July 2004; accepted 28 October 2004
Available online 21 November 2004
Abstract—A concise synthesis of 9-methoxycepharanone A is described. The key step is the benzotriazolyl-assisted assemblage of an
arylmethyleneisoindolinone ring system comprising the enol ether unit. Radical cyclization followed by deprotections and ultimate
formation of the methylenedioxy group complete the total synthesis of the title compound.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
phenanthrene nucleus. In particular, a certain number of
methoxylated models 1 (R1ZOCH3) which can be regarded
in one sense as having an enol ether moiety embedded in a
phenanthrene unit still remain inaccessible by these
conceptually different synthetic tactics. This is notably the
case of 9-methoxycepharanone A (1a) (Fig. 1) which has
been extracted from the roots of Aristolochia auricularia
and which has been found to contain the highest reported
amount of total aristolochic acids of any species.11 We wish
therefore to delineate in this paper a tactically new synthetic
approach to these methoxylated aristolactams illustrated by
the first total synthesis of 9-methoxycepharanone A (1a)
isolated from Annonaceae species.
Aristolactams 1 are a minor group of alkaloids biogeneti-
cally derived from isoquinolines and structurally related to
aporphines.1 The richest source of this family of alkaloids
which are characterized by a tetracyclic skeleton with a
phenanthrene core is undoubtedly plants of the family
Aristolochiaceae.2 The leaves and roots of Aristolochia
species have been used since antiquity in obstetrics and still
find some applications in folk medicine in Taiwan and
Southern China.3 They are also considered to be the
principal detoxification metabolites of aristolochic acids
which have been implicated in an endemic renalyse known
as CHN (Chinese Herbs Nephropathy).4 Several alternative
routes have been developed for the elaboration of these
highly fused phenanthrene lactams. The main general
synthetic approaches involve (i) the contraction of the
lactone ring of dibenzochromanone derivatives5 (route a),
(ii) the photoinduced electrocyclic ring closure of iodo-
stilbenic precursors6 (route b), (iii) the inter7 and intra8
benzyne cycloaddition of (di)enamides (routes c and d) and
(iv) the tributyltin-mediated radical cyclization of bromo-
arylmethyleneisoindolinones9 (route e) (retrosynthetic
Scheme 1).10
2. Results and discussion
We initially envisaged taking advantage of the transient
formation of adducts equipped with a metalated hydroxy-
benzyl appendage from the two complementary procedures
developed in our group for the building up of the
arylmethylene isoindolinones 39 (retrosynthetic Scheme 1).
These conceptually different procedures hinge upon a
Horner olefination process involving a phosphorylated
isoindolinone 4 (path a)9a and/or a hydroxylalkylation/
E1cb anti elimination sequence applied to an isoindolinone
precursor 5 (path b).9b For this purpose the unsubstituted
models 4a12 or 5a13 were initially synthesized by earlier
techniques developed in our laboratory (Scheme 2). They
were subsequently exposed to potassium bis(trimethylsilyl)-
amide (KHMDS, 1 equiv, THF, K78 8C) and the corre-
sponding metallated isoindolinones were then allowed to
However, most of these methods are inadequate for the
synthesis of models with diverse and dense functionalities
on their compact framework particularly with alkoxy and/or
hydroxy phenolic functions in specific positions on the basic
Keywords: Alkaloids; Aristolactams; Benzotriazole; Isoindolinones.
* Corresponding author. Tel.: C33 3 20 43 44 32; fax: C33 3 20 33 63 09;
e-mail: axel.couture@univ-lille1.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.079

666
V. Rys et al. / Tetrahedron 61 (2005) 665–671
Scheme 1.
methylating agents (MeI, MeOTf). In both cases the
elimination product 3 was invariably obtained and no
trace of the expected products 8 or 9 respectively, good
candidates for the elaboration of the stilbenic enol ether 10,
could be detected (Fig. 1).
One can reasonably assume that for the reaction carried out
with the phosphorylated parent compound 4, Horner
olefination occurs prior to in situ O-alkylation. The
exclusive formation of 3 upon O-methylation of adduct 7
still remains open to discussion. One can tentatively assume
that trans metallation between oxanion 7 and adduct 11
occurs followed by E1cb elimination leading to enelactam 3
and that additionally the methoxylate released from 12 is of
sufficient kinetic basicity to deprotonate the adduct 11 as it
is formed (Scheme 2), a precedented phenomenon.14
Figure 1.
We then conjectured that this problem could be circum-
vented by the assembly of an adduct structurally related to 6
or 7 but equipped this time with a temporary blocking group
Y easily connectable to the indolinone framework, liable to
allow the metallation-hydroxyalkylation-O-alkylation
sequence and to facilitate the ultimate creation of the
mandatory enol ether unit. The choice of benzotriazole was
react with ortho-bromobenzaldehyde to provide the
transient adducts 6 and 7 (Scheme 2). At this stage all
attempts to methylate in situ the oxanions 6 or 7 met with no
success even by varying the reaction conditions, namely by
employing different bases (LHMDS, NaHMDS) or varied
Scheme 2.

V. Rys et al. / Tetrahedron 61 (2005) 665–671
667
Scheme 3.
dictated by reliance on the ability of this remarkable
synthetic auxiliary15 to be involved in the generation of
a-aminocarbanionic entities16 and to generate N-acylena-
mines under basic and acidic conditions.17 Consequently,
we embarked on the synthesis of the methylenedioxy-
isoindolinone 13 with a pendant benzotriazolyl unit. We
assumed that the construction of this compound would be
achievable by using benzotriazole to trap the N-acyliminium
species which would be derived from the appropriate
hydroxylactam 14. For the synthesis of this N,O-hemiacetal
we initially synthesized the bromobenzamide derivative 15
from piperonal according to the synthetic route portrayed in
Scheme 3. Compound 15 was then sequentially exposed to
phenyllithium and n-butyllithium to induce the required
metallation/interconversion sequence followed by quench-
ing with DMF as the formylating agent. Unexpectedly this
operation led solely to the formation of the hydroxylactam
19. It is likely that due to the cooperative effect of the
carboxamide function and of the methylenedioxy group
which both rank highly in the hierarchy of ortho-directing
metalating groups18 metalation at their common ‘in
between’ site is promoted thus sparing the bromine atom.
Scheme 4.

668
V. Rys et al. / Tetrahedron 61 (2005) 665–671
Experimenting different bases under varied conditions did
not prevent the formation of this undesirable compound. We
then anticipated that bromine–lithium exchange should be
favored over metalation by replacement of the weakly
sterically demanding methylenedioxy group by bulky
dialkoxylated substitution patterns. For this purpose the
sterically hindered dibenzyl derivative 22 was synthesized
according to the four step sequence depicted in Scheme 3
starting from the benzyl protected isovaniline derivative 18.
Gratifyingly quenching with DMF of the dilithiated species
generated by sequential treatment of 22 with PhLi and
n-BuLi led to the desired hydroxylactam 23. The steric
congestion of the parent model 22 renders the ortho proton
inaccessible and in the competitive process involving
interconversion versus deprotonation the bromine/lithium
exchange is favored.
performed by syringe techniques. For flash chromato-
graphy, Merck silica gel 60 (40–63 m; 230–400 mesh
ASTM) was used. The melting points were obtained on a
Reichert-Thermopan apparatus and are not corrected. NMR
spectra: Bruker AM 300 (300 and 75 MHz, for 1H, and 13C),
CDCl3 as solvent, TMS as internal standard. Microanalyses
were performed by the CNRS microanalysis center.
3.1.1. 3-[1-(2-Bromophenyl)methyl-(E)-ene]-2-(4-meth-
oxybenzyl)-2,3-dihydro-1H-isoindol-1-one (3). Com-
pound 3 was obtained from 4a12 or 5a13 by following
already described procedures.9a,14 Pale yellow crystals;
1
yield 75–82%; mp 178–179 8C; H NMR (d) 3.77 (s, 3H,
OCH3), 5.08 (s, 2H, NCH2), 6.37 (s, 1H, CH]), 6.85 (d, JZ
8.6 Hz, 2H, aromatic H), 7.12 (d, JZ7.8 Hz, 1H, CH]),
7.16–7.35 (m, 5H, aromatic H), 7.44 (t, JZ7.6 Hz, 2H,
aromatic H), 7.64 (d, JZ7.1 Hz, 1H, aromatic H), 7.89 (d,
JZ7.3 Hz, 1H, aromatic H); 13C NMR (d) 42.8, 55.3, 110.9,
114.1, 123.0, 123.5, 124.8, 127.3, 128.6, 128.9, 129.5, 129.6,
130.4, 131.6, 131.8, 132.9, 134.9, 135.6, 136.4, 158.9, 166.7.
Anal. calcd for C23H18BrNO2 (420.3): C, 65.73; H, 4.32; N,
3.33%. Found: C, 65.65; H, 4.15; N, 3.08%.
Treatment of the N,O-hemiacetal 23 with para-toluene-
sulfonic acid (PTSA) and quenching of the transient
iminium salt with benzotriazole allowed the installation of
the benzotriazole unit on the isoindolinone framework. The
resulting compound 24 was smoothly deprotonated with
n-BuLi in THF at K78 8C followed by quenching with
2-bromobenzaldehyde. The transient oxanion 25 was
intercepted in situ with methyl trifluoromethanesulfonate
and the whole operation delivered the rather congested
adduct 26 which was treated without isolation with PTSA.
Gratyfyingly this operation induced elimination of the
temporary synthetic auxiliary according to the mechanistic
pathway depicted in Scheme 4 to provide the protected
isoindolinone 28 with the required pendant enol ether unit in
a fairly good yield (69%). The use of the bulky para-
methoxybenzylgroup (PMB) on the lactam nitrogen was
rewarded here: compound 28 was obtained as a mixture of Z
and E isomers but with the required Z isomer predominating
by a very large margin (Z/E 95:5). The oxidative radical
cyclization of the bromostilbenic intermediate (Z)-28
proceeded uneventfully to furnish the primarily annulated
compound 29 with a satisfactory yield (80%). Treatment of
this fused phenanthrene lactam with trifluoroacetic acid
(TFA) in the presence of the cation scavenger anisole
resulted in the concomitant removal of the benzyl protection
of the phenolic hydroxy groups and of the lactam nitrogen to
provide the methoxylated biphenolic compound 30. The
regeneration of the required methylenedioxy group was
readily secured by treatment of 30 with bromochloro-
methane in the presence of cesium carbonate and this simple
operation delivered the target natural product 9-methoxy-
cepharanone A (1a) in a very satisfactory overall yield (12%
over the last six steps). The spectral data of 1a were
identical to those reported for the natural product.3a
3.2. 2-Bromobenzoic acid derivatives
The benzaldehyde derivatives 17,19 1820 and 2021 were
synthesized according to literature methods.
The 2-bromobenzoic acid derivatives 1622 and 21 were
obtained by oxidation with Jones reagent23 of the corre-
sponding benzaldehyde derivatives 17 and 20.
3.2.1. 2-Bromo-4,5-dibenzyloxybenzoic acid (21). Yield
81%; mp 157–158 8C; 1H NMR (d) 5.17 (s, 2H, CH2), 5.19
(s, 2H, CH2), 7.21 (s, 1H, aromatic H), 7.32–7.45 (m, 10H,
aromatic H), 7.69 (s, 1H, aromatic H); 13C NMR (d) 71.1,
71.3, 115.8, 118.2, 119.7, 121.6, 127.3, 127.4, 128.1, 128.3,
128.6, 128.7, 135.7, 136.3, 147.4, 152.8. Anal. calcd for
C21H17BrO4 (413.3): C, 61.03; H, 4.15%. Found: C, 61.35;
H, 3.94%.
3.3. 2-Bromobenzamides 15 and 22
The carboxylic acids 16 and 21 were initially converted into
their corresponding acid chlorides (SOCl2, DMF cat.,
CH2Cl2) and then allowed to react under standard
conditions with para-methoxybenzylamine to furnish the
2-bromobenzamides 15 and 22.
3.3.1. 6-Bromo-1,3-benzodioxole-5-[N-(4-methoxy-
benzyl)carboxamide] (15). Yield 71%; mp 137–138 8C
(from hexane–toluene); H NMR (d) 3.78 (s, 3H, OCH3),
1
4.51 (d, JZ5.6 Hz, 2H, NCH2), 5.98 (s, 2H, OCH2O), 6.34
(t, JZ5.6 Hz, 1H, NH), 6.85 (d, JZ8.8 Hz, 2H, aromatic
H), 6.94 (s, 1H, aromatic H), 7.00 (s, 1H, aromatic H), 7.27
(d, JZ8.8 Hz, 2H, aromatic H); 13C NMR (d) 47.3, 55.3,
109.6, 110.7, 113.1, 114.0, 114.1, 129.4, 129.7, 130.9,
147.4, 146.9, 166.8. Anal. calcd for C16H14BrNO4 (364.2):
C, 52.77; H, 3.87; N, 3.85%. Found: C, 52.60; H, 3.94; N,
4.05%.
3. Experimental
3.1. General
Tetrahydrofuran (THF) was pre-dried with anhydrous
Na2SO4 and distilled over sodium benzophenone ketyl
under Ar before use. DMF, CH2Cl2, NEt3, and toluene were
distilled from CaH2. Dry glassware was obtained by oven-
drying and assembly under dry Ar. The glassware was
equipped with rubber septa and reagent transfer was
3.3.2. 4,5-Dibenzyloxy-2-bromo-N-(4-methoxybenzyl)-
carboxamide (22). Yield 77%; mp 145–146 8C (from

V. Rys et al. / Tetrahedron 61 (2005) 665–671
669
hexane–toluene); 1H NMR (d) 3.79 (s, 3H, OCH3), 4.53 (d,
JZ5.4 Hz, 2H, NCH2), 5.11 (s, 4H, 2!OCH2), 6.45 (t, JZ
5.4 Hz, 1H, NH), 6.87 (d, JZ8.6 Hz, 2H, aromatic H), 7.05
(s, 1H, aromatic H), 7.26–7.42 (m, 13H, aromatic H); 13C
NMR (d) 43.8, 55.3, 71.3, 110.4, 114.1, 116.1, 118.9, 127.3,
127.4, 128.1, 128.2, 128.6, 128.7, 129.3, 129.6, 129.8,
136.1, 136.4, 148.2, 150.6, 159.1, 166.6. Anal. calcd for
C29H26BrNO4 (532.4): C, 65.42; H, 4.92; N, 2.63%. Found:
C, 65.65; H, 4.94; N, 2.34%.
Na2CO3 (5%) then water and dried (Na2SO4). The solvent
was evaporated and the product was triturated with Et2O to
afford a white solid which was recrystallized from hexane–
toluene. Yield 601 mg (86%); mp 163–164 8C; 1H NMR (d)
3.71 (s, 3H, OCH3), 3.79 (d, JZ14.7 Hz, 1H, NCH2), 4.90
(d, JZ14.7 Hz, 1H, NCH2), 5.00 (s, 2H, OCH2), 5.28 (s, 2H,
OCH2), 6.41 (d, JZ8.3 Hz, aromatic H), 6.69 (d, JZ8.1 Hz,
2H, aromatic H), 6.75 (s, 1H, CH), 7.09–7.13 (m, 3H,
aromatic H), 7.17–7.49 (m, 12H, aromatic H), 7.57 (s, 1H,
aromatic H), 8.02 (d, JZ8.3 Hz, 1H, aromatic H); 13C NMR
(d) 43.4, 55.2, 71.0, 71.2, 71.7, 108.3, 108.4, 110.3, 114.0,
120.1, 124.5 (two peaks overlapping), 127.0, 127.3, 127.9,
128.0, 128.1, 128.2, 128.5, 128.7, 129.9, 130.6, 132.7,
135.6, 136.2, 147.0, 151.2, 153.1, 159.1, 167.0. Anal. calcd
for C36H30N4O4 (582.7): C, 74.21; H, 5.19; N, 9.62%.
Found: C, 73.98; H, 5.35; N, 9.57%.
3.4. General procedure for the synthesis of the
isoindolinones 19 and 23
A solution of PhLi (1.22 mL, 1.8 M in cyclohexane/diethyl
ether, 2.2 mmol) was added dropwise at K78 8C under Ar to
a stirred solution of the benzamide derivatives 15 or 22
(2.0 mmol) in THF (70 mL). After stirring for 20 min at
K78 8C n-BuLi (1.38 mL, 1.6 M in hexanes, 2.2 mmol) was
added dropwise followed by DMF (365 mg, 5.0 mmol). The
reaction mixture was stirred at K78 8C for 1 h then allowed
to warm to room temperature over a period of 2 h and finally
quenched by addition of saturated aqueous NH4Cl (20 mL).
The mixture was extracted with Et2O (3!50 mL) and the
combined organic layers were dried (MgSO4). Evaporation
of solvent in vacuo left a solid residue which was purified by
flash column chromatography with ethyl acetate/hexanes
(50:50) as eluent. Isoindolinones 19 and 23 were finally
purified by recrystallization from hexane–toluene.
3.4.4. 5,6-Dibenzyloxy-3-[1-(2-bromophenyl)-1-methoxy-
methyl-(Z)-ene]-2-(4-methoxybenzyl)-2,3-dihydro-1H-
isoindol-1-one (28). A solution of n-BuLi (0.7 mL, 1.6 M in
hexanes, 1.1 mmol) was added dropwise with stirring under
Ar at K78 8C to a solution of 24 (583 mg, 1.0 mmol) in THF
(20 mL). The red solution was stirred at K78 8C for 15 min
then a solution of ortho-bromobenzaldehyde (202 mg,
1.1 mmol) in THF (2 mL) was added dropwise. After
10 min the reaction mixture was allowed to warm to
K40 8C over 5 min then recooled to K78 8C. A solution of
methyltrifluoromethanesulfonate(181 mg, 1.1 mmol) inTHF
(1 mL) was added at once and the reaction mixture was
allowed to warm at room temperature. Water (20 mL) was
added and the resulting mixture was extracted with Et2O (3!
15 mL). The combined organic layers were dried (Na2SO4)
and the solvents were evaporated in vacuo to left a solid
residue which was dissolved in toluene (20 mL). After
addition of a catalytic amount of PTSA, the solution was
stirred at room temperature for 1 h. The toluene was
evaporated in vacuo and the residue dissolved in CH2Cl2
(30 mL). The solution was washed with aq. sat. NaHCO3,
brine and finally water and dried (MgSO4). After removal of
CH2Cl2 the crude product was purified by flash column
chromatography with ethyl acetate/hexanes (30:70) as eluent.
Yield 457 mg (69%); mp 170–171 8C; 1H NMR (d) 3.10 (s,
3H, OCH3), 3.77 (s, 3H, OCH3), 4.66 (s, 2H, OCH2), 5.18 (s,
2H, NCH2), 5.36 (s, 2H, OCH2), 5.46 (s, 1H, aromatic H), 6.84
(d, JZ8.5 Hz, 2H, aromatic H), 7.17–7.21 (m, 4H, aromatic
H),), 7.29–7.44 (m, 12H, aromatic H), 7.63 (d, JZ7.6 Hz, 1H,
aromatic H); 13C NMR (d) 45.4, 55.3, 55.9, 70.2, 70.9, 106.1,
107.5, 113.6, 119.6, 122.0, 125.9, 126.8, 127.2, 127.8, 127.9,
128.2, 128.4, 128.5, 130.0, 131.3, 131.4, 133.3, 133.5, 133.9,
136.4, 136.7, 138.6, 149.1, 151.7, 158.3, 167.0. Anal. calcd for
C28H32BrNO5 (662.6): C, 68.89; H, 4.87; N, 2.11%. Found: C,
69.03; H, 4.79; 2.40%.
3.4.1. 5-Bromo-8-hydroxy-7-(4-methoxybenzyl)-7,8-
dihydro-[1,3]dioxolo[4,5-e]isoindol-1-one (19). Yield
1
416 mg (53%); mp 187–188 8C; H NMR (d) 3.71 (s, 3H,
OCH3), 4.22 (d, JZ15.0 Hz, 1H, NCH2), 4.77 (d, JZ
15.0 Hz, 1H, NCH2), 5.62 (d, JZ9.0 Hz, 1H, CHOH), 6.17
(s, 1H, OCH2O), 6.24 (s, 1H, OCH2O), 6.82 (d, JZ9.0 Hz,
1H, OH), 6.88 (d, JZ8.5 Hz, 2H, aromatic H), 7.23 (d, JZ
8.5 Hz, 2H, aromatic H), 7.28 (s, 1H, aromatic H); 13C NMR
(d) 41.7, 55.1, 76.4, 103.5, 108.9, 113.6, 113.9, 122.7, 125.7,
129.2, 129.3, 142.5, 151.9, 158.5, 163.5. Anal. calcd for
C17H14BrNO5 (392.2): C, 52.06; H, 3.60; N, 3.57%. Found:
C, 52.31; H, 3.38; N, 3.49%.
3.4.2. 5,6-Dibenzyloxy-3-hydroxy-2-(4-methoxybenzyl)-
2,3-dihydro-1H-isoindol-1-one (23). Yield 587 mg
1
(61%); mp 148–149 8C; H NMR (d) 3.74 (s, 3H, OCH3),
4.16 (d, JZ14.4 Hz, 1H, NCH2), 4.90 (d, JZ14.4 Hz, 1H,
NCH2), 5.03 (s, 2H, OCH2), 5.08 (s, 2H, OCH2), 5.40 (d,
JZ11.4 Hz, 1H, OH), 6.80 (d, JZ8.6 Hz, 2H, aromatic H),
7.01 (d, JZ11.4 Hz, 1H, CH), 7.03 (s, 1H, aromatic H), 7.21
(d, JZ8.6 Hz, 2H, aromatic H), 7.25–7.39 (m, 11H,
aromatic H); 13C NMR 42.1, 55.2, 70.8, 71.0, 80.5, 107.2,
108.5, 114.1, 124.1, 127.2, 127.6, 128.0, 128.1, 128.5,
128.6, 129.2, 129.9, 136.2, 136.3, 138.0, 150.2, 152.4,
159.0, 167.5. Anal. calcd for C30H27NO5 (481.55): C, 74.83;
H, 5.65; N, 2.91%. Found: C, 75.68; H, 5.80; N, 2.72%.
3.4.5. 1,2-Dibenzyloxy-6-methoxy-5-(4-methoxybenzyl)-
4,5-dihydrodibenzo[cd,f]indol-4-one (29). To a solution of
28 (430 mg, 0.65 mmol) in dry degassed benzene (300 mL)
refluxing under Ar, was added a solution of n-Bu3SnH
(295 mg, 1.0 mmol) and AIBN (65.5 mg, 0.4 mmol) in dry
degassed benzene (50 mL) by syringe over a period of
10 min. Once addition had finished, refluxing was kept up
for a further 3 h. The benzene was evaporated under reduced
pressure, and the residue was dissolved in CH3CN (50 mL).
The solution was washed with hexane (3!30 mL) and
3.4.3. 3-(Benzotriazol-1-yl)-5,6-dibenzyloxy-2-(4-meth-
oxybenzyl)-2,3-dihydro-1H-isoindol-1-one (24). A solu-
tion of isoindolinone 23 (578 mg, 1.2 mmol), benzotriazole
(155 mg, 1.3 mmol) and PTSA (5 mg, cat) in 30 mL of
toluene was refluxed for 3 h. After evaporation of the
toluene under vacuum the crude reaction mixture was
dissolved in CH2Cl2 (30 mL), washed twice with aq

670
V. Rys et al. / Tetrahedron 61 (2005) 665–671
Pharmacology; Academic: New York, 1972; Vol. 25; p 574.
(b) Shamma, M.; Moniot, J. L. Isoquinoline Alkaloids
Research, 1972–77; Plenum: New York, 1978. (c)
´
Guinaudeau, H.; Leboeuf, M.; Cave, A. J. Nat. Prod. 1988,
´
51, 389–474. (d) Cave, A.; Leboeuf, M.; Cassels, B. K. In
concentrated in vacuo to a yellow oil which was purified by
flash column chromatography with ethyl acetate/hexanes
(40:60) as eluent. Recrystallization from EtOH afforded 29
as yellow crystals. Yield 303 mg (80%); mp 117–118 8C; 1H
NMR (d) 3.74 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 5.25 (s,
2H, NCH2), 5.30 (s, 2H, OCH2), 5.36 (s, 2H, OCH2), 6.83
(d, JZ8.1 Hz, 2H, aromatic H), 7.37–7.61 (m, 14H,
aromatic H), 7.92 (s, 1H, aromatic H), 8.12 (d, JZ8.1 Hz,
1H, aromatic H), 9.33 (d, JZ8.1 Hz, 1H, aromatic H); 13C
NMR (d) 44.7, 55.2, 62.8, 72.2, 75.1, 111.5, 113.9, 119.4,
120.8, 124.3, 124.9, 126.1, 127.4, 127.9, 128.0, 128.3,
128.4, 128.5, 128.6, 128.7, 128.8, 130.4, 131.0, 136.3,
136.4, 136.8, 150.4, 152.9, 158.8, 167.8. Anal. calcd for
C38H31NO5 (581.7): C, 78.47; H, 5.37; N, 2.41%. Found: C,
78.41; H, 5.13; N, 2.22%.
Brossi, A., Ed.; The Alkaloids; Academic: New York, 1989;
Vol. 25, pp 1–74. (e) Kametani, T. In The Total Synthesis of
Natural Products; Apsimon, J., Ed.; Wiley Interscience: New
York, 1977; Vol. 25, pp 1–272. (f) Castedo, L.; Tojo, G. In
Brossi, A., Ed.; The Alkaloids; Academic: New York, 1990;
Vol. 25, pp 99–138.
2. (a) Chen, Z.-L.; Zhu, D.-Y. In Brossi, A., Ed. The Alkaloids;
Academic: New York, 1987; Vol. 31, pp 29–65. (b) Han, D. S.;
Chung, B. S.; Chi, H. J.; Lee, H. S. Korean J. Pharmacogn.
(Saengyak Hakhoechi) 1989, 20, 1–5. (c) Lee, H. S.; Han,
D. S.; Won, D. K. Korean J. Pharmacogn. (Saengyak
Hakhoechi) 1990, 21, 52–55. (d) Daves, P. H.; Flora of
Turkey and East Aegean Islands; Edinburgh University Press:
Edinburgh, 1965; Vol. 7; p 551.
3.4.6. 1,2-Dihydroxy-6-methoxy-4,5-dihydrodibenzo[cd,
f]indol-4-one (30). A solution of 29 (290 mg, 0.5 mmol)
and anisole (550 mg, 5 mmol) in trifluoroacetic acid
(20 mL) was refluxed under Ar for 60 h. The solvent and
excess anisole were removed under vacuum. The residue
was dissolved in CH2Cl2 (20 mL) and NEt3 (1 mL) was
added with stirring. Water (2 mL) was then added, and the
organic layer was washed with brine, dried (Na2SO4), and
concentrated under vacuum to yield a solid residue which
was recrystallized from EtOH. Yellow crystals, yield
3. (a) Houghton, P. J.; Ogutveren, M. Phytochemistry 1991, 30,
253–254. (b) Kan, W. S. Pharmaceutical Botany; National
Research Institute of Chinese Medicine; Academic: Taiwan,
1979; p 247.
4. Schmeiser, H. H.; Bieler, C. A.; Wiessler, M.; Van Ypersele de
Strihou, C.; Cosyns, J. P. Cancer Res. 1996, 56, 2025–2028.
5. Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.; Castedo, L.
Tetrahedron Lett. 1992, 33, 5145–5146.
1
110 mg (78%); mp 326–327 8C; H NMR (DMSO-d6; d)
6. Castedo, L.; Guitian, E.; Saa, J. M.; Suau, R. Heterocycles
1982, 19, 279–280.
4.06 (s, 3H, OCH3), 7.53–7.59 (m, 3H, aromatic H), 8.15 (d,
JZ5.6 Hz, 1H aromatic H), 9.29 (s, 1H, aromatic H), 10.37
(s, 2H, 2!OH), 10.83 (s, 1H, NH); 13C NMR (DMSO-d6;
d) 60.7, 111.1, 112.2, 115.0, 120.8, 122.1, 125.0, 125.4,
126.4, 127.6, 128.1, 129.6, 133.8, 144.9, 148.3, 168.5. Anal.
calcd for C16H11NO4 (281.3): C, 68.33; H, 3.94; N, 4.98%.
Found: C, 68.49; H, 3.83; N, 5.27%.
7. (a) Castedo, L.; Guitian, E.; Saa, J. M.; Suau, R. Tetrahedron
Lett. 1982, 23, 457–458. (b) Atanes, N.; Castedo, L.; Guitian,
E.; Saa, C.; Saa, J. M.; Suau, R. J. Org. Chem. 1991, 56,
2984–2988.
8. (a) Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron
1995, 51, 10801–10810. (b) Estevez, J. C.; Estevez, R. J.;
Guitian, E.; Villaverde, M. C.; Castedo, L. Tetrahedron Lett.
1989, 30, 5785–5786.
3.5. 9-Methoxycepharanone A (1a)
9. (a) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C.
J. Org. Chem. 1998, 63, 3128–3132. (b) Rys, V.; Couture, A.;
Deniau, E.; Grandclaudon, P. Eur. J. Org. Chem. 2003,
1231–1237.
A suspension of 30 (80 mg, 0.28 mmol) and Cs2CO3
(204 mg, 0.63 mmol) in DMF (5 mL) was stirred at room
temperature for 30 min. Bromochloromethane (81 mg,
0.63 mmol) was added and the mixture was stirred at
50 8C for an additional 12 h. CH2Cl2 (50 mL) was then
added and the resulting solution was successively washed
with water, brine and dried (Na2SO4). After removal of the
solvent under vacuum, the crude solid residue was
recrystallized from EtOH. Yellow crystals; yield 45 mg
(55%). The analytical data of synthetic 1a matched those
reported for the natural product.3a
10. See also: (a) Gorecki, P.; Otta, H. Pharmazie 1975, 30,
337–338. (b) Kunimoto, J.; Murakami, Y.; Akasu, M.
J. Pharm. Soc. Jpn 1980, 100, 337–341. (c) Kunimoto, J.;
Murakami, Y.; Oshikata, M.; Shingu, T.; Akazu, M.; Lu, S. T.;
Chen, I. S. Phytochemistry 1980, 19, 2735–2739. (d) Crohare,
R.; Priestap, H. A.; Farina, M.; Cedola, M.; Ruveda, E. A.
Phytochemistry 1974, 13, 1957–1962.
11. Chia, Y.-C.; Chang, F.-R.; Teng, C.-M.; Wu, Y.-C. J. Nat.
Prod. 2000, 63, 1160–1163.
12. Couture, A.; Deniau, E.; Woisel, P.; Grandclaudon, P.
Synthesis 1997, 1439–1445.
Acknowledgements
13. Hoarau, C.; Couture, A.; Deniau, E.; Grandclaudon, P.
Synthesis 2000, 655–660.
This research was supported by the Centre National de la
Recherche Scientifique and MENESR (grant to V. R.). Also
we acknowledge helpful discussions and advice from Dr. T.
G. C. Bird (Astra-Zeneca Pharma).
14. (a) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.
J. Org. Chem. 2004, 69, 4527–4530. (b) Couture, A.; Deniau,
E.; Grandclaudon, P. Tetrahedron 1997, 53, 10313–10330.
15. Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409–548.
16. (a) Katritzky, A. R.; Yang, Z.; Lam, J. N. J. Org. Chem. 1991,
56, 6917–6923. (b) Katritzky, A. R.; Qi, M. Tetrahedron 1998,
54, 2647–2668. (c) Katritzky, A. R.; Qi, M.; Feng, D.; Nichols,
D. A. J. Org. Chem. 1997, 62, 4121–4124.
References and notes
1. (a) Shamma, M.; The Isoquinoline Alkaloids, Chemistry and

V. Rys et al. / Tetrahedron 61 (2005) 665–671
671
17. (a) Katritzky, A. R.; Ignatchenko, A. V.; Lang, H. J. Org.
Chem. 1995, 60, 4002–4005. (b) Katritzky, A. R.;
Ignatchenko, A. V.; Lang, H. Synth. Commun. 1995, 25,
1197–1204. (c) Deniau, E.; Enders, D. Tetrahedron Lett. 2002,
43, 8055–8058.
20. Gadekar, S. M.; Kotsen, A. M. J. Heterocycl. Chem. 1968, 5,
129–131.
21. Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc.
1987, 109, 5446–5452.
22. Brown, E.; Robin, J.-P.; Dahl, R. Tetrahedron 1982, 38,
2569–2579.
18. (a) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306. (b)
Snieckus, V. Chem. Rev. 1990, 90, 879–933.
23. (a) Fieser, L. F.; Fieser, M. In Reagents for Organic Synthesis,
Vol. 1; Wiley: New York, 1967; pp 142–144.
19. Reitz, A.; Avery, M. A.; Verlander, M. S.; Goodman, M.
J. Org. Chem. 1981, 46, 4859–4863.