First total synthesis of fumaridine

Article abstract of DOI:10.1016/S0040-4020(03)01067-6

The first total synthesis of the alkaloid fumaridine 1a is reported. The key step is the assemblage of the arylmethylene isoindolinone 2a (E) by Horner reaction between the phosphorylated isoindolinone 3a and the suitably substituted benzaldehyde 4. N-Lactam deprotection and concomitant E→Z isomerization complete the synthesis of the title compound.

Full text of DOI:10.1016/S0040-4020(03)01067-6

Tetrahedron 59 (2003) 6615–6619
First total synthesis of fumaridine
*
Veronique Rys, Axel Couture, Eric Deniau and Pierre Grandclaudon
´
´
Laboratoire de Chimie Organique Physique, UMR 8009 Chimie Organique et Macromoleculaire,
´ ˆ ´
Universite des Sciences et Technologies de Lille, Batiment C3(2), 59655 Villeneuve d’Ascq Cedex, France
Received 6 March 2003; revised 12 May 2003; accepted 24 June 2003
Abstract—The first total synthesis of the alkaloid fumaridine 1a is reported. The key step is the assemblage of the arylmethylene
isoindolinone 2a (E) by Horner reaction between the phosphorylated isoindolinone 3a and the suitably substituted benzaldehyde 4. N-Lactam
deprotection and concomitant E!Z isomerization complete the synthesis of the title compound.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
during their basic extraction since their biogenetic pre-
cursors have been reported to be present in all the previously
quoted Fumaria species.7 All these alkaloids share the same
structural feature and can be regarded in one sense as having
a (Z)-configured stilbenoid double bond embedded in a
phthalimidine skeleton. Curiously, structural assignments of
fumaridine have been a subject of controversy but it has
been unambiguously demonstrated that its chemical
behavior and structural requirement are only compatible
with structure 1a.8 Paradoxically, despite the fact that these
structures incorporate an isoindolinone ring system, which
is interesting due to the real and promising biological
properties of many of their derivatives9 notably the 3-aryl-
and alkylmethylene analogues,10 studies on their pharma-
cological potential, with the exception of their effects on the
cardiovascular system,11 are scanty.
Fumaridine 1a is one of the four secophthalideisoquinoline
ene lactams known to date along with fumaramine 1b,
fumaramidine 1c and narceine imide 1d (Fig. 1).
Their occurrence is limited to the plant families
Fumariaceae1 and Papaveraceae and in particular fumari-
dine (hydrastinimide) has been isolated from Fumaria
densiflora,2 schleicheri,3 vaillanti4 and parviflora5 plants
and more recently from the stem bark of Dactylicapnos
torulosa.6
These ene lactams are not generally considered to be true
alkaloids but are regarded conceivably as artifacts formed
In the course of our ongoing project dealing with the
synthesis and subsequent biological evaluation of a variety
of compounds comprising an arylmethylene isoindolinone
unit either in open systems12 or embedded in fused models,
e.g. aristolactams,13 we became recently interested in the
synthesis of these secophthalideisoquinoline ene lactams.
2. Results and discussion
In this study we were mainly concerned with the exemplary
representative fumaridine 1a whose elaboration requires
taking up a number of synthetic challenges namely (i) the
construction of an unsymmetrically disubstituted isoindoli-
none ring system, (ii) the connection of a pendant
arylmethylene unit with the mandatory Z geometry,
(iii) the presence of an unsubstituted nitrogen lactam in a
highly conjugated system which imposes a supplementary
protection-deprotection sequence, a precedented issue in
this series,14 and (iv) the presence of diverse and dense
Figure 1.
Keywords: N-acyliminium; alkaloids; ene lactams; Horner reaction;
isoindolinones.
*
Corresponding author. Tel.: þ33-0-3-20-43-44-32; fax: þ33-0-3-20-33-
63-09; e-mail: axel.couture@univ-lille1.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01067-6

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V. Rys et al. / Tetrahedron 59 (2003) 6615–6619
The target compound 1a would be obtained by N-lactam
deprotection of the parent arylmethylene isoindolinone 2.
This highly conjugated compound would be readily
assembled by Horner reaction between the phosphorylated
isoindolinone 3 and the suitably substituted benzaldehyde
derivative 4. Critical to the success of this strategy was then
to determine a nitrogen lactam protecting group that would
either influence the stereochemical outcome of the Horner
process or that would force its direct precursor 2 to adopt the
required Z geometry of the natural product upon removal.
Literature precedent, although scarce, gave support to the
resort of the para-methoxybenzyl group.16 We indeed
conjectured that the deprotection reaction, which is usually
carried out at relatively high temperatures and under strong
acidic conditions thus facilitating E!Z conversion,17 would
be highly stereoselective and yield the thermodynamically
more stable (Z)-ene lactam 1a.
We thus set out to prepare the phosphorylated N-para-
methoxybenzyl isoindolinone 3a and, for the first facet of
the synthesis, we initially envisaged to take advantage of our
newly developed aryne-mediated cyclization applied to
halogeno-N-[(diphenylphosphinoyl)methyl]benzamide
derivatives (Scheme 2, path a). For this purpose the required
parent phosphorylated benzamide 7 was initially syn-
thesized by coupling N-[(diphenyphosphinoyl)methyl]-N-
4-methoxybenzylamine 6 with the benzoyl chloride deriva-
tive 5. Somewhat disappointingly, compound 7 was totally
recalcitrant to the aryne-mediated cyclization reaction liable
to give access to the required phosphorylated isoindolinone
3a. Indeed exposure of 7 to potassium bis(trimethylsilyl)-
amide (KHMDS, 2 equiv.) at 2788C in THF led to a
complex mixture of products among which the undesired,
demethoxylated isoindolinone 8 was slightly predominant.
Scheme 1.
functionalities on the environmentally different aromatic
moieties. As far as we are aware no total synthesis of natural
product 1a has appeared in print and solely a semisynthetic
route to 1a based upon the basic treatment of b-hydrastine
methiodide has been reported.7
While embarking on the synthesis of this alkaloid, one of
our major concerns was to develop a general and
conceptually new approach that would tolerate a variety
of substitution patterns liable to have some implication on
the biological profile of these models. For the elaboration of
compound 1a we opted for the synthetic route depicted in
the retrosynthetic Scheme 1 that relies upon our long-
standing experience in the field of N-acylenamine
chemistry.15
We then decided to switch our plans and to adopt an
alternative strategy for the installation of the phosphoryl
appendage at the benzylic position of the heteroring unit.
This new synthetic route relies upon the sensitivity of
N-acyliminium ions to nucleophilic attack with carbon or
Scheme 2.

V. Rys et al. / Tetrahedron 59 (2003) 6615–6619
6617
heteroatom nucleophiles.18 Since alkoxy and hydroxyl-
actams18e,f are regarded as excellent precursors to the
cationic species, we therefore planned to synthesize 6,7-
dimethoxy-3-hydroxy-2-[(4-methoxyphenyl)methyl]-2,3-
dihydro-1H-isoindol-1-one 10 (Scheme 2). The most
frequently used methods to achieve the elaboration of
these hydroxylactams are partial reduction of the corre-
sponding carbonyl group of imides or anodic hydroxylation
of lactams18 but this strategy is often plagued by the
problem of poor regioselectivity for unsymmetrically
substituted models. This problem was circumvented by
the synthetic pathway depicted in Scheme 2 (path b), which
is based upon the interception of the dilithiated species
derived from the bromobenzamide 9 with dimethylforma-
mide (DMF). After experimenting a variety of reagents and
conditions it was found that the best results were obtained
by sequential deprotonation and bromine–lithium exchange
with phenyllithium (1.12 equiv.) and n-butyllithium,
respectively. Trapping with DMF delivered the desired
hydroxylactam with a satisfactory yield (59%). The
endocyclic N-acyliminium cation 11 was generated in
boiling toluene under acidic conditions and reacted
smoothly with diphenylphosphine oxide to yield the
corresponding 3-diphenylphosphinoyl-6,7-dimethoxy-2-
[(4-methoxyphenyl)methyl]-2,3-dihydro-1H-isoindol-1-
one 3a almost quantitatively.
E geometry, the configuration of the double bond being
established from its 1H NMR spectrum with the use of nOe
experiments. Thus the lactamic N-methylene H2 of 2a (d
5.00 ppm) showed a strong nOe (10%) with the vinylic H (d
6.19 ppm). The driving force arising from the high degree of
conjugation of these models incorporating a central stil-
benoid double bond and the presence of the bulky para-
methoxybenzyl group on the lactam nitrogen account for the
high yield and stereoselectivity of this synthesis of the ene
lactam 2a. The adoption of the para-methoxybenzyl pro-
tecting group for the nitrogen lactam was rewarded here:
treatment of the protected arylideneisoindolinone 2a in
boiling trifluoroacetic acid in the presence of anisole as the
carbocation scavenger produced selectively the thermo-
dynamically more stable product 1a with the Z geometry.
The constitution and stereochemistry of the target final com-
pound 1a was secured by matching its 1H and 13C NMR, IR,
UV and mass spectra with those published for the natural
and hemisynthetic compound by previous investigators.7,8
In summary the first total synthesis of fumaridine which
emphasizes the synthetic potential of phosphorylated
isoindolinones has been accomplished. We also believe
that this work demonstrates a general methodology, widely
adaptable for the preparation of other naturally occurring
Fumariaceae alkaloids as well as their biogenetically
related congeners.
With this phosphorylated lactam in hand, incorporation of
the pendant aminoalkylarylidene unit could be envisaged by
the agency of the Horner process (Scheme 3).
3. Experimental
3.1. General
Thus, compound 3a was deprotonated at 2788C using
1.1 equiv. of KHMDS in THF and the so formed carbanion
was reacted with the aromatic carboxaldehyde 4, a
degradation product of cryptopleurospermin.19,20 Warming
to room temperature ensured completion of the Horner
reaction and the arylmethyleneisoindolinone 2a was quanti-
tatively formed and isolated in high yield by this protocol.
Tetrahydrofuran (THF) and ether (Et2O) were pre-dried
with anhydrous Na2SO4 and distilled over sodium benzo-
phenone ketyl under Ar before use. CH2Cl2, NEt3, 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
performed by syringe techniques. For flash chromato-
graphy, Merck silica gel 60 (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, 75 and 121 MHz, for 1H, 13C and 31P,
respectively). For 1H, 13C NMR, CDCl3 as solvent, TMS as
internal standard; for 31P NMR, CDCl3 as solvent, H3PO4 as
external standard. Microanalyses were performed by the
CNRS microanalysis center.
Compound 2a was obtained exclusively with the undesired
The benzoyl chloride derivative 521 and the dimethyl-
aminoalkylbenzaldehyde 420 were prepared according to
literature methods. The phosphorylated amine 6 was also
synthesized according to a reported procedure.13a
3.1.1. 6-Bromo-N-[(diphenylphosphinoyl)methyl]-2,3-
dimethoxy-N-(4-methoxybenzyl)benzamide
(7).
A
solution of the benzoyl chloride derivative 5 (500 mg,
1.8 mmol) in dry CH2Cl2 (150 mL) was added dropwise at
08C to a solution of the phosphorylated amine 6 (630 mg,
1.80 mmol) and NEt3 (1.82 g, 18 mmol) in CH2Cl2 (20 mL).
The mixture was stirred at room temperature for 2 h. Water
(50 mL) was added. The organic layer was washed with
water and brine, dried (MgSO4), filtered, and concentrated
Scheme 3.

6618
V. Rys et al. / Tetrahedron 59 (2003) 6615–6619
in vacuo to afford a solid residue which was recrystallized
from hexane–toluene. Yield: 1.0 g (94%); mp 183–1848C;
1H NMR (d): 3.67 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.80
(s, 3H, OCH3), 4.03 (dd, J¼6.8, 15.4 Hz, 1H, NCH2P), 4.56
(d, J¼14.9 Hz, 1H, NCH2Ar), 4.77–4.88 (m, 2H, NCH2-
PþNCH2Ar), 6.73 (d, J¼8.8 Hz, 1H, aromatic H), 6.84 (d,
J¼8.6 Hz, 2H, aromatic H), 7.14 (d, J¼8.8 Hz, 1H,
aromatic H), 7.32–7.60 (m, 8H, aromatic H), 7.78–7.90
(m, 2H, aromatic H), 7.94–8.08 (m, 2H, aromatic H) ppm;
13C NMR (d): 41.2 (d, JCP¼76 Hz, NCHP), 52.4, 55.2,
56.0, 61.7, 109.4, 114.0, 114.1, 126.9, 128.2, 128.6 (d,
JCP¼11.5 Hz), 130.8, 131.0 (d, JCP¼10 Hz), 131.2 (d,
JCP¼98 Hz), 131.7 (d, JCP¼10 Hz), 132.0 (d, JCP¼15 Hz),
132.9, 146.3, 152.2, 159.2, 166.1 (CO) ppm; 31P NMR (d):
30.1 ppm. Anal. calcd for C30H29BrNO5P (594.5): C,
60.62; H, 4.92; N, 2.36%. Found: C, 60.32; H, 5.27; N,
2.57%.
ppm. Anal. calcd for C17H18BrNO4 (380.2): C, 53.70; H,
4.77; N, 3.68%. Found: C, 53.91; H, 5.02; N, 3.61%.
3.1.4. 3-Hydroxy-6,7-dimethoxy-2-(4-methoxybenzyl)-
2,3-dihydro-1H-isoindol-1-one (10). A solution of PhLi
(2.55 mL, 1.8 M in cyclohexane–ether 70:30, 4.5 mmol)
was added dropwise to a solution of bromobenzamide 9
(1.55 g, 4.1 mmol) in THF (150 mL) at 2788C under Ar.
The mixture was stirred at this temperature for 30 min and
then treated dropwise with a solution of BuLi (2.85 mL,
1.6 M in hexanes, 4.5 mmol). The mixture was kept at
2788C with stirring for 5 min and a solution of dimethyl-
formamide (DMF, 660 mg, 9 mmol) in THF (2 mL) was
added dropwise by syringe. Once addition had finished, the
reaction mixture was stirred for 1 h at 2788C and then
allowed to warm to room temperature for an additional 1 h.
Saturated aqueous NH4Cl (50 mL) was added, and the
mixture was extracted with Et2O (3£100 mL). The organic
layer was washed with water, brine, dried (MgSO4) and
concentrated in vacuo to a crude solid which was purified by
flash column chromatography with AcOEt–hexanes (30:70)
as eluent to furnish a white solid. Yield: 800 mg (59%); mp
3.1.2. 7-Bromo-3-diphenylphosphinoyl-4-methoxy-2-(4-
methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one (8).
A
solution of KHMDS (1.85 mL, 0.5 M in toluene,
0.92 mmol) was added dropwise over a period of 5 min to
a stirred solution of compound 7 (500 mg, 0.84 mmol) and
18-crown-6 (245 mg, 0.92 mmol) in THF (50 mL) at 2788C
under Ar. The solution was stirred for 30 min at this
temperature and then allowed to warm to room temperature
within 6 h. Aqueous NH4Cl was added, and the mixture
extracted with CH2Cl2 (2£50 mL). The organic layer was
washed with water and brine, dried (MgSO4), and
concentrated in vacuo to a light yellow oil which was
purified by flash column chromatography with acetone–
hexanes (50:50) as eluent to afford 8. Yield: 166 mg (35%);
1
137–1388C (hexane–toluene); H NMR (d): 3.72 (s, 3H,
OCH3), 3.79 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.21 (d,
J¼14.7 Hz, 1H, CH2), 4.85 (d, J¼14.7 Hz, 1H, CH2), 5.43
(s, 1H, CHO), 6.78 (d, J¼8.8 Hz, 2H, aromatic H), 6.94 (d,
J¼8.1 Hz, 1H, aromatic H), 7.16 (d, J¼8.1 Hz, 1H,
aromatic H), 7.24 (d, J¼8.8 Hz, 2H, aromatic H) ppm;
13C NMR (d): 41.9, 55.2, 56.4, 62.4, 78.9, 114.0, 116.0,
118.9, 123.2, 129.3, 130.0, 137.2, 146.1, 153.3, 158.9,
165.0 (CO) ppm. Anal. calcd for C18H19NO5 (329.4): C,
65.64; H, 5.81; N, 4.25%. Found: C, 65.52; H, 5.89; N,
4.44%.
1
mp 104–1058C (white crystals from hexane–toluene); H
NMR (d): 3.37 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 4.51–
4.62 (m, 2H, NCH2ArþNCHP), 4.94 (d, J¼14.7 Hz, 1H,
NCH2Ar), 6.81 (d, J¼8.7 Hz, 2H, aromatic H), 7.15–7.29
(m, 3H, aromatic H), 7.35–7.51 (m, 6H, aromatic H), 7.61–
7.75 (m, 5H, aromatic H) ppm; 13C NMR (d): 44.9, 53.8,
55.2, 61.5 (d, JCP¼65 Hz), 110.1, 111.8, 114.6, 128.1 (d,
JCP¼98 Hz), 128.3 (d, JCP¼12 Hz), 128.6 (d, JCP¼11 Hz),
129.7, 130.5, 130.9, 131.4 (d, JCP¼9.5 Hz), 131.5 (d,
JCP¼95 Hz), 131.6 (d, JCP¼10 Hz), 132.3 (d, JCP¼2 Hz),
133.1, 134.7, 153.6, 158.2, 166.8 (CO) ppm; 31P NMR
(d): 30.3 ppm. Anal. calcd for C29H25BrNO4P (562.4): C,
61.93; H, 4.48; N, 2.49%. Found: C, 61.75; H, 4.76; N,
2.73%.
3.1.5. 3-(Diphenyphosphinoyl)-6,7-dimethoxy-2-(4-
methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one (3a). A
solution of hydroxyisoindolinone 10 (700 mg, 2.13 mmol),
para-toluenesulfonic acid (PTSA, 50 mg, 0.3 mmol) and
diphenylphosphine oxide (475 mg, 2.34 mmol) in toluene
(100 mL) was refluxed under Ar for 3 h in a Dean–Stark
apparatus. The solvent was removed under vacuum and the
oily residue was dissolved in CH2Cl2 (100 mL). The organic
phase was then subsequently treated with aqueous NaHCO3,
water and brine and finally dried (MgSO4). Flash column
chromatography using AcOEt–hexanes (70:30) as eluent
afforded the crude phosphorylated isoindolinone and final
purification by recrystallization from toluene–hexane
furnished 3a as a white powder. Yield: 940 mg (86%); mp
152–1538C; 1H NMR (d): 3.75 (s, 3H, OCH3), 3.79 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 4.20 (d, J¼14.8 Hz, 1H, CH2),
5.16 (dd, J¼0.5, 9.3 Hz, 1H, NCHP), 5.28 (d, J¼14.8 Hz,
1H, CH2), 6.47 (dd, J¼1.0, 7.6 Hz, 1H, aromatic H), 6.77–
6.85 (m, 3H, aromatic H), 7.13 (d, J¼8.5 Hz, 2H, aromatic
H), 7.38–7.48 (m, 6H, aromatic H), 7.53–7.56 (m, 2H,
aromatic H), 7.62–7.69 (m, 2H, aromatic H) ppm; 13C
NMR (d): 44.6, 55.2, 56.6, 59.0 (d, JCP¼74 Hz, NCHP),
62.6, 114.0, 116.0 (d, JCP¼2.5 Hz), 119.3 (d, JCP¼3 Hz),
124.7, 127.7 (d, JCP¼93 Hz), 128.6 (d, JCP¼11.5 Hz), 128.7
(d, JCP¼11.5 Hz), 128.8, 129.0 (d, JCP¼94 Hz), 129.9,
131.7 (d, JCP¼9 Hz), 131.8, 132.1 (d, JCP¼9 Hz), 132.8
(d, JCP¼3 Hz), 132.9 (d, JCP¼2.0 Hz), 147.4, 152.7 (d,
JCP¼2 Hz), 159.1, 166.9 (d, JCP¼2.0 Hz) ppm; 31P NMR
(d): 31.2 ppm. Anal. calcd for C30H28NO5P (513.5): C,
3.1.3. 6-Bromo-2,3-dimethoxy-N-(4-methoxybenzyl)ben-
zamide (9). This secondary aromatic carboxamide was
obtained by coupling 4-methoxybenzylamine (2.7 g,
19.7 mmol) with the benzoyl chloride derivative 5 (5 g,
17.9 mmol) under classical Schotten–Baumann reaction
conditions as described above for benzamide 7. Final
purification by flash column chromatography with EtOAc–
hexanes–NEt3 (50:45:5) afforded 9 as white crystals. Yield:
5.24 g (77%); mp 92–938C (hexane–toluene); 1H NMR (d):
3.77 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.80 (s, 3H, OCH3),
4.57 (d, J¼5.6 Hz, 2H, CH2), 6.06 (s, 1H, NH), 6.74 (d,
J¼8.8 Hz, 1H, aromatic H), 6.84 (d, J¼8.5 Hz, 2H,
aromatic H), 7.19 (d, J¼8.8 Hz, 1H, aromatic H), 7.30 (d,
J¼8.5 Hz, 2H, aromatic H) ppm; 13C NMR (d): 43.4, 55.3,
56.0, 62.1, 109.7, 114.0, 128.1, 129.3 (two peaks over-
lapping), 129.9, 133.9, 147.0, 152.1, 159.0, 165.4 (CO)

V. Rys et al. / Tetrahedron 59 (2003) 6615–6619
6619
3. Kiriakov, K.; Mardirosyan, Z.; Panov, P. Doklady Bolgarskoi
Akademii Nauk 1980, 33, 1377–1379, Chem. Abstr. 1981, 94
188644.
70.17; H, 5.50; N, 2.73%. Found: C, 70.48; H, 5.67; N,
2.92%.
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3.1.6. (E)-3-({6-[2-(dimethylamino)ethyl]-1,3-benzo-
dioxol-5-yl}methylene)-6,7-dimethoxy-2-(4-methoxy-
benzyl)-2,3-dihydro-1H-isoindol-1-one (2a). A solution of
KHMDS (2.2 mL, 0.5 M in toluene, 1.1 mmol) was added
dropwise over a period of 15 min to a stirred solution of the
phosphorylated isoindolinone 3a (513 mg, 1 mmol) in THF
(25 mL) at 2788C under Ar. The solution was stirred for
15 min at this temperature and a solution of the benzal-
dehyde derivative 4 (221 mg, 1 mmol) in THF (2 mL) was
added by syringe. The mixture was kept at 2788C for
15 min and then warmed to room temperature over a period
of 1 h. Water was added and the mixture was extracted with
Et2O (2£50 mL). The ether extract was washed with water
and brine, dried over Na2SO4 and evaporated in vacuo.
Flash column chromatography on silica gel with AcOEt–
hexanes–NEt3 (90:5:5) as eluent allowed isolation of the
ene lactam 2a which was finally purified by recrystallization
from hexane–toluene. Pale yellow crystals; yield: 400 mg
(77%); mp 113–1148C; 1H NMR (d): 2.00 (s, 6H, N(CH3)2),
2.14–2.20 (m, 2H, CH2), 2.42–2.47 (m, 2H, CH2), 3.75 (s,
3H, OCH3), 3.83 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 5.00 (s,
2H, NCH2), 5.93 (s, 2H, OCH2O), 6.19 (s, 1H, vCHAr),
6.67–6.73 (m, 3H, aromatic H), 6.80–6.86 (m, 3H,
aromatic H), 7.21–7.26 (m, 2H, aromatic H) ppm; 13C
NMR (d): 31.6, 42.6, 45.2, 55.2, 56.5, 60.2, 62.5, 101.5
(OCH2O), 107.6, 109.8, 110.3, 114.1, 116.0, 119.1, 122.2,
127.2, 128.4, 128.8, 129.2, 133.2, 135.7, 146.0 (two peaks
overlapping), 147.5, 153.4, 158.9, 164.8 (CO) ppm. Anal.
calcd for C30H32N2O6 (516.6): C, 69.75; H, 6.24; N, 5.42%.
Found: C, 69.97; H, 6.50; N, 5.21%.
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´
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A solution of the arylmethylene isoindolinone 2a (240 mg,
0.47 mmol) and anisole (510 mg, 4.7 mmol) in trifluoro-
acetic acid (10 mL) was refluxed under Ar for 12 h. The
reaction mixture was concentrated under vacuum, the
residue was dissolved in CH2Cl2 (20 mL) and NEt3
(0.5 mL) was added with stirring. Water (20 mL) was then
added, and the organic layer was washed with brine, dried
(Na2SO4) and concentrated to yield a solid residue which
was recrystallized from EtOH. The analytical and spectral
data of synthetic 1a (170 mg, 91%) matched those reported
for the natural product.6,8
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Acknowledgements
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).
¨
Decroix, B.; Daıch, A. J. Org. Chem. 2001, 66, 4695–4703.
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