A short total synthesis of the alkaloids piperolactam C, goniopedaline, and stigmalactam

Article abstract of DOI:10.1002/ejoc.200390177

The total synthesis of the polyalkoxylated alkaloids piperolactam C, goniopedaline and stigmalactam by combinatorial metalation/cyclization strategies has been achieved. The synthetic route involved the preliminary construction of the polyalkoxylated isoindolinone template by Parham's technique. Benzylic lactam deprotonation allowed connection of a hydroxybenzyl appendage, and the synthesis of the target natural products was completed by subsequent E1cB elimination, radical cyclization and final deprotection. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390177

FULL PAPER
A Short Total Synthesis of the Alkaloids Piperolactam C, Goniopedaline, and
Stigmalactam
[a]
[a]
[a]
[a]
´
Veronique Rys, Axel Couture,* Eric Deniau, and Pierre Grandclaudon
Keywords: Alkaloids / Carbanions / Cyclization / Lactams / Total synthesis
The total synthesis of the polyalkoxylated alkaloids pipero-
a hydroxybenzyl appendage, and the synthesis of the target
lactam C, goniopedaline and stigmalactam by combinatorial natural products was completed by subsequent E1cB elim-
metalation/cyclization strategies has been achieved. The
synthetic route involved the preliminary construction of the
ination, radical cyclization and final deprotection.
polyalkoxylated isoindolinone template by Parham’s tech- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
nique. Benzylic lactam deprotonation allowed connection of
Germany, 2003)
Introduction
Uvaria hamiltonii,[21] whilst stigmalactam (3) is a new aris-
tolactamic compound recently extracted from Fissistigma
species found in a climbing shrub indigenous to the broad-
leafed tree zone of China and Taiwan.[18] As far as we are
aware, no total syntheses of natural products 2 or 3 have
appeared in print.
Aristolactams are a minor group of fused phenanthrene
lactam alkaloids structurally and biogenetically related to
aporphines.[1Ϫ4] The richest source of this class of alkaloids
is undoubtedly plants of the family Aristolochiaceae.[5,6] Ex-
tracts of these plants have been used since antiquity and still
find some applications in traditional medicine in Turkey,[7]
India,[8] Argentina[9] and southern China.[10] These phen- Results and Discussion
anthrene lactams are also considered to be the principal
detoxification metabolites of aristolochic acids,[11] which
The main general synthetic approaches to these phen-
have been implicated in an endemic renal fibrosis known as anthrene lactam compounds involve: (i) oxidation of dehy-
Chinese herbs nephropathy.[12] They have also been detected droaporphines,[22] (ii) metalation/carbonylation of bromo-
in urine and faeces from mammals, including humans, but phenanthrylamines,[23] (iii) metalation/carbonation of amino-
their exact mode of action has not yet been elucidated.[13]
phenanthrenes, and (iv) catalytic hydrogenation of the cor-
As a part of a program aiming to synthesize a range of responding aristolochic acids.[24] However, these methods
aristolactamic products with oxygenated functions at the 2- are inadequate for the synthesis of models with diverse
and 3-positions of the phenanthrene nucleus for subsequent and dense functionality on their compact framework, parti-
pharmacological evaluation, we were initially interested in cularly with hydrophenolic functions in specific positions
the synthesis of the representative naturally occurring alka- on the basic phenanthrene nucleus.
loids piperolactam C (1), goniopedaline (2) and stigmalac-
For the synthesis of the target natural products 1Ϫ3 we
tam (3). Piperolactam C (1) has been isolated from the stem initially envisaged the adoption of a strategy hinging on the
bark of Piper argyrophylum,[14] Piper wightii,[15] Piper acut- preliminary synthesis of the (arylmethylene)isoindolinones
isleginum[16] and from other Indian Piper species, namely P. 4Ϫ6 (retrosynthetic Scheme 1). Cyclization of these stilb-
boehimerifolium and P. longum.[17] Recent investigations of enic intermediates followed by sequential or concomitant
extracts from Fissistigma balansae and F. oldanii have also deprotection of the primarily annulated compounds should
resulted in the isolation of this trimethoxylactam.[18] It is then complete the synthesis of the desired alkaloids. A con-
worth noting that a short and skilful synthesis of this alka- tentious issue in the construction of the diversely func-
loid has recently been reported by V. Snieckus et al.[19] tionalized isoindolinones 4Ϫ6, each with
a pendant
Goniopedaline (2) has been isolated from the leaves and (haloaryl)methylene unit, was the initial judgement of the
twigs of Goniothalamus sesquipedalis[20] and very recently proper strategy for the stereoselective synthesis of the re-
quired models with the mandatory (E) stereochemistry. To
[a]
reach this goal we first opted for the synthetic route de-
picted in the retrosynthetic Scheme 1 (path a), which has
been successfully applied to the synthesis of other members
of the aristolactamic series.[25Ϫ27] This synthetic approach
Laboratoire de Chimie Organique Physique, ESA CNRS 8009,
´
Universite des Sciences et Technologies de Lille,
ˆ
´
Batiment C3(2), USTL, 59655 Villeneuve d’Ascq Cedex, France
Fax: (internat.) ϩ 33-3/20336309
E-mail: axel.couture@univ-lille1.fr
1231
Eur. J. Org. Chem. 2003, 1231Ϫ1237  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0407Ϫ1231 $ 20.00ϩ.50/0

V. Rys, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
functionality followed by classical oxidation of the resulting
bromobenzaldehyde 12 provided a 45% yield (over three
steps) of the bromobenzoic acid 13. Coupling of this car-
boxylic acid with the secondary phosphorylated amine 14
Ϫ obtained beforehand by treatment of the appropriate
hexahydrotriazine with diphenylphosphane oxide[15,25,33]
Ϫ
delivered the required parent bromobenzamide 9. Some-
what disappointingly, compound 9 was completely unamen-
able to the aryne-mediated cyclization conditions likely to
give access to the required phosphorylated isoindolinone 7
even after considerable experimentation with various sol-
vents, bases and temperatures, with or without crown
ethers, instead giving an inextricable mixture of compounds.
One can reasonably assume that this failure may be attribu-
table partly to intramolecular nucleophilic aromatic substi-
tution competing with the generation of the aryne func-
tionality, a phenomenon for which there is precedent.[34]
Scheme 1
Scheme 2
relies upon the construction of the (arylmethylene)isoindoli-
nones 4Ϫ6 by the Horner process, which is precisely gov-
erned by the bulkiness of the substituent connected to the
Consequently, we decided to change our plans and to ad-
lactam nitrogen atom.[25Ϫ28] It was assumed that the first opt the alternative synthetic tactics depicted in the retrosyn-
facet of this synthesis, the elaboration of the parent isoindo- thetic Scheme 1 (path b) to achieve the stereoselective prep-
linones 7 and 8, each with the phosphoryl appendage and aration of (E)-(arylmethylene)isoindolinones 4Ϫ6. This
the bulky p-methoxybenzyl protective group, should be ac- work was based on the following premises: (i) the instal-
complishable through aryne-mediated cyclization of the lation of the hydroxyalkyl appendage should be easily
halo-N-[(diphenylphosphoryl)methyl]benzamide derivatives achievable by metalation of the parent isoindolinones 18
9 and 10.[28,29]
and 19 and subsequent quenching with the appropriate
To test the feasibility of such a process on polyalkoxyl- halobenzaldehyde derivative,[35] and (ii) dehydration of
ated models we first set out to prepare the trimethoxy par- erythro and/or threo adducts 15Ϫ17 through an E1cB mecha-
ent model 9 (Scheme 2). The synthesis started with 2,3,4- nism would give rise selectively to the desired arylideneiso-
trimethoxybenzaldehyde, which was converted into the im- indolinones 4Ϫ6 with the (E) configuration.[36]
idazolidine derivative 11 in order to retain the formyl func-
Critical to the success of this strategy then was the con-
tionality and to direct lithiation to the ortho ring struction of the parent isoindolinones 18 and 19 with meth-
position.[30Ϫ32] Metalation with tert-butyllithium and sub- yl- or benzyl-protected hydroxy groups. Syntheses of these
sequent quenching with 1,2-dibromotetrachloroethane re- lactam compounds have been widely investigated, but the
sulted, as anticipated, in bromination exclusively adjacent application of traditional methods is quite limited and un-
to the imidazolidine group. Regeneration of the formyl satisfactory because of restrictions in the choice of substitu-
1232
Eur. J. Org. Chem. 2003, 1231Ϫ1237

Total Synthesis of Piperolactam C, Goniopedaline, and Stigmalactam
FULL PAPER
ents: namely in their nature, their number and their position between the C-3 and C-α protons, which is in agreement
on the aromatic nucleus.[29] We thus chose to adopt a new with the erythro configuration.[38,39] E1cB elimination was
conceptual approach in which the lactam ring would be as- performed by prior O-silylation of the hydroxyalkyl adducts
sembled by lithium/halogen exchange in the bromoaryl de- 15Ϫ17 followed by benzylic lactam deprotonation. Gratify-
rivative 24 and 25, followed by Parham-type cyclization of ingly, this technique exclusively delivered the (E)-configured
the resulting lithiated intermediate 26 (R1 ϭ Me, Bn), with arylideneisoindolinones 4Ϫ6,[36] suitable candidates for the
the carbamate group acting as the internal electrophile ultimate cyclization step. Oxidative radical cyclization of
(Scheme 3). The synthesis started with the elaboration of these stilbenic intermediates proceeded uneventfully to fur-
the dibenzylamine derivatives 22 and 23, which were readily nish the primarily annulated compounds 30Ϫ32 in fairly
obtained by reductive amination of the appropriate bromo- good yields (Scheme 3). Removal of the benzyl protection
benzaldehydes 20 and 21 with p-methoxybenzylamine. of the phenolic hydroxy groups of 31 and 32 and of the
Treatment of amines 22 and 23 with methyl chloroformate nitrogen lactams of 30Ϫ32 was achieved simultaneously by
delivered the carbamates 24 and 25 in excellent yields (73 treatment with trifluoroacetic acid, and this single oper-
and 69% for 24 and 25, respectively, over two steps). To ation delivered the target natural products piperolactam C
ensure the formation of the lithiated intermediate 26, a (1), goniopedaline (2) and stigmalactam (3) in 44, 31 and
THF solution of the aryl bromides 24 and 25 was treated 26% yields, respectively (over four steps).
with tert-butyllithium. The intramolecular ring-closure was
instantaneous, as demonstrated by the isolation solely of
the annulated compounds 18 and 19 upon immediate aque-
ous workup. This annulation reaction releases lithium me-
Conclusion
In conclusion, we have completed a new conceptual ap-
thoxide, and we assumed that this species might be of suf- proach to the synthesis of the contiguously polyalkoxylated
ficient kinetic basicity to induce the formation of the highly aristolactam alkaloids. This new route, illustrated by the
stabilized transient carbanion 27. To test this hypothesis, synthesis of three representative examples, hinges upon the
compounds 24 and 25 were treated with tert-butyllithium initial construction of the polyalkoxylated isoindolinone
and subsequently with the appropriate halobenzaldehydes template by the Parham procedure. Subsequent hydroxyal-
28 and 29. To our delight, this approach delivered single kylation of the lactam unit, dehydration of the adducts
compounds, unambiguously identified as alcohols 15Ϫ17 through an E1cB mechanism and final cyclization complete
with erythro configurations.[37] As an example, the 1H the total synthesis of the target natural products. The ad-
NMR spectrum of 15 showed a coupling constant of 3.2 Hz vantages of this synthesis, which lie mainly in the small
Scheme 3
Eur. J. Org. Chem. 2003, 1231Ϫ1237
1233

V. Rys, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
6-Bromo-2,3,4-trimethoxybenzoic Acid (13): A suspension of 12
(1 g, 3.6 mmol) in water (30 mL) was stirred at 75 °C, and a solu-
tion of KMnO4 (0.86 g, 5.5 mmol) in water (20 mL) was added
dropwise over a period of 20 min. After the mixture had been
stirred at 75 °C for a further 2 h and then allowed to cool to room
temperature, aqueous KOH (20%) was added until pH ϭ 12, and
the reaction mixture was filtered through Celite. The filtrate was
then acidified (HCl, 10%) until pH ϭ 2, and the mixture was then
extracted with Et2O (3 ϫ 50 mL). The dried (Na2SO4) extract was
concentrated and the residue was recrystallized from hexane/
CH2Cl2 to give the acid 13 (0.89 g, 85%), m.p. 112Ϫ114 °C (ref.[44]
113Ϫ114.5 °C). 13C NMR: δ ϭ 56.4, 60.5, 61.9, 111.3, 112.0, 125.3,
141.1, 150.3, 154.3, 166.3 (COOH) ppm.
number of steps, their procedural simplicity and high ef-
ficiency and the mildness of reaction conditions, provide a
strong incentive for the elaboration of similar structurally
modified naturally occurring alkaloids.
Experimental Section
General: Tetrahydrofuran (THF) and diethyl ether (Et2O) were pre-
dried with anhydrous Na2SO4 and distilled from sodium benzo-
phenone ketyl under Ar before use. Dichloromethane (CH2Cl2),
1,2-dichloroethane, triethylamine (NEt3), toluene and benzene were
distilled from CaH2. Dry glassware was obtained by oven-drying
and assembly under Ar. The glassware was fitted with rubber septa
and reagent transfer was performed by syringe techniques. For
flash chromatography, Merck silica gel 60 (230Ϫ400 mesh ASTM)
was used. The melting points were taken with a Reichert-Thermo-
pan apparatus and are not corrected. NMR: Bruker AM 300
(300 MHz, 75 MHz and 121 MHz, for 1H, 13C and 31P, respec-
6-Bromo-N-[(diphenylphosphoryl)methyl]-2,3,4-trimethoxy-N-(4-
methoxybenzyl)benzamide (9): A solution of acid 13 (882 mg,
3.0 mmol), HOBt (0.45 g, 3.35 mmol), EDCI (645 mg, 3.35 mmol)
and Et3N (460 mg, 4.6 mmol) in freshly distilled CH2Cl2 (50 mL)
was stirred at 0 °C under Ar for 1 h. A solution of the phosphoryl-
ated amine 14 (1.06 g, 3.0 mmol) in CH2Cl2 (20 mL) was added
dropwise, and the mixture was allowed to warm to room tempera-
ture overnight. Aqueous HCl (5%, 10 mL) was added and the sepa-
rated organic layer was subsequently washed with aqueous KOH
(5%, 10 mL), water (20 mL) and brine (20 mL). Concentration of
the dried extract left a solid residue, which was purified by flash
column chromatography with acetone/petroleum ether (2:3) as elu-
ent to afford the phosphorylated benzamide derivative 9, which
was finally recrystallized from hexane/toluene (1.27 g, 68%), m.p.
155Ϫ156 °C. 1H NMR: δ ϭ 3.66 (s, 3 H, OCH3), 3.78 (s, 3 H,
OCH3), 3.80 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 4.19 (dd, J ϭ
6.4, 15.5 Hz, 1 H, NCH2P), 4.63 (d, J ϭ 14.9 Hz, 1 H, NCH2),
4.70 (dd, J ϭ 4.3, 15.5 Hz, 1 H, NCH2P), 4.80 (d, J ϭ 14.9 Hz, 1
H, NCH2), 6.75 (s, 1 H, aromatic H), 6.84 (d, J ϭ 8.6 Hz, 2 H,
aromatic H), 7.35 (d, J ϭ 8.6 Hz, 2 H, aromatic H), 7.40Ϫ7.49 (m,
6 H, aromatic H), 7.84Ϫ7.97 (m, 4 H, aromatic H) ppm. 13C NMR:
δ ϭ 41.4 (d, JC,P ϭ 77 Hz, NCH2P), 52.4, 55.2, 56.3, 60.9, 61.8,
111.9, 113.2, 114.0, 124.7, 127.1, 128.6 (d, JC,P ϭ 12 Hz, 4 C),
130.5, 131.1 (d, JC,P ϭ 10 Hz), 131.6 (d, JC,P ϭ 10 Hz), 131.9 (d,
1
tively); for H and 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 microanal-
ysis centre. Bromobenzaldehyde derivatives 20,[40] 21,[41] 28[42] and
29[43] were prepared by literature methods. The phosphorylated am-
ine 14[25] was also synthesized by a reported procedure. The petro-
leum ether used had a boiling range of 40Ϫ60 °C. Abbreviations
that have been used in the descriptions that follow: HOBt ϭ
1-hydroxybenzotriazole, EDCl ϭ 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride.
Preparation of the Phosphorylated Benzamide Derivative 9
6-Bromo-2,3,4-trimethoxybenzaldehyde (12): A solution of 2,3,4-tri-
methoxybenzaldehyde (9.81 g, 50 mmol) and N,NЈ-dimethylethyl-
enediamine (5.43 g, 63 mmol) in toluene (100 mL) was heated at
reflux for 3 h in a DeanϪStark apparatus. Toluene was removed in
vacuo and the crude product was distilled to afford the 1,3-di-
methyl-2-(2,3,4-trimethoxyphenyl)imidazolidine (11) (oil, 11.05 g,
83%), b.p. 105Ϫ108 °C (0.2 Torr). 1H NMR: δ ϭ 2.16 (s, 3 H,
NCH3), 2.17 (s, 3 H, NCH3), 2.53Ϫ257 (m, 2 H, NCH2), 3.32Ϫ3.36
(m, 2 H, NCH2), 3.76 (s, 1 H, NCHN), 3.83 (s, 3 H, OCH3), 3.84
(s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 7.30 (d, J ϭ 8.8 Hz, 1 H,
aromatic H), 6.71 (d, J ϭ 8.8 Hz, 1 H, aromatic H) ppm. 13C
NMR: δ ϭ 39.7, 53.3, 55.9, 60.7, 61.2, 83.9, 108.0, 123.8, 125.0,
141.3, 153.1, 153.7 ppm. C14H22N2O3 (266.3): calcd. C 63.14, H
8.33, N 10.52; found C 62.86, H 8.53, N 10.21. tBuLi (9.8 mL, 1.7
 in pentane, 16.7 mmol) was added dropwise by syringe over
30 min to a stirred solution of freshly distilled imidazolidine 11
(2 g, 7.5 mmol) in Et2O (50 mL). The mixture was stirred under Ar
at room temperature for 6 h. A solution of dibromotetrachloroe-
thane (5.40 g, 16.6 mmol) in Et2O was then slowly added, and the
mixture was stirred at room temperature overnight. Hydrolysis of
the aminal was effected with aqueous HCl (ca. 150 mL, 2 ,
30 min, room temp.). The organic layer was separated and the
aqueous layer was extracted with CHCl3 (2 ϫ 50 mL). The com-
bined organic extracts were washed with saturated aqueous NH4Cl
J
C,P ϭ 95 Hz), 132.0 (d, JC,P ϭ 3 Hz), 132.2 (d, JC,P ϭ 3 Hz), 141.9,
151.0, 154.6, 159.2, 166.3 (NCϭO) ppm. 31P NMR: δ ϭ 30.9 ppm.
C31H31BrNO6P (624.5): calcd. C 59.63, H 5.00, N 2.24; found C
59.84, H 5.21, N 2.01.
Preparation of the Carbamates 24, 25
General Procedure for the Synthesis of the Dibenzylamine Deriva-
tives 22 and 23: p-Methoxybenzylamine (3.4 g, 25 mmol) and
bromobenzaldehyde derivative 20 or 21 (25 mmol) were mixed in
dry 1,2-dichloroethane (100 mL) and treated with NaBH(OAc)3
(7.5 g, 35 mmol). The mixture was stirred at room temperature un-
der Ar for 12 h. The reaction mixture was quenched by addition of
aqueous NaOH (1 , 10 mL) and the product was extracted with
Et2O (3 ϫ 50 mL). The organic extract was dried (Na2SO4) and
the solvents were evaporated to leave an oily residue. The 1H NMR
spectrum clearly indicated the exclusive presence of the dibenzyla-
mine 22 or 23, which was then used directly in the next step without
further purification.
N-(2-Bromo-3,4,5-trimethoxybenzyl)-N-(4-methoxybenzyl)amine
1
(100 mL). The organic layers were again combined, dried (MgSO4), (22): 9.5 g, 96%, oil. H NMR: δ ϭ 3.73 (s, 2 H, NCH2), 3.78 (s, 3
filtered and concentrated in vacuo. The crude product was purified
by flash column chromatography with Et2O/hexanes (3:7) as eluent
to afford the title compound 12, which was recrystallized from hex-
ane: (1.32 g, 64%), m.p. 51Ϫ52 °C (ref.[44] oil, b.p. 195 °C, 0.8 Torr).
H, OCH3), 3.81 (s, 2 H, NCH2), 3.84 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3), 3.87 (s, 3 H, OCH3), 5.27 (s, 1 H, NH), 6.80 (s, 1 H, aro-
matic H), 6.86 (d, J ϭ 8.5 Hz, 2 H, aromatic H), 7.26 (d, J ϭ
8.5 Hz, 2 H, aromatic H) ppm. 13C NMR: δ ϭ 52.6, 53.3, 55.3,
13C NMR: δ ϭ 56.4, 61.1, 62.4, 113.4, 119.7, 121.5, 142.0, 156.9, 56.1, 61.0, 61.1, 109.1, 109.9, 113.8, 129.4, 132.2, 134.9, 142.1,
157.8, 189.4 (CHϭO) ppm.
150.9, 152.6, 158.7 ppm.
1234
Eur. J. Org. Chem. 2003, 1231Ϫ1237

Total Synthesis of Piperolactam C, Goniopedaline, and Stigmalactam
FULL PAPER
N-(4-Benzyloxy-2-bromo-3,5-dimethoxy)-N-(4-methoxy-
benzyl)amine (23): 11.1 g, 94%, oil. 1H NMR: δ ϭ 3.77 (s, 2 H,
J ϭ 1.4, 7.6 Hz, 1 H, aromatic H), 7.46 (t, J ϭ 7.4 Hz, 1 H, aro-
matic H), 7.87 (d, J ϭ 7.4 Hz, 1 H, aromatic H) ppm. 13C NMR
NCH2), 3.80 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.85 (s, 2 H, ([D6]DMSO): δ ϭ 42.8, 55.0, 55.5, 60.8, 60.9, 62.2, 73.6, 97.2
NCH2), 3.91 (s, 3 H, OCH3), 5.04 (s, 2 H, OCH2), 5.30 (s, 1 H, (CϪI), 103.6, 113.9, 117.5, 127.7, 129.0, 129.7, 130.0, 130.2, 138.9,
NH), 6.84 (s, 1 H, aromatic H), 6.89 (d, J ϭ 8.6 Hz, 2 H, aromatic 139.2, 141.0, 142.3, 150.4, 155.0, 158.4, 166.5 (CϭO) ppm.
H), 7.30 (d, J ϭ 8.6 Hz, 2 H, aromatic H), 7.32Ϫ7.41 (m, 3 H, C26H26INO6 (575.4): calcd. C 54.27, H 4.55, N 2.43; found C 54.49,
aromatic H), 7.50Ϫ7.54 (m, 2 H, aromatic H) ppm. 13C NMR: δ ϭ
52.7, 53.3, 55.3, 56.2, 61.1, 75.5, 109.2, 110.0, 113.8, 128.1, 128.4
(four peaks overlapping), 129.4, 132.0, 135.2, 137.5, 141.0, 151.3,
152.9, 158.3 ppm.
H 4.29, N 2.17.
6-Benzyloxy-3-[(hydroxy)(2-iodophenyl)methyl]-5,7-dimethoxy-2-
(4-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one (16): 1.03 g, 72%,
m.p. 193Ϫ194 °C. 1H NMR ([D6]DMSO): δ ϭ 3.52 (s, 3 H, OCH3),
General Procedure for the Synthesis of the Carbamates 24 and 25: 3.71 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3), 4.19 (d, J ϭ 15.4 Hz, 1
A solution of methyl chloroformate (1.7 g, 18 mmol) in anhydrous
CH2Cl2 (5 mL) was added dropwise at 0 °C to a solution of diben-
H, NCH2), 4.63 (d, J ϭ 2.7 Hz, 1 H, CH), 4.91 (s, 2 H, OCH2),
5.19 (d, J ϭ 15.4 Hz, 1 H, NCH2Ar), 5.27 (br. s, 1 H, CHO), 5.70
zylamine 22 or 23 (12 mmol) and NEt3 (2.42 g, 24 mmol) in (s, 1 H, aromatic H), 5.93 (d, J ϭ 4.6 Hz, 1 H, OH), 6.89 (d, J ϭ
CH2Cl2 (100 mL). The mixture was allowed to warm to room tem- 8.5 Hz, 2 H, aromatic H), 7.12 (t, J ϭ 6.9 Hz, 1 H, aromatic H),
perature and was stirred for an additional 3 h. Water (25 mL) was 7.23 (d, J ϭ 8.5 Hz, 2 H, aromatic H), 7.31Ϫ7.63 (m, 7 H, aromatic
added, and the organic layer was dried with MgSO4. Evaporation
of the solvent left a residue, which was purified by flash column
chromatography with acetone/petroleum ether (3:7) as eluent.
Compound 24 was finally recrystallized from hexane/toluene.
H), 7.88 (d, J ϭ 7.8 Hz, 1 H, aromatic H) ppm. 13C NMR
([D6]DMSO): δ ϭ 42.9, 55.1, 55.6, 60.9, 62.3, 73.0, 97.3 (CϪI),
103.7, 114.0, 117.6, 127.7, 127.9, 128.0, 128.2, 129.1, 129.8, 130.0,
130.2, 137.6, 139.1, 140.0, 142.4, 150.6, 155.2, 158.5, 166.5 (CϭO)
ppm. C32H30INO6 (651.5): calcd. C 59.00, H 4.64, N 2.15; found
C 58.78, H 4.44, N 2.30.
Methyl N-(2-Bromo-3,4,5-trimethoxybenzyl)-N-(4-methoxybenzyl)-
1
carbamate (24): 4.0 g, 73%, m.p. 66Ϫ67 °C. H NMR: δ ϭ 3.77 (s,
3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.85 (s, 3 3-[(4-Benzyloxy-2-bromophenyl)(hydroxy)methyl]-5,6,7-trimethoxy-
H, OCH3), 3.87 (s, 3 H, OCH3), 4.36Ϫ4.53 (m, 4 H, NCH2Ar),
6.43 (s, 1 H, aromatic H), 6.83 (d, J ϭ 8.6 Hz, 2 H, aromatic H),
2-(4-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one (17): (1.03 g,
1
74%), m.p. 154Ϫ155 °C. H NMR ([D6]DMSO): δ ϭ 3.45 (s, 3 H,
7.11Ϫ7.20 (m, 2 H, aromatic H) ppm. 13C NMR: δ ϭ 49.4, 49.9, OCH3), 3.69 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 3.96 (s, 3 H,
53.0, 55.3, 56.1, 61.0, 61.1, 106.6, 108.1, 113.9, 128.9, 129.3, 129.7,
132.2, 150.8, 152.9, 157.4, 159.0 ppm. C20H24BrNO6 (454.3): calcd.
C 52.88, H 5.32, N 3.08; found C 53.01, H 5.39, N 3.13.
OCH3), 4.18 (d, J ϭ 15.4 Hz, 1 H, NCH2), 4.48 (br. s, 1 H, CH),
5.14 (s, 2 H, OCH2), 5.20 (d, J ϭ 15.4 Hz, 1 H, NCH2), 5.33 (br.
s, 1 H, CHO), 5.67 (s, 1 H, aromatic H), 5.80 (d, J ϭ 4.4 Hz, 1 H,
OH), 6.88 (d, J ϭ 8.3 Hz, 2 H, aromatic H), 7.11 (t, J ϭ 8.5 Hz, 1
H, aromatic H), 7.18 (d, J ϭ 8.3 Hz, 2 H, aromatic H), 7.28Ϫ7.44
(m, 7 H, aromatic H) ppm. 13C NMR ([D6]DMSO): δ ϭ 42.8, 55.1,
55.5, 60.8 (two peaks overlapping), 62.2, 68.4, 69.5, 103.3, 113.8,
113.9, 117.5, 118.6, 121.0, 127.6, 127.9, 128.5, 129.1, 129.6, 130.8,
131.5, 136.6, 138.9, 140.9, 150.4, 155.1, 158.4, 158.5, 166.4 (CϭO)
ppm. C33H32BrNO7 (634.5): calcd. C 62.47, H 5.08, N 2.21; found
C 62.71, H 4.92, N 2.46.
Methyl
N-(4-Benzyloxy-2-bromo-3,5-dimethoxy)-N-(4-methoxy-
1
benzyl)carbamate (25): 4.4 g, 69%, oil. H NMR: δ ϭ 3.76 (s, 3 H,
OCH3), 3.78 (s, 6 H, 2 ϫ OCH3), 3.88 (s, 3 H, OCH3), 4.38Ϫ4.56
(m, 4 H, NCH2Ar), 5.02 (s, 2 H, NCH2), 6.46 (s, 1 H, aromatic H),
6.85 (d, J ϭ 8.6 Hz, 2 H, aromatic H), 7.10Ϫ7.22 (m, 2 H, aromatic
H), 7.30Ϫ7.41 (m, 3 H, aromatic H), 7.49Ϫ7.56 (m, 2 H, aromatic
H) ppm. 13C NMR: δ ϭ 49.4, 50.0, 53.0, 55.3, 56.2, 61.0, 75.4,
106.9, 108.3, 113.9, 128.1, 128.3, 128.9, 129.4, 129.7, 132.3, 137.4,
141.3, 151.2, 152.3, 157.4, 159.0 ppm. C26H28BrNO6 (530.4): calcd. Preparation of Isoindolinones 18 and 19: Aqueous NH4Cl addition
C 58.88, H 5.32, N 2.64; found C 60.07, H 5.11, N 2.58.
to the crude reaction mixture resulting from treatment of 24 or 25
with tBuLi as described above allowed the isolation of the isoindol-
inones 18 and 19, which were obtained in very good yield by this
method.
General Procedure for the Synthesis of the Hydroxyalkylated Isoin-
dolinones 15؊17: A solution of carbamate 24 or 25 (2.2 mmol) in
dry THF (50 mL) was cooled to Ϫ100 °C under Ar, and tBuLi
(1.4 mL, 1.7  in pentane, 2.4 mmol) was added dropwise by syr-
inge. The reaction mixture was allowed to warm to Ϫ50 °C over a
5,6,7-Trimethoxy-2-(4-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-
one (18): (640 mg, 85%), m.p. 94Ϫ95 °C (from hexane/toluene). 1H
period of 30 min, and a solution of halobenzaldehyde 28 or 29 NMR: δ ϭ 3.75 (s, 3 H, OCH3), 3.84 (s, 6 H, 2 ϫ OCH3), 4.09 (s,
(2.4 mmol) in THF (5 mL) was then added dropwise. The mixture
2 H, NCH2), 4.12 (s, 3 H, OCH3), 4.62 (s, 2 H, NCH2), 6.60 (s, 1
was allowed to warm to 0 °C, followed by addition of saturated
H, aromatic H), 6.81 (d, J ϭ 8.7 Hz, 2 H, aromatic H), 7.19 (d,
aqueous NH4Cl and extraction with CH2Cl2 (3 ϫ 30 mL). The J ϭ 8.7 Hz, 2 H, aromatic H). 13C NMR: δ ϭ 45.5, 48.8, 55.3,
combined organic layers were dried (Na2SO4) and the solvents were
evaporated in a rotary evaporator to afford 15Ϫ17 as single dia-
stereomers, which were finally purified by recrystallization from
EtOH.
56.2, 61.4, 62.6, 101.3, 114.0, 117.4, 129.4, 129.5, 138.7, 141.0,
151.5, 157.0, 159.0, 166.8 (CϭO). C19H21NO5 (343.4): calcd. C
66.46, H 6.16, N 4.08; found C 66.36, H 6.07, N 3.95.
6-Benzyloxy-5,7-dimethoxy-2-(4-methoxybenzyl)-2,3-dihydro-1H-
1
3-[(4-Benzyloxy-2-iodophenyl)(hydroxy)methyl]-5,6,7-trimethoxy-2- isoindol-1-one (19): 755 mg, 82%, oil. H NMR: δ ϭ 3.76 (s, 3 H,
(4-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one (15): 960 mg, OCH3), 3.81 (s, 3 H, OCH3), 4.10 (s, 5 H, OCH3 ϩ NCH2), 4.64
1
76%, m.p. 209Ϫ210 °C. H NMR ([D6]DMSO): δ ϭ 3.50 (s, 3 H, (s, 2 H, NCH2), 5.01 (s, 2 H, OCH2), 6.60 (s, 1 H, aromatic H),
OCH3), 3.69 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 3.96 (s, 3 H, 6.84 (d, J ϭ 8.0 Hz, 2 H, aromatic H), 7.22 (d, J ϭ 8.0 Hz, 2 H,
OCH3), 4.15 (d, J ϭ 15.5 Hz, 1 H, NCH2), 4.58 (d, J ϭ 3.2 Hz, 1 aromatic H), 7.25Ϫ7.37 (m, 3 H, aromatic H), 7.48Ϫ7.50 (m, 2 H,
H, CH), 5.16 (d, J ϭ 15.5 Hz, 1 H, NCH2Ar), 5.22Ϫ5.24 (m, 1 H,
CHO), 5.65 (s, 1 H, aromatic H), 5.90 (d, J ϭ 4.8 Hz, 1 H, OH), 101.4, 114.1, 117.5, 128.0, 128.3, 128.5, 129.4, 129.5, 137.5, 138.9,
6.87 (d, J ϭ 8.6 Hz, 2 H, aromatic H), 7.11 (dt, J ϭ 1.5, 7.5 Hz, 1 140.6, 151.8, 157.3, 159.1, 166.8 (CϭO) ppm. C25H25NO5 (419.3):
H, aromatic H), 7.20 (d, J ϭ 8.6 Hz, 2 H, aromatic H), 7.33 (dd, calcd. C 71.58, H 6.01, N 3.34; found C 71.71, H 6.22, N 3.53.
aromatic H) ppm. 13C NMR: δ ϭ 45.6, 48.9, 55.3, 56.2, 62.6, 75.7,
Eur. J. Org. Chem. 2003, 1231Ϫ1237
1235

V. Rys, A. Couture, E. Deniau, P. Grandclaudon
FULL PAPER
General Procedure for the Synthesis of the (Arylmethylene)isoindoli-
residue was dissolved in CH3CN (100 mL). The solution was
nones 4؊6: Potassium bis(trimethylsilyl)amide (KHMDS, 3.3 mL, washed with hexane (3 ϫ 50 mL) and concentrated in vacuo to a
0.5  in toluene, 1.65 mmol) was added dropwise at Ϫ78 °C to a
stirred solution of 15Ϫ17 (1.5 mmol) in THF (50 mL). Freshly dis-
tilled Me3SiCl (180 mg, 1.65 mmol) was added, and the reaction
mixture was allowed to warm to room temperature over a period
of 1 h. The mixture was recooled to Ϫ78 °C, treated with KHMDS
(3.3 mL, 0.5  in toluene, 1.65 mmol), again allowed to warm to
room temperature and finally quenched with saturated aqueous
NH4Cl before extraction with Et2O (3 ϫ 20 mL) and CH2Cl2 (3 ϫ
25 mL). The organic extracts were combined, washed with water
(10 mL) and brine, and dried (Na2SO4). The solvent was removed
under reduced pressure to afford the (arylmethylene)isoindolinones
4Ϫ6, which were purified by flash column chromatography with
EtOAc/petroleum ether (2:3) as eluent and finally recrystallized
from hexane/toluene to obtain the pure products (E)-4Ϫ6.
solid residue, which was recrystallized from EtOH to afford 30Ϫ32.
1,2,3-Trimethoxy-5-(4-methoxybenzyl)-4,5-dihydrodibenzo[cdf]indol-
1
4-one (30): 195 mg, 78%, m.p. 108Ϫ109 °C. H NMR: δ ϭ 3.75 (s,
3 H, OCH3), 3.99 (s, 3 H, OCH3), 4.17 (s, 3 H, OCH3), 4.56 (s, 3
H, OCH3), 5.11 (s, 2 H, NCH2Ar), 6.83 (d, J ϭ 6.7 Hz, 2 H, aro-
matic H), 7.03 (s, 1 H, aromatic H), 7.31 (d, J ϭ 6.7 Hz, 2 H,
aromatic H), 7.47Ϫ7.56 (m, 2 H, aromatic H), 7.74Ϫ7.78 (m, 1 H,
aromatic H), 9.15Ϫ9.19 (m, 1 H, aromatic H) ppm. 13C NMR: δ ϭ
43.4, 55.3, 60.8, 61.6, 63.1, 105.5, 108.6, 114.1, 116.2, 124.7, 125.7,
126.4, 126.5, 126.8, 128.7, 128.8, 129.0, 133.2, 135.5, 146.3, 154.0,
156.9, 159.0, 165.5 (CϭO) ppm. C26H23NO5 (249.5): calcd. C
72.71, H 5.40, N 3.26; found C 72.59, H 5.55, N 3.30.
2-Benzyloxy-1,3-trimethoxy-5-(4-methoxybenzyl)-4,5-dihydro-
dibenzo[cdf]indol-4-(5H)-one (31): 380 mg, 75%, m.p. 96Ϫ97 °C. 1H
NMR: δ ϭ 3.84 (s, 3 H, OCH3), 4.18 (s, 3 H, OCH3), 4.50 (s, 3 H,
OCH3), 5.10 (s, 2 H, NCH2Ar), 5.14 (s, 2 H, OCH2), 6.85 (d, J ϭ
8.7 Hz, 2 H, aromatic H), 7.03 (s, 1 H, aromatic H), 7.34 (d, J ϭ
8.7 Hz, 2 H, aromatic H), 7.37Ϫ7.46 (m, 3 H, aromatic H),
7.50Ϫ7.60 (m, 4 H, aromatic H), 7.76Ϫ7.79 (m, 1 H, aromatic H),
9.17Ϫ9.23 (m, 1 H, aromatic H) ppm. 13C NMR: δ ϭ 43.4, 55.3,
61.0, 63.0, 76.1, 105.5, 108.7, 114.1, 116.3, 124.9, 125.7, 126.4,
126.8, 128.3, 128.5, 128.6, 128.8, 129.1, 133.3, 135.6, 137.2, 145.3,
154.2, 157.2, 159.0, 165.5 (CϭO) ppm. C32H27NO5 (505.6): calcd.
C 76.02, H 5.38, N 2.77; found C 76.04, H 5.47, N 2.87.
(E)-3-(2-Iodobenzylidene)-5,6,7-trimethoxy-2-(4-meth-
oxybenzyl)-2,3-dihydro-1H-isoindolin-1-one (4): 700 mg, 84%, m.p.
133Ϫ134 °C. 1H NMR: δ ϭ 3.44 (s, 3 H, OCH3), 3.77 (s, 3 H,
OCH3), 3.85 (s, 3 H, OCH3), 4.13 (s, 3 H, OCH3), 5.00 (s, 2 H,
NCH2), 6.19 (s, 1 H, aromatic H), 6.24 (s, 1 H, CHϭ), 6.85 (d, J ϭ
8.6 Hz, 2 H, aromatic H), 7.03 (t, J ϭ 8.0 Hz, 1 H, aromatic H),
7.29 (d, J ϭ 8.6 Hz, 2 H, aromatic H), 7.35 (t, J ϭ 7.9 Hz, 1 H,
aromatic H), 7.44 (d, J ϭ 7.8 Hz, 1 H, aromatic H), 7.93 (d, J ϭ
8.0 Hz, 1 H, aromatic H) ppm. 13C NMR: δ ϭ 42.6, 55.3, 55.7,
61.4, 62.5, 101.1 (CϪI), 102.1, 113.4, 114.1, 115.1, 127.9, 128.7,
129.1, 129.4, 129.5, 130.9, 132.0, 136.0, 139.8, 142.9, 151.1, 156.7,
158.8, 164.9 (CϭO) ppm. C26H24INO5 (557.4): calcd. C 56.03, H
4.34, N 2.51; found C 56.31, H 4.08, N 2.32.
9-Benzyloxy-1,2,3-trimethoxy-5-(4-methoxybenzyl)-4,5-dihydro-
dibenzo[cdf]indol-4-(5H)-one (32): (370 mg, 69%), m.p. 98Ϫ99 °C.
1H NMR: δ ϭ 3.75 (s, 3 H, OCH3), 3.99 (s, 3 H, OCH3), 4.03 (s,
3 H, OCH3), 4.57 (s, 3 H, OCH3), 5.09 (s, 2 H, NCH2), 5.27 (s, 2
H, OCH2), 6.83 (d, J ϭ 8.5 Hz, 2 H, aromatic H), 6.97 (s, 1 H,
aromatic H), 7.24 (dd, J ϭ 2.5, 8.8 Hz, 1 H, aromatic H),
7.30Ϫ7.43 (m, 5 H, aromatic H), 7.50Ϫ7.52 (m, 2 H, aromatic H),
7.68 (d, J ϭ 8.8 Hz, 1 H, aromatic H), 8.76 (d, J ϭ 2.5 Hz, 1 H,
aromatic H) ppm. 13C NMR: δ ϭ 43.4, 55.2, 60.8, 61.6, 63.1, 70.1,
105.5, 108.7, 109.6, 114.1, 115.8, 116.8, 124.9, 127.3, 127.7, 127.9,
128.0, 128.5, 128.6, 128.7, 129.1, 129.8, 133.8, 137.1, 146.0, 154.1,
156.8, 156.9, 159.0, 165.3 (CϭO) ppm. C33H29NO6 (535.6): calcd.
C 74.00, H 5.46, N 2.62; found C 74.12, H 5.61, N 2.51.
(E)-6-Benzyloxy-3-(2-iodobenzylidene)-5,7-dimethoxy-2-(4-
methoxybenzyl)-2,3-dihydro-1H-isoindolin-1-one (5): 780 mg, 82%,
1
m.p. 118Ϫ119 °C. H NMR: δ ϭ 3.43 (s, 3 H, OCH3), 3.77 (s, 3
H, OCH3), 4.09 (s, 3 H, OCH3), 5.01 (s, 4 H, OCH2 ϩ NCH2),
6.21 (s, 1 H, aromatic H), 6.28 (s, 1 H, CHϭ), 6.86 (d, J ϭ 8.7 Hz,
2 H, aromatic H), 7.03 (t, J ϭ 7.4 Hz, 1 H, aromatic H), 7.25Ϫ7.38
(m, 6 H, aromatic H), 7.45Ϫ7.49 (m, 3 H, aromatic H), 7.93 (d,
J ϭ 8.0 Hz, 1 H, aromatic H) ppm. 13C NMR: δ ϭ 42.6, 55.3, 55.8,
62.6, 75.7, 101.1 (CϪI), 102.2, 113.4, 114.1, 115.2, 127.9, 128.1,
128.3, 128.4, 128.8, 129.2, 129.4, 130.9, 132.2, 136.1, 137.3, 139.3,
139.9, 142.0, 151.5, 157.0, 158.9, 165.0 (CϭO) ppm. C32H28INO5
(633.5): calcd. C 60.67, H 4.46, N 2.21; found C 60.93, H 4.49,
N 2.46.
General Procedure for the Synthesis of the Target Products 1؊3:
A solution of 30Ϫ32 (0.5 mmol) and anisole (1.07 g, 10 mmol) in
trifluoroacetic acid (30 mL) was heated at reflux under Ar for 12 h
(for 30) or for 60 h (for 31 and 32). 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
(MgSO4) and concentrated to yield a solid residue, which was
recrystallized from EtOH. The analytical data of synthetic 1Ϫ3
matched those reported for the natural products.
(E)-3-(4-Benzyloxyl-2-bromobenzylidene)-5,6,7-trimethoxy-2-(4-
methoxybenzyl)-2,3-dihydro-1H-isoindolin-1-one (6): 720 mg, 78%,
1
m.p. 107Ϫ108 °C. H NMR: δ ϭ 3.44 (s, 3 H, OCH3), 3.76 (s, 3
H, OCH3), 3.85 (s, 3 H, OCH3), 4.12 (s, 3 H, OCH3), 4.98 (s, 2 H,
OCH2), 5.08 (s, 2 H, NCH2), 6.21 (s, 1 H, aromatic H), 6.43 (s, 1
H, CHϭ), 6.84 (d, J ϭ 8.6 Hz, 2 H, aromatic H), 6.90 (dd, J ϭ
2.5, 8.5 Hz, 1 H, aromatic H), 7.26Ϫ7.39 (m, 9 H, aromatic H)
ppm. 13C NMR: δ ϭ 42.5, 55.3, 55.8, 61.4, 62.5, 70.2, 102.0, 109.2,
114.0, 115.2, 119.1, 125.4, 127.3, 128.2, 128.3, 128.6, 128.7, 129.2,
132.1, 132.2, 135.9, 136.1, 142.9, 151.1, 156.6, 158.8, 164.8 (CϭO)
ppm. C33H30BrNO6 (616.5): calcd. C 64.29, H 4.90, N 2.27; found
C 64.05, H 5.11, N 2.04.
Acknowledgments
This research was supported by the Centre National de la Recher-
che Scientifique and MENESR (grant to V. R.). We also acknowl-
edge helpful discussions and advice from Dr. T. G. C. Bird (Astra-
Zeneca Pharma).
General Procedure for the Synthesis of the Annulated Compounds
30؊32: A solution of nBu3SnH (378 mg, 1.3 mmol) and AIBN
(164 mg, 1 mmol) in dry degassed benzene (50 mL) was added by
syringe over a period of 30 min to a solution of (E)-4Ϫ6 (1 mmol)
in dry degassed benzene (500 mL) at reflux under Ar. Once ad-
dition was complete, heating at reflux was continued for a further
3 h. The benzene was evaporated under reduced pressure, and the
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