A new route to aristocularine alkaloids: Total synthesis of aristoyagonine

Article abstract of DOI:10.1021/jo049869g

A short and efficient synthesis of aristocularines, involving the sequential construction of phosphorylated 4-alkoxyisoindolinones, Horner-type reaction, and ultimate cyclization by diaryl ether coupling, is disclosed. The success of this new conceptual a

Full text of DOI:10.1021/jo049869g

The synthetic route going via the dioxocularines 4a ,b was
more appealing since these compounds could be readily
accessible from the 4-hydroxysarcocapnine epimers 6a ,b5
isolated from natural sources8 or obtained by a Ullman
coupling reaction of 1-(2-bromobenzyl)-8-hydroxyisoquin-
oline derivatives.9 They could be alternatively assembled
by intramolecular cyclization of an aminoacetaldehyde
dimethyl acetal derived from 5a ,b.10 Recently, the di-
oxocularine 4b was also inadvertently obtained along
with the aristocularine 2b and some xanthene derivatives
by cyclization of the aryloxyphenyl acetamide 7b, and a
rather sophisticated mechanism to account for the pro-
motion of this annulation process by oxalyl chloride/
stannyl chloride has been proposed.3,11 All these strate-
gies with the exception of the last one have been exploited
for the synthesis of the exemplary representative aris-
toyagonine (2a ).
We delineate here a tactically new five-step synthesis
of aristocularines that relies upon our longstanding
experience in the field of N-acylenamine and isoindoli-
none chemistry12 and we wish to disclose the success of
our new conceptual approach by describing the third total
synthesis of the Fumariaceae alkaloid aristoyagonine
(2a ).
Resu lts a n d Discu ssion . The main issue that had to
be addressed for the synthesis of the diversely substituted
aristocularines 2a ,c,d was judging the proper order for
the construction of the heterocyclic units embedded in
their skeleton. Within this context it appeared that the
oxepine ring system could be conceivably assembled by
diaryl ether formation from a cis-stilbenoid system bear-
ing the mandatory hydroxy and halogenated functional-
ities. This conceptual approach then entailed the gen-
eration of the appropriate bromoarylmethylene hydroxy-
isoindolinones 8-10 which suggested the simple ret-
rosynthetic Scheme 2.
Compounds 8-10 would be reasonably obtained by
reliance on a Horner-type reaction13 involving the suit-
ably substituted benzaldehydes 11-13 and the 3-phos-
phorylated isoindolinones 14-16. Of central importance
for this strategy then was the ability to identify a
synthetic tactic liable to give access to the requisite
A New Rou te to Ar istocu la r in e Alk a loid s:
Tota l Syn th esis of Ar istoya gon in e
Anne Moreau, Axel Couture,* Eric Deniau, and
Pierre Grandclaudon
Laboratoire de Chimie Organique Physique, UMR 8009
“Chimie Organique et Macromole´culaire”, Universite´ des
Sciences et Technologies de Lille, Baˆtiment C3(2),
F-59655 Villeneuve d’Ascq Cedex, France
axel.couture@univ-lille1.fr
Received J anuary 23, 2004
Abstr a ct: A short and efficient synthesis of aristocularines,
involving the sequential construction of phosphorylated
4-alkoxyisoindolinones, Horner-type reaction, and ultimate
cyclization by diaryl ether coupling, is disclosed. The success
of this new conceptual approach is demonstrated by the total
synthesis of the aristocularine alkaloid aristoyagonine.
Cularinoids are a group of isoquinoline alkaloids
consisting of about 60 members. Their richest natural
source is the plant families Fumariaceae,1 particularly
the genus Sarcocapnos enneaphylla.2 They are also
characterized by a benzoxepine nucleus but they occur
naturally in a large variety of oxidation states. Besides
the largest group, the cularines (1), this family includes
other highly oxidized members and among them the
aristocularines (2), notably the eminent example aris-
toyagonine (2a ), which occupies a special place since it
is the only example to date of a natural cularine alkaloid
incorporating a five-membered lactam (Scheme 1). Due
to their low natural occurrence in conjunction with their
biological activity against various cell lines3 several
synthetic tactics have been disclosed for the synthesis of
these structurally unusual alkaloids.
The main approach to the synthesis of aristocularines,
which has been confined to the construction of the sole
models 2a ,b, relies upon the initial construction of the
dibenzoxepine skeleton (Scheme 1). In this perspective
two general intermediates, the lactones 3a ,b4 and the
dioxocularines 4a ,b,5 have been synthesized. A closer
analysis of the literature reveals that improvement of
these elegant, skillful, and complementary synthetic
approaches has been limited to the development of
alternative methods for the synthesis of these key models.
Thus the lactones 3a ,b have been obtained by a Parham-
type cyclization of appropriate brominated carbamates4,6
derived from the dihydrodibenz[b,f]oxepin-10-ones 5a ,b.6
(6) Paleo, R. M.; Lamas, C.; Castedo, L.; Dominguez, D. J . Org.
Chem. 1992, 57, 2029-2033.
(7) Lamas, C.; Garcia, A.; Castedo, L.; Dominguez, D. Tetrahedron
Lett. 1989, 30, 6927-6928.
(8) Castedo, L.; Dominguez, D.; Rodriguez de Lera, A.; Tojo, E.
Tetrahedron Lett. 1984, 25, 4573-4576.
(9) Rodriguez de Lera, A.; Saa, J . M.; Suau, R.; Castedo, L. J .
Heterocycl. Chem. 1987, 24, 613-622.
(10) Garcia, A.; Castedo, L.; Dominguez, D. Tetrahedron 1995, 51,
8585-8598.
(11) Suau, R.; Lopez-Romero, J . M.; Rico, R. Tetrahedron Lett. 1996,
37, 9357-9360.
* Corresponding author. Fax: +33 (0)3 20 33 63 09.
(1) Campello, M. J .; Castedo, L.; Dominguez, D.; Rodriguez de Lera,
A.; Saa, J . M.; Suau, R.; Tojo, E.; Vidal, M. C. Tetrahedron Lett. 1984,
25, 5933-5936.
(12) (a) Couture, A.; Grandclaudon, P. Synthesis 1986, 576. (b)
Couture, A.; Grandclaudon, P.; Hooijer, S. J . Org. Chem. 1991, 56,
4977. (c) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron Lett.
1993, 34, 1479. (d) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau,
C. J . Org. Chem. 1998, 63, 3128-3132. (e) Lebrun, S.; Couture, A.;
Deniau, E.; Grandclaudon, P. Org. Biomol. Chem. 2003, 1, 1701-1706.
(f) Hoarau, C.; Couture, A.; Cornet, H.; Deniau, E.; Grandclaudon, P.
J . Org. Chem. 2001, 66, 8064-8069. (g) Hoarau, C.; Couture, A.;
Deniau, E.; Grandclaudon, P. J . Org. Chem. 2002, 67, 5846-5849.
(13) (a) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber. 1958,
91, 61. (b) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber. 1959,
92, 2499. (c) Boutagy, J .; Thomas, R. Chem. Rev. 1974, 74, 87.
(2) Tojo, E.; Dominguez, D.; Castedo, L. Phytochemistry 1991, 30,
1005-1010.
(3) Suau, R.; Rico, R.; Lopez-Romero, J . M.; Najera, F.; Ruiz, A.;
Ortiz-Lopez, F. J . Arkivoc (Zurich, Switz.) 2002, 5, 62-72.
(4) Lamas, C.; Castedo, L.; Dominguez, D. Tetrahedron Lett. 1990,
31, 6247-6248.
(5) de Lera, A. R.; Suau, R.; Castedo, L. J . Heterocycl. Chem. 1987,
24, 313-319.
10.1021/jo049869g CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/28/2004
J . Org. Chem. 2004, 69, 4527-4530
4527

SCHEME 1. Ma in Syn th etic Rou tes to Ar istocu la r in es
SCHEME 2. Retr osyn th etic Sch em e
pated that they could be alternatively involved in a
nucleophilic aromatic substitution process (SNAr), notably
with a methoxy group acting as the internal nucleofuge.
Literature precedent gave support to the feasibility of
such an approach. Indeed the sensitivity of alkoxy groups
with respect to nucleophilic attack has been skillfully
exploited in SNAr reactions, this process being activated
by ester,14 amide,15 and above all oxazoline groups16 (the
Meyers reaction) at the ortho site on the aromatic
nucleus.
The first facet of the synthesis then was the elaboration
of the polyalkoxylated and phosphorylated benzamide
derivatives 17-19. This was readily accomplished by
coupling the suitably substituted benzoic acid derivatives
20-22 via their acyl chlorides to the appropriate phos-
phorylated amines 23 and 24. Exposure of the phosphor-
ylated benzamides 17-19 to potassium bis(trimethyl-
silyl)amide (KHMDS, 1.1 equiv) at -78 °C in the pres-
ence of 18-crown-6 induced the formation of the phos-
phoryl-stabilized R-aminocarbanion.12a,f Subsequent o-
methoxy displacement by the transient carbanionic species
occurred through the SNAr process portrayed in Scheme
3 and brought about the intramolecular arylation reac-
tion thus giving rise to the desired phosphorylated
isoindolinones 14-16 after conventional workup. Inter-
estingly D2O quenching at this stage led to exclusive
incorporation of deuterium at the 3-position of the lactam
ring.17 One can reasonably assume that deprotonation
of the phosphorylated benzylic position might be ensured
by the methoxylate released upon the annulation step.
This phenomenon had some obvious implications on the
course of the synthesis since it meant that the metalated
isoindolinones 25, candidates for the planned Horner-
contiguously mono- or disubstituted isoindolinones 14-
16 incorporating a protected phenolic function at the
4-position of the aromatic moiety and further bearing the
phosphoryl auxiliary. We have recently developed a new
synthetic concept for the assemblage of phosphorylated
isoindolinones that hinges upon the base-induced aryne-
mediated cyclization of phosphorylated o-halogeno-
benzamides.10 One major criticism that we have to make
about this technique relies upon the participation of a
transient aryne moiety, which inevitably precludes the
elaboration of any 4-substituted models. However, a
synthetic strategy implying such R-aminocarbanionic
species was deemed worthy of pursuit since we antici-
(14) For a recent paper, see: Hattori, T.; Takeda, A.; Suzuki, K.;
Koike, N.; Koshiishi, E.; Miyano, S. J . Chem. Soc., Perkin Trans. 1
1998, 3661-3671.
(15) Clayden, J .; Menet, C. J . Tetrahedron Lett. 2003, 44, 3059-
3062.
(16) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297-2360.
(17) Evaluation of deuterium incorporation in compound 14 was
assayed by 1H NMR spectroscopy at 300 MHz and integration indicated
(78 ( 5)% D at C-3 with a less extensively split signal for the benzylic
proton (δ 4.87 ppm).
4528 J . Org. Chem., Vol. 69, No. 13, 2004

SCHEME 3. Syn th esis of Ar istoya gon in e (2a ) a n d Ar istocu la r in es (2c,d )
type reaction, could be intercepted by addition of the
appropriate bromobenzaldehyde derivatives 11-13
through a simple one-pot reaction. Gratifyingly, conduct-
ing the reaction according to this procedure afforded
straightforwardly the arylmethylene isoindolinones 26-
28. Compounds 27 and 28 were obtained exclusively in
Z forms while model 26 was obtained in both Z and E
forms with the Z form predominant by a large margin
(Z/E 70:30).
overall yield of 26% for the four steps (starting from the
precursor 20).
In summary, the new synthetic protocol consisting of
sequential construction of phosphorylated 4-alkoxyisoin-
(18) Irradiation of the N-methyl H3 (δ 2.90 ppm) in 27 led to
increased intensity of the downfield aromatic proton at C-6′ (δ 7.30
ppm, 5%) whereas the effect of irradiation of the O-methyl H3 (δ 3.99
ppm) was an increased intensity of the vinylic proton (δ 7.25 ppm,
8%). nOe experiments with (Z)-26 displayed enhancements between
the N-methyl H3 (δ 2.89 ppm) and the aromatic proton at C-6′ (δ 6.94
ppm, 7%) and between the vinylic proton (δ 7.21 ppm, 16%) and the
O-benzyl H2 (δ 5.20 ppm). For the minor isomer (E)-26 enhancements
of 25% were observed between N-methyl H3 (δ 3.39 ppm) and the
vinylic proton (δ 6.47 ppm) and of 4% between the O-benzyl H2 (δ 4.31
ppm) and the aromatic proton at C-6′ (δ 6.47 ppm).
The configuration of the double bond was unambigu-
1
ously established from their H NMR spectra with nOe
experiments.18 Retrieval of the phenolic functions by
treatment of 26 and 28 by BCl3 and 27 by BBr3 proceeded
uneventfully to deliver the deprotected models 8-10,
candidates for the annulation step. Noteworthily this
operation did not spare the stereochemistry of the exo-
cyclic double bond as witnessed by the exclusive forma-
tion of the Z-configured isomer 8 by treatment of (Z,E)-
26. The Z configuration was unambiguously confirmed
on the basis of nOe effects in the 1H NMR spectra.19
Stereochemical considerations about the central double
bond were not crucial for the creation of the diaryl ether
linkage ensuring the construction of the dibenzoxepine
ring system. As a means of assembling this heterocyclic
unit the diaryl ether coupling was accomplished utilizing
a recently published catalytic copper-mediated method20
[5 mol % of (CuOTf)2‚PhMe, Cs2CO3, pyridine, 110 °C,
24 h)]. Gratifyingly, this protocol delivered the annulated
models 2c,d and thus afforded straightforwardly the
target natural product aristoyagonine (2a ) with an
J . Org. Chem, Vol. 69, No. 13, 2004 4529

layer was washed with brine, dried over Na2SO4, and evaporated
under vacuum to leave a crude solid residue that was purified
by recrystallization in EtOH.
dolinones, Horner-type reaction, deprotection, and ulti-
mate diaryl ether coupling has been applied to an
efficient construction of the aristocularine skeleton. The
advantage of this synthesis lies in the small number of
synthetic steps and the ease of elaboration of the inter-
mediates involved in the assembly of these alkaloids. The
synthetic potential of this method also has been demon-
strated by the third known total synthesis of the alkaloid
aristoyagonine.
(Z)-4-Ben zyloxy-3-(2-br om o-3,4-d im eth oxyben zylid en e)-
5-m eth oxy-2-m eth yl-2,3-dih ydr o-1H-isoin dol-1-on e (26). The
arylmethyleneisoindolinone 26 was obtained as a mixture of
unseparable Z and E isomers (0.96 g, 42%). The isomeric ratio
(Z/ E 70:30) was determined from the 1H NMR spectrum and
integration of the N-CH3 protons [δ 2.89 ppm for (Z)-26 and δ
3.39 ppm for (E)-26]. The crude mixture dissolved in hexane (100
mL) was refluxed overnight with cat. I2 to give rise exclusively
and quantitatively to the Z isomer, which was ultimately
purified by recrystallization in EtOH to afford (Z)-26 as pale
Exp er im en ta l Section
1
yellow crystals; mp 132-133 °C; H NMR (300 MHz, CDCl3) δ
Typ ica l P r oced u r e for th e Syn th esis of th e P h osp h o-
r yla ted Isoin d olin on es 14-16. A solution of KHMDS (0.5 M
in toluene, 8.8 mL, 4.4 mmol) was added dropwise to a carefully
degassed solution of the phosphorylated 2-methoxybenzamide
derivative 17-19 (4.0 mmol) and 18-crown-6 (1.16 g, 4.4 mmol)
in THF (50 mL) at -78 °C under Ar. The solution was stirred
for 15 min and then allowed to warm to room temperature over
a period of 2 h. Aqueous NH4Cl solution (10%, 10 mL) was added
and after dilution with water the mixture was extracted with
Et2O (2 × 25 mL) and CH2Cl2 (2 × 25 mL). The organic extracts
were washed with water and brine, dried over Na2SO4, and
evaporated in vacuo. Flash column chromatography on silica gel
with ethyl acetate/hexanes (9:1) as eluent followed by recrys-
tallization from hexane-toluene afforded the phosphorylated
isoindolinones 14-16.
2.89 (s, 3 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 3.96 (s, 3 H), 5.20 (s, 2
H), 6.85 (d, J ) 8.5 Hz, 1 H), 6.94 (d, J ) 8.5 Hz, 1 H), 7.04 (d,
J ) 8.3 Hz, 1 H), 7.21 (s, 1 H), 7.30-7.36 (m, 3 H), 7.51 (d, J )
7.8 Hz, 2 H), 7.60 (d, J ) 8.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
δ 30.4, 56.1, 56.4, 60.6, 74.7, 110.6, 111.1, 113.1, 119.6, 120.1,
122.6, 126.6, 128.3, 128.5, 128.6, 129.4, 129.6, 135.5, 136.9, 143.0,
152.8, 156.4, 168.5. Anal. Calcd for C26H24BrNO5: C, 61.19; H,
4.74; N, 2.74. Found: C, 60.98; H, 4.84; N, 2.50.
Typ ica l P r oced u r e for th e Syn th esis of th e Dep r otected
3-Ar ylm eth ylen eisoin d olin on es 8-10. A solution of BCl3 (1
M in CH2Cl2, 1.06 mL, 1.06 mmol, 2 equiv, for 26 and 28) or
BBr3 (1 M in CH2Cl2, 1.06 mL, 1.06 mmol, 2 equiv, for 27) was
added by syringe to a cooled solution (-78 °C) of the protected
arylmethylene isoindolinone 26-28 (0.53 mmol) in CH2Cl2 (15
mL). The reaction mixture was stirred at -78 °C for 2 h and
MeOH (5 mL) was subsequently added three times. The organic
solvents were removed in a vacuum, the crude solid residue was
dissolved in Et2O (25 mL), and the resulting ethereal solution
was washed with brine and dried over Na2SO4. Flash column
chromatography on silica gel with ethyl acetate/hexanes (1:1)
as eluent afforded the phenolic derivatives 8-10.
4-Ben zyloxy-3-d ip h en ylp h osp h in oyl-5-m eth oxy-2-m eth -
yl-2,3-d ih yd r o-1H-isoin d ol-1-on e (14). White solid, 1.29 g
1
(67%); mp 161-162 °C; H NMR (300 MHz, CDCl3) δ 3.00 (s, 3
H), 3.85 (s, 3 H), 4.74 (s, 2 H), 4.87 (d, J HP ) 7.6 Hz, 1 H), 6.98
(d, J ) 8.1 Hz, 1 H), 7.09-7.13 (m, 2 H), 7.25-7.47 (m, 12 H),
7.61-7.68 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 30.8, 56.3, 63.6
(d, J CP ) 70 Hz), 74.4, 113.7, 119.6, 126.9 (d, J CP ) 2 Hz), 127.9
(d, J CP ) 97 Hz), 128.2, 128.21 (d, J CP ) 12 Hz), 128.25 (d, J CP
(Z)-3-(2-Br om o-3,4-d im eth oxyben zylid en e)-4-h yd r oxy-5-
m eth oxy-2-m eth yl-2,3-d ih yd r o-1H-isoin d ol-1-on e (8). Pale
1
) 12 Hz), 128.26, 128.7, 130.8 (d, J CP ) 96 Hz), 131.6 (d, J CP
)
yellow crystals from EtOH, 174 mg (78%); mp 207-208 °C; H
9 Hz), 131.7 (d, J CP ) 8 Hz), 132.2 (d, J CP ) 3 Hz), 132.4 (d, J CP
) 3 Hz), 132.8 (d, J CP ) 3 Hz), 137.0, 142.5 (d, J CP ) 3 Hz),
155.2 (d, J CP ) 2 Hz), 168.3; 31P NMR (121 MHz, CDCl3) δ 30.3.
Anal. Calcd for C29H26NO4P: C, 72.04; H, 5.42; N, 2.90. Found:
C, 72.35; H, 5.20; N, 3.09.
NMR (300 MHz, CDCl3) δ 2.92 (s, 3 H), 3.87 (s, 3 H), 3.89 (s, 3
H), 3.95 (s, 3 H), 6.53 (s, 1 H), 6.86 (d, J ) 8.5 Hz, 1 H), 6.95 (d,
J ) 8.2 Hz, 1 H), 7.02 (d, J ) 8.5 Hz, 1 H), 7.09 (s, 1 H), 7.40 (d,
J ) 8.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 30.2, 56.1, 56.6,
60.5, 110.6, 110.7, 110.9, 115.4, 120.1, 122.3, 122.9, 126.7, 129.6,
Typ ica l P r oced u r e for th e Syn th esis of th e 3-Ar ylm eth -
ylen eisoin d olin on es 26-28. The synthesis was initially car-
ried out as described above. After addition of the metalating
agent at -78 °C, the reaction mixture was stirred for an
additional 15 min and then treated by dropwise addition of a
solution of 2-bromobenzaldehyde derivative 11-13 (4.0 mmol)
in THF (10 mL). The mixture was stirred at -78 °C for 30 min,
warmed to 0 °C over a period of 1 h, and subsequently warmed
to room temperature for a longer period (2 h). Aqueous NH4Cl
solution (10%, 10 mL) was added followed by water and the
aqueous phase was extracted with Et2O (2 × 30 mL). The organic
135.6, 141.1, 146.4, 149.9, 152.7, 168.6. Anal. Calcd for C19H18
BrNO5: C, 54.30; H, 4.32; N, 3.33. Found: C, 54.44; H, 4.24; N,
3.52.
-
Typ ica l P r oced u r e for t h e Syn t h esis of t h e Ar ist o-
cu la r in es 2a ,c,d . A solution of compound 8-10 (0.6 mmol), Cs2-
CO3 (277 mg, 0.85 mmol), and copper(I) trifluoromethane-
sulfonate toluene complex (15.5 mg, 0.03 mmol) in pyridine (10
mL) was refluxed for 24 h. The reaction mixture was poured
into 1 M HCl (5 mL) and extracted with ethyl acetate (2 × 15
mL). The organic layer was stirred with 10% NaOH solution (20
mL) and then washed with water and brine, dried over MgSO4,
filtered, and concentrated to give a yellow solid. Aristoyagonine2
(2a ) was obtained by recrystallization from MeOH as bright
yellow crystals, 163 mg (80%).
(19) For example, a sizable nOe effect (10%) of the aromatic proton
C-6′ (δ 7.02 ppm) was observed upon irradiation of the N-methyl group
(δ 2.92) for compound 8.
Ack n ow led gm en t. This research was supported by
the Centre National de la Recherche Scientifique and
MENESR (grant to A.M.). We also acknowledge helpful
discussions and advice from Dr. T. G. C. Bird (Astra-
Zeneca Pharma).
Su p p or tin g In for m a tion Ava ila ble: General methods
and materials and characterization for all other substrates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) (a) Xing, X.; Padmanaban, D.; Yeh, L.-A.; Cuny, G. D. Tetra-
hedron 2002, 58, 7903-7910. (b) Marcoux, J . F.; Doyen, S.; Buchwald,
S. L. J . Am. Chem. Soc. 1997, 119, 10539-10540.
J O049869G
4530 J . Org. Chem., Vol. 69, No. 13, 2004