First synthesis of marine alkaloid (±)-bengacarboline

Article abstract of DOI:10.1055/s-2003-40836

Bengacarboline 1, a marine alkaloid, potent inhibitor of topoisomerase II, has been synthesized in nine steps from indol-3-carboxylic acid and tryptamine.

Full text of DOI:10.1055/s-2003-40836

1488
LETTER
First Synthesis of Marine Alkaloid (±)-Bengacarboline
First Synthesis of
M
n
a
rine
A
lkal
n
oid ( )-Beng
i
acarbo
e
line Pouilhès,a Yves Langlois,*a Angèle Chiaronib
a
Laboratoire de Synthèse des Substances Naturelles, Associé au CNRS, Bâtiment 410, Université de Paris-Sud, 91405, Orsay, France
Fax +33(1)69154679; E-mail: langlois@icmo.u-psud.fr
b
Cristallochimie, Institut de Chimie des Substances Naturelles, CNRS, 91198, Gif-sur-Yvette, France
Received 17 April 2003
Cbz
H2N
H
Abstract: Bengacarboline 1, a marine alkaloid, potent inhibitor of
topoisomerase II, has been synthesized in nine steps from indol-3-
carboxylic acid and tryptamine.
N
X–
NH
NH
+
1
Key words: alkaloid, indole, imine, cyclization, total synthesis
N
N
H
N
H
H
N
H
NH
NSO2Ph
Bengacarboline 1 a marine alkaloid, extracted from the
Fijian ascidian Didemnum sp. has been described six
years ago by Ireland and co-workers.1 This alkaloid is an
inhibitor of topoisomerase II and displays an in vitro toxi-
city with a mean of 0.9 mg/mL (0.4 mmol/mL) toward 26
cell line tumor panel. The structure of bengacarboline 1 is
characterized by a tetrahydro-b-carboline core linked at
C1 with a tryptamine and an indol units. Absolute config-
uration of the quaternary center in bengacarboline (1) has
not yet been determined, but the CD spectrum of this
alkaloid showed a strong positive peak at 247 nm.
2
Bengacarboline 1
NHCbz
H2N
O
+
N
H
N
H
NSO2Ph
4
3
The original structure as well as the interesting biological
activity of bengacarboline 1 led us to plan a total synthesis
of this alkaloid following the retrosynthetic analysis
shown in Scheme 1. We envisioned making the quaterna-
ry center by a nucleophilic attack of the indole unit at the
intermediate iminium salt 2 in a Pictet–Spengler type cy-
clization.2 The imine precursor of the iminium 2 should be
obtained by condensation between the keto derivative 3
and tryptamine (4). In a first set of reactions, ketone 3
could be prepared using indole-3-carboxylic derivative 5
and an additional tryptamine unit (4).
O
OH
H2N
+
N
SO2Ph
N
H
4
5
Scheme 1
Condensation of tryptamine (4) with the keto compound 3
using a wide range of classical reaction conditions failed.
Fortunately, the use of microwave irradiation in 1,4-
xylene in the presence of zinc dichloride afforded the
expected imine derivative 10 in 67% yield (Scheme 3).6
The preparation of the keto derivative 3 is summarized in
Scheme 2. Protection of nitrogen in indole-3-carboxylic
acid (6) affording the N-sulfonyl derivative 53 was fol-
lowed by acid chloride formation and acylation of
tryptamine.
The construction of the quaternary center, a corner stone
in this synthesis, was next examined. However, no cy-
clization was observed under a variety of reaction condi-
tions in the presence of Brønsted or Lewis acids.7 We
hypothesise that the inactivity of the imine toward nucleo-
philic attack of indole could be due to several factors such
as instability of the imine group, steric hindrance and con-
jugation of the imine with indole nitrogens despite the
presence of a sulfonyl protecting group for one of them.
We therefore turned our attention to the use of trifluoro-
acetic anhydride which generated a highly electrophilic
acyl iminium intermediate. Under reflux in dichlo-
romethane, this reagent afforded the expected tetrahydro-
b-carboline (11) as trifluoroacetamide derivative
(Scheme 3).8
Amide 7 was isolated in good overall yield. Compound 7
was in turn submitted to a Bischler–Napieralski cycliza-
tion in the presence of phosphorous oxychloride.4 The re-
sulting dihydro-b-carboline (8) was then acylated with
carbobenzyloxy chloride under Schotten–Baumann con-
ditions. Nucleophilic addition of hydroxy anion on the
acyl iminium intermediate 9 was followed by spontaneous
ring opening affording the anticipated keto derivative 3 in
42% overall yield from 7 (Scheme 2).5
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1488,1490,ftx,en;G08703ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Synthesis of Marine Alkaloid (±)-Bengacarboline
1489
O
At this stage, we were not able to crystallize compound 11
for X-ray analysis to secure the formation of the quaterna-
ry center. However, N-sulfonylation with 4-nitrophenyl-
sulfonyl chloride afforded compound 12,9 which
crystallized as small needles by diffusion of pentane in an
ethyl acetate solution of 12. The structure of compound 12
is shown in Figure 1.10 Unexpectedly, an additional ring
was formed in 12 by nucleophilic attack of the indole
nitrogen of the tryptamine moiety on trifluoroacetamide
carbonyl.
OH
a, b
5
N
H
6
O
N
c, d
H
N
N
H
SO2Ph
7
N
f
e
N
H
NSO2Ph
8
X–
+
Cbz
N
3
N
H
NSO2Ph
HO–
9
Scheme 2 Reagents and conditions: a) BuLi, THF, –60 °C to
–40 °C, 30 min; b) PhSO2Cl, –60 °C to 20 °C, 20 h, 88%; c) SOCl2,
neat, 20 °C, 3 h; d), 4, K2CO3, EtOAc–H2O, 20 °C, 20 h, 98%;
e) POCl3, neat, 80 °C, 3 h; f) CbzCl, Na2CO3, CH2Cl2–H2O, 20 °C,
20 h, 42%.
Cbz
H
N
Figure 1 X-ray Structure of compound 12.
N
a
3
Final deprotections on compound 11 were then performed
in two steps. Hydrogenolysis of carbobenzyloxy group
under classical conditions generated the tryptamine side
chain. In a final step, alkaline hydrolysis of both trifluoro-
acetyl and phenyl sulfonyl goups afforded ( )-bengacar-
boline (1).8 The modest yield observed during the last step
is probably due to the instability of bengacarboline (1) in
alkaline media.1
N
H
N
H
10
NSO2Ph
H
Cbz
N
NCOCF3
b
During hydrogenolysis of the Cbz–protecting group in 11,
we also observed the formation of a new compound 13,
obtained by an apparent exchange of protecting group be-
tween trifluoroacetamide and Cbz carbamate. A tetrahy-
dro carboline ring opening followed by a competitive ring
closure between the tryptamine nitrogens in the iminium
intermediate 14 as depicted in Scheme 4 is more likely. If
this equilibrium can be performed with an acidic catalysis
in the presence of an enantiomerically pure acid, like cam-
phorsulfonic acid, it opens the way to a possible dynamic
resolution of racemic bengacarboline (1). This point is un-
der investigation.
N
HN
H
NSO2Ph
11
c, d
(±)-1
Scheme 3 Reagents and conditions: a) 4, ZnCl2 10%, (w/w),
1,4-Me2C6H4, microwave, 130 °C, 1 h, 67%; b) TFAA, CH2Cl2,
reflux, 15 h, 69%; c) H2, Pd–C, MeOH, 20 °C, 20 h, 50%;
d) K2CO3, MeOH–H2O, 60 °C, 20 h, 37%.
Synlett 2003, No. 10, 1488–1490 © Thieme Stuttgart · New York

1490
A. Pouilhès et al.
LETTER
CbzHN
References
(1) Foderato, T. A.; Barrows, L. R.; Lassota, P.; Ireland, C. M.
J. Org. Chem. 1997, 62, 6064.
NCOCF3
(2) For a review concerning the Pictet–Spengler cyclization,
see: Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
(3) (a) Mouhaddid, A.; Joseph, B.; Hasnaoui, A.; Mérour, J.-Y.
Synthesis 2000, 549. (b) Bennasar, M. L.; Roca, T.; Griera,
R.; Bassa, M.; Bosh, J. J. Org. Chem. 2002, 67, 6268.
(4) For a review concerning the use of POCl3, see: Sharma, S.
D.; Kanwar, S. Indian J. Chem., Sect. B 1998, 37, 965.
(5) For a related reaction, see: (a) Siddiqui, S.; Siddiqui, B. S.;
Naeed, A.; Begum, S.; Khan, K. A.; Ahmad, A. Fitoterapia
1990, 5, 425. (b) Faizi, S.; Naz, A. Tetrahedron 2002, 58,
6185.
N
H
N
H
NSO2Ph
11
a
CbzHN
F3COCHN
a
(6) A mixture of compound 3 (236 mg, 0.4 mmol), tryptamine
(131 mg, 0.8 mmol), ZnCl2 (24 mg, 0.18 mmol) in xylene
(0.7 mL) was irradiated under microwave (Synthewave 402,
Prolabo) at 130 °C for 60 min. After evaporation under
vacuum, the crude residue was purified by chromatography
(SiO2, EtOAc–heptane 40:60) affording imine 10 (197 mg,
67%).
(7) For other examples of Pictet–Spengler cyclization between
indole and ketimine, see: (a) Spadoni, G.; Balsamini, C.;
Bedini, A.; Duranti, E.; Tontini, A. J. Heterocycl. Chem.
1992, 29, 305. (b) Rodriguez, J. G.; Gil-Lopetegui, P. J.
Heterocycl. Chem. 1993, 30, 373. (c) Carrasco, N.; Urzua,
A.; Cassels, B. K. J. Org. Chem. 1973, 38, 4342.
(8) Typical Procedure for Preparation of Compound 11:
A solution of imine 10 (392 mg, 0.55mmol) and trifluoro-
acetic anhydride (2 mL) in CH2Cl2 (20 mL) was stirred at
45 °C for 15 h. After cooling at r.t., the solution was
concentrated in vacuo. The residue was dissolved in CH2Cl2
and washed with an aq solution of NaHCO3 (10%). The
layers were separated and the aq solution was extracted
additionally with CH2Cl2. The combined organic layers were
washed with H2O, dried over anhyd Na2SO4, filtrated and
evaporated in vacuo yielding crude carboline 11.
b
N
H
N
+
H
NSO2Ph
b
14
F3COCHN
NCbz
N
H
N
H
NSO2Ph
13
Scheme 4
Purification by flash chromatography (SiO2, EtOAc–
heptane 40:60) afforded compound 11 (306 mg, 67%).
Analytical data: 1H NMR (250MHz, CDCl3): d = 7.88 (d,
J = 7.6 Hz, 1 H), 7.79 (d, J = 6.9 Hz, 2 H), 7.53 (d, J = 6.9
Hz, 1 H), 7.57–7.06 (m, 17 H), 6.92 (t, J = 7.6 Hz, 1 H), 6.77
(d, J = 7.6 Hz, 1 H), 5.28 (d, J = 12.5 Hz, 1 H), 5.13 (bs,
1 H), 5.08 (d, J = 12.5 Hz, 1 H), 3.79 (d, J = 9.7 Hz, 1 H),
3.44–3.15 (m, 4 H), 2.98–2.74 (m, 2 H), 2.73–2.57 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 157.62, 138.22–118.89,
113.51, 112.47, 109.61, 105.23, 67.48, 60.21, 41.33, 38.22,
24.68, 22.21. IR(film): n = 3324, 3060, 2928, 1700 cm–1.
MS(electrospray): m/z = 838 [M + Na], 816 [M + H].
HRMS: Calcd for C45H36F3N5O5SNa: 838.2287. Found:
838.2254. ( )-Bengacarboline (1). HRMS: Calcd for
C29H28N5 [M + H]: 446.2345. Found: 446.2347.
In summary, we were able to complete in nine steps the
first synthesis of the cytotoxic marine alkaloid bengacar-
boline (1). The main features of this synthesis are the use
of a microwave irradiation procedure for a ketimine
formation and of trifluoroacetic anhydride to induce a
tetrahydro-b-carboline ring closure.
Acknowledgment
We thank Drs. A. Loupy and A. Petit for their helpful advices in
using microwave irradiation procedure and CNRS and Université
de Paris-sud for financial supports.
(9) A solution of compound 11 (0.06 mmol) in THF (2 mL) was
treated at –78 °C under argon with KHMDS in solution in
toluene (3 equiv) for 30 min. p-Nitrosulfonyl chloride (1.5
equiv) in THF (0.8 mL) was added. After 45 min, the
reaction mixture was warmed to r.t. in 1 h and 30 min. The
reaction mixture was extracted with CH2Cl2, washed with an
aq solution of Na2CO3 (10%). After evaporation, the crude
mixture was purified by chromatography (SiO2, EtOAc–
heptane 50:50) affording compound 12 in 73% yield.
(10) The details of X-ray structure of compound 12 (Figure 1)
will be given in a full paper (Service de cristallochimie,
Institut de Chimie des Substances Naturelles).
Synlett 2003, No. 10, 1488–1490 © Thieme Stuttgart · New York