Efficient synthetic approaches to the common scaffold of indole alkaloids

Article abstract of DOI:10.1021/ol701493k

Birch reductive alkylation of 2-aminobiphenyls affords access to highly functionalized polyenes that react through a Pd(ll)-catalyzed oxidative amination cascade or through a double 1,4-addition process to provide the tetracyclic skeleton of indole alkalo

Full text of DOI:10.1021/ol701493k

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3913-3916
Efficient Synthetic Approaches to the
Common Scaffold of Indole Alkaloids
Redouane Beniazza,† Julie Dunet,† Fre´de´ric Robert,† Kurt Schenk,‡ and
Yannick Landais*,†
UniVersite´ Bordeaux 1, Institut des Sciences Mole´culaires, UMR-CNRS 5255, 351,
Cours de la libe´ration, F-33405 Talence cedex, France, and UniVersity of Lausanne,
Institut de Cristallographie, BCP, CH-1015 Dorigny-Lausanne, Switzerland
y.landais@ism.u-bordeaux1.fr
Received June 22, 2007
ABSTRACT
Birch reductive alkylation of 2-aminobiphenyls affords access to highly functionalized polyenes that react through a Pd(II)-catalyzed oxidative
amination cascade or through a double 1,4-addition process to provide the tetracyclic skeleton of indole alkaloids with up to four stereogenic
centers created in a single-pot operation.
Alkaloids of the aspidospermine groups 1 and 2 and
pseudoaspidospermidine family including pandoline 3, iso-
lated from iboga, possess a common pentacyclic framework,
with an embedded indole fragment and one or two quaternary
carbon centers that have focused the attention of synthetic
chemists for more than 40 years (Scheme 1).1 Among this
class of alkaloids, vindoline has attracted the most interest
as a synthetic precursor of carcinostatic vinblastine and
vincristine.2 These compounds are biosynthetically related
with a common precursor at the origin of the generation of
both groups of alkaloids.3 Although several elegant ap-
proaches to alkaloids 1-34 and to the Bu¨chi ketone inter-
mediate 45 have been reported, development of flexible and
Scheme 1. Alkaloids of the Aspidospermine Group
† Universite´ Bordeaux 1.
‡ University of Lausanne.
(1) Saxton, J. E. In The Alkaloids, Alkaloids of the Aspidospermine
Group; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51,
p 1.
more straightforward approaches to the tetra- and pentacyclic
core of these compounds is still required.
Among the most efficient strategies that may be envisioned
for the construction of polycyclic architectures, those relying
on cascade processes have attracted a lot of interest, ensuring
a rapid increase of the structural complexity and high bond
forming efficiency.6 We report herein two complementary
(2) (a) Saxton, J. E. Nat. Prod. Rep. 1995, 385. (b) Kuehne, M. E.;
Podhorez, D. E.; Mulamba, T.; Bornmann, W. G. J. Org. Chem. 1987, 52,
347. (c) Mangeney, P.; Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y.;
Potier, P. J. Am. Chem. Soc. 1979, 101, 2243.
(3) (a) Scott, A. I. Acc. Chem. Res. 1970, 3, 151. (b) Wenkert, E. J. Am.
Chem. Soc. 1962, 84, 98.
(4) (a) Saxton, J. E. In The Alkaloids, Synthesis of Aspidosperma
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol.
50, p 343 and refs cited. (b) Kuehne, M. E.; Kirkemo, C. L.; Matsko, T.
H.; Bohnert, J. C. J. Org. Chem. 1980, 45, 3259.
(5) (a) Ando, M.; Bu¨chi, G.; Ohnuma, T. J. Am. Chem. Soc. 1975, 97,
6880. (b) Heureux, N.; Wouters, J.; Marko, I. E. Org. Lett. 2005, 7, 5245.
10.1021/ol701493k CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/08/2007

ring. Cyclohexadiene 6, thus obtained in reproducible yield,
possesses the suitable nitrogen functional groups and con-
stitutes a valuable precursor for testing the Pd(II)-mediated
oxidative amination on 1,4-dienes.
PdII-catalyzed oxidative amination of olefins and 1,3-
dienes has recently received a great deal of attention as an
atom-economical process, allowing the elaboration of highly
functionalized heterocycles.9 On the basis of these premises,
we investigated the possible extension of the process to our
1,4-dienes, by treating precursor 6 with Pd(OAc)2 and O2 in
DMSO as a solvent.10 Without additives, oxidative amination
of 6 effectively provided the cyclized product 7 but in
moderate yield (Table 1, entry 1). A significantly better result
was obtained when using NaOAc as a base (entry 2).
Figure 1. Retrosynthetic analysis.
approaches to the tetracyclic core of alkaloids above (i.e., I,
Figure 1) based on cascade processes and desymmetrization
of cyclohexa-2,5-diene intermediates II and III, accessible
from a simple biaryl IV through Birch reductive alkylation.
The present BRAD (Birch reductive alkylation-desymme-
trization)7 strategy relies on two distinct processes, i.e., a
PdII-mediated domino oxidative amination of a cyclohexa-
diene II and a double 1,4-nucleophilic addition onto a
cyclohexadienone III. In both strategies, the stereochemistry
of the quaternary stereocenter and that of rings B and C are
controlled simultaneously. The symmetrical nature of II and
III also implies that the Pd cascade and the double Michael
process may in principle be extended to an enantioselective
series.
On the basis of some recent work from our laboratory,8 it
was envisaged that dienes such as II could be prepared via
a regioselective Birch reductive alkylation of a biaryl IV.
While these studies demonstrated that such a process is
efficient when at least one electron-rich arene is present on
the biaryl, there was no precedent on simple ortho-amino
biphenyls such as IV. The Birch reduction was thus tested
on commercially available 2-aminobiphenyl, protected with
various electron-withdrawing groups (Piv, Boc, and SO2Et).
While modest results were obtained with Piv- and Boc-
protective groups, excellent yields were observed starting
from sulfonamide 5 (Scheme 2). Deprotonation of 5 with
Table 1. PdII-Catalyzed Oxidative Amination of Diene 6
additives
(equiv)
temp
[°C]
time
(h)
entry
solvent
yielda
b
1
2
3
4
5
6
DMSO
DMSO
DMSO
toluene
DMSO
DMSO
-
55
55
55
80
55
55
24
24
30
30
24
24
50%
75%
49%
52%
91%
84%
NaOAc (2)b
CuOAc (2)b
pyridineb
NaOAc (2)/Cb
NaOAc (2)/Cc
a
b
c
Isolated yield of 7. 10 mol % of Pd(OAc)2 was used. 5 mol % of
Pd(OAc)2 was used.
Other additives such as pyridine10b and CuOAc led to no
improvement (entries 3 and 4). It was observed that oxygen
concentration was a critical factor, indicating that Pd0
reoxidation is the turnover limiting step of the process.11
Inefficient reoxidation of Pd0 into PdII leads to aggregation
of Pd0 and precipitation of Pd metal.12 Charcoal (noted as C
in Table 1) was thus added to the mixture to prevent the Pd0
aggregation.13 To our delight, this resulted in a significant
improvement of the yield and also allowed a reduction of
Pd loading (entries 5 and 6).
Scheme 2. Birch Reductive Alkylation of Biaryl 5
(9) (a) Rogers, M. M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org.
Lett. 2006, 8, 2257. (b) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem.,
Int. Ed. 2002, 41, 164. (c) Ba¨ckvall, J.-E.; Andersson, P. G. J. Am. Chem.
Soc. 1990, 112, 3683. (d) Verboom, R. C.; Persson, B. A.; Ba¨ckvall, J.-E.
J. Org. Chem. 2004, 69, 3102. (e) Hosokawa, T.; Miyagi, S.; Murahashi,
S.-I.; Sonoda, A. J. Org. Chem. 1978, 43, 2752. (f) Hegedus, L. S.;
McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444.
(10) (a) van Benthem, R. A. T. M.; Hiemstra, H.; Longarela, G. R.;
Speckamp, W. N. Tetrahedron Lett. 1994, 35, 9281. (b) Ro¨nn, M.; Ba¨ckvall,
J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749. (c) Larock, R.
C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996,
61, 3584.
n-BuLi prior to the addition of Li/NH3 was found to be
essential, “protecting” the o-aminophenyl ring from reduction
and directing the reductive alkylation onto the unsubstituted
(6) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Poli, G.; Giambastani,
G.; Heumann, A. Tetrahedron 2000, 56, 5959.
(7) (a) Abd Rahman, N.; Landais, Y. Curr. Org. Chem. 2002, 6, 1369.
(b) Studer, A.; Schleth, F. Synlett 2005, 3033. (c) Lebeuf, R.; Robert, F.;
Landais, Y. Org. Lett. 2006, 8, 4755.
(11) (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Gligorich,
K. M.; Sigman, M. S. Angew. Chem., Int. Ed. 2006, 45, 6612.
(12) Deposition of black Pd metal was effectively observed in some cases.
(13) (a) Mahaim, C.; Carrupt, P.-A.; Hagenbuch, J-P.; Florey, A.; Vogel,
P. HelV. Chim. Acta 1980, 63, 1149. (b) Steunenberg, P.; Jeanneret, V.;
Zhu, Y.-H.; Vogel, P. Tetrahedron: Asymmetry 2005, 16, 337.
(8) Lebeuf, R.; Robert, F.; Landais, Y. Org. Lett. 2005, 7, 4557.
3914
Org. Lett., Vol. 9, No. 20, 2007

With these conditions in hand, we then turned our attention
to the consecutive formation of rings B and C. Precursors
8a,b, having orthogonal protecting groups, were first pre-
pared through reduction of the nitrile and conversion of the
resulting amine into the desired amides (Scheme 3). When
generated with the stereochemistry as shown and thus de-
livers, during reductive elimination, the acetate group bound
to palladium on the bottom face and at the less-hindered C4
site to give 9a,b as single regio- and stereoisomers.16,17 The
consecutive formation of rings B and C is further supported
by the access to 9a,b from 7 through a three-step sequence,
including a reduction of the nitrile function of 7 and acylation
of the resulting amino group, followed by oxidative amina-
tion, which led to 9a,b, respectively, in 53 and 52% overall
yield (see Supporting Information).
Scheme 3. Oxidative Amination Cascade on Dienes 8a,b and
X-Ray Crystal Structure of 9b
Encouraged by these results, we then turned our attention
to the second approach that was anticipated to provide a
similar tetracyclic skeleton but with different functionaliza-
tion on ring E.18 The alternative approach using a double
1,4-addition19 was thus investigated starting from diene 8a,
which was tentatively oxidized into the desired dienone using
various conditions.20 Allylic oxidation of 8a with Mn(OAc)3
(Scheme 4, conditions A) interestingly led to the correspond-
Scheme 4. Allylic Oxidation of Diene 8a
subjected to the conditions above, 8a, led after double
oxidative amination, in a one-pot operation, to tetracyclic
compound 9a haVing four new stereogenic centers, as a
single regio- and stereoisomer. 9a was obtained in only four
steps and 41% overall yield from biaryl 5.
ing peroxide 10 instead of the expected dienone. It is worth
noticing that the same oxidation performed on an analogue
of 8a, lacking the NHSO2Et group, directly provided the
cyclohexadienone. We observed that dihydrate Mn(OAc)3
in the presence of molecular sieves afforded the best yields.
When the hexahydrate was used, various amounts of a mono-
1,4-addition product (involving the sulfonamide group) were
detected which could not be separated from minor byprod-
ucts. More reproducible results were obtained following
Corey’s method using Pd/C-t-BuOOH (Scheme 4, conditions
Oxidative amination of precursor 8b having an acrylamide
moiety was also tested and led as above to tetracyclic allylic
acetate 9b whose structure was secured through X-ray
crystallography, thus supporting the relative configuration
of 9a (1H NMR) and the regiochemistry of the acetate
incorporation. The formation and the stereochemistry of the
tetracyclic skeleton of 9a,b may be tentatively explained as
follows. Formation of ring B probably occurs prior to ring
C due to higher acidity of the NHSO2Et group.14 Ring B is
thus formed with subsequent â-elimination of an hydrido-
Pd species to generate a 1,3-cyclohexadiene such as 7.15 Pd0
is then reoxidized by oxygen into PdII which can catalyze
the second oxidative amination with the amido group
approaching anti relative to ring B to form a π-allyl-Pd
acetate such as V (Figure 2). Assuming an anti-amino palla-
dation step during the formation of ring C, V is then
(14) We noticed that quenching the reaction between 8a,b and Pd(OAc)2
before complete consumption of the starting material led to the formation
in a small amount of a monocyclized product analogous to 7.
(15) With 1,4-dienes, allylic C-H activation followed by amination of
the resulting π-allyl-Pd(II) intermediate might also be considered. For recent
studies, see: Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007,
129, 7274.
(16) Stahl recently proposed that oxidative amination of olefins with
tosylamine occurred through a syn pathway. See: Liu, G.; Stahl, S. S. J.
Am. Chem. Soc. 2007, 129, 6328. This cannot be ruled out in our case.10
(17) Trapping of π-allyl-Pd(II) intermediates such as V with various
nucleophiles in an intramolecular fashion has led so far to low yield of the
desired pentacyclic systems. Investigations on this approach are still in
progress.
(18) This feature is important in the context of the functionalization of
this ring for the synthesis of Aspidosperma and Iboga alkaloids.
(19) (a) Martin, S. F.; Campbell, C. L. J. Org. Chem. 1988, 53, 3184.
(b) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117,
11106. (c) Bland, D.; Chambournier, G.; Dragan, V.; Hart, D. J. Tetrahedron
1999, 55, 8953. (d) Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043.
(20) (a) Page, P. C. B.; McCarthy, T. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol.
7, p 83. (b) Mu¨ller, P. M.; Pfister, R. HelV. Chim. Acta 1983, 66, 771. (c)
Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149.
Figure 2. Tentative rationale for the acetate insertion.
Org. Lett., Vol. 9, No. 20, 2007
3915

B).21 Again, despite the different conditions employed,22b
only the particularly stable peroxide 10 was formed.
Various attempts at converting peroxide 10 into the desired
dienone were then carried out. After extensive experimenta-
tions, it was finally found that when heating 10 in the
presence of DBU (2 equiv)22 cyclohexadienone 11 was
formed but reacted spontaneously to provide the double 1,4-
addition product 12, an analogue of Bu¨chi ketone 4, whose
structure was unambiguously assigned through X-ray crystal-
lography (Scheme 5).
The diene oxidation-double 1,4-addition sequence may
finally be carried out in a single-pot operation, providing 12
directly from 8a in a reasonable yield (Scheme 6). This
Scheme 6. One-Pot Preparation of Protected Bu¨chi Ketone 12
from Diene 8a
Scheme 5. Synthesis of Protected Bu¨chi Ketone 12 from
Peroxide 10 and X-Ray Crystal Structure of 12
sequential cascade process thus provides a useful intermedi-
ate, i.e., 12, in the synthesis of the titled alkaloids in only
five steps and 22% overall yield from commercially available
2-aminobiphenyl.
In summary, we have described two efficient approaches
to the tetracyclic core of aspidosperma alkaloids based on a
one-pot double oxidative amination reaction and a double
1,4-addition process. The starting diene is easily at hand from
commercially available 2-aminobiphenyl using a regiose-
lective Birch reductive alkylation. This strategy to polycyclic
indole alkaloids with significant savings in effort is actively
pursued in our laboratory, with a particular emphasis on the
asymmetric version of the above processes.
Interestingly, the use of a catalytic amount of a stronger
base such as t-BuOK at room temperature led to a mixture
of products in which the monocyclized product was again
present. The role of the base is critical as heating 10 at 65
°C in the absence of a base left the peroxide unchanged.
The isolation of the stable peroxide 10 is noteworthy as it
allows a control of the double 1,4-addition, which is not
possible with dienone 11, which reacts spontaneously. Such
a feature should be helpful in the perspective of an extension
of the approach into an enantioselective series.
Acknowledgment. We thank the CNRS, MNERT, and
Re´gion Aquitaine for financial support. We gratefully
acknowledge Prof. P. Vogel (University of Lausanne) for
helpful suggestions, J. C. Lartigue and C. Vitry for NMR
and mass spectrometry experiments, Dr. R. Lebeuf for
preliminary studies, and Dr. V. Desvergnes (ISM, Universite´
Bordeaux-1) for fruitful discussions.
Supporting Information Available: Representative ex-
perimental procedures including product characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) (a) Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727. (b) The use of
Pd(OAc)2-t-BuOOH led to a similar result.
(22) 10 was found to react similarly with benzyl amine and Hu¨nig’s base
(i-Pr2NEt).
OL701493K
3916
Org. Lett., Vol. 9, No. 20, 2007