A Straightforward synthetic entry to cleavamine-type indole alkaloids by a ring-closing metathesis-vinyl halide heck cyclization strategy

Article abstract of DOI:10.1021/ol200437k

An indole-templated ring-closing metathesis has been used to create the central nine-membered ring of the cleavamine-type alkaloids. A subsequent intramolecular vinyl halide Heck reaction upon the resulting azacyclononene ring completes the assembly of th

Full text of DOI:10.1021/ol200437k

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2042–2045
A Straightforward Synthetic Entry to
Cleavamine-Type Indole Alkaloids by a
Ring-Closing Metathesis-Vinyl Halide
Heck Cyclization Strategy
ꢀ
M.-Llu¨ısa Bennasar,* Daniel Sole, Ester Zulaica, and Sandra Alonso
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institut de Biomedicina
(IBUB), University of Barcelona, Barcelona 08028, Spain
bennasar@ub.edu
Received February 17, 2011
ABSTRACT
An indole-templated ring-closing metathesis has been used to create the central nine-membered ring of the cleavamine-type alkaloids. A
subsequent intramolecular vinyl halide Heck reaction upon the resulting azacyclononene ring completes the assembly of the strained
1-azabicyclo[6.3.1]dodecane framework of the alkaloids. The usefulness of the approach is illustrated with the synthesis of (()-cleavamine
and (()-dihydrocleavamine.
Indole alkaloids belonging to the Iboga family have long
caught the attention of synthetic organic chemists owing to
their complex architecture as well as their diverse and
important biological activities.1 Most of these alkaloids
(e.g., catharanthine, Figure 1) are structurally character-
ized by a pentacyclic skeleton with indole and isoquinucli-
dine rings fused by a seven-membered C ring. However,
there is a small subgroup of natural bases (cleavamine,
velbanamine, or (þ)-20R-dihydrocleavamine) that exhibit
a 16,21-seco structure, featuring a bridged 1-azabicyclo-
[6.3.1]dodecane framework. The cleavamine alkaloids are
of particular interest not only because they have provided
key synthetic intermediates for pentacyclic Iboga deriva-
tives2 but also because they constitute the indole upper half
of the antitumoral bisindole Catharanthus alkaloids vin-
blastine and vincristine.3
Our long-standing interest in the synthesis of indole
alkaloids led us to envisage a straightforward synthetic
approach to the bridged cleavamine framework, relying on
an indole-templated ring-closing metathesis (RCM)4 to
construct the central nine-membered ring and a vinyl
halide Heck cyclization5 to close the piperidine ring.
As shown in Scheme 1, the metathetic ring closure of a
2,3-dialkenylindole would provide a tricyclic ABC sub-
structure (i.e., azonino[5,4-b]indole I), from which the
carbon skeleton would be completed by inserting a
2-ethylpropene unit between the aliphatic nitrogen
and C-5. Thus, after N-alkylation with the appropriate
haloalkenyl halide, an intramolecular Heck coupling
upon the 2-allylindole moiety would serve to close the
piperidine ring and at the same time install the requisite
20-ethyl group. This Letter describes the development
of the above annulation chemistry and its use in the total
(1) For reviews, see:(a) Cordell, G. A. In Indoles, The Monoterpenoid
Indole Alkaloids; Saxton, J. E., Ed.; Wiley: New York, 1983; Vol. 25, Part 4,
Chapter 10. (b) Saxton, J. E. In Monoterpenoid Indole Alkaloids; Saxton,
J. E., Ed.; Wiley: Chichester, 1994; Supplement to Vol. 25, Part 4, Chapter
10.
(4) For general reviews, see: (a) Grubbs, R. H., Ed. Handbook of
Metathesis; Wiley-VCH: Weinheim, 2003; Vol. 2. (b) Deiters, A.; Martin,
S. F. Chem. Rev. 2004, 104, 2199–2238.
(2) Sundberg, R. J.; Smith, S. Q. In The Alkaloids; Cordell, G. A., Ed.;
Academic Presss: Amsterdam, 2002; Vol. 59, Chapter 2.
(3) Brossi, A.; Suffness, M., Eds. The Alkaloids, Vol. 37; Academic
Press: San Diego, 1990.
€
(5) For general reviews, see: (a) Brase, S.; de Meijere, A. In Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A.; Diederich, F., Eds.;
Wiley-WCH: New York, 2004; pp 217-316. (b) Zeni, G.; Larock, R. C.
Chem. Rev. 2006, 106, 4644–4680.
r
10.1021/ol200437k
Published on Web 03/10/2011
2011 American Chemical Society

Scheme 1. Synthetic Strategy
rare.11 In this context, we have recently become involved in
vinyl halide Heck reactions upon azocine rings for the total
synthesis of apparicine.12
Figure 1. Iboga and Catharanthus indole alkaloids.
We set out to study the indole-templated RCM en route
to cleavamine, targeting azonino[5,4-b]indoles I, with the
5,6 double bond functionality required for the Heck
coupling. To this end, indole 4 (Scheme 2), which is
equipped with a Boc group at the aliphatic nitrogen and a
robust phenylsulfonyl at the indole nitrogen, was selected as
the starting diene. This compound was efficiently prepared
from the protected tryptophol 113 by successive introduc-
tion of the required alkenyl appendages. Thus, the exposure
of 1 to excess LDA and CuCN followed by the reaction of
the intermediate organocopper with allyl bromide led to
2-allylindole 2 (65%), which was uneventfully converted
synthesis of (()-cleavamine and its 14,20-cis-dihydro
derivative.
Although the RCM methodology has become a power-
ful tool for the synthesis of medium sized rings,6 the
construction of nine-membered rings can be challenging.7
Based on our previous RCM synthesis of azocinoindoles,8
we assumed that both the fused indole ring and the
nitrogen carbamate would operate synergistically, thus
favoring the ring closure. On the other hand, although
Heck couplings of vinyl halides and elaborated
cyclohexenes9 or cycloheptenes10 have proved to be useful
for the assembly of the bridged core of several indole
alkaloids, cyclizations upon higher cycloalkenes to pro-
duce strained bridged systems similar to our proposal are
Scheme 2. Synthesis and RCM of Diene 4
(6) (a) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073–2077. (b)
Yet, L. Chem. Rev. 2000, 100, 2963–3007. (c) Michaut, A.; Rodriguez, J.
Angew. Chem., Int. Ed. 2006, 45, 5740–5750.
(7) For instance, see: (a) Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C.
Org. Lett. 2003, 5, 89–92. (b) Enders, D.; Lenzen, A.; Backes, M.;
Janeck, C.; Catlin, K.; Lannou, M.-I.; Runsink, J.; Raabe, G. J. Org.
Chem. 2005, 70, 10538–10551. (c) Schwartz, K. D.; White, J. D. Org.
Lett. 2011, 13, 248–251.
ꢀ
(8) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Tetrahedron
2007, 63, 861–866.
(9) (a) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695–
1698. (b) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030–3031. (c) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59,
ꢀ
ꢀ
2685–2686. (d) Sole, D.; Bonjoch, J.; Garcıa-Rubio, S.; Peidro, E.;
´
Bosch, J. Chem.;Eur. J. 2000, 6, 655–665. (e) Eichberg, M. J.; Dorta,
R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.; Vollhardt, K. P. C.
J. Am. Chem. Soc. 2001, 123, 9324–9337. (f) Mori, M.; Nakanishi, M.;
Kahishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801–9807. (g)
Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D. J.
Am. Chem. Soc. 2008, 130, 5368–5377. (h) Martin, D. B. C.; Vanderwal,
C. D. J. Am. Chem. Soc. 2009, 131, 3472–3473.
(10) (a) Birman, V. B.; Rawal, V. H. J. Org. Chem. 1998, 63, 9146–
ꢀ
9147. (b) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Synlett 2008,
667–670.
(11) For related Heck processes involving more robust aryl halides,
see: (a) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998, 39,
4139–4142. (b) Ribelin, T. P.; Judd, A. S.; Akritopoulou-Zanze, I.;
Henry, R. F.; Cross, J. L.; Whittern, D. N.; Djuric, S. W. Org. Lett. 2007,
9, 5119–5122. (c) See also ref 7b.
Org. Lett., Vol. 13, No. 8, 2011
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into diene 4 by alkylation of the corresponding tosylate 3
with allylamine and subsequent protection of the resulting
secondary amine (75% for the two steps). As anticipated,
ring closure of diene 4 proceeded in the presence of the
second-generation Grubbs catalyst in refluxing CH2Cl2.
Satisfactorily, the reaction was completed in2 h 30min and
azoninoindole 5, with the Z configuration of the double
bond, was isolated in 75% yield.
At this point, access to the more advanced synthetic
intermediate 6 required the manipulation of the aliphatic
nitrogen of 5 to install the haloalkenyl chain for the
subsequent Heck reaction. The N-Boc group was success-
fully removed using a mild acid protocol (1.2 M HCl in
MeOH at rt), and the resulting secondary amine was
directly alkylated with (Z)-3-bromo-2-ethyl-1-iodopro-
pene14 to give 6 in a 79% overall yield (Scheme 3).
precatalysts [Pd(PPh3)4, Pd2dba3], ligands (BINAP, dppe),
and additives (proton-sponge, Et3N, diisopropylethyl-
amine) in refluxing toluene, we obtained mixtures of the
starting material and variable amounts of tetracycle 9,
which presumably arose from 8 by oxidation. Although we
were able to isolate 8 when using shorter reaction times or
lower temperatures, it proved to be highly unstable,
slowly being converted into 9 under extractive workup
or column chromatography.15 Fortunately, after screen-
ing other conditions for the Heck reaction, we found
that the outcome of the cyclization changed completely
on exposure of vinyl iodide 6 to Pd2dba3/xantphos and
K2CO3 in toluene-Et3N at 80 °C within a short reaction
time (1.5 h). Tetracycle 7, embodying a trisubstituted
bridgehead double bond, was isolated in a yield as high
as 85%. In contrast to its regioisomer 8, tetracycle 7
showed no tendency to undergo oxidation. Its two-
vinylic proton structure was clearly confirmed by a
combination of bidimensional NMR techniques (1H-1H
COSY, HSQC, and HMBC).
Scheme 3. Assembly of the 1-Azabicyclo[6.3.1]dodecane
Framework by Heck Cyclization
With the 1-azabicyclo[6.3.1]dodecane framework in
hand, the synthesis of (()-cleavamine only required the
deprotection of the indole nitrogen and the selective
reduction of the bridgehead double bond. Thus, reductive
removal (Mg, MeOH, rt) of the phenylsulfonyl group of 7
led to 10, which was subjected to catalytic hydrogenation
in AcOEt (Scheme 4). Gratifyingly, (()-cleavamine 11
could be isolated as the major product (40% yield) after
a short reaction time (1 h), although minor amounts of
14,20-cis-dihydrocleavamine 12 were also formed. As ex-
pected, longer reaction times (5 h) gave 12 as the only
1
product (43%). Synthetic cleavamines displayed H and
13C NMR spectral data identical to those reported for the
natural products.16,17
Scheme 4. Completion of the Synthesis of Cleavamines
The stage was now set for the assembly of the cleavamine
skeleton by intramolecular coupling of the vinyl iodide and
the double bond included in the azonine ring. We expected
tetracycle 8 to be preferentially formed after an exo
cyclization with generation of a disubstituted, indole-con-
jugated double bond. Our first assays were discouraging
since under a variety of conditions, including palladium
ꢀ
(12) (a) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Chem.
ꢀ
Commun. 2009, 3372–3374. (b) Bennasar, M.-L.; Zulaica, E.; Sole, D.;
Roca, T.; Garcıa-Dıaz, D.; Alonso, S. J. Org. Chem. 2009, 74, 8359–
8368.
(13) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.;
Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.; Shakespeare, W. C.;
Sprengeler, P. A.; Hamley, P.; Smith, A. B., III; Reisine, T.; Raynor, K.;
Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri,
M. R.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550–12568.
(14) Zhang, Y.; Herndon, J. W. Org. Lett. 2003, 5, 2043–2045.
´
´
In conclusion, we have developed a concise entry to
the bridged tetracyclic core of cleavamine alkaloids via a
(15) The structure of 8 could be determined by 1H NMR analysis of
its corresponding hydrochloride (see Supporting Information for
details).
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Org. Lett., Vol. 13, No. 8, 2011

sequence that features an indole-templated RCM to
build their tricyclic ABC substructure and a challenging
vinyl halide Heck cyclization to finally assemble the
bridged skeleton. This double annulation strategy has been
applied to the total synthesis of (()-cleavamine and its
14,20-cis-dihydro derivative, which requires a total of 10
steps from tryptophol 1 and proceeds via eight isolated
intermediates. The application of the strategy to the synth-
esis of other alkaloids embodying indolo-fused bridged
systems is in progress in our laboratory.
Acknowledgment. We thank the Ministerio de Ciencia e
ꢀ
Innovacion, Spain, for financial support (Project
CTQ2009-07175) and the University of Barcelona
for a grant to S.A.
(16) For NMR data of cleavamine, see: (a) Kutney, J. P.; Brown, R.;
Piers, E. Can. J. Chem. 1965, 43, 1545–1552. (b) Imanishi, T.; Nakai, A.;
Yagi, N.; Hanaoka, M. Chem. Pharm. Bull. 1981, 29, 901–903. (c)
Wenkert, E.; Hagaman, E. W.; Kunesch, N.; Wang, N.-Y. Helv. Chim.
Acta 1976, 59, 2711–2723.
Supporting Information Available. Experimental de-
1
tails and copies of H and 13C NMR spectra of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) For NMR data of (þ)-20R-dihydrocleavamine, see: van Beek,
T. A.; Verpoorte, R.; Svendsen, A. B. Tetrahedron 1984, 40, 737–748.
Org. Lett., Vol. 13, No. 8, 2011
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