Organocatalytic enantioselective total synthesis of (-)-arboricine

Article abstract of DOI:10.1021/ol900888e

The tetracyclic indole alkaloid (-)-arboricine has been prepared using an asymmetric organocatalytic Pictet - Spengler reaction as the key step followed by a diastereoselective Pd-catalyzed iodoalkene/enolate cyclization. The absolute stereochemistry was unequivocally proven by X-ray crystallographic analysis and appeared to be opposite to the published structure in the original paper.

Full text of DOI:10.1021/ol900888e

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2579-2581
Organocatalytic Enantioselective Total
Synthesis of (-)-Arboricine
Martin J. Wanner,† Rowan N. A. Boots,† Bram Eradus,† Rene´ de Gelder,‡
Jan H. van Maarseveen,*,† and Henk Hiemstra*,†
Van’t Hoff Institute for Molecular Sciences, UniVersity of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS, Amsterdam, The Netherlands, and
Institute for Molecules and Materials, Radboud UniVersity, ToernooiVeld 1,
6525 ED Nijmegen, The Netherlands
j.h.VanmaarseVeen@uVa.nl; h.hiemstra@uVa.nl
Received April 23, 2009
ABSTRACT
The tetracyclic indole alkaloid (-)-arboricine has been prepared using an asymmetric organocatalytic Pictet-Spengler reaction as the key
step followed by a diastereoselective Pd-catalyzed iodoalkene/enolate cyclization. The absolute stereochemistry was unequivocally proven by
X-ray crystallographic analysis and appeared to be opposite to the published structure in the original paper.
The deplancheine-type tetracyclic indole alkaloid arboricine
1 was isolated from the leafs of Kopsia arborea by Kam
Scheme 1. Arboricine Retrosynthesis
and co-workers and showed a moderate ability to reverse
multidrug resistance in vincristine-resistant KB (VJ300)
cells.1 We have recently published studies on the asymmetric
binolphosphoric acid-catalyzed Pictet-Spengler (PS) reaction
of benzyltryptamines arriving at a variety of ꢀ-carbolines.2
As an extension of this work, we report herein a concise
and scalable synthesis of arboricine based on an asymmetric
PS reaction of 4-oxo-pentanal and Nb-iodoolefin-function-
alized tryptamine followed by a Pd(0)-catalyzed enolate
cyclization (Scheme 1).
† University of Amsterdam.
‡ Radboud University.
(1) Lim, K. H.; Komiyama, K.; Kam, T. S. Tetrahedron Lett. 2007, 48,
1143–1145.
The synthesis started with the known tryptamine 4,3 made
in one step by alkylation of tryptamine with Z-2-iodo-2-
butene-1-ol mesylate in 84% yield (not shown).4 PS con-
(2) (a) Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder, R.;
van Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405–6408.
For other recent enantioselective catalytic Pictet-Spengler reactions, see:
(b) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558–
10559. (c) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006,
128, 1086–1087. (d) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K.;
van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485–
7487. (e) Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887–890. (f)
Bou-Hamdan, F. R.; Leighton, J. L. Angew. Chem., Int. Ed. 2009, 48, 2403–
2406.
(3) Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi, N. Tetrahedron
Lett. 1997, 38, 5307–5310.
(4) Prepared via iodination of crotonaldehyde (see Supporting Informa-
tion): Krafft, M. E.; Cran, J. W. Synlett 2005, 1263–1266.
10.1021/ol900888e CCC: $40.75
Published on Web 05/19/2009
 2009 American Chemical Society

densation of 4 with aldehyde 3a mediated by (R)-3,3′-
triphenylsilyl-binol phosphoric acid 5a ((R)-binol-PA, 5 mol
%) in toluene in the presence of 4 Å molecular sieves at
room temperature for 18 h gave ꢀ-carboline (S)-2a5 together
with aminal 6 in 55% yield and a 75/25 ratio, respectively,
and an unacceptable 38% ee for both (S)-2a and 6, as
determined by chiral HPLC (Scheme 2). Gratifyingly,
Scheme 3.
Palladium-Catalyzed Iodoalkene/Enolate Cyclizationa
Scheme 2. Asymmetric Pictet-Spengler Reaction
a With 5 mol % of Pd(PPh3)4 and 3 h reflux, the yield dropped to 33%,
and also substantial amounts of an analogue of 8 were formed in which the
double bond shifted into conjugation.
we selected the procedure published by Sole and Bonjoch
relying on potassium phenoxide as a mild base to avoid
migration of the isolated exocyclic double bond to a
conjugated system with an endocyclic double bond.8 After
refluxing of 7 in THF for 30 min in the presence of Pd(PPh3)4
(10 mol %) and KOPh (2.5 equiv), all starting material was
converted followed by workup to give 8 in 55% isolated
yield as a single diastereoisomer.
protection of ketone 3a as the dioxolane 3b6 not only avoided
aminal formation thus exclusively providing (S)-2b in 81%
yield but also raised the ee to 78%. It is remarkable that
installing the acetal protecting group, which is quite remote
from the iminium intermediate, improves not only the ee
but also the rate of the PS reaction allowing lower catalyst
loadings down to 1%. The mildness of the process is
underscored by the fact that the dioxolane-protected ketone
remained unaffected. Obviously, (R)-2b was obtained starting
from (S)-binol-PA. The best ee was obtained using the
sterically slightly more demanding catalyst (R)-H8-binol-PA
5c that gave (S)-2b in 86% yield and 89% ee. Scaling up
the reaction to 5 mmol only required 1 mol % of catalyst 5a
furnishing (S)-2b in an isolated yield of 92% and 78% ee.
To avoid possible racemization via acid-catalyzed scission
of the bond between the asymmetric carbon atom and Nb or
a retro PS process7 during the hydrolysis of the acetal moiety,
a Boc-protecting group was installed on the indole-nitrogen
(Scheme 3). Treatment of 2b with Boc2O and DMAP
followed by diluted HCl in acetone gave ketone 7 in 96%
overall yield.
A single recrystallization from the EtOAc/PE mixture gave
enantiomerically pure 8 for which the X-ray structure
confirmed the 3S,15R absolute stereochemistry as depicted
9
in Figure 1.
Now the stage was set for closure of the piperidine ring
by a Pd(0)-catalyzed vinyl iodide-enolate coupling for which
(5) In preliminary catalyst screening experiments, we always used (R)-
binol phosphoric acid. Our previous work (ref 2a and 2d) shows that this
will lead to ꢀ-carbolines with the S configuration at C3.
Figure 1. X-ray crystal structure of 8.
(6) Prepared from ethyl levulineate via acetalization and DIBAL-H
reduction (see Supporting Information). This aldehyde is very sensitive for
air-oxidation and is always chromatographed before use. The corresponding
carboxylic acid is an efficient Pictet-Spengler catalyst, and the ee
immediately drops when this acid is present.
(-)-Arboricine 1 was obtained after TFA-mediated re-
moval of the Boc-protecting group of 8 in an isolated yield
of 81%.10 Synthetic arboricine was enantiopure as determined
(7) Kumpaty, H. J.; Van Linn, M. L.; Kabir, M. S.; Fo¨rsterling, F. H.;
Deschamps, J. R.; Cook, J. M. J. Org. Chem. 2009, 74, 2771–2779.
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Org. Lett., Vol. 11, No. 12, 2009

with chiral HPLC. The sign of the optical rotation of our
synthetic product (i.e., [R]D -281 (c 0.23, CHCl3)) and that
of the natural material ([R]D -110 (c 0.14, CHCl3)) was the
same showing that we had obtained the natural enantiomer.
This means that the stereochemistry as suggested previously
by Kam must be revised.
At this stage, we wondered if we could also synthesize
arboricine without sacrificing the ee by omitting the indole-
N-Boc-protecting group. Dissolving 2b in diluted HCl in
acetone gave quantitatively a mixture of 2a together with
aminal 6 in a 2/3 ratio, respectively. Gratifyingly, under the
slightly basic conditions of the final Pd(0)-catalyzed cycliza-
tion, an equilibrium between 2a and 6 existed enabling an
efficient and diastereoselective conversion to arboricine 1
in a yield of 78%, albeit with an ee that dropped from 86%
to 65%.
In conclusion, an efficient six-step synthesis starting from
tryptamine gave the tetracyclic ꢀ-carboline arboricine in 33%
overall yield using an enantioselective organocatalytic
Pictet-Spengler reaction and a stereoselective intramolecular
Pd(0)-catalyzed vinyl iodide-enolate coupling as the key
steps. An alternative three-step route starting from tryptamine
without the use of protecting groups gave arboricine in an
overall yield of 35% but with a significantly lower ee.
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) (a) Sole, D.; Urbaneja, X.; Bonjoch, J. AdV. Synth. Catal. 2004, 346,
1646–1650. For a similar reaction, see also: (b) Yu, J. M.; Wang, T.; Liu,
X. X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X. B.; Cook, J. M J.
Org. Chem. 2003, 68, 7565–7581.
(9) CCDC 727699 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www. ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, U.K.; fax (+44)1223-336-
033; or deposit@ccdc.cam.ac.uk). The crystallographic data are also
available in the CIF file in the Supporting Information.
OL900888E
(10) The 1H and 13C NMR spectra of synthetic arboricine were identical
to the natural compound (see ref 1).
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