First total synthesis of trimeric indole alkaloid, psychotrimine

Article abstract of DOI:10.1021/ol702637r

The first total synthesis of (±)-psychotrimine, a novel trimeric indole alkaloid isolated from Psychotria rostrata, was achieved. In the total synthesis, the copper-mediated intramolecular and intermolecular aminations of halobenzenes, which respectively

Full text of DOI:10.1021/ol702637r

ORGANIC
LETTERS
2008
Vol. 10, No. 1
125-128
First Total Synthesis of Trimeric Indole
Alkaloid, Psychotrimine
Yohei Matsuda, Mariko Kitajima, and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
htakayam@p.chiba-u.ac.jp
Received October 30, 2007
ABSTRACT
The first total synthesis of (±)-psychotrimine, a novel trimeric indole alkaloid isolated from Psychotria rostrata, was achieved. In the total
synthesis, the copper-mediated intramolecular and intermolecular aminations of halobenzenes, which respectively contributed to the construction
of a pyrrolidinoindoline core and the installation of a third tryptamine unit, were used as key steps.
A number of polymeric-tryptamine-related alkaloids com-
prising two to eight pyrrolidinoindoline units have been
isolated from rubiaceous plants,1,2 some of which show
analgesic activity involving opioid or NMDA receptors.3 Our
continuous chemical and pharmacological studies of indole
alkaloids possessing analgesic activity4 have led to the
isolation of a new trimeric-tryptamine-related alkaloid named
psychotrimine from Psychotria rostrata, a rubiaceous plant
indigenous to Malaysia.5 All hitherto known polymeric-
tryptamine-related indole alkaloids are composed of pyrro-
lidinoindoline units linked at C3a-C3a′ and/or C3a-C7′
positions (Figure 1). In contrast, psychotrimine (1) is the first
(1) For recent reviews, see: (a) Anthoni, U.; Christophersen, C.; Nielsen,
P. H. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W.,
Ed.; Pergamon: New York, 1999; Vol. 13, pp 163-236. (b) Steven, A.;
Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 2-23.
(2) For recent reports of the synthesis of pyrrolidinoindoline alkaloid,
see: (a) Dounary, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-
2964. (b) Kodanko, J. J.; Overman. L. E. Angew. Chem., Int. Ed. 2003, 42,
2528-2531. (c) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.;
MacMillan, D. W. C. PNAS 2004, 101, 5482-5487. (d) Monozzi, C.; Dalko
P. I.; Cossy, J. Chem. Commun. 2006, 4638-4640 and references cited
therein.
Figure 1. General structure of known polypyrrolidinoindoline
alkaloids (left) and psychotrimine.
(3) (a) Amador, T. A.; Verrota, L.; Nunes, D. S.; Elisabetsky, E. Planta
Med. 2000, 66, 770-772. (b) Amador, T. A.; Verrota, L.; Nunes, D. S.;
Elisabetsky, E. Phytomedicine 2001, 8, 202-206. (c) Verrota, L.; Orsini,
F.; Sbacchi, M.; Scheildler, M. A.; Amador, T. A.; Elisabetsky, E. Bioorg.
Med. Chem. 2002, 10, 2133-2142. (d) Kodanko, J. J.; Hiebert, S.; Peterson,
E. A.; Sung, L.; Overman, L. E.; Linck, V. M.; Goerck, G. C.; Amador, T.
A.; Leal, M. B.; Elisabetsky, E. J. Org. Chem. 2007, 72, 7909-7914.
example of this class of alkaloid that contains tryptamine
and pyrrolidinoindoline units in the same molecule as well
as possesses new linkage modes between the Na function of
tryptamine residue and the C3a and C7 positions of pyrro-
10.1021/ol702637r CCC: $40.75
© 2008 American Chemical Society
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lidinoindoline core. In this paper, We report the first total
synthesis of (()-psychotrimine, thereby establishing the
structure of this novel indole alkaloid.
Scheme 2
Scheme 1. Initial Retrosynthetic Analysis
indole by MnO2 oxidation, and hydrolysis of the cyano
group. By applying Fukuyama et al.’s conditions (CuI, Cs2-
CO3, DMSO),6d desired oxindole 3 was obtained in excellent
yield. However, we could not obtain aldehyde 9 via oxidative
cleavage of the allyl group, probably due to the instability
of the indole moiety under the employed conditions.
Then, we embarked on the development of a new method
to construct the pyrrolidinoindoline skeleton using amidine
13. The conversion of R-amino nitrile 7 into amidine 13 is
shown in Scheme 3. Here, conjugate addition reaction of 7
Our initial synthetic plan is depicted in Scheme 1.
Installation of a lower tryptamine segment in the last stage
by copper-mediated intermolecular amination6 of pyrrolidi-
noindoline derivative 2 was expected to enable the total
synthesis of 1. Further, we envisioned that the pyrrolidi-
noindoline skeleton, the central part of this alkaloid, would
be constructed by copper-mediated intramolecular amination6a,c
of 4, followed by appropriate transformation of resultant
oxindole 3. We anticipated that the quaternary carbon center
in 4, which corresponded to the characteristic C3a position
in 1, would be prepared from indoline (5) via the Strecker
reaction and successive allylation at the R-position of the
cyano function.
Scheme 3
Initially, we attempted the copper-mediated intramolecular
amidation to construct 3 using amide substrate 4, which was
prepared from indoline (5) and aldehyde 6 via a four-step
operation (Scheme 2) that included the Strecker reaction,
alkylation with allyl bromide, transformation of indoline to
(4) (a) Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi,
N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto,
L. T.; Watanabe, K.; Murayama, T.; Horie, S. J. Med. Chem. 2002, 45,
1949-1956. (b) Matsumoto, K.; Horie, S.; Ishikawa, H.; Takayama, H.;
Aimi, N.; Ponglux, D.; Watanabe, K. Life Sci. 2004, 74, 2143-2155. (c)
Takayama, H.; Misawa, K.; Okada, N.; Ishikawa, H.; Kitajima, M.; Hatori,
Y.; Murayama, T.; Wongseripipatana, S.; Tashima, K.; Matsumoto, K.;
Horie, S. Org. Lett. 2006, 8, 5705-5708 and references cited therein.
(5) Takayama, H.; Mori, I.; Kitajima, M.; Aimi, N.; Lajis, N. H. Org.
Lett. 2004, 6, 2945-2948.
(6) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421-7428. (b) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 11684-11688. (c) Yamada, K.; Kubo, T.; Tokuyama,
H.; Fukuyama, T. Synlett 2002, 231-234. (d) Okano, K.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2003, 5, 4987-4990. (e) Ley, S. V.; Thomas, A.
W. Angew. Chem., Int. Ed. 2003, 42, 5400-5449.
with nitroethylene7 followed by DDQ oxidation of the
indoline moiety provided indole 10 in 90% overall yield.
The nitro group was reduced with iron powder in aqueous
126
Org. Lett., Vol. 10, No. 1, 2008

hydrochloric acid and EtOH to give primary amine 11, which
was spontaneously cyclized to amidine 12. Protection of
pyrrolidine nitrogen with the tert-butoxycarbonyl (Boc) group
gave amidine 13 in 88% overall yield from 10.
tive 15 by reducing both imine and Boc groups with Red-
Al. Thus, we have established a new method for the synthesis
of pyrrolidinoindoline derivative using copper-mediated
intramolecular amination.
Having succeeded in the synthesis of amidine 13, the stage
was set for the copper-mediated intramolecular amination
to construct the pyrrolidinoindoline core. As shown in Table
1, copper iodide was selected as the source of copper(I), and
Next, we turned our attention to the construction of the
trimeric skeleton core using the copper-mediated intermo-
lecular amination. To carry out this reaction, 15 was
converted into iodide 20 as follows (Scheme 4). After
Scheme 4
Table 1. Copper-Mediated Intramolecular Amination
CuI
entry (mol %) (mol %)
liganda
time
(h)
yield
(%)c
base
solventb
1
2
3
4
5
6
20
20
10
100
100
100
L1:40
L2:40
L3:40
-
-
-
K3PO4
K3PO4
Cs2CO3 DME
Cs2CO3 DMSO
K2CO3
toluene
toluene
16
16
41
trace
trace
10
2.5 decomp.
2.5 60
1.5 91
d
DMSO
DMSO
d
K3PO4
a
L1: N,N′-dimethylethylenediamine. L2: trans-N,N′-dimethylcyclo-
hexanediamine. L3: 1,10-phenanthroline. b Degassed solvent was used.
c Isolated yield. d 1.5 equiv of base was used.
protection of the aniline nitrogen with the Boc group, the
resulting carbamate was treated with sec-BuLi and quenched
with iodine to give iodide 16 in good yield.9 Side chain
extension at the indole â-position in 16 was achieved by the
conjugate addition reaction with nitroethylene in the presence
of InBr3 as a Lewis acid.10 After reduction of the aliphatic
nitro group with iron powder and AcOH, the resulting
primary amine was protected as o-nitrobenzenesulfonamide
(Ns-amide),11 followed by N-methylation via treatment with
DBU and dimethyl sulfate12 to give 19 in excellent yield.
Finally, the Boc group was removed with TMSOTf and 2,6-
lutidine to afford iodide 20, the key substrate for the final
conversion.
optimization of the other conditions (ligand, solvent, base)
was undertaken. First, Buchwald’s conditions using diamine
compound (L1-L3) as ligand6a,b were examined (entries
1-3). Under these conditions, the desired cyclization product
was obtained in very low yield, probably due to the low
reactivity of amidine nitrogen compared with aliphatic
nitrogen.8 Then, we examined ligand-free conditions using
a stoichiometric amount of copper iodide.6c,d We tested
several bases in DMSO at 80 °C and found that the choice
of base was quite important for this transformation (entries
4-6): Cs2CO3 gave a complex mixture, while K2CO3 gave
desired cyclization product 14 in 60% yield. The best result
was obtained when K3PO4 was used as a base. Cyclization
product 14 was transformed into pyrrolidinoindoline deriva-
The final stage of the total synthesis of 1 was the copper-
mediated intermolecular coupling of iodide 20 with tryptamine
(9) (a) Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J.
Am. Chem. Soc. 2002, 124, 9008-9009. (b) Iwao, M.; Kuraishi, T. Org.
Synth. 1996, 73, 85-93.
(7) (a) Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A. K.;
Iyengar, R. J. Org. Chem. 1980, 45, 1185-1189. (b) Tsuge, O.; Ueno, K.;
Kanemasa, S.; Yorozu, K. Bull. Chem. Soc. Jpn. 1987, 60, 3347-3358.
(8) Under these conditions, the coupling reaction between 13 and ligand
(L1 or L2) was observed. This type of N-arylation was reported by
Buchwald’s group. See ref 6b.
(10) (a) Bandini, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A.
Synthesis 2002, 1110-1114. (b) Bandini, M.; Cozzi, P. G.; Melchiorre, P.;
Umani-Ronchi, A. J. Org. Chem. 2002, 67, 5386-5389.
(11) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373-6374.
(12) Biron, E.; Kessler, H. J. Org. Chem. 2005, 70, 5183-5189.
Org. Lett., Vol. 10, No. 1, 2008
127

derivative 22, the latter of which was prepared from
diamine as ligand and K3PO4 as base, the desired coupling
tryptamine via a two-step operation (Scheme 5):
product 23 was obtained in 72% yield.
Finally, the Ns group of both upper and lower tryptamine
units was removed by conventional procedure to furnish the
target molecule 1 in good yield. Synthetic 1 was completely
identical in all respects (chromatographic behavior; mass;
IR; UV; 1H and 13C NMR) with natural psychotrimine except
for the optical property. Hence, the structure of psycho-
trimine, which was proposed on the basis of spectroscopic
analyses, was confirmed to be formula 1.
Scheme 5
In conclusion, we have achieved the first total synthesis
of (()-psychotrimine in 16 steps and 13.2% overall yield
from indoline. The synthesis features the copper-mediated
intramolecular amination of amidine substrate to form the
pyrrolidinoindoline core, and the copper-mediated intermo-
lecular amination to construct the trimeric skeleton. Further
synthetic study of this class of alkaloids is underway in our
laboratory.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures for 3, 4, 7, 8, 10, 13-23, S1, S2, and synthetic (()-
1
psychotrimine (1), and copies of H and 13C NMR spectral
data for 3, 7, 8, 10, 13-23, synthetic (()-psychotrimine (1),
and natural psychotrimine. This material is available free of
charge via the Internet at http://pubs.acs.org.
protection of primary amine with the Ns group and
methylation with DBU and dimethyl sulfate. After several
experiments, it was revealed that the ligand-base combina-
tion was an important factor for this coupling reaction. When
the reaction was carried out using N,N′-dimethylethylene-
OL702637R
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Org. Lett., Vol. 10, No. 1, 2008