Determination of absolute configuration of trimeric indole alkaloid, psychotrimine, by first asymmetric total synthesis

Article abstract of DOI:10.1039/b923918a

The first asymmetric total synthesis of psychotrimine, a trimeric indole alkaloid, was accomplished via an asymmetric Ireland-Claisen rearrangement to construct a chiral quaternary carbon center, thereby establishing the absolute configuration of psychotr

Full text of DOI:10.1039/b923918a

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Determination of absolute configuration of trimeric indole alkaloid,
psychotrimine, by first asymmetric total synthesisw
Nobuaki Takahashi, Takeshi Ito, Yohei Matsuda, Noriyuki Kogure,
Mariko Kitajima and Hiromitsu Takayama*
Received (in Cambridge, UK) 16th November 2009, Accepted 13th January 2010
First published as an Advance Article on the web 1st February 2010
DOI: 10.1039/b923918a
The first asymmetric total synthesis of psychotrimine, a trimeric
center in 4, the key step in this synthesis, was expected by the
asymmetric Ireland–Claisen rearrangement of chiral allylic
ester 5 via a chirality transfer process. Compound 5 would
be prepared from indoline (6), 2-bromophenylacetic acid (7),
and known chiral allylic alcohol 8.9
indole alkaloid, was accomplished via an asymmetric Ireland–
Claisen rearrangement to construct
a chiral quaternary
carbon center, thereby establishing the absolute configuration of
psychotrimine.
Chiral allylic ester 5 was prepared from 2-bromophenylacetic
acid (7) in five steps (Scheme 2). Esterification of 7 followed by
radical bromination at the benzylic position (NBS, AIBN,
CCl4) gave dibromo compound 9 in 98% yield. After alkaline
hydrolysis of the methyl ester in 9, the resulting carboxylic acid
was coupled with chiral allylic alcohol 8 in the presence of
pyridine-3-carboxylic anhydride (3-PCA)10 and DMAP in
CH2Cl2 to give 10 in 67% yield (2 steps). Next, indoline unit
(6) was installed in 10 (TBAI, K2CO3, DMF) to afford
Ireland–Claisen rearrangement precursor 5 in 73% yield as a
diastereomeric mixture.
A number of polymeric-tryptamine-related alkaloids comprising
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 In our continuous
chemical and pharmacological studies of indole alkaloids
possessing analgesic activity,4 we isolated psychotrimine, a
new trimeric-tryptamine-related alkaloid, from a Malaysian
rubiaceous plant, Psychotria rostrata.5 All the hitherto known
polymeric-tryptamine-related indole alkaloids are composed
of pyrrolidinoindoline units linked at C3a–C3a0 and/or
C3a–C70 positions (Fig. 1). In contrast, psychotrimine (1) is
the first example of this class of alkaloids that contains
tryptamine and pyrrolidinoindoline units in the same molecule
as well as possessing new linkage modes between the Na
function of the tryptamine residue and the C3a and C7
positions of the pyrrolidinoindoline core. Recently, we
accomplished the first total synthesis of (ꢀ)-psychotrimine
via copper-mediated intramolecular and intermolecular
aminations of halobenzenes.6 Although an elegant total synthesis
of (ꢀ)-1 was also reported by Newhouse and Baran,7 its
absolute configuration is still unknown.
With chiral ester 5 in hand, the utility of the asymmetric
Ireland–Claisen rearrangement in constructing
a chiral
quaternary carbon center at C3a in 1 was examined
(Table 1). Amphoteric product 4 from the Ireland–Claisen
rearrangement was converted without purification into amide
11 (HATU, i-Pr2NEt, NH4Cl, DMF) and the enantiomeric
excess was determined by chiral HPLC analysis. Preliminary
investigation suggested that the combination of KHMDS and
THF as base and solvent is appropriate for this Ireland–Claisen
rearrangement. Then, to realize chelation control (vide
infra), such metal salts as LiCl, ZnCl2, MgCl2, TiCl4, and
CoCl2 were investigated as additives. Among them, ZnCl2
(entry 1) offered moderate chemical yield (58%) and
enantiomeric excess (46% ee). By using ZnI2 instead of ZnCl2
and optimizing the reaction temperature and time (entry 2),
the best result was obtained (79% yield, 74% ee). Interestingly,
when LiCl was employed (entry 3), the product obtained in
43% yield contained the antipode predominantly (57% ee). The
absolute configuration of the chiral product was determined as
We herein report the first asymmetric total synthesis of
psychotrimine via an asymmetric Ireland–Claisen rearrangement,8
which enabled us to determine the absolute configuration of
the natural product.
Our synthetic plan is depicted in Scheme 1. Utilizing our
previous work6 on the synthesis of (ꢀ)-1, chiral pyrrol-
idinoindoline derivative 2 was synthesized for use as the
key intermediate for the asymmetric synthesis of 1. Pyrrol-
idinoindoline 2 would be transformed from chiral oxindole 3,
which could be prepared from an amide derivative of carboxylic
acid 4 via the copper-mediated intramolecular amination of
bromobenzene. The construction of a quaternary chiral carbon
Graduate School of Pharmaceutical Sciences, Chiba University,
1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
E-mail: htakayam@p.chiba-u.ac.jp; Fax: +81 43 290 2901;
Tel: +81 43 290 2901
w Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data, and copies of 1H and 13C NMR
spectra. CCDC 754033. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b923918a
Fig. 1 General structure of known polypyrrolidinoindoline alkaloids
(left) and the structure of psychotrimine (right).
ꢁc
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Scheme 1 Retrosynthetic analysis.
Scheme 3
by treating ester 5 with KHMDS and metal salt would have
two chair-like transition states 12a and 12b, both of which
favor the pseudo-equatorial position of the phenyl group.
Using Zn salts, chelation between the nitrogen of the indoline
part and the oxygen of the enolate would take place, producing
the new chiral center (S) in high optical purity via the chirality
transfer process. In case of entry 3, using LiCl as additive, the
R enantiomer 4b is produced dominantly, probably via a
non-chelation-controlled transition state 12b.8
Next, amide 11a, whose enantiomeric excess could be
increased to 96% ee by recrystallization from AcOEt, was
subjected to copper-mediated intramolecular amination of
bromobenzene by treatment with CuI in the presence of
Scheme 2
follows. The product obtained in entry 2 (74% ee) was
converted into nitrile derivative 13, which was recrystallized
from AcOEt–n-hexane to give an enantiomerically pure
(99.9% ee as determined by chiral HPLC analysis) crystal
(mp 155–157 1C). X-Ray crystallographic analysis revealed
that this compound ([a]2D0 +150 (c 0.63, CHCl3)) had the S
configuration at the quaternary carbon center.w
Cs2CO3 in DMSO to give oxindole
3 in 80% yield
(Scheme 4). Oxidative cleavage of the double bond and
installation of a nitrogen function in the side chain were
performed as follows. 3 was treated with OsO4 to give a diol
intermediate, which was cleaved with Pb(OAc)4 and then
reduced with NaBH4 to afford primary alcohol 14 in 90%
yield. Subsequently, an azide group was introduced to 14 in
99% yield in two steps ((i). MsCl, Et3N, CH2Cl2, (ii). NaN3,
DMF) to give 15. The indoline function in 15 was converted
into indole in a quantitative yield by DDQ oxidation. The
introduction of a Boc group to Na of the oxindole unit in 16
and the subsequent partial reduction of the amide function in
oxindole 17 with NaBH4 provided hemiaminal 18 in 93%
yield. Next, the azide group was reduced with PPh3 in
THF–H2O to afford a primary amine, which spontaneously
cyclized to give pyrrolidinoindoline 19 in 85% yield. Reductive
methylation (HCHO, NaCNBH3, MeOH) of Nb of the pyrrol-
idinoindoline unit furnished optically active key intermediate 2
in 85% yield.
Based on the results described above, a possible mechanism
for the asymmetric Ireland–Claisen rearrangement was
considered, as shown in Scheme 3. Ketene acetal 12 generated
Table 1 Effects of additives on Ireland–Claisen rearrangement
Entry
Additive
Yield (%)
ee (%)c
Having succeeded in the synthesis of chiral intermediate 2,
we focused our energies on the completion of the asymmetric
synthesis of psychotrimine by utilizing the method for the
synthesis of racemic 16 (Scheme 5). The seven-step trans-
formation involved: (1) regioselective iodination of the benzene
ring of the pyrrolidinoindoline unit to give 20, (2) installation
of the side chain at the b position of the indole ring using
1a
2b
3a
ZnCl2
ZnI2
LiCl
58
79
43
46 (S)
74 (S)
57 (R)
a
Reaction conditions: (i) ꢂ78 1C, 30 min, (ii) ꢂ78 1C, 30 min, then rt,
b
c
1 h. Reaction conditions: (i) ꢂ78 1C, 1 h, (ii) rt, 1 h. Determined by
chiral HPLC analysis.
ꢁc
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([a]D, NMR, mass) with the natural one ([a]1D8 +179 (c 0.2,
CHCl3)). Therefore, the absolute configuration of psycho-
trimine was established, as shown in formula 1.
Synthetic (+)-psychotrimine was evaluated for its cytotoxic
activity against three tumor cell lines, A549, HT29, and
HTC116. As a result, 1 showed moderate cytotoxicity to only
HT-29 (human colon adenocarcinoma grade II cell line;
IC50 = 3.00 mg mLꢂ1).
In conclusion, we have achieved the first asymmetric total
synthesis of cytotoxic psychotrimine (1) via an asymmetric
Ireland–Claisen rearrangement to construct a chiral quaternary
carbon center, which enabled us to determine the absolute
configuration of the natural product.
This work was supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science.
Notes and references
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P. H. Nielsen, in Alkaloids: Chemical and Biological Perspectives,
ed. S. W. Pelletier, Pergamon, New York, 1999, vol. 13,
pp. 163–236; (b) A. Steven and L. E. Overman, Angew. Chem.,
Int. Ed., 2007, 46, 5488–5508.
2 For recent reports of the synthesis of pyrrolidinoindoline alkaloids,
see: (a) A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103,
2945–2964; (b) J. J. Kodanko and L. E. Overman, Angew. Chem.,
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Scheme 4
nitroethylene–InBr3 to afford 21, (3) reduction of the nitro
group with Fe–AcOH, followed by protection of the resulting
primary amine with nitrobenzenesulfonamide (Ns-amide), (4)
N-methylation, (5) removal of the Boc group to yield 24, (6)
coupling with tryptamine derivative 25 by copper-mediated
intermolecular amination to give trimeric product 26, and (7)
removal of the Ns group to furnish psychotrimine in 75%
yield. Synthetic 1 ([a]D24 +221 (c 0.3, CHCl3)) with 3aS and
8aR stereochemistry was completely identical in all respects
and
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Scheme 5
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2501–2503 | 2503