General approach for the total synthesis of the sarpagine related indole alkaloids (+)-Na-methyl-16-epipericyclivine, (-)-alkaloid Q3 and (-)-panarine via the asymmetric Pictet-Spengler reaction

Article abstract of DOI:10.1016/S0040-4039(02)02618-7

The stereospecific total synthesis of (+)-N_a-methyl-16-epipericyclivine (1) was completed [from D-(+)-tryptophan methyl ester] in an overall yield of 42% (eight reaction vessels). The optical rotation {[α]_D +22.8 (c 0.50, CHCl_3<

Full text of DOI:10.1016/S0040-4039(02)02618-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 543–547
General approach for the total synthesis of the sarpagine related
indole alkaloids (+)-Na-methyl-16-epipericyclivine, (−)-alkaloid
Q3 and (−)-panarine via the asymmetric Pictet–Spengler reaction
Jianming Yu, Xiangyu Z. Wearing and James M. Cook*
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Received 30 October 2002; revised 12 November 2002; accepted 13 November 2002
Abstract—The stereospecific total synthesis of (+)-Na-methyl-16-epipericyclivine (1) was completed [from D-(+)-tryptophan methyl
ester] in an overall yield of 42% (eight reaction vessels). The optical rotation {[h]D +22.8 (c 0.50, CHCl3)} obtained on this
material confirmed that the reported optical rotation {[h]D 0 (c 0.50, CHCl3)} was biogenetically unreasonable. The first total
synthesis of (−)-alkaloid Q3 (5) and (−)-panarine (6), via the intermediate vellosimine (18), is also described. © 2002 Elsevier
Science Ltd. All rights reserved.
During the past few decades more than 90 sarpagine/
macroline-related indole alkaloids have been isolated
from Alstonia macrophylla Wall, Alstonia muelleriana
Domin, and other Alstonia species.1–3 Some of them
have been used in traditional medicine as remedies for
malaria and other ailments including tumors.4,5 Surpris-
ingly, only a few Alstonia alkaloids have been evaluated
for biological activity due to the paucity of isolable
material.6–8 It has become apparent recently7,9,10 that
further work on the biological and chemical con-
stituents of these medicinal plants is warranted. Among
these bases, a few sarpagine-related monomeric alka-
loids such as Na-methyl-16-epipericyclivine (1)11 and
bisindole alkaloids such as desformoundulatine (3)12
Figure 1.
* Corresponding author. E-mail: capncook@csd.uwm.edu
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02618-7

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J. Yu et al. / Tetrahedron Letters 44 (2003) 543–547
loid Q3. Based on chemical transformations, alkaloid
Q3 (5) was converted into 16-epipericyclivine (2), a
material which had not yet been isolated as a natural
product. However, the optical rotation of 2 reported by
Quaisuddin14 {[h]D +37.7 (c 0.13, MeOH)} was not
consistent with that reported by Bu¨chi et al.15 {[h]D
+3.6 (c 1.00, MeOH)}. Furthermore, because only a few
physical properties were reported, the identity of alka-
loid Q3 could not be established unambiguously.
Angenot et al.16 in 1988 isolated two closely related
quaternary alkaloids including panarine (6) from a
Venezuelan curare. This material was prepared by the
Panare Indians from the bark of Strychnos toxifera
Rob. Schomb. Ex Lindley. Its structure has been estab-
(from Alstonia undulata), form a subgroup of alkaloids
which contain a methyl ester function at C-16 (Fig. 1).
Bisindole alkaloids have been shown to exhibit anti-
malarial activity against a drug resistant (K-1) strain of
Plasmodia falciparum7,10 and dimeric alkaloids are usu-
ally much more potent than the monomeric units which
comprise them against P. falciparum malaria.6–8 It was
therefore of interest to synthesize and evaluate these
bisindole alkaloids. It has previously been demon-
strated by Le Men-Olivier et al.13 that natural Na-
methyl-16-epipericyclivine (1) couples with the natural
monomeric alkaloid cabucraline to provide bisindole 4
on treatment with DDQ. Interestingly, the optical rota-
tion of 1 was reported as zero,11 which was biogeneti-
1
lished unequivocally by H and 13C NMR spectra and
cally unreasonable. As
a consequence, the total
synthesis of 1 and eventually bisindoles 3 and 4 has
become of interest. Potential new drug candidates could
emerge from these bisindoles and material is required to
study the mechanism of action at the cellular level.
X-ray crystallographic analysis.16 Another related qua-
ternary alkaloid 16-epipanarine (7) was isolated from
Stemmadenia minima in 1991 by Achenbach et al.17 In
order to directly compare an authentic sample of 7 with
6 and establish the correct configuration of 7, chemical
correlations were carried out. The three steps included
esterification with thionyl chloride in methanol to
Quaisuddin14 in 1980 isolated a quaternary alkaloid 5
from Aspidosperma perba which was designated as alka-
Scheme 1. Reagents and conditions: (a) 5% Pd/C, H2, EtOH/HCl, rt, 5 h, 94%; (b) Z-1-bromo-2-iodo-2-butene 12, K2CO3, THF,
reflux, 90%; (c) 3 mol% Pd(OAc)2, 30 mol% PPh3, 1 equiv. Bu4NBr, 4 equiv. K2CO3, DMF–H2O (9:1), 65°C, 30 h, 82%; (d)
MeOCH2PPh3Cl, KOt-Bu, benzene, rt, 24 h; 2N HCl/THF, 55°C, 5 h, 90%; (e) KOH, I2, MeOH, rt, 2 h, 94%.

J. Yu et al. / Tetrahedron Letters 44 (2003) 543–547
545
provide 8, epimerization on treatment of 8 with potas-
sium t-butanolate to obtain 5, and alkaline hydrolysis
of 5 to afford 6 as the only product.17 However, no
report of the total synthesis of these quaternary alka-
loids has appeared in the literature, to date, and the
reported11 rotation of 1 was in question.
intramolecular cyclization took place stereospecifically
to afford the desired ketone 14 in 82% yield.19 Ketone
14 was then converted into Na-methylvellosimine (15)
which had also been isolated from Rauvolfia nitida.20
The total synthesis of 15 had not been previously
reported.21 Oxidation of the C-17 aldehyde function of
15 to the desired ester afforded Na-methyl-16-epipericy-
clivine (1)22 in 94% yield on treatment with I2 and KOH
in MeOH.23,24 This sequence provided stereospecific
access to (+)-Na-methyl-16-epipericyclivine (1) in eight
reaction vessels (42% overall yield). All spectral data
The synthesis of 1 began from Na-methyl, Nb-benzyl
tetracyclic ketone 10 which could be prepared on 150 g
scale (>98% ee) from
D
-(+)tryptophan methyl ester in
three reaction vessels via the asymmetric Pictet–Spen-
gler reaction/Dieckmann protocol (Scheme 1).18 The
Nb-benzyl group was removed via catalytic hydrogena-
tion to afford the Nb-H ketone 11 in 94% yield. This
base was reacted with the Z-1-bromo-2-iodo-2-butene
12 in the presence of K2CO3 to afford alkylated ketone
13 in 90% yield. Palladium-mediated enolate driven
1
(e.g. H and 13C NMR, IR, and MS) for synthetic 1
were in good agreement with data reported for the
natural product.11 However, the optical rotation of
synthetic Na-methyl-16-epipericyclivine (1) {[h]D +22.8
(c 0.50, CHCl3)} was different from that reported {[h]D
0 (c 0.50, CHCl3)}.11
Scheme 2. Reagents and conditions: (a) KOH, I2, MeOH, rt, 2 h, 88%; (b) LiAlH4, THF, reflux, 2 h, 92%; (c) MeI, MeOH, rt,
4 h, 90%; (d) AgCl, MeOH, 85%; (e) 0.1N NaOH, then 0.1N HCl, 90%.

546
J. Yu et al. / Tetrahedron Letters 44 (2003) 543–547
References
As shown in Scheme 2, vellosimine (17) was chosen as
an important intermediate for the total synthesis of
(−)-alkaloid Q3 (5) and (−)-panarine (6). Tao et al.25
reported a concise and efficient synthesis of vellosimine
(17) which provided gram quantities of this alkaloid.
1. Hamaker, L. K.; Cook, J. M. In Alkaloids: Chemical and
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5. Hartwell, J. L. Lloydia 1967, 30, 379.
Consequently,
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-(+)tryptophan methyl ester (9) was
converted into the Na-H, Nb-benzyl tetracyclic ketone
16 via a two vessel process.26 Tetracyclic ketone 16 was
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cifically in five steps. Oxidation of the aldehyde 17 at
C-17 to provide the ester 18 was best accomplished in
85% yield again by using I2 and KOH in MeOH. The
optical rotation of synthetic 18 {[h]D +4.6 (c 1.00,
MeOH)} was in agreement with that of Bu¨chi and not
of Quaisuddin.14,15 Since the absolute configuration of
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reduced with LiAlH4 to give the monol 19 in 92% yield.
The spectroscopic and physical data {1H and 13C
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identical in all respects with the published data,15,27–29
which confirmed the correct configuration of 19 and 18
(vide infra) as well. Subsequent quarternization of the
Nb-nitrogen moiety in 18 with MeI provided the Nb-
methiodide salt 20 which was, upon exposure to
AgCl,30 converted into the chloride 5 in 85% yield. The
1H NMR spectrum and optical rotation of 5 are in
good agreement with that of the reported values.17
Hydrolysis of the ester function of 5 with 0.1N NaOH,
followed by neutralization with 0.1 HCl afforded (−)-
panarine (6) in 90% yield.31 The 1H and 13C NMR
spectra of synthetic 6 were identical to that of natural
panarine kindly supplied by Professor Luc Angenot.
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of signals in the 13C NMR. The two compounds are
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6. Keawpradub, N.; Houghton, P. J.; Eno-Amooquaye, E.;
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In summary, the concise synthesis of (+)-Na-methyl-16-
epipericyclivine (1) was completed in stereospecific,
enantiospecific fashion in 42% overall yield in eight
reaction vessels. The optical rotation {[h]D +22.8 (c
0.50, CHCl3)} of synthetic material (>98% ee) indicated
that the reported optical rotation {[h]D 0 (c 0.50,
CHCl3)} was biogenetically unreasonable. In addition,
this (+)-Na-methyl-16-epipericyclivine (1) could be
employed to prepare the bisindole alkaloid 4 analogous
to the earlier work of Le Men-Olivier et al.11 Studies on
the total synthesis of bisindoles 3 and 4 are currently
underway in our laboratory. The first total synthesis of
the two quaternary alkaloids, (−)-alkaloid Q3 (5) and
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Acknowledgements
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1470 cm−1. H NMR (300 MHz, CDCl3) l 1.64 (3H, dt,
J=6.8, 1.9 Hz), 1.76 (1H, ddd, J=12.6, 2.6, 1.4 Hz), 2.18
(1H, ddd, J=12.2, 10.0, 1.9 Hz), 2.61 (1H, dd, J=7.8, 1.4
Hz), 2.74 (1H, dd, J=15.8, 1.0 Hz), 3.25 (2H, m), 3.61
(3H, s), 3.70 (3H, s), 3.76 (3H, m), 4.40 (1H, d, J=9.1
Hz), 5.42 (1H, q, J=6.7 Hz), 7.11 (1H, ddd, J=8.9, 7.9,
The authors wish to thank the NIMH for support (in
part) of this work. We are grateful to Professor Luc
Angenot (Institut de Pharmacie, Universite´ de Lie`ge)
for providing an authentic sample of natural panarine.

J. Yu et al. / Tetrahedron Letters 44 (2003) 543–547
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547
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3.03 (3H, s), 3.24 (1H, dd, J=17.3, 5.0 Hz), 3.36 (1H, br
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