Enantiospecific total synthesis of (-)-anhydromacrosalhine-methine and partial synthesis of the antiamoebic bisindole alkaloid (-)-macrocarpamine

Article abstract of DOI:10.1021/jo971570t

An enantiospecific total synthesis of (-)-anhydromacrosalhine-methine (7a) was completed from D-(+)-tryptophan via the asymmetric Pictet-Spengler reaction. In addition, a partial synthesis of (-)-anhydromacrosalhine- methine (7a) was carried out from the

Full text of DOI:10.1021/jo971570t

1478
J . Org. Chem. 1998, 63, 1478-1483
En a n tiosp ecific Tota l Syn th esis of
(-)-An h yd r om a cr osa lh in e-m eth in e a n d P a r tia l Syn th esis of th e
An tia m oebic Bisin d ole Alk a loid (-)-Ma cr oca r p a m in e1
Tong Gan and J ames M. Cook*
Department of Chemistry, University of WisconsinsMilwaukee, Milwaukee, Wisconsin 53201
Received August 22, 1997
An enantiospecific total synthesis of (-)-anhydromacrosalhine-methine (7a ) was completed from
D-(+)-tryptophan via the asymmetric Pictet-Spengler reaction. In addition, a partial synthesis of
(-)-anhydromacrosalhine-methine (7a ) was carried out from the natural product (+)-ajmaline (10).
The coupling reaction of plant-derived (+)-pleiocarpamine (8) with synthetic diene 7a provided the
antiamoebic bisindole alkaloid (-)-macrocarpamine (1) in 75% yield. This sequence serves as the
first example of the action of a nucleophile at [at C(2)] on a protonated form [C(3)] of pleiocarpamine
8 in the Alstonia series to provide a bisindole alkaloid.
Sch em e 1
During the last several decades, more than 80 macro-
line/sarpagine-related indole alkaloids have been isolated
from Alstonia macrophylla Wall, Alstonia muelleriana
Domin, and other Alstonia species.2,3 Among these
alkaloids, at least 18 are bisindoles including (-)-macro-
carpamine (1), villalstonine (2), and macralstonine (3a ).
Interest in macroline/sarpagine alkaloids isolated from
Alstonia species originated as a result of folk tales that
described the medicinal properties of these plants.4,5 For
example, the hypotensive base macralstonine 3a , isolated
from A. macrophylla Wall,6,7 is a member of this family.
The biomimetic interconversions of Alstonia alkaloids and
the coupling reactions of monomeric indoles into bisin-
doles were pioneered by LeQuesne.8-11 Recently, the
total synthesis of macroline 412 has resulted in the partial
synthesis of macralstonine 3a (Scheme 1); the addition
of 4 to natural alstophylline 511 was carried out under
the same conditions employed for the partial synthesis
of the antimalarial alkaloid villastonine (2).13
The bisindole (-)-macrocarpamine (1) was first isolated
from the bark of A. macrophylla Wall by Hesse et al. in
1978.14 Moreover, in 1988, Ghedira et al. reported the
isolation of the related bisindoles 10-methoxymacrocar-
pamine (6) and 10-methoxymacrocarpamine N-4′-oxide
from the leaves of Alstonia angustifolia.15 Macrocar-
pamine is comprised of a unit of anhydromacrosalhine-
methine (7a ) and pleiocarpamine (8). Anhydromacro-
salhine-methine (7a ) was first reported as a dehydration
product of macrosalhine,16 a quaternary salt related to
macroline. In 1978, Hesse and Mayerl reported the
fragmentation of (-)-macrocarpamine (1) into anhydro-
macrosalhine-methine (7a ) and pleiocarpamine (8) under
pyrolytic conditions. It was proposed by Hesse et al. that
under biomimetic conditions the coupling reaction of 7a
and 8 would provide 1. It is important to note that diene
7a also comprises the northern portion of pandicine (9),
a bisindole isolated from the leaves of Pandacastrum
saccharatum Pichon.17,18
(1) A portion of this study was reported in preliminary form in: (a)
Gan, T.; Cook, J . M. Tetrahedron Lett. 1996, 37, 5033. (b) Gan, T.;
Cook, J . M. Tetrahedron Lett. 1996, 37, 5037.
(2) Bi, Y.; Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline
Related Alkaloids. In Studies in Natural Products Chemistry, Bioactive
Natural Products, Part A; Basha, F. Z., Rahman, A., Ed.; Elsevier
Science: Amsterdam, 1993; Vol. 13; p 383.
(3) Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline Related
Sarpagine Alkaloids. In Alkaloids: Chemical and Biological Perspec-
tives; Pelletier, S. W., Ed.; Elsevier Science: New York, 1995; Vol. 9;
p 23.
(4) Cook, J . M.; LeQuesne, P. W. Phytochemistry 1971, 10, 437.
(5) Chatterjee, A.; Banerji, J .; Banerji, A. J . Indian Chem. Soc. 1949,
51, 156.
(6) Isidro, N.; Manalo, G. D. J . Phillipine Pharm. Assoc. 1967, 53,
8.
(7) Talapatra, S. K.; Adityachaudhury, N. Sci. Cult. 1958, 24, 243.
(8) Garnick, R. L. Ph.D. Thesis, Northeastern University, 1977.
(9) Garnick, R. L.; LeQuesne, P. W. J . Am. Chem. Soc. 1978, 100,
4213.
(10) Esmond, R. W.; LeQuesne, P. W. J . Am. Chem. Soc. 1980, 102,
7116.
(11) Burke, D. E.; DeMarkey, C. A.; LeQuesne, P. W.; Cook, J . M.
J . Chem. Soc., Chem. Commun. 1972, 1346.
(12) Bi, Y.; Cook, J . M. Tetrahedron Lett. 1993, 34, 4501.
(13) Bi, Y.; Cook, J . M.; LeQuesne, P. W. Tetrahedron Lett. 1994,
35, 3877.
There is a need for new therapeutic agents in the
tropics where diseases caused by protozoa and/or resis-
(14) Mayerl, F.; Hesse, M. Helv. Chim. Acta 1978, 61, 337.
(15) Ghedira, K.; Zeches-Hanrot, M.; Richard, B.; Massiot, G.; Le
Men-Olivier, L.; Sevenet, T.; Goh, S. H. Phytochemistry 1988, 27, 3955.
(16) Khan, Z. M.; Hesse, M.; Schmid, H. Helv. Chim. Acta 1967, 50,
1002.
(17) Kan-Fan, C.; Massiot, G.; Das, B. C.; Potier, P. J . Org. Chem.
1981, 46, 1481.
S0022-3263(97)01570-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/10/1998

Synthesis of (-)-Anhydromacrosalhine-Methine
J . Org. Chem., Vol. 63, No. 5, 1998 1479
tant strains of parasites are responsible for many deaths.
With respect to the macroline/sarpagine alkaloids, Wright
et al.19 reported on the antiprotozoal activity of nine
alkaloids from A. angustifolia against Entamoeba his-
tolytica and Plasmodium falciparum in vitro. Of the nine
alkaloids tested, macrocarpamine (1), villalstonine (2),
and macralstonine acetate (3b) were found to possess
significant activity against both protozoa. Macrocar-
pamine (1) was found to the most active antiamoebic
compound against E. histolytica of the series [ED50 (95%
C.I.) ) 8.12 (7.76-8.48) µM], although it was only one-
fourth as potent as the standard drug emetine. Villal-
stonine (2) was found to be the most potent alkaloid
against P. falciparum [ED50 (95% C.I.) ) 2.92 (1.11-3.14)
µM] of the alkaloids tested. The results of these in vitro
studies provide some basis for the traditional use of A.
angustifolia for the treatment of amoebic dysentery and
malaria by the people of the Malaya peninsula.19 It was
also reported that the monomeric alkaloids possessed
virtually no antiprotozoal activity. This suggests that
at least part of both of the ring systems present in the
dimeric alkaloids are essential for activity. The struc-
tures and studies via molecular modeling of the standard
antiamoebic drug emetine and the base usambarensine
also support this suggestion.20 The cytotoxic activity of
villalstonine (2) against KB cells was also tested and
found to be similar to its antiamoebic activity.19 How-
ever, the standard antiamoebic drug emetine is highly
toxic to KB cells and is three times less toxic to amoebas
than to KB cells. Therefore, villalstonine (2) appears to
have a more favorable antiamoebic/cytotoxic ratio as
compared with emetine. Consequently, the synthesis of
bisindole alkaloids has become more important since
these studies may lead to more selective antiprotozoal
agents in the future. In 1993, a partial synthesis of the
antimalarial alkaloid (+)-villalstonine (2) was completed
by coupling synthetic macroline (4) with plant-derived
pleiocarpamine (8).13 This provided additional stimulus
for the synthesis of macrocarpamine.
Since a number of ring-A alkoxylated macroline/
sarpagine indole alkaloids have been isolated from Al-
stonia species,2,3 a route to 1 was chosen that could later
be extended to 6 and to other ring-A alkoxylated alka-
loids. This approach was based on the proposed coupling
reaction of (-)-anhydromacrosalhine-methine (7a ) with
(+)-pleiocarpamine (8) to provide (-)-macrocarpamine (1)
analogous to the biogenetic proposal of Mayerl and
Hesse.14 In keeping with this interest in the total
synthesis of Alstonia bisindoles,21-23 we wish to describe
an enantiospecific total synthesis of (-)-anhydromacro-
salhine-methine (7a ) and a partial synthesis of (-)-
macrocarpamine (1). To our knowledge,21-23 this is the
first example of the addition of a vinylogous enol ether
(diene 7a ) to an iminium ion to provide a bisindole
alkaloid and serves as a potential route to pandicine17
and other bisindole alkaloids.
To obtain an authentic sample of 7a , a partial synthe-
sis from (+)-ajmaline (10) was first carried out. Ajmaline
(10) exhibits important antiarrhythmic activity and is
stereochemically identical to the macroline/sarpagine
alkaloids at C(3), C(5), and C(15). Degradation of ajma-
line (10) to provide hemiacetal 11 was accomplished
following the improved procedure of Sakai.24 As il-
lustrated in Scheme 3, dehydration of 11 to provide
deoxyalstonerine 1225 was executed in 95% yield by
stirring 11 with 1.1 equiv of p-toluenesulfonic acid in
refluxing benzene. Initial attempts to introduce a func-
tional group into the C-19 position of enol ether 12 were
carried out via allylic bromination with NBS, which
resulted in an inseparable mixture of alkaloidal material.
Allylic oxidation with various reagents including SeO2
was also employed to introduce a hydroxyl group at the
C-19 position of 12. These reactions failed or gave
mixtures of inseparable material. Consequently, the
regioselective oxyselenation of the olefin 12 was carried
out with N-(phenylseleno)phthalimide26 in CH2Cl2 in the
presence of 2-3 equiv of water and 1.3 equiv of p-
toluenesulfonic acid to afford 13 in 90% yield. Allylic
alcohol 14 was obtained in 90% yield by selenoxide
elimination of 13 on treatment with NaIO4. Although
treatment of 14 with 2,4-dinitrobenzenesulfonyl chlo-
ride27 in the presence of triethylamine produced diene
7a in 55% yield, the 1,4-elimination in 14 was improved
by simply stirring this olefin with 1.1 equiv of p-
toluenesulfonic acid in dry THF to provide anhydromac-
rosalhine-methine (7a ) in 85% yield (Scheme 3). The
spectral properties of this material were identical to those
reported by Mayerl and Hesse.14 This synthesis confirms
for the first time the absolute configuration of 7a at
stereogenic centers C(3), C(5), C(15), and C(16).
(18) A potential biomimetic route to pandicine 9 is illustrated below.
Other pathways are also possible.
Since a sample of 7a was now in hand, the enantiospe-
cific total synthesis of 7a was initiated via the 1,3 chiral
(21) Zhang, L. H.; Cook, J . M. J . Am. Chem. Soc. 1990, 112, 4088.
(22) Fu, X.; Cook, J . M. J . Am. Chem. Soc. 1992, 114, 6910.
(23) Bi, Y.; Zhang, L. H.; Hamaker, L. K.; Cook, J . M. J . Am. Chem.
Soc. 1994, 116, 9027.
(24) Takayama, H.; Phisalaphong, C.; Kitajima, M.; Aimi, N.; Sakai,
S. Tetrahedron 1991, 47, 1383.
(25) Kishi, T.; Hesse, M.; Gemenden, C. W.; Taylor, W. I.; Schmid,
H. Helv. Chim. Acta 1965, 48, 1349.
(26) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P.
J . Am. Chem. Soc. 1979, 101, 3704.
(19) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J . D.; Said, I. M.;
Kirby, G. C.; Warhurst, D. C. Phytother. Res. 1992, 6, 121.
(20) Quetin-Leclercq, J .; Dupont, L.; Wright, C. W.; Philipson, J . D.;
Warhurst, D. C.; Angenot, L. J . Pharm. Belg. 1991, 46, 82.
(27) Reich, H. J .; Wollowitz, S. J . Am. Chem. Soc. 1982, 104, 7051.

1480 J . Org. Chem., Vol. 63, No. 5, 1998
Gan and Cook
Sch em e 2
Sch em e 3
Ta ble 1. 1H NMR Da ta for
(-)-An h yd r om a cr osa lh in e-m eth in e (7a )
transfer28,29 developed in the enantiospecific Pictet-
Spengler reaction [from D-(+)-tryptophan].2,3 The opti-
cally active tetracyclic ketone 15 (>98% ee) was prepared
from D-(+)-tryptophan by a stereospecific regiospecific
method developed in our laboratory and is now readily
available.29 This ketone was enantiospecifically con-
verted into alstonerine 16, as previously reported.23 The
reduction of alstonerine with sodium borohydride pro-
vided the allylic alcohol 17 in 90% yield. Dehydration of
17 with p-toluenesulfonic acid gave (-)-anhydromacro-
salhine-methine (7a ) in 92% yield identical in all respects
with material prepared from 10. The chemical shifts and
coupling constants of the 1H NMR of (-)-anhydromac-
rosalhine-methine 7a (from alstonerine) as well as the
literature values from the report of Hesse14 are depicted
in Table 1.
proton
lit.14 δ (J , Hz)
synthetic material δ (J , Hz)
2H
1H
NbCH3
1H
1.95-2.05 (m)
2.13 (dt, 13, 4 Hz)
2.36 (s)
1.96-2.03 (m)
2.12 (dt, 13.1, 3.8 Hz)
2.34 (s)
2.33-2.43 (m)
2.54 (d, 16 Hz)
3.12 (d, 7 Hz)
3.34 (dd, 16, 7 Hz)
3.65 (s)
2.30-2.40 (m)
2.52 (d, 16.5 Hz)
3.10 (d, 6.7 Hz)
3.33 (dd, 16.5, 6.9 Hz)
3.64 (s)
H (6)
H (5)
H (6)
NaCH3
H (3)
H (17)
H (18)
H (17)
H (18)
H (19)
H (21)
H (10)
H (11)
H (12)
H (9)
3.92 (br, s)
3.91 (br, s)
4.04 (dd, 11, 3 Hz)
4.40 (d, 17 Hz)
4.40 (t, 11 Hz)
4.55 (d, 11 Hz)
6.00 (dd, 17, 11 Hz)
6.46 (s)
4.02 (dd, 10.9, 3.2 Hz)
4.38 (d, 17.4 Hz)
4.39 (t, 11.3 Hz)
4.54 (d, 10.8 Hz)
5.99 (dd, 17.5, 10.9 Hz)
6.45 (s)
7.11 (t, 8 Hz)
7.21 (t, 8 Hz)
7.32 (d, 8 Hz)
7.51(d, 8 Hz)
7.10 (t, 7.4 Hz)
7.20 (t, 7.5 Hz)
7.31 (d, 8.2 Hz)
7.50 (d, 7.7 Hz)
When anhydromacrosalhine-methine 7a was coupled
with natural pleiocarpamine (8) under aqueous acidic
conditions (0.2 N aqueous HCl), the enol ether 7a was
converted into byproducts of hydration. It was deter-
mined that diene 7a was unstable when maintained
under aqueous acidic conditions for extended periods of
time. However, addition of 6 equiv of 7a (portionwise)
to 8 in 0.2 N anhydrous HCl/THF provided (-)-macro-
carpamine (1) in 75% yield (Scheme 5). Nucleophilic
attack of the diene 7a did occur on the cup-shaped
(28) Zhang, L. H.; Cook, J . M. Heterocycles 1988, 27, 2795.
(29) Zhang, L. H.; Bi, Y.; Yu, F.; Menzia, G.; Cook, J . M. Heterocycles
1992, 34, 517.

Synthesis of (-)-Anhydromacrosalhine-Methine
J . Org. Chem., Vol. 63, No. 5, 1998 1481
Sch em e 4
Sch em e 5
Ta ble 2. 1H NMR Da ta for (-)-Ma cr oca r p a m in e (1)
alkaloid, pleiocarpamine (8), from the bottom face of the
2,3-indole double bond as planned.30 The spectroscopic
properties (MS, NMR) of 1 were virtually identical to
those reported by Mayerl and Hesse.14 The chemical
shifts and coupling constants of the 1H NMR of (-)-
macrocarpamine (1) as well as the literature values from
the report of Hesse14 are depicted in Table 2.
proton
lit.14 δ (J , Hz)
synthetic material δ (J , Hz)
CH3 (18)
8H
N′bCH3
H (6′)
H (7)
4H
H (5′)
H (15)
H (6′)
N′aCH3
CO2CH3
H (3′)
1.55 (dd, 7, 2 Hz)
not able to interpret
2.33 (s)
2.46 (d, 16 Hz)
2.60 (dd, 11, 7 Hz)
2.89-2.97 (m)
3.05 (d, 7 Hz)
3.15 (qa, 4 Hz)
3.28 (dd, 16, 7 Hz)
3.68 (s)
1.58 (dd, 6.8, 2.0 Hz)
1.75-2.20 (m)
2.31 (s)
2.44 (d, 16.8 Hz)
2.64 (br, dd, 11.2, 7.8 Hz)
2.90-3.10 (m)
3.03 (d, 6.7 Hz)
3.15 (m)
This sequence serves as the first example of a proton-
mediated coupling reaction between two monomeric units
in the Alstonia series to provide a bisindole alkaloid. In
the biomimetic syntheses of LeQuesne,8-11 the Michael
acceptor (macroline) served as the electrophile and its
addition to pleiocarpamine was not readily reversible in
acidic solution. In contrast, in the condensation between
pleiocarpamine (8) and the diene 7a the electrophile is a
proton. Since protonation of the indole double bond of 8
is a readily reversible process, the sequence illustrated
here is unique. The diene 7a must be added to an acidic
solution of 8 in small portions to immediately quench the
iminium ion intermediate; otherwise, only products of
diene decomposition are obtained. Although at least four
bisindoles21-23 have been isolated which could presum-
ably be formed by condensation of a diene such as 7a
with another monomeric indole unit, to our knowledge
this is the first example of a coupling reaction between
a vinylogous enol ether (diene 7a ) of this type and an
iminium ion. In addition to alkaloids in the macrocar-
pamine series, there is at least one other bisindole,
plumocraline (18), (Figure 1) whose biogenesis can be
rationalized by the action of a nucleophile on a protonated
form of pleiocarpamine 8.31
3.26 (dd, 16.7, 6.3 Hz)
3.65 (s)
3.71 (s)
3.70 (s)
3.86 (br, s)
3.84 (br, s)
H (17′)
H (16)
H (17′)
H (21)
H (18′)
H (19)
H (19′)
H (12)
H (21′)
H (10)
H (11)
H (9)
3.95 (dd, 11, 4 Hz)
4.18 (d, 4 Hz)
4.26 (t, 11 Hz)
4.32 (br, d, 13 Hz)
4.85 (d, 16 Hz)a
5.37 (qa, 6 Hz)
5.44 (d, 16 Hz)
5.84 (d, 8 Hz)
6.27 (s)
6.51 (t, 7 Hz)
6.74 (t, 8 Hz)
6.91 (d, 7 Hz)
7.10 (t, 8 Hz)
7.23 (t, 8 Hz)
7.36 (d, 8 Hz)
7.44(d, 8 Hz)
3.94 (dd, 11.1, 3.2 Hz)
4.13 (d, 3.5 Hz)
4.26 (t, 11.3 Hz)
4.43 (br, d, 12.7 Hz)
4.52 (d, 16.3 Hz)
5.43 (m)
5.48 (d, 15.8 Hz)
5.83 (d, 8.1 Hz)
6.27 (s)
6.53 (t, 7.4 Hz)
6.79 (t, 7.7 Hz)
6.90 (d, 7.2 Hz)
7.08 (t, 7.4 Hz)
7.22 (t, 8.1 Hz)
7.35 (d, 7.8 Hz)
7.42 (d, 7.9 Hz)
H (10′)
H (11′)
H (12′)
H (9′)
The literature value for H (18′) for 1 is 4.85 ppm.14 We believe
this is a typographical error since the literature values for H (18)
of anhydromacrosalhine-methine (7a ),14 10-methoxymacrocarpam-
ine (6),15 and 10-methoxymacrocarpamine N-4′ oxide15 are 4.55,
4.56, and 4.49 ppm, respectively.
a
constitutes the first partial synthesis of the antiamoebic
alkaloid (-)-macrocarpamine (1) as well as the enan-
tiospecific total synthesis of 7a and supports the earlier
Further work is in progress to extend this approach to
the preparation of 10-methoxymacrocarpamine (6) via
D-(+)-5-methoxytryptophan, recently synthesized in opti-
cally pure form from 3-methyl-5-methoxyindole in our
laboratory.32-35 In summary, the work described above
(31) J aquier, M. J .; Vercauteren, J .; Massiot, G.; Le Men-Olivier,
L.; Pussett, J .; Sevenett, T. Phytochemistry 1982, 21, 2973.
(32) Zhang, P.; Cook, J . M. Synth. Commun. 1995, 25, 3883.
(33) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 3103.
(34) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 7411.
(35) Zhang, P.; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 9133.
(30) Burke, D. E.; Cook, G. A.; Cook, J . M.; Haller, K. G.; Lazar, H.
A.; LeQuesne, P. W. Phytochemistry 1973, 12, 1467.

1482 J . Org. Chem., Vol. 63, No. 5, 1998
Gan and Cook
tography (silica gel, EtOAc-hexane, 2:3), and the solid that
resulted was recrystallized from ether to afford enol ether 12
as colorless prisms (270 mg, 95%). 12: mp 166-167 °C (from
ether); IR (KBr) 2900 (br), 1670, 1470, 1380, 1130, 760 cm-1
1H NMR (250 MHz, CDCl3) δ 0.81 (t, J ) 7.5 Hz, 3 H), 1.65-
2.04 (m, 8 H), 2.33 (s, 3 H), 2.49 (d, J ) 16.5 Hz, 1 H), 3.08 (d,
J ) 6.9 Hz, 1 H), 3.30 (dd, J ) 16.5 and 6.9 Hz, 1 H), 3.64 (s,
3 H), 3.90-3.95 (m, 2 H), 4.19 (t, J ) 10.9 Hz, 1 H), 6.14 (s, 1
H), 7.11 (t, J ) 7.8 Hz, 1 H), 7.20 (td, J ) 7.8 and 0.9 Hz, 1
H), 7.31 (d, J ) 8.0 Hz, 1 H), 7.51 (d, J ) 7.9 Hz, 1 H); 13C
NMR (62.90 MHz, CDCl3) δ: 12.9, 23.0, 23.5, 27.1, 29.0, 33.1,
40.6, 41.9, 53.8, 55.3, 66.3, 106.5, 108.8, 117.4, 118.0, 118.8,
120.8, 126.7, 133.6, 137.2, 138.1; CIMS (CH4) m/e (relative
intensity) 323 (M + 1, 100); EIMS (70 eV) m/e (relative
intensity) 322 (M+, 100), 307 (12.5) 279 (33.0), 253 (45.1), 224
(26.9), 212 (21.3), 197 (69.7), 182 (29.7), 170 (67.8), 149 (47.9).
Anal. Calcd for C21H26N2O‚1/3H2O: C, 76.79; H, 8.18; N, 8.53;
Found: C, 76.73; H, 7.95; N, 8.47.
;
F igu r e 1.
Oxyselen a tion of En ol Eth er (12) w ith N-(P h en ylse-
len o)p h th a lim id e To P r ovid e a Mixtu r e of Hyd r oxy
Selen id es 13a ,b. To a solution of enol ether 12 (200 mg, 0.62
mmol) in CH2Cl2 (10 mL) were added N-(phenylseleno)phthal-
imide26 (244 mg, 0.81 mmol), p-toluenesulfonic acid (130 mg,
0.68 mmol), and 1 drop of H2O. The reaction mixture was
stirred at rt for 5 h, diluted with CH2Cl2, and brought to
alkaline pH with 15% aqueous NH4OH at 0 °C. The aqueous
layer was extracted with CH2Cl2. The combined organic layers
were dried (K2CO3) and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel,
EtOAc) to afford 13a as an amorphous powder (76 mg, 24.7%)
and 13b as a crystalline solid (210 mg, 68.2%, from EtOAc).
Hydroxy selenide 13a was composed of a mixture of diaster-
eomers that could not readily be separated. It was used
directly in the next step. 13a : EIMS (70 eV) m/e (relative
intensity) 496 (M+, 13.3), 339 (27.5), 321 (20.1), 252 (13.6), 197
(100), 182 (37.7), 170 (35.6), 157 (66.8), 144 (29.8). 13b:
colorless crystals; mp 208-211 °C; IR (KBr) 3450 (br), 2940,
biogenetic proposal of Hesse in regard to the origin of
bisindole 1.14 In addition, the enantiospecific synthesis
of diene 7a provides a route to the northern portion of
pandicine (9),17 a bisindole with a structure very different
from that of 1 and 6 in keeping with the synthetic
potential of the asymmetric Pictet-Spengler reaction.2,3,36
Exp er im en ta l Section
Melting points were taken on a Thomas-Hoover melting
point apparatus or an Electrothermal model IA8100 digital
melting point apparatus and are uncorrected. Microanalyses
were performed on a Perkin-Elmer 240C carbon, hydrogen,
and nitrogen analyzer. All samples submitted for CHN
analyses were first dried under high vacuum for a minimum
of 6 h using a drying pistol with methylene chloride or
isopropyl alcohol as the solvent with phosphorus pentoxide in
the drying bulb. Proton and carbon high-resolution nuclear
magnetic resonance spectra were obtained on a Bruker 250-
MHz multiple probe NMR instrument or a GE 500-MHz NMR
spectrometer. The low-resolution mass spectra (EI/CI) were
obtained on a Hewlett-Packard 5985B gas chromatography-
mass spectrometer, while high-resolution spectra were re-
corded on a Finnigan HR mass spectrometer. Infrared spectra
were recorded on a Nicolet MX-1 FT-IR or a Perkin-Elmer 1600
Series FT-IR spectrometer.
1
2890, 1470, 1435, 1380, 1070, 1020, 740 cm-1; H NMR (500
MHz, CDCl3) δ 0.90 (t, J ) 7.5 Hz, 3 H), 0.97 (m, 1 H), 1.47
(m, 1 H), 1.55 (s, 1 H), 1.81 (m, 1 H), 2.35 (s, 3 H), 2.42 (d, J
) 3.0 Hz, 1 H), 2.49 (d, J ) 16.0 Hz, 1 H), 2.72 (td, J ) 13 and
4 Hz, 1 H), 2.90 (m, 1 H), 3.00 (d, J ) 7.0 Hz, 1 H), 3.28 (dd,
J ) 7.0 and 16.5 Hz, 1H), 3.53 (s, 3 H), 3.61 (dd, J ) 4.5 and
11.5 Hz, 1 H), 3.89 (s, br, 1 H), 4.52 (t, J ) 11.5 Hz, 1 H), 5.00
(s, 1 H), 6.74 (t, J ) 7.5 Hz, 2 H), 7.04 (t, J ) 7.5 Hz, 1 H),
7.14 (t, J ) 7.5 Hz, 1 H), 7.19 (t, J ) 7.5 Hz, 1 H), 7.21-7.25
(m, 3 H), 7.54 (d, J ) 7.5 Hz, 1 H); EIMS (70 e/V) m/e (relative
intensity) 496 (M+, 12.5), 339 (79.6), 321 (63.1), 252 (25.8), 197
(100), 182 (37.1), 158 (32.0), 144 (26.0). This material was
employed directly in the next step.
Analytical thin-layer chromatography plates used were E.
Merck Brinkmann UV-active silica gel (Kieselgel 60 F254) on
plastic. Silica gel 60A, grade 60 for flash and gravity chro-
matography, was purchased from E. M. Laboratories.
Alkaloids were visualized with Dragendorf’s reagent or a
saturated solution of ceric ammonium sulfate in 50% sulfuric
acid, or with an aqueous solution of 2,4-dinitrophenylhydrazine
in 30% sulfuric acid. Methanol (MeOH) and ethanol (EtOH)
were dried by distillation over magnesium metal and iodine.
Tetrahydrofuran (THF), benzene, toluene, dioxane, and diethyl
ether were dried by distillation from sodium-benzophenone
ketyl. Methylene chloride was dried over MgSO4 and then
distilled over P2O5. N-(Phenylseleno)phthalimide was pre-
pared following the procedure of Nicolaou26 while all other
chemicals were purchased from Aldrich Chemical Co.
Deh yd r a tion of Hem ia ceta l (11) w ith p-TSA To P r o-
vid e En ol Eth er (12). A solution of hemiacetal 11 (300 mg,
0.88 mmol), prepared by the method of Sakai,24 and p-
toluenesulfonic acid (185 mg, 0.97 mmol) in dry benzene (10
mL) was heated to reflux under an N2 atmosphere for 3 h.
The reaction mixture was allowed to cool and was then diluted
with EtOAc and brought to alkaline pH with 15% aqueous
NH4OH at 0 °C. The aqueous layer was extracted with EtOAc
(3 × 80 mL). The combined organic layers were washed with
brine and dried (Na2SO4). The solvent was removed under
reduced pressure. The residue was purified by flash chroma-
Selen oxid e Elim in a tion of 13a ,b w ith Na IO4 To P r o-
vid e th e Mixtu r e of Allylic Alcoh ols 14a ,b. To a stirred
solution of 13a or 13b (130 mg, 0.262 mmol) in THF (11 mL)
at 0 °C was added a solution of NaIO4 (82 mg, 0.384 mmol) in
H2O (2.4 mL). The reaction mixture was allowed to stir at rt
for 5 h. The precipitate that formed was removed by filtration,
and the reaction mixture was concentrated, after which it was
brought to alkaline pH with 15% aqueous NH4OH at 0 °C. The
aqueous layer was extracted with CHCl3. The organic extracts
were washed with brine, dried (K2CO3), and then concentrated
under reduced pressure. The residue was purified by flash
chromatography (silica gel, MeOH-CHCl3, 1:9) to provide a
mixture of allylic alcohols 14a ,b as an amorphous powder (80
mg, 90%). 14a ,b: IR (KBr) 3350 (br), 2900, 1450, 1000, 750
cm -1; CIMS (CH4) m/e (relative intensity) 339 (M + 1, 100),
321 (57.9); EIMS (70 eV) m/e (relative intensity) 338 (M+, 23.2),
320 (5.0), 197 (100), 181 (43.7), 170 (50.1), 154 (20.9), 144
(17.5). This material was employed in the next step without
further purification.
Th e 1,4-Elim in a tion of Wa ter fr om Allylic Alcoh ols
14a ,b w ith p-TSA To P r ovid e Dien e 7a . A solution of allylic
alcohols represented by 14 (14 mg, 0.041 mmol) and p-
toluenesulfonic acid (13 mg, 0.068 mmol) in dry THF (2 mL)
was stirred at rt for 5 h. The reaction mixture was brought
to alkaline pH with 10% aqueous NH4OH solution and
(36) Cox, E. D.; Cook, J . M. Chem. Rev. (Washington, D.C.) 1995,
95, 1797.

Synthesis of (-)-Anhydromacrosalhine-Methine
J . Org. Chem., Vol. 63, No. 5, 1998 1483
extracted with CHCl3. The combined organic extracts were
dried (K2CO3). The solvent was removed under reduced
pressure. The residue was purified by flash chromatography
(silica gel, EtOAc-hexane, 3:2) to afford anhydromacrosalhine-
methine 7a (11.3 mg, 85%). The solid was recrystallized from
EtOAc to provide 7a as colorless crystals: mp 146-150 °C
(from EtOAc); IR (KBr) 3420, 2890, 1630, 1470, 740 cm-1; 1H
NMR (500 MHz, CDCl3) δ 2.03-1.96 (m, 2 H), 2.12 (dt, J )
13.1, 3.8 Hz, 1 H), 2.34 (s, 3 H), 2.40-2.30 (m, 1 H), 2.52 (d, J
) 16.5 Hz, 1 H), 3.10 (d, J ) 6.7 Hz, 1 H), 3.33 (dd, J ) 16.5,
6.9 Hz, 1 H), 3.64 (s, 3 H), 3.91 (s, br, 1 H), 4.02 (dd, J ) 10.9,
3.2 Hz, 1 H), 4.38 (d, J ) 17.4 Hz, 1 H), 4.39 (t, J ) 11.3 Hz,
1 H), 4.54 (d, J ) 10.8 Hz, 1 H), 5.99 (dd, J ) 17.5, 10.9 Hz,
1 H), 6.45 (s, 1 H), 7.10 (t, J ) 7.4 Hz, 1 H), 7.20 (t, J ) 7.5
Hz, 1 H), 7.31 (d, J ) 8.2 Hz, 1 H), 7.50 (d, J ) 7.7 Hz, 1 H);
13C NMR (62.90 MHz, CDCl3) δ 22.9, 23.6, 29.0, 32.4, 39.3,
41.9, 54.0, 55.1, 87.1, 106.4, 106.7, 108.8, 116.9, 118.1, 119.0,
120.9, 126.8, 133.5, 134.3, 137.3, 145.5; CIMS (CH4) m/e
(relative intensity) 321 (M+, 100); EIMS (70 eV) m/e (relative
intensity) 320 (M + 1, 100), 251 (38.0), 222 (15.9), 197 (64.6),
181 (34.8), 170 (64.1). Anal. Calcd for C21H24N2O‚1/2H2O: C,
76.56; H, 7.65; N, 8.50; Found: C, 76.60; H, 7.64; N, 8.30. The
spectral data for 7a were identical to those reported by Hesse
in ref 14.
Red u ction of Alston er in e (16) w ith Na BH4 To P r ovid e
a Mixtu r e of Allylic Alcoh ols Rep r esen ted by 17a ,b. To
a solution of alstonerine (16)21 (28 mg, 0.0833 mmol) in dry
MeOH (2 mL) at 0 °C was added sodium borohydride (70 mg)
in one portion, and the mixture was allowed to stir at 0 °C for
20 min, after which time it was stirred at rt for 9 h. Additional
sodium borohydride (60 mg) was added, and the reaction
mixture was allowed to stir at rt for 1.5 h. The mixture was
diluted with water and extracted with CH2Cl2 (3 × 30 mL).
The extracts were combined, washed with water, and dried
(K2CO3). The solvent was removed under reduced pressure.
The residue was purified by flash chromatography (silica gel,
5% MeOH/CHCl3) to afford 25.4 mg (90%) of a diastereomeric
mixture of allylic alcohols represented by 17a ,b. 17a ,b: 1H
NMR (500 MHz, CDCl3) δ 1.13 and 1.05 (d, J ) 6.4 Hz, 3 H),
2.30 (s, 3 H), 2.49 (dd, J ) 16.4, 5.4 Hz, 1 H), 3.08 (d, J ) 6.0
Hz, 1 H), 3.30 (dd, J ) 16.4, 6.5 Hz, 1 H), 3.62 (s, 3 H), 3.88
(br s, 1 H), 4.25 (t, J ) 11.3 Hz, 1 H), 6.47 and 6.43 (s, 1 H),
7.09 (t, J ) 7.3 Hz, 1 H), 7.19 (t, J ) 7.4 Hz, 1 H), 7.30 (d, J
) 8.0 Hz, 1 H), 7.49 (d, J ) 7.6 Hz, 1 H); CIMS (CH4) m/e
(relative intensity) 339 (M + 1, 19), 321 (100), 197 (7). The
alcohols were employed directly in the next step without
further purification.
0.084 mmol) in dry THF (8 mL) was stirred at rt for 2.5 h.
The reaction mixture was diluted with CH2Cl2 and brought to
alkaline pH with a solution of 15% aqueous NH4OH at 0 °C.
The mixture was extracted with CH2Cl2 (3 × 40 mL). The
organic layer was dried (K2CO3), and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography (silica gel, EtOAc-hexane, 3:2) to afford 12.2
mg (92%) of anhydromacrosalhine-methine 7a as colorless
crystals. The spectral data for 7a prepared here were identical
to those for 7a prepared above.
Th e P a r tia l Syn th esis of Ma cr oca r p a m in e (1). To a
solution of plant-derived pleiocarpamine 8 (5 mg, 0.0155 mmol)
in 0.2 N HCl (anhydrous) in dry THF (1 mL) was added
anhydromacrosalhine-methine 7a (7.5 mg, 0.0234 mmol).
After the reaction mixture was allowed to stir at rt for 6 h, an
additional 5 mg (0.0156 mmol) of 7a was added. The reaction
mixture was allowed to stir at rt overnight, after which another
6 mg (0.0187 mmol) of 7a was added. After the mixture was
stirred for 10 h, another 6.5 mg (0.0203 mmol) of 7a was added.
After the mixture was stirred for 14 h, 5 mg (0.0156 mmol)
more of 7a was added. In essence, the diene 7a was added
until all of the pleiocarpamine (8) had been used up as
indicated by TLC (total of 6 equiv of 7a was added). The
reaction mixture was stirred at rt for an additional 6 h and
then poured into a solution of 15% aqueous NH4OH at 0 °C.
The mixture was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with brine and dried
(K2CO3), and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography (silica gel,
4% MeOH/CHCl3 to 8% MeOH/CHCl3) to provide 7.5 mg (75%)
of macrocarpamine (1) as an amorphous powder. 1: 1H NMR
(500 MHz, CDCl3) δ 1.58 (dd, J ) 6.8, 2.0 Hz, 3 H), 1.75-2.20
(m, 8 H), 2.31 (s, 3 H), 2.44 (d, J ) 16.8 Hz, 1 H), 2.64 (t, J )
9.4 Hz, 1 H), 2.90-3.10 (m, 4 H), 3.03 (d, J ) 6.7 Hz, 1 H),
3.15 (m, 1 H), 3.26 (dd, J ) 16.7, 6.3 Hz, 1 H), 3.65 (s, 3 H),
3.71 (s, 3 H), 3.84 (s, br, 1 H), 3.94 (dd, J ) 11.1, 3.2 Hz, 1 H),
4.13 (d, J ) 3.5 Hz, 1 H), 4.26 (t, J ) 11.3 Hz, 1 H), 4.43 (d,
br, J ) 12.7 Hz, 1 H), 4.52 (d, J ) 16.3 Hz, 1 H), 5.43 (m, 1 H),
5.48 (d, J ) 15.8 Hz, 1 H), 5.83 (d, J ) 8.1 Hz, 1 H), 6.27 (s,
1 H), 6.53 (t, J ) 7.4 Hz, 1 H), 6.79 (t, J ) 7.7 Hz, 1 H), 6.90
(d, J ) 7.2 Hz, 1 H), 7.08 (t, J ) 7.4 Hz, 1 H), 7.22 (t, J ) 8.1
Hz, 1 H), 7.35 (d, J ) 7.8 Hz, 1 H), 7.42 (d, J ) 7.9 Hz, 1 H);
EIMS (70 eV) m/e (relative intensity) 642 (M+, 39), 583 (18),
321 (14), 320 (11), 263 (15), 197 (100), 170 (67), 135 (59), 107
(49); exact mass calcd for C41H46N4O3 642.3609, found 642.3570.
The spectral data for 1 were virtually identical to those
reported by Hesse in ref 14 (see Table 2).
Deh yd r a tion of th e Mixtu r e of Allylic Alcoh ols 17a ,b
To P r ovid e th e Dien e 7a . A solution of the allylic alcohols
17a ,b (14 mg, 0.041 mmol) and p-toluenesulfonic acid (16 mg,
J O971570T