Total synthesis of indole alkaloids of the ervatamine group. A biomimetic approach

Full text of DOI:10.1021/jo9600058

1916
J . Org. Chem. 1996, 61, 1916-1917
Sch em e 1
Tota l Syn th esis of In d ole Alk a loid s of th e
Er va ta m in e Gr ou p . A Biom im etic
Ap p r oa ch
M.-Llu¨ısa Bennasar,* Bernat Vidal, and J oan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, 08028 Barcelona, Spain
Received J anuary 2, 1996
The ervatamine alkaloids1 (19,20-dehydroervatamine,2
ervatamine,2 methuenine,3 and silicine4 ) constitute a
group of 2-acylindole alkaloids with an unusual structure,
in which the tryptamine carbon atoms (C5 and C6)5 are
in a rearranged situation, forming C5-C16 and C6-C16
bonds. Other remarkable features are the presence of a
methoxycarbonyl group at C-16, absent in the methue-
nine-silicine series, a seven-membered C ring included
in a cis-fused6 bicyclic system, and an ethyl or (E)-
ethylidene group at C-20.
The biogenetic pathway to this structural arrangement
probably involves a key intermediate A, formed from a
vobasine N-oxide equivalent as illustrated in Scheme 1,
which would be transformed into 19,20-dehydroervat-
amine by closure of the C ring by cyclization of the
enamine moiety upon the 3-methyleneindoleninium cat-
ion (bond formed C6-C16).7
These alkaloids have received little attention from a
synthetic standpoint: only the total synthesis of (()-6-
oxosilicine has been reported so far.8 Additionally, the
syntheses of several related tetracyclic structures,9 in-
cluding a N(a)-methyl-16-epi-20-epi derivative of ervata-
mine, have been described.8
We present here a synthetic entry to the tetracyclic
ring system of the alkaloids of the ervatamine group
based on a biomimetic cyclization and the first total
synthesis of the alkaloids 19,20-dehydroervatamine and
20-epiervatamine. The C6-C16 seco derivative 8 was
envisaged as the synthetic equivalent of the key bioge-
netic intermediate A as the 3-[(dimethylamino)methyl]-
indole moiety can be considered as a latent 3-methyle-
neindoleninium cation. On the other hand, the func-
tionalized two-carbon appendage on C-20 in the inter-
mediate 8 could be further elaborated into the C-20 ethyl
or ethylidene chain present in the natural products.
The crucial biomimetic intermediate 8 would be pre-
pared taking advantage of the methodology we have
recently developed10 for the synthesis of 4-substituted 1,4-
dihydropyridines bearing two different electron-with-
drawing groups at the â-positions, based on the nucleo-
philic addition of a 2-acetylindole enolate11 to a
3-acylpyridinium salt, with trapping of the initially
formed 1,4-dihydropyridine with trichloroacetic acid an-
hydride (TCAA).12 The application of this methodology
to the synthesis of 8 required the protection of the
nitrogen atom of the starting 2-acetylindole.13 Thus,
reaction of the enolate derived from N-benzylated 2-acetyl-
indole 1 with 3-acetylpyridinium salt 2 followed by in situ
treatment with TCAA gave dihydropyridine 3 in 14%
yield (minor amounts of the regioisomeric 3,5-disubsti-
tuted 1,2-dihydropyridine were also detected). A subse-
quent haloform-type reaction of 3 with MeONa in MeOH-
THF afforded dihydropyridine 4 in 91% yield (Scheme
2). Dihydropyridines 3 and 4 were crystalline solids,
stable enough to be fully characterized.14
Stereoselective reduction of the vinylogous amide
moiety of dihydropyridine 4 was achieved by catalytic
hydrogenation in THF-MeOH15 to give the cis-tetrahy-
dropyridine 516 in 45% yield. Deprotection of the indole
ring of 5 with AlCl317 followed by reduction of the ketone
carbonyl groups with LiBEt3H in the resulting N-unsub-
(10) Bennasar, M.-L.; Vidal, B.; Bosch, J . J . Org. Chem. 1995, 60,
4280.
(11) For a recent review on the nucleophilic addition of indole-
containing enolates to pyridinium salts and its application to the
synthesis of bridged indole alkaloids, see: Bosch, J .; Bennasar, M.-L.
Synlett 1995, 587.
(12) The addition of stabilized carbon nucleophiles to N-alkyl-â-
acylpyridinium salts for alkaloid synthesis was first used by Wen-
kert: (a) Wenkert, E. Pure Appl. Chem. 1981, 53, 1271. (b) Wenkert,
E.; Guo, M.; Pestchanker, M. J . ; Shi, Y.-J .; Vankar, Y. D. J . Org. Chem.
1989, 54, 1166 and references cited therein. See also: (c) Spitzner, D.;
Arnold, K.; Stezowski, J . J .; Hildenbrand, T.; Henkel, S. Chem. Ber.
1989, 122, 2027. (d) Amann, R.; Spitzner, D. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1320.
(13) Reaction of the dianion derived from 2-acetylindole with pyri-
dinium salt 2 followed by TCAA treatment gave the corresponding 3,5-
diacylated 1,4-dihydropyridine in very low yield. The use of other
N-protected (BOC, C6H5SO2) 2-acetylindoles was also unsuccessful.
(14) All yields are from material purified by column chromatogra-
phy. Satisfactory analytical and spectral data were obtained from all
new compounds.
(1) (a) J oule, J . A. Indoles, The Monoterpenoid Indole Alkaloids. In
The Chemistry of Heterocyclic Compounds; Saxton, J . E., Weissberger,
A., Taylor, E. C., Eds.; Wiley: New York, 1983; Vol. 25, Part 4, pp
232-239. (b) Alvarez, M.; J oule, J . Monoterpenoid Indole Alkaloids.
In The Chemistry of Heterocyclic Compounds; Saxton, J . E., Taylor, E.
C., Eds.; Wiley: Chichester, 1994; Vol. 25, Supplement to Part 4, pp
234-236.
(2) Knox, J . R.; Slobbe, J . Aust. J . Chem. 1975, 28, 1813 and 1825.
(3) Bui, A.-M.; Debray, M.-M.; Boiteau, P.; Potier, P. Phytochemistry
1977, 16, 703.
(4) Vecchietti, V.; Ferrari, G.; Orsini, F.; Pelizzoni, F.; Zajotti, A.
Phytochemistry 1978, 17, 835.
(5) The biogenetic numbering is used throughout this paper for all
tetracyclic compounds. Le Men, J .; Taylor, W. I. Experientia 1965, 21,
508.
(6) The trans C/D ring junction is present in isomethuenine (16-
epimethuenine) and 6-oxo-16-episilicine.
(7) The biogenetic relationship between the alkaloids of the vobasine
and ervatamine groups through an intermediate like A has been
demonstrated: (a) Husson, A.; Langlois Y.; Riche, C.; Husson, H.-P.;
Potier, P. Tetrahedron 1973, 29, 3095. (b) Thal, C.; Dufour, M.; Potier,
P.; J aouen, M.; Mansuy, D. J . Am. Chem. Soc. 1981, 103, 4956.
(8) Husson, H.-P.; Bannai, K.; Freire, R.; Mompon, B.; Reis, F. A.
M. Tetrahedron 1978, 34, 1363.
(9) (a) Langlois, Y.; Potier, P. Tetrahedron 1975, 31, 423. (b)
Grierson, D. S.; Bettiol, J .-L.; Buck, I.; Husson, H.-P.; Rubiralta, M.;
D´ıez, A. J . Org. Chem. 1992, 57, 6414.
(15) Concomitant reduction of the acetyl group was observed when
pure MeOH was used as the solvent for the hydrogenation.
(16) The isomeric cis-tetrahydropyridine resulting from reduction
of the vinylogous urethane double bond was isolated as a minor
byproduct (13% yield).
(17) Murakami, Y.; Watanabe, T.; Kobayashi, A.; Yokoyama, Y.
Synthesis 1984, 738.
0022-3263/96/1961-1916$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 6, 1996 1917
Sch em e 2a
lamino group as a methiodide. Further NaCNBH3 re-
duction of the resulting iminium salt 9 followed by MnO2
reoxidation of the benzylic-type hydroxy group gave (()-
19-hydroxy-20-epiervatamine (10) in 25% overall yield
from 7.
The synthesis of (()-19,20-didehydroervatamine (13)
was completed in 70% yield by DBU treatment of the
mesylate 11 derived from alcohol 10. The stereoselective
formation of an (E)-ethylidene double bond in this anti
elimination allowed the relative stereochemistry at C-19
in 7-10 to be established. On the other hand, a radical
reduction of chloride 12, obtained in 71% yield from
alcohol 10 via mesylate 11, gave (()-20-epiervatamine
(14) in 73% yield. Given that 19,20-didehydroervatamine
had been previously converted into ervatamine (15) by
catalytic hydrogenation,2 the above synthesis also con-
stitutes a formal synthesis of the latter alkaloid. The
1H and 13C NMR spectra of our synthetic ervatamines
were identical to those reported18 for the natural prod-
ucts.
The above results not only provide the first synthetic
entry to the C-16 methoxycarbonyl-substituted ervata-
mine alkaloids and present chemical evidence of the
viability of the biogenetic proposal outlined in Scheme 1
but also significantly expand the scope and the potential
of the methodology for indole alkaloid synthesis based
on the reactivity of N-alkyl-3-acylpyridinium salts with
indole-containing enolates.19 After the initial nucleophilic
attack on the γ-position, the intermediate 1,4-dihydro-
pyridine is further functionalized to give a 3,5-diacyl-1,4-
dihydropyridine and then reduced to a tetrahydropyri-
dine,20 ultimately leading to a cis-fused pentasubstituted
piperidine with generation of the C-16 quaternary center.
Ack n ow led gm en t. Financial support from the DGI-
CYT, Spain (Project PB94-0214) is gratefully acknowl-
edged. Thanks are also due to the “Comissionat per a
Universitats i Recerca”, Generalitat de Catalunya, for
Grant GRQ93-1059 and for a fellowship to B.V.
a
Key: (i) LDA, THF, -30 °C, 1.5 h; (ii) TCAA, 0 °C, 3 h; (iii)
MeONa, MeOH-THF, rt, 3 min; (iv) H2, PtO2, MeOH-THF, rt,
10 h; (v) AlCl3, C6H6, rt, 3 h; (vi) LiBEt3H, -70 °C, 45 min; (vii)
Me2N+dCH2 I-, CH2Cl2, rt, 1 h; (viii) ICH3, DMSO, rt, 30 min,
then 70 °C, 4 h; (ix) NaCNBH3, MeOH, rt, 45 min; (x) from 11;
MnO2, CHCl3, rt, 1.5 h; (xi) MsCl, Et3N, 0 °C, 1 h; (xii) LiCl,
acetone, reflux, 1 h; (xiii) DBU, DMSO-toluene, 80-100 °C, 4 h;
(xiv) from 12; n-Bu3SnH, AIBN, C6H6, reflux, 1 h.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of all new compounds and copies of
their 1H and 13C NMR spectra (22 pages).
J O9600058
stituted indole 6 gave a single diol 7 (undetermined
stereochemistry at the benzylic-type carbon) in 54%
overall yield.
The above reduction of the 2-acylindole moiety was
necessary for the success of the subsequent aminomethy-
lation of the indole ring. Thus, treatment of diol 7 with
N,N-dimethylmethyleneimmonium iodide (Eschenmoser’
salt) gave the key intermediate 8, which underwent a
biomimetic cyclization after activation of the dimethy-
(18) Clivio, P.; Richard, B.; Zeches, M.; Le Men-Olivier, M.; Goh, S.
H.; David, B.; Sevenet, T. Phytochemistry 1990, 29, 2693.
(19) For the use of this methodology in a biomimetic synthesis of
ervitsine, see: Bennasar, M.-L.; Vidal, B.; Bosch, J . J . Am. Chem. Soc.
1993, 115, 5340.
(20) There are very few examples of the reduction of 1,4-dihydro-
pyridines generated by nucleophilic addition to N-alkylpyridinium
salts: (a) Lounasmaa, M.; Koskinen, A. Tetrahedron Lett. 1982, 23,
349. (b) Lavilla, R.; Gotsens, T.; Gullo´n, F.; Bosch, J . Tetrahedron 1994,
50, 5233.