Biomimetic total synthesis of ervitsine and indole alkaloids of the ervatamine group via 1,4-dihydropyridines

Article abstract of DOI:10.1021/jo9623301

Addition of the enolate derived from 2-acetylindole la to pyridinium salt 2 followed by in situ trapping of the initially formed 1,4-dihydropyridine 3a with Eschenmoser's salt gives tetracycle 5a. Subsequent elaboration of the exocyclic methylene and E-ethylidene substituents leads to N(a)-methylervitsine (17a). A similar sequence from the N(a)-protected 2-acetylindole 1c establishes the first total synthesis of the 2-acylindole alkaloid ervitsine. Alternatively, dihydropyridine 3a is trapped with BrSePh to give the tetracyclic selenide 7a, which is then converted to N(a)-methylervitsine by way of selenoxide 20. The synthesis of the alkaloids of the ervatamine group starts with the addition of the enolate derived from 2-acetyl-1-benzylindole (1g) to pyridinium salt 24 and the conversion of the resulting 1,4-dihydropyridine to 3,5-diacylated dihydropyridine 26g. Chemoselective reduction of the vinylogous amide moiety of 26g, followed by deprotection of the indole ring and LiEt₃BH reduction leads to diol 37b. On sequential treatment with Eschenmoser's salt, methyl iodide, NaCNBH₃, and MnO₂, 37b is converted to the tetracyclic 2-acylindole 39, from which the first total synthesis of 19,20-didehydroervatamine and 20-epiervatamine is accomplished by manipulation of the 1-hydroxyethyl chain. The above syntheses can be considered as biomimetic, as cyclization of the key intermediates I and II mimics the key steps of the biosynthesis of the title alkaloids.

Full text of DOI:10.1021/jo9623301

J . Org. Chem. 1997, 62, 3597-3609
3597
Biom im etic Tota l Syn th esis of Er vitsin e a n d In d ole Alk a loid s of
th e Er va ta m in e Gr ou p via 1,4-Dih yd r op yr id in es
M.-Llu ¨ı sa Bennasar,* Bernat Vidal, and J oan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
Received December 12, 1996X
Addition of the enolate derived from 2-acetylindole 1a to pyridinium salt 2 followed by in situ
trapping of the initially formed 1,4-dihydropyridine 3a with Eschenmoser’s salt gives tetracycle
5
a . Subsequent elaboration of the exocyclic methylene and E-ethylidene substituents leads to N
methylervitsine (17a ). A similar sequence from the N -protected 2-acetylindole 1c establishes the
first total synthesis of the 2-acylindole alkaloid ervitsine. Alternatively, dihydropyridine 3a is
trapped with BrSePh to give the tetracyclic selenide 7a , which is then converted to N
a
-
a
a
-
methylervitsine by way of selenoxide 20. The synthesis of the alkaloids of the ervatamine group
starts with the addition of the enolate derived from 2-acetyl-1-benzylindole (1g) to pyridinium salt
2
4 and the conversion of the resulting 1,4-dihydropyridine to 3,5-diacylated dihydropyridine 26g.
Chemoselective reduction of the vinylogous amide moiety of 26g, followed by deprotection of the
indole ring and LiEt BH reduction leads to diol 37b. On sequential treatment with Eschenmoser’s
salt, methyl iodide, NaCNBH , and MnO , 37b is converted to the tetracyclic 2-acylindole 39, from
3
3
2
which the first total synthesis of 19,20-didehydroervatamine and 20-epiervatamine is accomplished
by manipulation of the 1-hydroxyethyl chain. The above syntheses can be considered as biomimetic,
as cyclization of the key intermediates I and II mimics the key steps of the biosynthesis of the title
alkaloids.
1
The ervitsine-ervatamine alkaloids constitute a group
The structural similarities between ervitsine and the
alkaloids of the ervatamine group are a consequence of
their common biogenetic origin from a vobasine N-oxide
equivalent, as illustrated in Scheme 1.9 Thus, 19,20-
didehydroervatamine would be derived from the inter-
mediate A by closure of the C ring by cyclization of the
enamine moiety upon the 3-methyleneindoleninium cat-
2
of 2-acylindole alkaloids of the Corynanthean type, with
an unusual skeleton in which the tryptamine carbon
3
atoms (C
5
-C
6
) are in a rearranged situation, forming
-C16 bonds. In ervitsine, a minor alkaloid
C
5
-C16 and C
6
4
isolated from Pandaca boiteaui, there is an additional
link between C-5 and the indole 3-position (C-7) and,
consequently, this bridged alkaloid incorporates a seven-
membered C ring and a piperidine moiety bearing two
different (16-methylene and 20E-ethylidene) exocyclic
double bonds. On the other hand, in the alkaloids of the
ervatamine group (19,20-didehydroervatamine, ervat-
amine, methuenine, and silicine ) the indole 3-position
is attached to C-6; the seven-membered C ring is now
ion (bond formed C -C16), followed by reduction of the
6
10
resulting iminium cation B. Hydrolysis of B would give
rise to acid C, the decarboxylation of which can account
for the biogenetic formation of both ervitsine and the C-16
unsubstituted ervatamine alkaloids: decarboxylative
fragmentation of C followed by cyclization of the resulting
conjugated iminium cation D on the indole 3-position
(1,2-addition) would result in the formation of ervitsine
5
5
6
7
8
included in a cis-fused bicyclic system bearing an ethyl
(
bond formed C
5
7
-C ), whereas either simple decarboxyl-
or E-ethylidene group at C-20 and a methoxycarbonyl
group at C-16, which is not present in the methuenine-
silicine series.
ation of C or cyclization of D via a 1,4-addition, followed
by reduction, would lead to methuenine.11
These alkaloids have received little attention from the
synthetic standpoint: total syntheses of only (()-6-
oxosilicine12 and (()-6-oxo-16-episilicine have been
reported so far. Additionally, several synthetic ap-
X
Abstract published in Advance ACS Abstracts, May 1, 1997.
13
(
1) (a) J oule, J . A. Indoles, The Monoterpenoid Indole Alkaloids;
Saxton, J . E., Ed. In The Chemistry of Heterocyclic Compounds;
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; Saxton, J . E., Ed. In The Chemistry of Heterocyclic Com-
pounds; Taylor, E. C., Ed.; Wiley: Chichester, 1994; Vol. 25, Supple-
ment to Part 4, pp 234-236.
14
proaches to simplified analogs of ervitsine and the
(9) Atta-ur-Rahman; Basha, A. Biosynthesis of Indole Alkaloids;
Clarendon Press: Oxford, 1983.
(2) Kisak u¨ rek, M. V.; Leeuwenberg, A. J . M.; Hesse, M. Alkaloids:
(10) 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.
(11) Ervitsine and a methuenine-type compound have been cor-
related in vitro: see reference 4.
(12) Husson, H.-P.; Bannai, K.; Freire, R.; Mompon, B.; Reis, F. A.
M. Tetrahedron 1978, 34, 1363.
(13) Bennasar, M.-L.; Vidal, B.; Bosch, J . Chem. Commun. 1996,
2755.
(14) (a) Grierson, D. S.; Harris, M.; Husson, H.-P.; Tetrahedron 1983,
39, 3683. (b) Bosch, J .; Rubiralta, M.; Domingo, A.; Bol o´ s, J .; Linares,
A.; Minguill o´ n, C.; Amat, M.; Bonjoch, J . J . Org. Chem. 1985, 50, 1516.
(c) Bosch, J .; Rubiralta, M.; Bol o´ s, J . Tetrahedron 1987, 43, 391. (d)
Salas, M.; J oule, J . A. J . Chem. Res. (M) 1990, 664. (e) Rubiralta, M.;
Marco, M.-P.; Bol o´ s, J .; Trap e´ , J . Tetrahedron 1991, 47, 5585.
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1983; Chapter 5.
(
3) The biogenetic numbering is used throughout this paper for all
tetracyclic compounds. Le Men, J .; Taylor, W. I. Experientia 1965, 21,
08.
4) Andriantsiferana, M.; Besseli e` vre, R.; Riche, C.; Husson, H.-P.
Tetrahedron Lett. 1977, 2587.
5
(
(
(
5) Knox, J . R.; Slobbe, J . Aust. J . Chem. 1975, 28, 1813 and 1825.
6) Bui, A.-M.; Debray, M.-M.; Boiteau, P.; Potier, P. Phytochemistry
1
977, 16, 703.
7) Vecchietti, V.; Ferrari, G.; Orsini, F.; Pelizzoni, F.; Zajotti, A.
Phytochemistry 1978, 17, 835.
8) The trans C/D ring junction is present in isomethuenine (16-
(
(
epimethuenine), 6-oxo-16-episilicine, and 16-episilicine: Clivio, P.;
Richard, B.; Nuzillard, J .-M.; Z e` ches-Hanrot, M. Phytochemistry 1995,
0, 987.
4
S0022-3263(96)02330-4 CCC: $14.00 © 1997 American Chemical Society

3
598 J . Org. Chem., Vol. 62, No. 11, 1997
Bennasar et al.
Sch em e 2. Syn th etic Str a tegy
Sch em e 1. Biosyn th esis a n d Biogen etic
Nu m ber in g
ethylidene (or ethyl) chain present in these natural
products.
Both biomimetic key intermediates I and II would be
prepared by taking advantage of the general procedure
for the generation of 4-substituted 1,4-dihydropyridines
based on the addition of stabilized carbon nucleophiles
(in this case enolates derived from 2-acetylindoles) to
pyridinium salts bearing an electron-withdrawing sub-
stituent at the â-position. Reaction of the resultant 1,4-
synthesis of tetracyclic structures related to ervatamine
1
5
a
alkaloids, including a N -methyl-16-epi-20-epi deriva-
tive of ervatamine,12 have been described.
+
dihydropyridines with an electrophile (X ) would promote
In this paper we report a synthetic entry to the
tetracyclic ring systems of ervitsine and ervatamine
cyclization to the bridged tetracyclic ring system of
ervitsine through dihydropyridinium cations I. On the
other hand, reaction of the above intermediate dihydro-
pyridines with an acylating agent would result in the
formation of 4-substituted 3,5-diacyl-1,4-dihydropyr-
idines, from which we could have access to the required
enamines II by partial reduction of the dihydropyridine
ring followed by aminoalkylation at the indole 3-position.
9
,16
alkaloids based on biomimetic considerations
as the first total syntheses of the alkaloids ervitsine,
as well
1
9,20-didehydroervatamine, and 20-epiervatamine.
The synthesis of ervitsine was planned through dihy-
dropyridinium cations I, which were envisaged as syn-
thetic equivalents of the biogenetic intermediate D as
they incorporate (i) a substituent X that either constitutes
a latent exocyclic methylene group or can allow a later
introduction of this group, and (ii) an electron-withdraw-
ing substituent Y that can be elaborated into the E-
ethylidene substituent present in the alkaloid (Scheme
Resu lts a n d Discu ssion
Syn th esis of Er vitsin e. The tandem nucleophilic
addition of an indole-containing enolate to a pyridinium
salt-acid cyclization of the intermediate 1,4-dihydro-
pyridine has been successfully used for the synthesis of
2
6
). On the other hand, the C -C16 seco derivatives II
were considered as synthetic equivalents of the key
intermediate A in the biogenetic pathway to ervatamine
alkaloids: the 3-[(dimethylamino)methyl]indole moiety
is a latent 3-methyleneindoleninium cation whereas the
substituent Y could again be transformed into the C-20
17
bridged indole alkaloids belonging to several structural
18
types.
In previous work we had employed enolates
derived from indoleacetic esters, which give rise to
19
tetracyclic systems bearing a six-membered C ring. The
(
15) (a) Langlois, Y.; Potier, P. Tetrahedron 1975, 31, 423. (b)
(17) (a) For a review, see: Bosch, J .; Bennasar, M.-L. Synlett 1995,
587. For more recent work, see: (b) Bennasar, M.-L.; Zulaica, E.;
Ram ´ı rez, A.; Bosch, J . J . Org. Chem. 1996, 61, 1239. (c) Bennasar,
M.-L.; Zulaica, E.; Sufi, B. A.; Bosch, J . Tetrahedron 1996, 52, 8601.
(d) Bennasar, M.-L.; J im e´ nez, J .-M.; Sufi, B. A.; Bosch, J . Tetrahedron
Lett. 1996, 37, 9105.
Grierson, D. S.; Bettiol, J .-L.; Buck, I.; Husson, H.-P.; Rubiralta, M.;
D ´ı ez, A. J . Org. Chem. 1992, 57, 6414.
(16) Husson, H.-P. In Indole and Biogenetically Related Alkaloids;
Phillipson, J . D., Zenk, M. H., Eds.; Academic Press: London, 1980;
Chapter 10.

Total Synthesis of Ervitsine and Ervatamine Alkaloids
J . Org. Chem., Vol. 62, No. 11, 1997 3599
Sch em e 3. Syn th esis of
The best results were obtained from 1c, with the isolation
(
()-16-Dem eth ylen eer vitsin e (10) a n d
a
of N -SEM protected tetracycle 4c in 15% yield. From
acetylindole 1d , the corresponding tetracycle 4d was
obtained in a lower yield (7%).
F u n ction a liza tion a t C-16
The exocyclic E-ethylidene substituent was incorpo-
rated in a stereoselective manner by taking advantage
of the â-(tetrahydro-3-pyridyl)acrylate moiety of tetra-
cycles 4.22 Thus, treatment of 4c with refluxing 4 N HCl
brought about the hydrolysis and decarboxylation of the
acrylic portion, with simultaneous deprotection of the
indole ring, to give an iminium ion, which was then
reduced with NaBH
reoxidized with MnO
4
.
2
The resulting alcohol 9 was
to give 10, the 16-demethylene
analog of ervitsine, in 38% overall yield from 4c.
similar sequence from the N -unsubstituted tetracycle
b, which was conveniently prepared (48% yield) by
deprotection of 4c (BF -Et O, Triton B), led to (()-16-
A
a
4
3
2
demethyleneervitsine (10) in 50% yield.
The extension of these studies to the synthesis of
ervitsine required the functionalization at C-16 in order
to then incorporate the exocyclic methylene substituent.
This was achieved by a slight modification of the above
methodology, consisting of the trapping of the initially
formed 1,4-dihydropyridine 3 with an electrophile other
than a proton to generate the key dihydropyridinium
cation I necessary for the cyclization.23 Reactions of the
a
model dihydropyridine 3a (incorporating a N -methyl
substituent) with several one-carbon electrophiles were
first investigated. However, reaction of 3a either with
formaldehyde or with several alkyl halides (ClCH
2
SPh,
ClCH SO Ph, and BrCH SePh) under a variey of experi-
2
2
2
mental conditions resulted in failure. In all cases, the
only identifiable product was the anhydro base 14 result-
ing from oxidation of 3a . The desired functionalization
at C-16 was achieved when dihydropyridine 3a was
treated with N,N-dimethylmethyleneiminium iodide
(
Eschenmoser’s salt).24 The best results were obtained
when lithium cyclohexylisopropylamide (LICA) was used
as the base to generate the enolate derived from 1a :
under these conditions tetracycle 5a was obtained in 18%
yield. The use of LDA gave this tetracycle in lower yield
(
14%) along with minor amounts of tetracycle 6a , prob-
aim of our first experiments in the ervitsine field was to
evaluate if, starting from a 2-acetylindole enolate, this
nucleophilic addition-cyclization sequence could be used
for the construction of the bridged tetracyclic 1,5-meth-
+
2 2
ably formed by reaction of 3a with CH dN (i-Pr) , which
would result from the interaction of LDA or diisopropyl-
amine with Eschenmoser’s salt.
As could be expected from the results obtained in the
above nucleophilic addition-acid cyclization sequence
when using the dianion derived from acetylindole 1b,
interaction of this dianion with salt 2 followed by in situ
treatment of the resulting 1,4-dihydropyridine 3b with
Eschenmoser’s salt gave the C-16 substituted tetracycle
anoazonino[4,3-b]indole skeleton characteristic of er-
vitsine.20
Thus, whereas exposure of pyridinium salt 2 to the
enolate derived from acetylindole 1a and then to acid
(
HCl-C
dihydropyridine 3a in 20% yield, the procedure could not
be satisfactorily extended to the preparation of the N
6 6
H ) had led to the expected tetracycle 4a through
5
2
b in only 5% yield. The use of the SEM-protected
-acetylindole 1c gave a better result, tetracycle 5c being
a
-
unsubstituted tetracycle 4b, which was isolated in a yield
lower than 5% (Scheme 3).21 For this reason, we then
obtained in 15% yield. Although this is clearly not a high
chemical yield,25 it must be noted that the construction
of the bridged tetracycles 5 involves the formation of
studied the use of N-protected 2-acetylindoles 1c and 1d .
(
18) 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.
(22) For a review, see: Bosch, J .; Bennasar, M.-L. Heterocycles 1983,
20, 2471.
(23) For a preliminary report of this part of the work, see: Bennasar,
M.-L.; Vidal, B.; Bosch, J . J . Am. Chem. Soc. 1993, 115, 5340.
(24) There are few examples of aminomethylation of cyclic enam-
ines: (a) Barnett, C. J .; Copley-Merriman, C. R.; Maki, J . J . Org. Chem.
1989, 54, 4795. (b) Mitch, C. H.; Zimmerman, D. M.; Snoddy, J . D.;
Reel, J . K.; Cantrell, B. E. J . Org. Chem. 1991, 56, 1660.
(25) The moderate or low yields usually associated with the nucleo-
philic addition-cyclization sequence leading to bridged tetracyclic
indole-containing systems are due both to the reversibility of the first
step and to the fact that polymerization occurs to some extent during
cyclization.
1
989, 54, 1166 and refs cited therein. See also: (c) Spitzner, D.; Arnold,
K.; Stezowski, J . J .; Hildenbrand, T.; Henkel, S. Chem. Ber. 1989, 122,
027. (d) Amann, R.; Arnold, K.; Spitzner, D.; Majer, Z.; Snatzke, G.
Liebigs Ann. Chem. 1996, 349.
19) Bennasar, M.-L.; Alvarez, M.; Lavilla, R.; Zulaica, E.; Bosch,
J . J . Org. Chem. 1990, 55, 1156.
20) For a preliminary report of this part of the work, see: Bennasar,
M.-L.; Zulaica, E.; Vidal, B.; Bosch, J . Tetrahedron Lett. 1992, 33, 3895.
21) Bennasar, M.-L.; Vidal, B.; Bosch, J . J . Org. Chem. 1995, 60,
280.
2
(
(
(
4

3
600 J . Org. Chem., Vol. 62, No. 11, 1997
Bennasar et al.
three new C-C bonds on the pyridine ring by successive
γ-nucleophilic, â-electrophilic, and R-nucleophilic attacks
in a one-pot, three-step sequence.
Sch em e 4. Syn th esis of (()-Er vitsin e a n d
(()-N -Meth yler vitsin e
a
At this point we decided to explore the reactivity of
the intermediate 1,4-dihydropyridines 3 toward hetero-
atom-centered electrophiles in order to develop alterna-
tive procedures for the generation of the biomimetic
intermediate I. However, dihydropyridine 3a did not
react with ClP(OEt)
on treatment with [Me
2
, ClPO(OEt)
2
, or Me
3
SiCl,26 whereas
+
-
27
2
SSMe] BF
4
(DMTSF) it led
to a mixture of the expected C-16 functionalized tetra-
cycle 8a (6%) and the rearranged sulfenamides 11 and
1
2 (12% overall yield). Formation of these sulfenamides
can be rationalized by considering that a further meth-
ylthiolation on the tetrahydropyridine nitrogen28 of 8a
promotes the opening of the tetrahydropyridine ring to
give a 3-alkylideneindoleninium cation that undergoes
recyclization by nucleophilic attack of C-18 to C-5.29
Reaction of 3a with NCS was not chemoselective either,
as the 16,18-dichloro tetracycle 13 was obtained (6%) as
the only isolable product. More interestingly from the
synthetic standpoint (vide infra), interaction of 3a with
BrSePh led to the C-16 functionalized tetracycle 7a in
2
0% yield as the only isolable product.
The relative configuration at C-16 in tetracycles 5-8
and 13 was inferred from the multiplicity of 5-H in the
1
H NMR spectra. This proton appears as a singlet, as
expected from the approximate dihedral angle (90°)
Sch em e 5. Alter n a tive Syn th esis of
()-N -Meth yler vitsin e
formed by the H-C
5
-C16-H bond system when 5-H and
(
a
1
6-H are located trans with respect to the partially
reduced pyridine ring (see Dreiding stereomodels).
With a method in hand for the construction of tetra-
cyclic ervitsine-type systems 5 bearing latent methylene
and E-ethylidene substituents at C-16 and C-20, respec-
tively, we next studied the formation of the two exocyclic
double bonds. Initially, tetracycle 5a was stereoselec-
tively converted into the E-ethylidene derivative 18
(
Scheme 4) by the usual hydrolysis-decarboxylation-
reduction sequence, although in this case reduction of the
intermediate iminium cation was chemoselectively ac-
complished without reduction of the 2-acylindole carbonyl
4
group by using only a slight excess of NaBH . Alterna-
tively, the (dimethylamino)methyl group of 5a was first
converted into the exocyclic C-16 methylene substituent
by Cope elimination of the corresponding N-oxide, and
then the doubly vinylogous urethane moiety was elabo-
rated as above into the 20E-ethylidene group. Thus,
oxidation of 5a with m-CPBA (63% yield), followed by
heating of the resulting N-oxide 15a in refluxing toluene
gave (79%) tetracycle 16a , which was converted (55%
1
hydrolytic conditions of the latter step. The H NMR and
MS data of synthetic ervitsine were identical to those
4
13
reported for the natural product, whereas the C NMR
spectrum was in full agreement with the one expected
for this structure.
The biomimetic synthesis of ervitsine here reported
constitutes the first total synthesis of this alkaloid. The
complex structure of ervitsine has been assembled in a
straightforward sequence from very accessible starting
products, acetylindole 1c and pyridinium salt 2.
In order to demonstrate the versatility of the above
methodology for the synthesis of ervitsine, an alternative
yield) into (()-N
a
-methylervitsine (17a ) by treatment
with 4 N HCl and then with NaBH
4
.
As expected, the successive formation of the exocyclic
1
6-methylene and 20E-ethylidene substituents from the
a
N -protected C-16 functionalized tetracycle 5c, as in the
above a series, gave 16c (through 15c; overall yield 45%)
and then the target alkaloid ervitsine (17b, 65%). Clearly,
deprotection of the indole ring took place under the
a
synthesis of (()-N -methylervitsine (17a ) was completed
3
0
(
26) 4-Alkylidene-1,4-dihydropyridine 14 and tetracycle 4a were
formed in some runs.
27) Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
A., Ed.; Wiley: Chichester, 1995; Vol. 3, pp 2102-2104.
28) (a) Caserio, M. C.; Kim, J . K. J . Am. Chem. Soc. 1982, 104,
231. (b) Kim, J . K.; Souma, Y.; Beutow, N.; Ibbeson, C.; Caserio, M.
C. J . Org. Chem. 1989, 54, 1714.
29) A DMTSF-promoted displacement of the C-16 methylthio group
by iodide ion can account for the formation of the C-16 iodo derivative
2.
from the 16-selenenyl tetracycle 7a (Scheme 5). Thus,
after 7a was stereoselectively converted (60% yield) into
the C-20 E-ethylidene derivative 19 by the usual treat-
ment, the phenylseleno group of 19 allowed the introduc-
tion of the exocyclic C-16 methylene substituent by
(
(
3
(
(30) For a preliminary report of this part of the work, see: Bennasar,
M.-L.; Vidal, B.; Bosch, J . J . Chem. Soc., Chem. Commun. 1995, 125.
1

Total Synthesis of Ervitsine and Ervatamine Alkaloids
J . Org. Chem., Vol. 62, No. 11, 1997 3601
Sch em e 6
Sch em e 7. Syn th esis of
3
,5-Dia cyld ih yd r op yr id in es
oxidation with m-CPBA, followed by methylation (LDA,
MeI) at the R-position of the resulting selenoxide 20 and
subsequent thermal elimination (30% overall yield from
1
9).
Syn th esis of Er va ta m in e Alk a loid s. We have re-
cently reported a procedure for the preparation of 3-(meth-
oxycarbonyl)-4-[(2-indolylcarbonyl)methyl]-1,4-dihydro-
pyridines bearing an additional electron-withdrawing
substituent at the 5-position.21 The method consists of
the nucleophilic addition of a 2-acetylindole enolate to a
3
-acylpyridinium salt, with trapping of the initially
formed 1,4-dihydropyridine with trichloroacetic acid an-
hydride (TCAA) and subsequent conversion of the trichlo-
roacetyl group to methoxycarbonyl by treatment with
MeONa in MeOH. According to our synthetic plan, these
dihydropyridines were considered to be potential precur-
made evident that, as in the above synthesis of ervitsine,
it was necessary to operate with N-protected acetyl-
indoles.
sors of the C
required for the synthesis of ervatamine alkaloids.
In order to evaluate if the biomimetic cyclization by
6
-C16 seco derivatives (II, Scheme 2)
More satisfactorily, interaction of the N-Boc acetyl-
indole 1e with salt 24 followed by treatment with TCAA
gave the expected 1,4-dihydropyridine 25e (13%) together
with the corresponding enol trichloroacetate 29 (11%) and
4-alkylidene-1,4-dihydropyridine 30 (12%). However,
reaction of 25e or 29 (or a mixture of 25e and 29) with
MeONa in MeOH to simultaneously promote the halo-
form-type reaction32 and the deprotection of the indole
ring gave a mixture of the expected 1,4-dihydropyridine
26b and the regioisomeric 1,2-dihydropyridine 28b.
Clearly, under the reaction conditions, equilibration of
the initially formed 1,4-dihydropyridine to a mixture of
1,2- and 1,4-dihydropyridines had occurred. Protection
of the indole nitrogen with a phenylsulfonyl group was
not synthetically useful either: after the addition-
trichloroacetylation sequence from acetylindole 1f and
salt 24, the desired 1,4-dihydropyridine 25f was obtained
in only 7% yield along with trace amounts of the
bis(trichloroacetyl) product 31 and, in several runs, 1,2-
dihydropyridine 27f. The best results were obtained
when using a benzyl group as the indole protecting group:
formation of C -C16 bond could be effected at the dihy-
6
dropyridine stage, we first studied the aminoalkylation
of dihydropyridines 2121 and 22, the latter prepared by
4
NaBH reduction of 21 (Scheme 6). Whereas no reaction
was observed when 2-acylindole 21 was treated with
Eschenmoser’s salt,31 most probably as a consequence of
the deactivation exerted by the carbonyl group, alcohol
2
2
2 did react (CH
3. However, all attempts to induce cyclization, either
2 2
Cl , rt) with this reagent to give gramine
directly (rt, 24 h) or through the corresponding methio-
dide (CH I, rt, 48 h), gave only decomposition products.
3
For this reason we then focused our efforts on the
generation of gramine-tetrahydropyridine derivatives II.
This required the preparation of a suitable 3,5-disubsti-
tuted 4-[(indolylcarbonyl)methyl]-1,4-dihydropyridine, the
chemoselective reduction of one of the dihydropyridine
double bonds, and finally the introduction of the (di-
methylamino)methyl substituent at the 3-position of the
indole ring. Whereas the methoxycarbonyl group at one
of the dihydropyridine â-positions would correspond to
the characteristic C-16 methoxycarbonyl substituent of
ervatamine alkaloids, we selected the acetyl group as the
substituent Y, precursor of the two-carbon C-20 append-
age of these alkaloids. Consequently, 3-acetylpyridinium
salt 24 was used as the starting pyridinium salt. How-
ever, although the nucleophilic addition-TCAA acylation
sequence from the enolate derived from acetylindole 1a
and salt 24 had satisfactorily led to (trichloroacetyl)-
dihydropyridine 25a , which was then efficiently con-
verted into dihydropyridine ester 26a 21 (Scheme 7), the
3
3
reaction of the enolate derived from N-benzyl-2-
acetylindole (1g) with pyridinium salt 24, followed by in
situ treatment with TCAA, gave a 2:1 mixture of dihy-
dropyridines 25g and 27g in 21% overall yield. Subse-
quent treatment of 25g with MeONa in MeOH accom-
plished the conversion of the trichloroacetyl group to
methoxycarbonyl to give dihydropyridine 26g in 91%
yield.
Although the reduction of 1,4-dihydropyridines to the
corresponding tetrahydropyridines or piperidines is a
(
32) (a) Harbuck, J . W.; Rapoport, H. J . Org. Chem. 1972, 37, 3618.
(b) Bates, H. A.; Rapoport, H. J . Am. Chem. Soc. 1979, 101, 1259.
3
33) For the debenzylation of N-benzyl-2-acylindoles with AlCl ,
extension of the procedure to the N
acetylindole 1b proved to be unsuccessful. This result
a
-unsubstituted
(
see: (a) Murakami, Y.; Watanabe, T.; Kobayashi, A.; Yokoyama, Y.
Synthesis 1984, 738. (b) Watanabe, T.; Kobayashi, A.; Nishiura, M.;
Takahashi, H.; Usui, T.; Kamiyama, I.; Mochizuki, N.; Noritake, K.;
Yokoyama, Y.; Murakami, Y. Chem. Pharm. Bull. 1991, 39, 1152.
2 2
dNMe
]+ Cl-,
(31) For the aminomethylation of indoles with [CH
see: Kozikowski, A. P.; Ishida, H. Heterocycles 1980, 14, 55.

3
602 J . Org. Chem., Vol. 62, No. 11, 1997
Bennasar et al.
Ta ble 1. Ca ta lytic Hyd r ogen a tion of
The cis relative configuration of tetrahydropyridines
3-35 is the result of the hydrogen uptake from the most
1
,4-Dih yd r op yr id in es 26
3
accessible face of the dihydropyridine ring and implies
the pseudoaxial disposition of the bulky C-4 substituent
(
to relieve the steric A1 interactions with C-5 acyl
,2
38
group) and the equatorial disposition of the acetyl (or
hydroxyethyl) substituent. Of diagnostic value from the
1
stereochemical standpoint was the H NMR signal at-
tributable to 2-Hax, which appears as a triplet with J ∼
1
2 Hz due to the geminal and vicinal (with 3-Hax)
couplings in the cis isomers 33-35. In contrast, in the
trans-tetrahydropyridines 32, 2-Hax appears as a doublet
of doublets (J ∼13 and 4 Hz) as a result of the axial
disposition of the acetyl group. The above stereochemical
1
3
assignments agree with the shielding of C-5 in the
C
NMR spectra of trans-tetrahydropyridines 32, as com-
pared with 33-35, due to the γ-effect induced by the axial
acetyl group.
Both cis-tetrahydropyridines 33g and 34g were con-
sidered a priori to be good substrates for conversion into
ervatamine alkaloids. However, the reluctance shown
by 2-acylindoles toward aminoalkylation at C-3 and the
tendency of alcohols 34 to undergo cyclodehydration to
give enol ethers 36 made evident that reduction of the
dihydro-
entry pyridine
conditions
products (yield, %)
2
-acylindole carbonyl group was necessary for the success
1
2
3
4
26a
26a
26g
26g
MeOH, 12 h
MeOH, 24 h
MeOH, 18 h
32a (7), 33a (25),
3
of our synthetic plan. The synthetic possibilities of
alcohol 34g were first investigated. In a model study
with the N
a
-methyl derivative 34a we were able to
convert this unstable alcohol into diol 37a (one dia-
4a (30), 35a (20)
32a (7), 34a (55),
5a (20)
32g (6), 34g (40),
5g (13)
1:1 MeOH-THF, 10 h 32g (6), 33g (45),
5g (13)
3
3
stereomer of undetermined stereochemistry at C-3 and
C-19) in 75% yield by reduction with LiBEt
3
H. The same
3
reaction applied to alcohol 34g gave a single diol 37g in
known process,34 there are few examples of the reduction
of 1,4-dihydropyridines generated by addition of stabi-
lized carbanions to pyridinium salts,35 probably due to
the reversibility of the addition. In our case, the higher
stability of the 3,5-diacyl substituted 1,4-dihydro-
8
3% yield (Scheme 8).
As expected, treatment of 37g with Eschenmoser’s salt
gave the key intermediate II (R ) Bn), which underwent
a biomimetic cyclization after activation of the dimethyl-
39
amino group as a methiodide.
Further NaCNBH
3
pyridines 26a and 26g made their catalytic hydrogena-
reduction of the resulting iminium salt gave the ervat-
amine-type tetracycle 38g in 40% overall yield. Unfor-
tunately, all attempts to regenerate the 2-acylindole
carbonyl group by MnO oxidation were unsuccessful,
2
a
probably due to the presence of the bulky N -benzyl
tion possible.3
6,37
The results are given in Table 1.
Favorable to our synthetic interest, hydrogenation of
these dihydropyridines using platinum as the catalyst
took place predominantly on the vinylogous amide moiety
to give the R,â-unsaturated esters 33 and 34, with a cis
relative configuration between the tetrahydropyridine
substituents. Only minor amounts of the trans isomers
group.
This result clearly indicated that the benzyl group had
to be removed prior to the key cyclization step. Taking
into account the sensitivity of alcohols 34 to acids, we
3
2 were formed. Reduction of the vinylogous urethane
double bond leading to the R,â-unsaturated ketones 35
occurred to a lesser extent. On prolonged reaction times
the acetyl group of 33 undergoes a further reduction to
give alcohols 34 (a single stereoisomer of undetermined
stereochemistry at C-19 in each series), whose manipula-
tion was difficult since traces of acid caused their
transformation into the corresponding enol ethers 36.
Interestingly, reduction of 26g could be stopped at the
acetyl stage using a 1:1 MeOH-THF mixture as the
solvent.
4
0
turned our attention to ketone 33g. Deprotection of the
3
3
indole ring of 33g with AlCl
unsubstituted indole 33b, which was then stereoselec-
tively reduced with LiBEt H to give (72%) diol 37b.
3
a
gave (75%) the N -
3
Biomimetic cyclization as above, by successive treatment
of 37b with Eschenmoser’s salt, methyl iodide, and
NaCNBH
selectively oxidized to the tetracyclic 2-acylindole 39 with
MnO in 25% overall yield from 37b. The relative
stereochemistry of 39 was determined from its H and
3
, gave tetracycle 38b, which could be chemo-
2
1
1
3
1
1
C NMR data, with the aid of 2D experiments ( H- H
(34) (a) Eisner, U.; Kuthan, J . Chem. Rev. 1972, 72, 1. (b) Stout, D.;
Meyers, A. I. Chem. Rev. 1982, 82, 233. (c) Sausins, A.; Duburs, G.
Heterocycles 1988, 27, 291. (d) Rosentreter, U. Synthesis 1985, 210.
COSY and HMQC). The triplet (J ) 11.5 Hz) corre-
sponding to 21-Hax was of diagnostic value as it indicates
that the vicinal hydroxyethyl substituent is equatorial.
Taking into account the 15-H/20-H cis relationship (vide
(
35) (a) Lounasmaa, M.; Koskinen, A. Tetrahedron Lett. 1982, 23,
3
5
49. (b) Lavilla, R.; Gotsens, T.; Gull o´ n, F.; Bosch, J . Tetrahedron 1994,
0, 5233.
(
36) However, fragmentation to the starting products was the only
process observed when dihydropyridine 21 was treated with Et SiH-
TFA, Et SiH-AcOH, n-Bu SnH-TFA, or NaBH CN-AcOH under the
3
3
3
3
(38) J ohnson, F. Chem. Rev. 1968, 68, 375.
conditions reported for the reduction of the carbon-carbon double bond
in vinylogous urethanes: Rosentreter, U.; Born, L.; Kurz, J . J . Org.
Chem. 1986, 51, 1165.
(39) For examples of alkylation of enamines with gramines, see: (a)
Sundberg, R. J .; Ligon, W. V.; Lin, L.-S. J . Org. Chem. 1971, 36, 2471.
(b) Sainsbury, M. Synthesis 1977, 437, and references cited therein.
(40) For a preliminary report of this part of the work, see: Bennasar,
M.-L.; Vidal, B.; Bosch, J . J . Org. Chem. 1996, 61, 1916.
(37) For related hydrogenations, see: Bennasar, M.-L.; Vidal, B.;
L a´ zaro, A.; Kumar, R.; Bosch, J . Tetrahedron Lett. 1996, 37, 3541.

Total Synthesis of Ervitsine and Ervatamine Alkaloids
J . Org. Chem., Vol. 62, No. 11, 1997 3603
Sch em e 8. Syn th esis of Er va ta m in e Alk a loid s
In summary, we have completed biomimetic total
syntheses of the 2-acylindole alkaloids ervitsine, 19,20-
didehydroervatamine, and 20-epiervatamine. The key
synthetic intermediates
I
(X ) CH
2 2
NMe ; Y )
CH)CHCO Me) and II (Y ) CHOHMe) (Scheme 2)
2
mimic the biogenetic intermediates D and A (Scheme 1),
respectively, and undergo biomimetic cyclizations that
reproduce the key steps of the biosynthesis of these
alkaloids. The results here reported significantly expand
the scope and potential of the methodology for indole
alkaloid synthesis based on the reactivity of N-alkyl-3-
acylpyridinium salts with indole-containing enolates.
After the initial nucleophilic attack on the γ-position, the
intermediate 1,4-dihydropyridine is further functional-
ized to ultimately lead to tetracyclic ervitsine- or ervat-
amine-type systems.
Exp er im en ta l Section
Melting points were determined in a capillary tube and are
uncorrected. Unless otherwise noted, NMR spectra were
1
recorded in CDCl
5
3
3
solution at 200, 300, or 500 MHz ( H) and
1
-1
0.3 or 75 MHz ( C). Only noteworthy IR absorptions (cm
)
2
are listed. TLC was carried out on SiO (silica gel 60 F254,
Merck, 0.063-0.200 mm), and the spots were located with
iodoplatinate reagent. Column chromatography was carried
out on SiO
chromatography was carried out on SiO
.040-0.060 mm). Drying of organic extracts during the
4
workup of reactions was performed over anhydrous Na SO .
2
(silica gel 60, SDS, 0.060-0.2 mm). Flash
2
(silica gel 60, SDS,
0
2
Evaporation of solvents was accomplished with a rotatory
evaporator. Microanalyses and HMRS were performed by
Centro de Investigaci o´ n y Desarrollo (CSIC), Barcelona. All
compounds were synthesized in the racemic series. The
biogenetic numbering is used to describe the 13C NMR spectra
of tetracyclic compounds 11, 12, 17b, and 39.
2
-Acetylin d ole (1b). MeLi (1.6 M in Et
mmol) was slowly added to a suspension of lithium indole
-carboxylate (4 g, 24 mmol) in anhydrous DME (300 mL)
cooled at 0 °C, and the mixture was refluxed for 1 h.
Additional MeLi (1.6 M in Et O, 30 mL, 48 mmol) was added
at rt, and the mixture was refluxed for 7 h. The reaction was
quenched by addition of saturated aqueous NH Cl, diluted
with Et O, and extracted with Et O. The organic extracts were
washed with H O, dried, and evaporated to give acetylindole
2
O, 30 mL, 48
2
2
4
2
2
supra), this equatorial disposition is only compatible with
a cis C/D ring junction. This stereochemistry was the
expected one by considering the stereochemical outcome
of the cyclization of the key biogenetic intermediate A
2
44
1
1
b
after column chromatography (CH
2 2
Cl ): 3.7 g (97%); H
NMR (200 MHz) 2.59 (s, 3 H), 7.00-7.40 (m, 3 H), 7.45 (d, J
1
3
) 8 Hz, 1 H), 7.69 (d, J ) 8 Hz, 1 H), 9.70 (br s, 1 H);
NMR (50.3 MHz) 25.7, 110.1, 112.4, 120.9, 123.0, 126.4, 127.5,
35.4, 137.7, 191.1.
-Acetyl-1-{[2-(tr im eth ylsilyl)eth oxy]m eth yl}in dole (1c).
C
Scheme 1).41
(
1
Finally, treatment of the mesylate derived from alcohol
2
3
9 with DBU afforded (()-19,20-didehydroervatamine
A solution of 2-acetylindole (1b, 2 g, 12.5 mmol) in DMF (32
mL) was added dropwise to a suspension of NaH (55%, 0.6 g,
(41) in 70% yield. The stereoselective formation of an
E-ethylidene double bond in this anti elimination allowed
the relative stereochemistry at C-19 in alcohols 37b, 38b,
and 39 to be established.42 On the other hand, reduction
of chloride 40, obtained in 71% yield from alcohol 39 via
1
3.8 mmol) in anhydrous THF (3 mL), and the resulting
mixture was stirred at rt for 1 h. [2-(Trimethylsilyl)ethoxy]-
methyl chloride (2.2 mL, 12.5 mmol) was slowly added at 0
°C, and the resulting solution was stirred at rt for 1 h. The
reaction mixture was poured into H
Et O. The organic extracts were washed with H
evaporated to give a residue which was chromatographed (85:
2
O-ice and extracted with
the corresponding mesylate, with n-Bu
3
SnH-AIBN gave
2
2
O, dried, and
(
1
()-20-epiervatamine (43) in 73% yield. Given that
9,20-didehydroervatamine had previously been con-
1
1
5 hexane-AcOEt) to give 1c as an oil: 3.4 g (93%); IR (film)
5
verted into ervatamine by catalytic hydrogenation, the
above synthesis also constitutes a formal synthesis of the
latter alkaloid. The 1H and C NMR spectra of our
synthetic ervatamines were completely identical to those
reported43 for the natural products.
1
667; H NMR (200 MHz) -0.15 (s, 9 H), 0.82 (t, J ) 8 Hz, 2
H), 2.57 (s, 3 H), 3.48 (t, J ) 8 Hz, 2 H), 5.98 (s, 2 H), 7.10-
7.40 (m, 3 H), 7.50 (d, J ) 8.4 Hz, 1 H), 7.65 (d, J ) 8 Hz, 1
H); 13C NMR (50.3 MHz) -1.8, 17.4, 27.7, 65.3, 72.9, 111.5,
114.0, 121.4, 122.7, 126.4, 126.1, 134.6, 140.2, 191.3. Anal.
13
2
Calcd for C16H23NO Si: C, 66.39; H, 8.01; N, 4.83. Found: C,
+
66.48; H, 8.23; N, 4.98.
(41) A related Me
2
N dCH
2
-induced cyclization from a 19-deoxo
analog of 2-acylindole 33a has been reported to lead to the trans C/D
ring junction: see ref 12.
2-Acetyl-1-[(2-m eth oxyeth oxy)m eth yl]in d ole (1d ). Op-
erating as above, from acetylindole 1b (1.5 g, 9.4 mmol) and
(
42) This relative stereochemistry is the one predicted by Cram and
Felkin-Anh models for the reduction of the acetyl group of 33b.
43) Clivio, P.; Richard, B.; Zeches, M.; Le Men-Olivier, L.; Goh, S.
H.; David, B.; Sevenet, T. Phytochemistry 1990, 29, 2693.
(
(44) (a) Chastrette, F. Bull. Soc. Chem. Fr. 1970, 1151. (b) Bhandari,
K. S.; Snieckus, V. Can. J . Chem. 1971, 49, 2354.

3
604 J . Org. Chem., Vol. 62, No. 11, 1997
Bennasar et al.
(2-methoxyethoxy)methyl chloride (1.1 mL, 9.4 mmol) was
at 0 °C, and stirred at 0 °C for 1 h. The solvent was removed,
obtained acetylindole 1d (1.7 g, 73%) as an oil after column
and the residue was partitioned between H
2 2
O and Et O. The
1
chromatography (3:7 hexane-AcOEt): IR (film) 1664; H NMR
organic extracts were dried and evaporated to give crude
1
(200 MHz) 2.60 (s, 3 H), 3.31 (s, 3 H), 3.45 and 3.58 (2 m, 4
alcohol 9: 50 mg; H NMR (200 MHz) 1.71 (dd, J ) 6.7 and
H), 6.07 (s, 2 H), 7.15-7.50 (m, 3 H), 7.58 (d, J ) 8.4 Hz, 1 H),
1.7 Hz, 3 H), 1.80-3.50 (m, 8 H), 2.14 (s, 3 H), 4.37 (br s, 1 H),
5.20 (dd, J ) 4.8 and 12 Hz, 1 H), 5.53 (q, J ) 6.7 Hz, 1 H),
7
7
1
.68 (d, J ) 8 Hz, 1 H); 13C NMR (50.3 MHz) 27.7, 58.6, 66.9,
1
3
1.3, 73.7, 111.5, 114.2, 121.5, 122.7, 126.1, 126.5, 134.5, 140.2,
7.10-7.40 (m, 3 H), 7.65 (d, J ) 8 Hz, 1 H); C NMR (50.3
91.5. Anal. Calcd for C14
H
17NO
3
: C, 68.00; H, 6.93; N, 5.66.
MHz) 12.1 (CH
3
), 29.3 (CH), 36.3 (CH
2 2 3
), 42.3 (CH ), 43.0 (CH ),
Found: C, 68.07; H, 7.02; N, 5.69.
53.4 (CH), 57.2 (CH
2
), 67.6 (CH), 105.5 (C), 110.8 (CH), 118.2
Met h yl 2-Met h yl-7-oxo-8{[2-(t r im et h ylsilyl)et h oxy]-
m eth yl}-2,5,6,7-tetr a h yd r o-1,5-m eth a n o-1H-a zon in o[4,3-
b]in d ole-4(E)-a cr yla te (4c). LDA (2.5 mmol) was slowly
(CH), 119.5 (CH), 121.2 (CH), 121.6 (CH), 130.5 (C), 133.6 (C),
135.6 (C), 140.7 (C). A suspension of alcohol 9 (50 mg, 0.17
mmol) and MnO (0.3 g, 3.5 mmol) in CHCl (20 mL) was
2 3
added under N
mmol) in anhydrous THF (45 mL) cooled at -70 °C, and the
resulting solution was stirred at -70° C for 30 min. Then,
2
to a solution of acetylindole 1c (0.7 g, 2.4
stirred at rt for 16 h. The mixture was filtered and evaporated
to give ketone 10 (38 mg, 50% overall yield from 4b) after
column chromatography (AcOEt): mp 210 °C (acetone); IR
4
5
1
pyridinium iodide 2 (0.74 g, 2.4 mmol) was added in portions,
and the mixture was allowed to rise to 0 °C, stirred at this
temperature for 3 h 30 min, and cooled to -30 °C. Enough of
(KBr) 1637, 3450; H NMR (200 MHz) 1.66 (dd, J ) 6.8 and
1.4 Hz, 3 H), 2.08 (s, 3 H), 2.20-3.30 (m, 7 H), 4.65 (dd, J )
5.5 and 1.5 Hz, 1 H), 5.45 (q, J ) 6.8 Hz, 1 H), 7.10-7.40 (m,
1
3
a saturated C
6
H
6
solution of dry HCl was added dropwise to
3 H), 7.76 (d, J ) 8 Hz, 1 H), 9.20 (br s, 1 H); C NMR (50.3
bring the pH to 3.5-4, and the mixture was allowed to rise to
rt. After being stirred at rt for 2 h, the reaction mixture was
poured into saturated aqueous Na
MHz) 12.0 (CH
53.5 (CH), 54.2 (CH
(CH), 126.4 (CH), 134.7 (C), 136.1 (C), 136.3 (C). Anal. Calcd
for C18 O: C, 77.11; H, 7.19; N, 9.99. Found: C, 76.88;
3
), 28.8 (CH), 34.4 (CH
2 3 2
), 43.7 (CH ), 49.0 (CH ),
2
), 112.1 (CH), 116.6 (C), 120.8 (CH), 122.0
2 3
CO and extracted with
2
Et O. Evaporation of the dried extracts followed by column
20 2
H N
chromatography (85:15 hexane-AcOEt) gave tetracycle 4c:
H, 7.18; N, 9.89.
0
1
.17 g (15%); mp 162 °C (MeOH-Et
2
O); IR (KBr) 1577, 1640,
Meth od B. F r om Tetr a cycle 4c. Operating as above,
from 4c (70 mg, 0.15 mmol) was obtained ketone 10: 16 mg
(38%).
1
690; H NMR (200 MHz) 0.00 (s, 9 H), 0.92 (t, J ) 7.6 Hz, 2
H), 2.65 (m, 2 H), 2.90 (s, 3 H), 3.05 (m, 2 H), 3.42 (dd, J ) 15
and 6.6 Hz, 1 H), 3.54 (t, J ) 7.6 Hz, 2 H), 3.80 (s, 3 H), 5.01
Meth yl (1RS,5RS,13SR)-13-[(Dim eth yla m in o)m eth yl]-
(
2
7
t, 1 H), 5.50 (d, J ) 15 Hz, 1 H), 5.72 and 6.00 (2d, J ) 10 Hz,
2
,8-d im et h yl-7-oxo-2,5,6,7-t et r a h yd r o-1,5-m et h a n o-1H -
a zon in o[4,3-b]in d ole-4(E)-a cr yla te (5a ). n-BuLi (1.6 M in
hexane, 2.7 mL, 4.3 mmol) was added under N to a solution
H), 6.39 (s, 1 H), 7.30-7.50 (m, 3 H), 7.62 (d, J ) 8 Hz, 1 H),
.87 (d, J ) 8 Hz, 1 H); 13C NMR (50.3 MHz) -1.7 (CH
), 17.5
), 26.6 (CH), 31.4 (CH ), 41.6 (CH ), 47.7 (CH ), 50.4 (CH),
0.7 (CH ), 65.7 (CH ), 73.1 (CH ), 103.2 (CH), 106.3 (C), 111.6
3
2
(CH
2
2
3
2
of isopropylcyclohexylamine (0.73 mL, 4.3 mmol) in anhydrous
5
3
2
2
THF (7 mL) cooled at -70 °C, and the resulting solution was
(
1
(
CH), 119.9 (C), 120.1 (CH), 121.7 (CH), 126.2 (CH), 126.6 (C),
33.2 (C), 138.4 (C), 143.7 (CH), 146.6 (CH), 169.2 (C), 196.5
C). Anal. Calcd for C26 Si: C, 66.92; H, 7.34; N, 6.00.
46
stirred at -70 °C for 30 min. A solution of acetylindole 1a
(0.5 g, 2.89 mmol) in anhydrous THF (40 mL) was slowly
34 2 4
H N O
added, and stirring was continued at -70 °C for 45 min. Then,
pyridinium iodide 2 (0.88 g, 2.89 mmol) was added in portions,
and the mixture was allowed to rise to -30 °C and stirred at
this temperature for 1 h 30 min. N,N-Dimethylmethylene-
iminium iodide (Eschenmoser’s salt, 1.6 g, 8.6 mmol) was
added, and the mixture was stirred at 0 °C for 4 h. Workup
as in the preparation of 4c gave a residue, which was
chromatographed (hexane-AcOEt, increasing polarity and
Found: C, 67.01; H, 7.45; N, 5.97.
Meth yl 8-[(2-Meth oxyeth oxy)m eth yl]-2-m eth yl-7-oxo-
2
4
,5,6,7-tetr a h yd r o-1,5-m eth a n o-1H-a zon in o[4,3-b]in d ole-
(E)-a cr yla te (4d ). Operating as above, from acetylindole 1d
(
0.5 g, 2 mmol) and pyridinium iodide 2 (0.62 g, 2 mmol) was
obtained tetracycle 4d (60 mg, 7%) after column chromatog-
O); IR
KBr) 1567, 1661,1687; H NMR (200 MHz) 2.56 (m, 2 H), 2.83
s, 3 H), 2.98 (m, 2 H), 3.32 (s, 3 H), 3.50 (m, 5 H), 3.72 (s, 3
raphy (75:25 hexane-AcOEt): mp 134 °C (acetone-Et
2
1
(
(
9
5:5 AcOEt-MeOH) to give 5a : 210 mg (18%); mp 227 °C
1
(
acetone); IR (KBr) 1575, 1643, 1695; H NMR (200 MHz) 2.29
H), 4.91 (t, 1 H), 5.44 (d, J ) 15 Hz, 1H), 5.70 and 5.93 (2d, J
(s, 6 H), 2.30 (m, 2 H), 2.65 (m, 2 H), 2.85 (s, 3 H), 2.90 (dd, J
)
10 Hz, 2 H), 6.32 (s, 1 H), 7.20-7.45 (m, 3 H), 7.59 (d, J )
)
15 and 2.5 Hz, 1 H), 3.35 (dd, J ) 15 and 5 Hz, 1 H), 3.71
s, 3 H), 3.88 (s, 3 H), 4.98 (br s, 1 H), 5.42 (d, J ) 15.5 Hz, 1
H), 6.26 (s, 1 H), 7.20-7.42 (m, 4 H), 7.88 (d, J ) 7.5 Hz, 1 H);
13
13
8
Hz, 1H), 7.77 (d, J ) 8 Hz, 1 H); C NMR (50.3 MHz) 26.5
), 41.6 (CH ), 47.6 (CH ), 50.4 (CH), 50.7 (CH ),
), 67.2 (CH ), 71.5 (CH ), 74.0 (CH ), 103.2 (CH),
06.3 (C), 111.7 (CH), 120.0 (CH), 121.5 (C), 121.7 (CH), 126.3
(
(
5
1
CH), 31.3 (CH
2
3
2
3
8.8 (CH
3
2
2
2
C NMR (50.3 MHz) 30.4 (CH), 32.0 (CH
CH ), 45.8 (CH ), 47.8 (CH ), 50.7 (CH ), 51.7 (CH), 63.6 (CH
02.9 (CH), 104.6 (C), 110.5 (CH), 118.6 (C), 120.5 (CH), 120.8
CH), 125.8 (CH), 126.2 (C), 133.6 (C), 138.2 (C), 142.7 (CH),
29 3 3
47.2 (CH), 169.3 (C), 195.9 (C). Anal. Calcd for C24H N O :
3
), 38.9 (CH), 41.8
(
1
(
1
3
3
2
3
2
),
(CH), 126.6 (C), 133.2 (C), 138.5 (C), 143.7 (CH), 146.6 (CH),
1
6
69.2 (C), 196.5 (C). Anal. Calcd for C24
5.15; H, 6.83; N, 6.33. Found: C, 64.80; H, 6.68; N, 6.10.
H
28
N
2
O
5
2
‚H O: C,
Meth yl 2-Meth yl-7-oxo-2,5,6,7-tetr a h yd r o-1,5-m eth a n o-
C, 70.90; H, 6.95; N, 10.34. Found: C, 70.53; H, 7.10; N, 10.04.
When LDA instead of LICA was used as the base, tetra-
1
H-a zon in o[4,3-b]in d ole-4(E)-a cr yla te (4b). BF
3
2
‚Et O (0.1
mL, 0.85 mmol) was added to a solution of tetracycle 4c (50
mg, 0.1 mmol) in anhydrous CH Cl (7 mL) at 0 °C, and the
resulting mixture was stirred at 0 °C for 10 min and at rt for
0 min. The reaction mixture was poured into saturated
aqueous NaHCO and extracted with CH Cl . After evapora-
tion of the organic extracts, the residue was dissolved in
CH CN (7 mL) and treated with Triton B (40% MeOH, 2
drops). The resulting solution was refluxed for 2 h and
partitioned between H O and Et O. The organic extracts were
washed with H O, dried, and evaporated to give tetracycle 4b
cycles 5a (14%) and 6a (4%) were obtained after column
chromatography. 6a : IR (KBr) 1581, 1656, 1698; H NMR
2
2
1
(
2
200 MHz) 1.00 and 1.07 (2d, J ) 6.6 Hz, 12 H), 2.40 (m, 2 H),
.55 (m, 1 H), 2.75 (m, 1 H), 2.78 (s, 3 H), 2.90 (dd, J ) 14.3
and 3 Hz, 1 H), 3.07 (m, 2 H), 3.38 (dd, J ) 14.3 and 5.7 Hz,
H), 3.73 (s, 3 H), 3.88 (s, 3 H), 5.02 (s, 1 H), 5.42 (d, J ) 15.1
Hz, 1 H), 6.28 (s, 1 H), 7.20-7.42 (m, 4 H), 7.78 (d, J ) 7.5
3
3
2
2
1
3
13
Hz, 1 H); C NMR (50.3 MHz) 19.9 (CH
CH), 32.2 (CH ), 40.0 (CH), 41.7 (CH ), 47.8 (CH), 48.2 (CH
0.7 (CH ), 50.8 (CH), 102.7 (CH), 104.9 (C), 110.5 (CH), 118.9
C), 120.0 (CH), 120.8 (CH), 125.6 (CH), 126.1 (C), 133.7 (C),
3
), 21.9 (CH
3
), 30.0
2
2
(
5
(
3
3
2
),
2
1
2
3
(
16 mg, 48%).
(E)-Eth ylid en e-2-m eth yl-7-oxo-2,3,4,5,6,7-h exa h yd r o-
,5-m eth a n o-1H-a zon in o[4,3-b]in d ole [(()-16-Dem eth yl-
4
1
38.0 (C), 142.7 (CH), 147.1 (CH), 169.1 (C), 196.1 (C).
1
Meth yl (1RS,5RS,13SR)-13-[(Dim eth yla m in o)m eth yl]-
-m et h yl-7-oxo-2,5,6,7-t et r a h yd r o-1,5-m et h a n o-1H -a zo-
en eer vitsin e, 10]. Meth od A. F r om Tetr a cycle 4b.
A
2
solution of 4b (92 mg, 0.27 mmol) in 4 N HCl (11 mL) was
refluxed for 3 h and then evaporated. The residue was
dissolved in MeOH (10 mL), treated with NaBH (0.1 g, excess)
4
n in o[4,3-b]in d ole-4(E)-a cr yla te (5b). Operating as above,
from acetylindole 1b (0.5 g, 3.14 mmol) and LDA (7.9 mmol)
was obtained tetracycle 5b: 50 mg (4%); mp 275 °C (i-Pr
2
O-
(
45) Besseli e` vre, C.; Beugelmans, R.; Husson, H.-P. Tetrahedron
Lett. 1976, 3447.
(46) Diels, O.; K o¨ llisch, A. Chem. Ber. 1911, 44, 263.

Total Synthesis of Ervitsine and Ervatamine Alkaloids
J . Org. Chem., Vol. 62, No. 11, 1997 3605
1
1
MeOH); IR (KBr) 1571, 1647, 1690, 3440; H NMR (200 MHz)
1578, 1663, 1690; H NMR (200 MHz) 2.31 (s, 3 H), 2.88 (s, 3
2
2
3
.20 (m, 2 H), 2.27 (s, 6 H), 2.55 (m, 2 H), 2.80 (dd, J ) 15 and
.5 Hz, 1 H), 2.96 (s, 3 H), 3.45 (dd, J ) 15 and 5 Hz, 1 H),
.71 (s, 3 H), 4.98 (s, 1 H), 5.45 (d, J ) 15 Hz, 1 H), 6.24 (s, 1
H), 2.95 (dd, J ) 14 Hz and 1.5 Hz, 1 H), 3.05 (m, 1 H), 3.40
(dd, J ) 14 and 15 Hz, 1 H), 3.60 (br s, 1 H), 3.72 (s, 3 H), 3.88
(s, 3 H), 4.93 (s, 1 H), 5.43 (d, J ) 15.3 Hz, 1 H), 6.30 (s, 1 H),
1
3
H), 7.15-7.40 (m, 4 H), 7.88 (d, J ) 7.5 Hz, 1 H), 9.40 (br s, 1
7.20-7.50 (m, 4 H), 7.80 (d, J ) 7.5 Hz, 1 H); C NMR (50.3
MHz) 15.2 (CH ), 32.2 (CH ), 33.1 (CH), 42.1 (CH ), 47.7 (CH ),
48.5 (CH), 50.9 (CH ), 55.4 (CH), 103.8 (CH), 110.4 (C), 110.6
1
3
H); C NMR (50.3 MHz) 29.6 (CH), 38.9 (CH), 42.4 (CH
3
), 44.8
), 103.2
CH), 105.1 (C), 112.2 (CH), 118.3 (C), 120.8 (CH), 121.3 (CH),
26.5 (CH), 127.5 (C), 132.3 (C), 136.1 (C), 142.5 (CH), 147.2
3
3
3
2
(
(
1
CH
2
), 46.0 (CH
3
), 50.9 (CH
3
), 51.9 (CH), 63.6 (CH
2
3
(CH), 117.1 (C), 119.9 (CH), 121.1 (CH), 125.7 (C), 125.9 (CH),
133.5 (C), 138.2 (C), 142.1 (CH), 146.6 (CH), 168.8 (C), 194.5
1
1
(CH), 169.0 (C), 193.4 (C). Anal. Calcd for C23
H
27
N
3
O
3
‚ /
(C). Anal Calcd for C22
H
24
N
2
O
3
S‚ /
2
H
2
O: C, 65.16; H, 6.21;
2
H
2
O: C, 68.13; H, 7.01; N, 10.44. Found: C, 68.98; H, 6.99;
N, 6.90; S, 7.90. Found: C, 65.48; H, 6.14; N, 6.84; S, 7.69.
Tetracycle 11: 78 mg (6%); H NMR (500 MHz, assignment
1
N, 10.20.
Meth yl (1RS,5RS,13SR)-13-[(Dim eth yla m in o)m eth yl]-
-m e t h yl-7-oxo-8-{[2-(t r im e t h ylsilyl)e t h oxy]m e t h yl}-
aided by 1H- H COSY and HMQC) 2.29 and 2.32 (2s, 6 H,
SMe), 2.85 (s, 3 H, NMe), 3.02 (dd, J ) 14.5 and 3.5 Hz, 1 H,
14-H), 3.47 (dd, J ) 14.5 and 6 Hz, 1 H, 14-H), 3.67 (t, J ) 1.5
Hz, 1 H, 16-H), 3.74 (s, 3 H, OMe), 3.85 (s, 3 H, NMe), 4.30
(m, 1 H, 15-H), 4.92 (t, J ) 1.5 Hz, 1 H, 5-H), 6.50 (s, 1 H,
19-H), 7.20-7.40 (m, 3 H, indole), 7.54 (s, 1 H, 21-H), 7.75 (d,
J ) 8 Hz, 1 H, 9-H); 13C NMR (75 MHz, assignments aided by
HMQC) 15.3 and 19.8 (SMe), 32.2 (NMe), 33.4 (C-15), 42.5
(NMe), 48.6 (C-16), 50.6 (C-14), 52.1 (OMe), 55.6 (C-5), 105.3
(C-18), 108.0 (C-20), 110.8 (C-12), 117.1 (C-7), 119.7 (C-9),
121.2 (C-10), 125.8 (C-8), 125.9 (C-11), 133.1 (C-2), 138.0 (C-
13), 146.5 (C-19), 149.1 (C-21), 168.5 and 196.4 (CO); MS, m/ z
1
2
2
4
,5,6,7-tetr a h yd r o-1,5-m eth a n o-1H-a zon in o[4,3-b]in d ole-
(E)-a cr yla te (5c). Operating as above, except for the
temperature and reaction time with the pyridinium salt (0 °C,
h), from acetylindole 1c (0.5 g, 1.73 mmol) and LICA (2.6
mmol) was obtained tetracycle 5c as an oil: 136 mg (15%); IR
3
1
(CHCl
3
) 1580, 1650; H NMR (200 MHz) 0.00 (s, 9 H), 0.85 (t,
J ) 8.5 Hz, 2 H), 2.20 (m, 2 H), 2.33 (s, 6 H), 2.65 (m, 2 H),
2
1
5
6
.86 (s, 3 H), 2.95 (dd, J ) 15 and 2.5 Hz, 1 H), 3.40 (dd, J )
5 and 5 Hz, 1 H), 3.47 (m, 2 H), 3.71 (s, 3 H), 4.99 (s, 1 H),
.42 (d, J ) 15.3 Hz, 1 H), 5.65 and 5.93 (2 d, J ) 10 Hz, 2 H),
1
3
+
.27 (s, 1 H), 7.20-7.60 (m, 4 H), 7.90 (d, J ) 7.5 Hz, 1 H);
), 17.7 (CH ), 30.8 (CH), 38.8 (CH),
), 47.8 (CH ), 50.8 (CH ), 51.8 (CH), 63.7
), 73.1 (CH ), 103.3 (CH), 104.4 (C), 111.4 (CH),
20.2 (C), 120.3 (CH), 121.5 (CH), 126.1 (CH), 126.6 (C), 133.0
C
(rel intensity) 442 (M , 100), 395 (M - 47, 20), 364 (20); HRMS
calcd for C23H N O S 442.1384, found 442.1386.
26 2 3 2
NMR (50.3 MHz) -1.5 (CH
1.8 (CH ), 45.6 (CH
CH ), 65.7 (CH
3
2
4
(
1
3
3
2
3
Meth yl (1RS,5RS,13RS)-13-Ch lor o-2,8-d im eth yl-7-oxo-
2,5,6,7-tetr a h yd r o-1,5-m eth a n o-1H-a zon in o[4,3-b]in d ole-
4-(r-ch lor o)a cr yla te (13). Operating as above, but using
NCS (695 mg, 5.2 mmol) as electrophile, from acetylindole 1a
(0.3 g, 1.73 mol) was obtained tetracycle 13 (43 mg, 6%) after
column chromatography (hexane-AcOEt, increasing polar-
2
2
2
(C), 138.3 (C), 142.4 (CH), 146.8 (CH), 168.9 (C), 195.5 (C).
1
Anal. Calcd for C29
Found: C, 65.39; H, 8.13; N, 7.48.
H
41
N
3
O
4
2 2
‚ / H O: C, 65.38; H, 7.94; N, 7.88.
Meth yl (1RS,5RS,13RS)-2,8-Dim eth yl-7-oxo-13-(p h en -
ylselen o)-2,5,6,7-tetr a h yd r o-1,5-m eth a n o-1H-a zon in o[4,3-
b]in d ole-4(E)-a cr yla te (7a ). Acetylindole 1a (0.5 g, 2.89
mmol) in anhydrous THF (40 mL) was allowed to react with
LDA (2.89 mL, 4.3 mmol) and then with pyridinium iodide 2
2
ity): mp 230 °C (i-Pr O-MeOH); IR (KBr) 1561, 1648, 1694;
1
H NMR (300 MHz) 2.92 (s, 3 H), 3.13 (dd, J ) 14.8 and 3 Hz,
1 H), 3.38 (dd, J ) 14.8 and 6.1 Hz, 1 H), 3.78 (s, 3 H), 3.87 (s,
3 H), 3.98 (m, 1 H), 4.97 and 5.00 (2 t, J ) 2 Hz, 2 H), 6.64 (s,
1
3
1 H), 7.26 (m, 1 H), 7.40 (m, 3 H), 7.75 (d, J ) 8 Hz, 1 H);
NMR (75 MHz) 32.2 (CH ), 37.1 (CH), 42.3 (CH ), 50.3 (CH
52.5 (CH ), 57.6 (CH), 57.8 (CH), 101.5 (C), 107.1 (CH), 110.8
C
(
8
0.88 g, 2.89 mmol) at -30 °C for 1 h 30 min. PhSeBr (2 g,
3
3
2
),
.67 mmol) was slowly added to the mixture, and stirring was
3
continued at 0 °C for 3 h. Workup as above gave a crude
residue, which was chromatographed (hexane-AcOEt, in-
creasing polarity) to give tetracycle 7a : 285 mg (20%); mp
(CH), 115.0 (C), 119.6 (CH), 121.5 (CH), 125.6 (C), 126.1 (CH),
133.0 (C), 138.2 (C), 139.2 (CH), 144.9 (CH), 165.2 (C), 195.2
(C). Anal. Calcd for C21
20 2 3 2
H N O Cl : C, 60.15; H, 4.81; N, 6.68.
1
2
(
3
40-242 °C (acetone); IR (KBr) 1588, 1650, 1690; H NMR
Found: C, 59.87; H, 4.90; N, 6.38.
200 MHz) 2.84 (s, 3 H), 2.92 (dd, J ) 14.4 and 2.7 Hz, 1 H),
.10 (m, 1 H), 3.32 (dd, J ) 14.4 and 5.8 Hz, 1 H), 3.72 (s, 3
H), 3.86 (s, 3 H), 4.19 (s, 1 H), 4.93 (s, 1 H), 5.40 (d, J ) 15.2
Hz, 1 H), 6.33 (s, 1 H), 7.10-7.70 (m, 10 H); C NMR (50.3
MHz) 32.6 (CH ), 33.6 (CH), 42.0 (CH ), 44.7 (CH ), 48.0 (CH ),
0.9 (CH ), 55.4 (CH), 103.9 (CH), 110.6 (CH), 117.1 (C), 119.7
CH), 121.1 (CH), 125.4 (C), 125.8 (CH), 133.2 (C), 138.1 (C),
42.3 (CH), 146.4 (CH), 168.8 (C), 194.6 (C). Anal. Calcd for
3-[(E)-2-(Meth oxycar bon yl)vin yl]-1-m eth yl-4-[[(1-m eth -
yl-2-in d olyl)ca r b on yl]m et h ylen e]-1,4-d ih yd r op yr id in e
(14). This compound was obtained when dihydropyridine 3a
1
3
2 2
failed to react with electrophiles (PhSCH Cl, PhSeCH Br,
3
3
2
2
HCHO): mp 249 °C (acetone-MeOH); IR (KBr) 1523, 1636,
1
5
(
1
3
1703; H NMR (200 MHz) 3.54 (s, 3 H), 3.78 (s, 3 H), 4.11 (s,
3 H), 5.87 (s, 1 H), 6.19 (d, J ) 15 Hz, 1 H), 7.00 (s, 1 H),
7.10-7.40 (m, 6 H), 7.63 (d, J ) 8 Hz, 1 H), 9.01 (d, J ) 9.8
1
13
C
27
H
26
N
2
O
3
Se‚ /
2
H
2
O: C, 63.03; H, 5.28; N, 5.44. Found: C,
Hz, 1 H); C NMR (50.3 MHz) 31.8, 42.8, 51.6, 90.7, 105.3,
6
2.98; H, 5.13; N, 5.33.
110.0, 114.8, 117.4, 120.1, 121.7, 122.4, 123.8, 126.5, 130.8,
139.4, 139.5, 140.5, 141.8, 151.8, 167.8. Anal. Calcd for
C H N O : C, 72.40; H, 5.79; N, 8.04. Found: C, 72.31; H,
21 20 2 3
In ter a ction of Acetylin d ole 1a w ith P yr id in iu m Iod id e
a n d DMTSF . Operating as above but using DMTSF (1.13
2
g, 5.8 mmol) instead of PhSeBr, from acetylindole 1a (0.5 g,
.89 mmol) was obtained a crude residue, which was chro-
5.81; N, 8.06.
2
Meth yl 2,8-Dim eth yl-13-m eth ylen e-7-oxo-2,5,6,7-tetr a -
h yd r o-1,5-m et h a n o-1H -a zon in o[4,3-b]in d ole-4(E)-a cr y-
matographed (hexane-AcOEt, increasing polarity). On suc-
cessive elution the following compounds were isolated. Tet-
la te (16a ). A. m-CPBA (246 mg, 1 mmol) in CH
was added to a solution of 5a (270 mg, 0.66 mmol) in CH
(20 mL) at -10 °C, and the mixture was stirred at -10 °C for
2 h. Na CO (excess) was then added, and the reaction
2
Cl
2
(5 mL)
1
racycle 12: 90 mg (6%); H NMR (500 MHz, assignments aided
2
Cl
2
1
1
by H- H COSY and HMQC) 2.28 (s, 3 H, SMe), 2.90 (s, 3 H,
NMe), 3.08 (dd, J ) 14.5 and 3 Hz, 1 H, 14-H), 3.24 (dd, J )
2
3
1
4.5 and 6 Hz, 1 H, 14-H), 3.75 (s, 3 H, OMe), 3.84 (s, 3 H,
mixture was allowed to stand for 15 min at rt, filtered over
Celite, and evaporated. The resulting residue was chromato-
NMe), 4.55 (m, 1 H, 15-H), 5.06 (t, J ) 2 Hz, 1 H, 5-H), 5.21
(
t, J ) 2 Hz, 1 H, 16-H), 6.58 (s, 1 H, 19-H), 7.20-7.40 (m, 3
2 2
graphed (flash, 7:3 CH Cl -MeOH) to give N-oxide 15a as a
1
3
1
H, indole), 7.58 (s, 1 H, 21-H), 7.68 (d, J ) 8 Hz, 1 H, 9-H);
NMR (75 MHz, assignments aided by HMQC) 20.3 (SMe), 26.4
C
foam: 177 mg (63%); H NMR (200 MHz) 2.75 (m, 1 H), 2.90
(s, 3 H), 3.10-3.50 (m, 5 H), 3.35 and 3.50 (2s, 6 H), 3.70 (s, 3
H), 3.90 (s, 3 H), 5.45 (d, J ) 15 Hz, 1 H), 5.55 (s, 1 H), 6.40
(
(
C-16), 32.2 (NMe), 39.2 (C-15), 42.5 (NMe), 50.8 (C-14), 52.1
OMe), 60.2 (C-5), 104.6 (C-18), 108.7 (C-20), 110.8 (C-12),
1
3
(s, 1 H), 7.20-7.50 (m, 4 H), 7.90 (d, J ) 8 Hz, 1 H); C NMR
(50.3 MHz) 32.1 (CH ), 33.6 (CH), 36.3 (CH), 41.8 (CH ), 47.1
(CH ), 50.8 (CH ), 54.6 (CH), 57.7 (CH ), 61.1 (CH ), 75.1 (CH ),
1
1
1
15.7 (C-7), 119.6 (C-9), 121.4 (C-10), 125.0 (C-8), 126.0 (C-
1), 133.0 (C-2), 138.1 (C-13), 145.9 (C-19), 148.9 (C-21), 168.5,
95.8 (CO); MS, m/ z (rel intensity) 522 (M , 1), 396 (1); HRMS
3
3
2
3
3
3
2
+
103.3 (C), 103.5 (CH), 110.3 (CH), 117.7 (C), 120.6 (CH), 120.9
(CH), 125.8 (CH), 126.2 (C), 133.0 (C), 138.0 (C), 143.7 (CH),
146.3 (CH), 168.6 (C), 194.5 (C).
calcd for C22
23 2 3
H N O SI 522.0473, found 522.0435. Meth yl
(
1RS,5RS,13RS)-2,8-Dim eth yl-13-(m eth ylth io)-7-oxo-2,5,6,7-
t et r a h yd r o-1,5-m et h a n o-1H -a zon in o[4,3-b]in d ole-4(E)-
a cr yla te (8a ): 70 mg (6%); mp 168-169 °C (acetone); IR (KBr)
B. A solution of N-oxide 15a (100 mg, 0.24 mmol) in
anhydrous toluene (30 mL) was refluxed for 1 h. The mixture

3
606 J . Org. Chem., Vol. 62, No. 11, 1997
Bennasar et al.
was poured into H O and extracted with Et O. Evaporation
of the organic extracts followed by flash chromatography (3:2
2
2
(()-Er vitsin e (17b). Operating as above, from tetracycle
16c (80 mg, 0.17 mmol) was obtained 17b: 32 mg (65%); mp
1
hexane-AcOEt) gave 16a : 68 mg (79%); mp 235 °C (acetone);
173 °C (acetone); IR (KBr) 1638, 3400; H NMR (500 MHz,
1
1
1
IR (KBr) 1580, 1642, 1680; H NMR (200 MHz) 2.83 (s, 3 H),
assignments aided by H- H COSY and HMQC) 1.68 (dd, J
) 6.5 and 2.5 Hz, 3 H, 18-H), 2.23 (s, 3 H, NMe), 2.80 (d, J )
14.5 Hz, 1 H, 21-H), 2.93 (dd, J ) 17 and 4 Hz, 1 H, 14-H),
2.98 (dd, J ) 17 and 5 Hz, 1 H, 14-H), 3.06 (br d, J ) 14.5 Hz,
1 H, 21-H), 3.76 (dd, J ) 4 and 5 Hz, 1 H, 15-H), 4.94 (s, 1 H,
5-H), 5.07 and 5.08 (2s, 2 H, 6-H), 5.38 (qd, J ) 6.5 and 2 Hz,
1 H, 19-H), 7.16 (m, 1 H, 10-H), 7.35 (m, 2 H, 11-H and 12-H),
3
.02 (m, 1 H), 3.44 (m, 2 H), 3.72 (s, 3 H), 3.87 (s, 3 H), 5.19
and 5.26 (2s, 2 H), 5.25 (s, 1 H), 5.44 (d, J ) 15.3 Hz, 1 H),
1
3
6
.29 (s, 1 H), 7.20-7.40 (m, 4 H), 7.81 (d, J ) 8.1 Hz, 1 H);
NMR (50.3 MHz) 32.3 (CH ), 36.4 (CH), 41.3 (CH ), 48.6 (CH
0.8 (CH ), 58.1 (CH), 103.4 (CH), 105.6 (C), 110.6 (CH), 111.7
CH ), 117.6 (C), 119.9 (CH), 121.0 (CH), 125.4 (C), 125.8 (CH),
33.1 (C), 138.3 (C), 142.5 (C), 143.4 (CH), 145.5 (CH), 168.9
: C, 72.91; H, 6.12;
C
3
3
2
),
5
(
1
3
2
1
3
7.78 (dd, J ) 8.5 and 1 Hz, 1 H, 9-H), 9.06 (br s, 1 H, NH); C
(C), 195.2 (C). Anal. Calcd for C22
H
22
N
2
O
3
NMR (75 MHz, assignments aided by HMQC) 12.0 (C-18), 38.9
(C-15), 42.6 (NMe), 50.2 (C-14), 53.4 (C-21), 61.7 (C-5), 111.2
N, 7.73. Found: C, 72.94; H, 6.16; N, 7.65.
(
1
2
C-6), 112.1 (C-12), 117.1 (C-7), 120.8 (C-10), 121.0 (C-19),
21.7 (C-9), 126.5 (C-11), 127.8 (C-8), 133.9 (C-2), 135.2 (C-
0), 136.5 (C-13), 145.6 (C-16), 193.9 (C-3); HRMS calcd for
Meth yl 2-Meth yl-13-m eth ylen e-7-oxo-8-{[2-(tr im eth yl-
silyl)eth oxy]m eth yl}-2,5,6,7-tetr a h yd r o-1,5-m eth a n o-1H-
a zon in o[4,3-b]in d ole-4(E)-a cr yla te (16c). A. Operating as
above, from tetracycle 5c (250 mg, 0,48 mmol) was obtained
C
19
H
20
N
2
O 292.1575, found 292.1577.
1
(1RS,5RS,13RS)-4(E)-E t h ylid en e-2,8-d im et h yl-7-oxo-
N-oxide 15c as a foam: 155 mg, 60%; H NMR (200 MHz) 0.00
(
3
(
s, 9 H), 1.05 (t, J ) 7.5 Hz, 2 H), 2.90 (m, 1 H), 3.05 (s, 3 H),
.20-3.70 (m, 7 H), 3.50 and 3.60 (2s, 6 H), 3.90 (s, 3 H), 5.59
d, J ) 15 Hz, 1 H), 5.70 (s, 1 H), 5.80 and 6.15 (2d, J ) 10
13-(p h en ylselen o)-2,3,4,5,6,7-h exa h yd r o-1,5-m eth a n o-1H-
a zon in o[4,3-b]in d ole (19). Operating as above, from tetra-
cycle 7a (265 mg, 0.52 mmol) was obtained 19 after flash
chromatography (95:5 hexane-AcOEt): 141 mg (60%); mp 113
Hz, 2 H), 6.60 (s, 1 H), 7.30-7.75 (m, 4 H), 8.05 (d, J ) 8 Hz,
1
1
3
°C (acetone), IR (KBr) 1650; H NMR (200 MHz) 1.67 (dd, J )
1
3
(
(
H); C NMR (50.3 MHz) -1.5 (CH
6.2 (CH), 41.9 (CH ), 47.2 (CH ), 50.9 (CH
), 61.3 (CH ), 65.7 (CH ), 73.0 (CH ), 75.1 (CH
C), 103.8 (CH), 111.2 (CH), 119.6 (C), 120.6 (CH), 121.4 (CH),
26.3 (CH), 126.5 (C), 132.7 (C), 138.3 (C), 143.8 (CH), 146.3
3
), 17.5 (CH
), 54.6 (CH), 57.5
), 103.3
2
), 33.8 (CH),
6
.8 and 1.8 Hz, 3 H), 2.03 (s, 3 H), 2.80 (m, 4 H), 3.45 (m, 1
3
2
3
H), 3.93 (s, 3 H), 4.08 (t, J ) 2 Hz, 1 H), 5.00 (d, J ) 2 Hz, 1
CH
3
3
2
2
2
1
3
H), 5.65 (q, J ) 6.8 Hz, 1 H), 7.10-7.80 (m, 9 H); C NMR
(
(
1
1
50.3 MHz) 12.2 (CH
CH), 51.8 (CH ), 54.4 (CH
20.6 (CH), 120.9 (CH), 122.8 (CH), 125.6 (CH), 127.5 (C),
33.7 (C), 135.3 (C), 138.3 (C), 196.2 (C). Anal. Calcd for
OSe: C, 66.81; H, 5.83; N, 6.23. Found: C, 66.82;
H, 5.86; N, 6.18.
()-N -Meth yler vitsin e (17a ) fr om Tetr a cycle 19. A.
m-CPBA (60 mg, 0.24 mmol) in CH Cl (5 mL) was added to a
solution of tetracycle 19 (0.1g, 0.22 mmol) in CH Cl (10 mL)
at -70 °C, and the resulting mixture was stirred at -70 °C
for 20 min. K CO (excess) was added, and the mixture was
allowed to stand at rt for 15 min, diluted with H O, and
extracted with CH Cl . Evaporation of the organic extracts
gave crude selenoxide 20: 85 mg (82%).
3
), 32.1 (CH
3 3
), 37.0 (CH), 43.5 (CH ), 50.6
1
2
2
), 59.5 (CH), 110.3 (CH), 114.8 (C),
(
CH), 168.7 (C), 194.5 (C).
B. Operating as above, from N-oxide 15c (90 mg, 0,17
mmol) was obtained tetracycle 16c (60 mg, 75%) as a foam
after flash chromatography (4:1 hexane-AcOEt): IR (film)
1
25 26 2
C H N
1
584, 1611, 1660, 1695; H NMR (200 MHz) 0.00 (s, 9 H), 0.91
(
a
(
3
t, J ) 8 Hz, 2 H), 2.94 (s, 3 H), 3.10 (m, 1 H), 3.50 (m, 4 H),
2
2
.82 (s, 3 H), 5.25 and 5.37 (2s, 2 H), 5.36 (s, 1 H), 5.55 (d, J
15.3 Hz, 1 H), 5.74 and 6.01 (2d, J ) 10.6 Hz, 2 H), 6.40 (s,
13
2
2
)
1
H), 7.30-7.70 (m, 4 H), 7.90 (d, J ) 8 Hz, 1 H); C NMR
), 17.8 (CH ), 36.5 (CH), 41.2 (CH ), 48.7
), 58.1 (CH), 65.8 (CH ), 73.3 (CH ), 103.8
CH), 105.7 (C), 111.7 (CH), 111.9 (CH ), 119.4 (C), 119.9 (CH),
21.8 (CH), 125.9 (C), 126.3 (CH), 133.0 (C), 138.6 (C), 142.3
C), 143.2 (CH), 145.5 (CH), 168.9 (C), 195.3 (C); HRMS calcd
for C27 Si 478.2287, found 478.2290.
1RS,5RS,13SR)-13-[(Dim eth yla m in o)m eth yl]-4(E)-eth -
2
3
(
(
(
50.3 MHz) -1.5 (CH
3
2
3
2
CH ), 50.9 (CH
2
3
2
2
2
2
2
1
(
B. LDA (0.4 mL, 0.60 mmol) was slowly added to a solution
of 20 (50 mg, 0.11 mmol) in anhydrous THF (10 mL) cooled at
34 2 4
H N O
-
70 °C, and the resulting solution was stirred at -70 °C for
5 min. Then, MeI (0.048 mL, 0.77 mmol) in anhydrous THF
1 mL) was added, and the mixture was allowed to rise to rt
(
4
yliden e-2,8-dim eth yl-7-oxo-2,3,4,5,6,7-h exah ydr o-1,5-m eth -
a n o-1H-a zon in o[4,3-b]in d ole (18). A solution of tetracycle
5
mL) was refluxed for 2 h. The solvents were removed, and
the residue was dissolved in MeOH (40 mL). The resulting
(
and stirred at rt for 1 h. Glacial AcOH (0.05 mL, 0.88 mmol)
and diisopropylamine (0.6 mL, 4.4 mol) were consecutively
added, and the mixture was refluxed for 1 h. The reaction
mixture was poured into H O and extracted with Et O. The
2 2
organic extracts were evaporated to give 17a (12 mg, 35%)
a (330 mg, 0.81 mmol) in EtOH (18 mL) and 4 N HCl (30
solution was treated with NaBH
stirred at 0 °C for 1 h. The solvent was evaporated, and the
residue was partitioned between H O and Et O. Evaporation
of the organic extracts followed by flash chromatography (98:2
Et O-DEA) gave 18 as a foam: 150 mg (53%); IR (KBr) 1648;
4
(38 mg, 1 mmol) at 0 °C and
after flash chromatography (AcOEt).
2
2
2
-Acetyl-1-(ter t-bu toxycar bon yl)in dole (1e). DMAP (0.19
g, 1.57 mmol) and di-tert-butyl dicarbonate (4.1 g, 18.5 mmol)
were added to a solution of acetylindole 1b (2.5 g, 15.7 mmol)
2
1
H NMR (200 MHz) 1.67 (d, J ) 6.6 Hz, 3 H), 1.98 (s, 3 H),
in CH
poured into H
extracts were dried and evaporated. Flash chromatography
hexane-AcOEt, increasing polarity) of the residue gave 1e:
3
CN (50 mL). The mixture was stirred at rt for 2.5 h,
2
.27 (s, 6 H), 2.30-3.20 (m, 7 H), 3.24 (m, 1 H), 3.93 (s, 3 H),
2
O, and extracted with Et O. The organic
2
4
2
3
.50 (s, 1 H), 5.52 (q, J ) 6.6 Hz, 1 H), 7.17 (m, 1 H), 7.36 (m,
H), 7.80 (d, J ) 8 Hz, 1 H); 1 C NMR (50.3 MHz) 12.1 (CH
3
3
),
), 51.9
2
), 110.3 (CH), 116.4 (C),
(
3
2.1 (CH
3
), 33.6 (CH), 42.1 (CH), 43.6 (CH
), 56.9 (CH), 64.4 (CH
3 3
), 46.2 (CH
1
.3 g (80%); mp 59 °C (cyclohexane); IR (KBr) 1677, 1735; H
(CH
2
), 54.8 (CH
2
NMR (300 MHz) 1.62 (s, 9 H), 2.56 (s, 3 H), 7.08 (s, 1 H), 7.26
1
1
C
20.6 (CH), 121.3 (CH), 121.9 (CH), 125.4 (CH), 127.4 (C),
(
td, J ) 8 and 0.9 Hz, 1 H), 7.42 (td, J ) 8 and 1.3 Hz, 1 H),
34.6 (C), 135.5 (C), 138.2 (C), 197.5 (C). Anal. Calcd for
13
1
7.61 (d, J ) 8 Hz, 1 H), 8.04 (d, J ) 8 Hz, 1 H); C NMR (75
MHz) 27.7, 28.7, 84.7, 114.4, 114.7, 122.4, 123.3, 127.2, 127.4,
22
H
29
N
3
O‚ /
3
H
2
O: C, 73.91; H, 8.36; N, 11.75. Found: C,
7
3.94; H, 8.28; N, 11.38.
1
6
3
38.2, 138.8, 149.6, 191.3. Anal. Calcd for C15H17NO : C,
9.48; H, 6.61; N, 5.40. Found: C, 69.55; H, 6.60; N, 5.41.
(
()-N -Meth yler vitsin e (17a ). Operating as above, from
a
tetracycle 16a (130 mg, 0.36 mmol) was obtained 17a as a foam
after flash chromatography (AcOEt): 60 mg (55%); IR (KBr)
1
2
In ter a ction of Acetylin d ole 1e w ith P yr id in iu m Sa lt
2
4 a n d TCAA. Acetylindole 1e (0.5 g, 2 mmol) was allowed
1
647; H NMR (200 MHz) 1.62 (dd, J ) 6.9 and 1.9 Hz, 3 H),
to react with LDA (1.45 mL, 2.18 mmol) at -70 °C for 30 min
.08 (s, 3 H), 2.88 (m, 4 H), 3.70 (t, J ) 4 Hz, 1 H), 3.84 (s, 3
and then with pyridinium iodide 2447 (0.5 g, 2 mmol) at -30
H), 4.94 (s, 1 H), 4.98 and 4.99 (2s, 2 H), 5.36 (q, J ) 6.9 Hz,
°
C for 3 h 30 min. TCAA (1.1 mL, 6 mmol) was slowly added,
1
3
1
H), 7.14 (m, 1 H), 7.30 (m, 2 H), 7.72 (d, J ) 8 Hz, 1 H);
NMR (50.3 MHz) 12.6 (CH ), 32.8 (CH ), 40.6 (CH), 43.0 (CH
), 62.0 (CH), 110.8 (CH), 110.9 (CH
C
and the mixture was stirred at 0 °C for 3 h. The reaction
mixture was poured into saturated aqueous Na CO and
extracted with Et O. The organic extracts were dried and
3
3
3
),
),
2
3
5
1
1
3.4 (CH
2
), 54.3 (CH
2
2
2
16.7 (C), 121.2 (CH), 121.5 (2 CH), 126.3 (CH), 127.6 (C),
35.4 (2 C), 139.3 (C), 146.7 (C), 196.8 (C); HRMS calcd for
C
20
H
22
N
2
O 306.1732, found 306.1729.
(47) Ginsburg, S.; Wilson, I. B. J . Am. Chem. Soc. 1957, 79, 481.

Total Synthesis of Ervitsine and Ervatamine Alkaloids
J . Org. Chem., Vol. 62, No. 11, 1997 3607
evaporated. Column chromatography (hexane-AcOEt, in-
creasing polarity) of the residue gave the following compounds
on successive elution. 4-{[1-(ter t-Bu toxyca r bon yl)-2-in -
d olyl]ca r bon ylm eth yl}-1-m eth yl-5-[1-(tr ich lor oa cetoxy)-
vin yl]-3-(tr ich lor oa cetyl)-1,4-d ih yd r op yr id in e (29): 146
126.0 (CH), 126.4 (CH), 126.7 (CH), 126.8 (C), 128.3 (CH),
134.8 (C), 138.7 (C), 139.3 (CH), 140.1 (C), 145.2 (CH), 178.8
(C), 192.0 (C), 194.6 (C). Anal. Calcd for C27
23 2 3 3
H N O Cl : C,
61.20; H, 4.37; N, 5.28. Found: C, 61.10; H, 4.49; N, 5.18.
3-Acet yl-4-[[(1-b en zyl-2-in d olyl)ca r b on yl]m et h yl]-5-
(m eth oxyca r bon yl)-1-m eth yl-1,4-d ih yd r op yr id in e (26g).
A solution of dihydropyridine 25g (0.5 g, 0,94 mmol) in
MeOH-THF (1:1, 40 mL) was slowly added to a solution of
MeONa (2.8 mmol) in MeOH (20 mL), and the resulting
mixture was stirred at rt for 3 min. The solvents were
1
mg (11%); H NMR (200 MHz) 1.60 (s, 9 H), 3.01 and 3.10 (2
dd, J ) 12.5 and 5 Hz, 2 H), 3.25 (s, 3 H), 4.45 (t, J ) 5 Hz, 1
H), 5.10 and 5.40 (2 d, J ) 3 Hz, 2 H), 6.33 (s, 1 H), 7.05 (s, 1
H), 7.20-7.40 (m, 2 H), 7.60 (d, J ) 8 Hz, 1 H), 7.74 (s, 1 H),
7
.99 (d, J ) 8 Hz, 1 H). 3-Acet yl-4-{[[1-(ter t-bu t oxyca r -
bon yl)-2-in d olyl]ca r bon yl]m eth yl}-1-m eth yl-5-(tr ich lor o-
a cetyl)-1,4-d ih yd r op yr id in e (25e): 140 mg (13%); H NMR
removed, and the residue was partitioned between H
2
O and
1
2
Et O. Evaporation of the dried extracts gave a crude residue
(
1
(
300 MHz) 1.59 (s, 9 H), 2.25 (s, 3 H), 3.05 and 3.15 (2 dd, J )
2.6 and 5 Hz, 2 H), 3.31 (s, 3 H), 4.49 (t, J ) 5 Hz, 1 H), 6.90
s, 1 H), 7.02 (s, 1 H), 7.25 (t, J ) 7.5 Hz, 1 H), 7.40 (t, J ) 7.5
Hz, 1 H), 7.60 (d, J ) 7.5 Hz, 1 H), 7.70 (s, 1 H), 7.93 (d, J )
which was chromatographed (flash, 8:2 hexane-AcOEt and
AcOEt) to give 26g: 380 mg (91%); mp 155 °C (hexane-
1
AcOEt); IR (KBr) 1568, 1644, 1699; H NMR (300 MHz) 2.19
(s, 3 H), 2.93 (d, J ) 6 Hz, 2 H), 3.02 (s, 3 H), 3.64 (s, 3 H),
4.49 (t, J ) 6 Hz, 1 H), 5.77 and 5.82 (2 d, J ) 16.5 Hz, 2 H),
6.86 (s, 1 H), 7.02 (s, 1 H), 7.03-7.30 (m, 8 H), 7.54 (s, 1 H),
1
3
7
.5 Hz, 1H); C NMR (75 MHz) 24.8 (CH
3 3
), 27.7 (CH ), 29.0
(
(
(
CH), 42.4 (CH ), 43.9 (CH ), 84.4 (C), 96.0 (C), 104.7 (C), 114.4
CH), 115.4 (CH), 118.6 (C), 122.5 (CH), 123.2 (CH), 127.0
CH), 127.4 (CH), 137.9 (C), 139.0 (C), 139.8 (CH), 145.9 (CH),
3
2
1
3
7.75 (d, J ) 8 Hz, 1 H); C NMR (75 MHz) 24.6 (CH
3
), 29.9
(CH), 41.3 (CH ), 46.4 (CH ), 47.9 (CH ), 51.2 (CH ), 107.1 (C),
3
2
2
3
1
49.4 (C), 178.7 (C), 192.7 (C), 194.8 (C). 3-Acetyl-4-{[[1-(ter t-
110.7 (CH), 113.4 (CH), 116.3 (C), 120.6 (CH), 123.1 (CH),
125.8 (CH), 126.0 (C), 126.1 (CH), 126.3 (CH), 128.2 (CH),
135.0 (C), 138.5 (C), 139.4 (CH), 139.9 (C), 141.3 (CH), 166.7
bu toxyca r bon yl)-2-in d olyl]ca r bon yl]m eth ylen e}-1-m eth -
yl-1,4-d ih yd r op yr id in e (30): 95 mg (12%); H NMR (200
1
MHz) 1.62 (s, 9 H), 2.44 (s, 3 H), 3.58 (s, 3 H), 5.60 (s, 1 H),
26 2 4
(C), 192.5 (C), 194.7 (C). Anal. Calcd for C27H N O : C,
6
.80 (s, 1 H), 7.10-7.60 (m, 4 H), 7.90 (s, 1 H), 8.05 (d, J ) 8
73.28; H, 5.92; N, 6.33. Found: C, 73.22; H, 5.92; N, 6.32.
Ca ta lytic Hyd r ogen a tion of Dih yd r op yr id in e 26a . A
solution of 26a 21 (0.2 g, 0.5 mmol) in MeOH (15 mL) was
Hz, 1 H), 8.90 (d, J ) 9.5 Hz, 1 H).
In ter a ction of Acetylin d ole 1f w ith P yr id in iu m Sa lt
2
4 a n d TCAA. Operating as above, from acetylindole 1f48 (250
2
hydrogenated over PtO (40 mg) for 12 or 24 h. The catalyst
mg, 0.84 mmol) were isolated the following compounds.
-Acetyl-1-m eth yl-4-{[[1-(p h en ylsu lfon yl)-2-in d olyl]ca r -
b on yl]m et h yl}-5-(t r ich lor oa cet yl)-1,4-d ih yd r op yr id in e
was filtered off, and the solution was evaporated to give a
crude residue which was chromatographed (hexane-AcOEt,
increasing polarity and 9:1 AcOEt-MeOH). The results are
given in Table 1.
3
1
(
25f): 34 mg (7%); H NMR (300 MHz) 2.26 (s, 3 H), 2.92 (dd,
J ) 13.4 and 4.6 Hz, 1 H), 3.18 (dd, J ) 13.4 and 5.3 Hz, 1 H),
tr a n s-3-Acet yl-5-(m et h oxyca r b on yl)-1-m et h yl-4-[[(1-
m et h yl-2-in d olyl)ca r b on yl]m et h yl]-1,2,3,4-t et r a h yd r o-
p yr id in e (32a ): H NMR (300 MHz) 2.20 (s, 3 H), 2.72 (dd, J
3
1
1
2
.31 (s, 3 H), 4.56 (dd, J ) 5.3 and 4.6 Hz, 1 H), 6.95 (d, J )
Hz, 1 H), 7.29 (t, J ) 8 Hz, 1 H), 7.45-7.65 (m, 7 H), 7.68 (s,
1
1
3
H), 8.04 (m, 2 H), 8.16 (d, J ) 8 Hz, 1 H); C NMR (75 MHz)
) 15.6 and 11.0 Hz, 1 H), 2.89 (m, 1 H), 3.07 (s, 3 H), 3.22 (dd,
J ) 13.2 and 4.1 Hz, 1 H), 3.48 (ddd, J ) 13.2, 2.4, and 1.7
Hz, 1 H), 3.58 (dd, J ) 15.6 and 3.2 Hz, 1 H), 3.71 (s, 3 H),
3.82 (dm, J ) 11.0 Hz, 1 H), 4.12 (s, 3 H), 7.20 (m, 1 H), 7.39
(s, 1 H), 7.42 (m, 2 H), 7.56 (s, 1 H), 7.65 (d, J ) 8 Hz, 1 H);
3 3 2
4.9 (CH ), 29.7 (CH), 42.6 (CH ), 43.9 (CH ), 104.2 (C), 115.4
(
1
(
CH), 118.2 (C), 119.9 (CH), 123.1 (CH), 124.0 (CH), 127.8 (C),
27.9 (CH), 138.9 (C), 139.4 (C), 139.9 (CH), 146.1 (CH), 178.8
C), 194.9 (C), 191.0 (C). 3-Acetyl-1-m eth yl-4-{2-[1-(p h en yl-
1
3
su lfon yl)-2-in d olyl]-2-(tr ich lor oa cetoxy)vin yl}-5-(tr ich lo-
3 3
C NMR (75 MHz) 27.1 (CH ), 29.3 (CH), 32.2 (CH ), 43.0
1
r oa cetyl)-1,4-d ih yd r op yr id in e (31): 18 mg (3%); H NMR
2 3 2 3
(CH ), 43.1 (CH ), 46.2 (CH ), 47.4 (CH), 50.5 (CH ), 93.1 (C),
(
6
300 MHz) 2.35 (s, 3 H), 3.38 (s, 3 H), 5.03 (d, J ) 9 Hz, 1 H),
110.2 (CH), 112.3 (CH), 120.7 (CH), 123.1 (CH), 125.8 (C),
126.0 (CH), 134.5 (C), 140.1 (C), 146.7 (CH), 168.0 (C), 193.1
(C), 207.3 (C).
.10 (d, J ) 9 Hz, 1 H), 6.79 (s, 1 H), 7.03 (s, 1 H), 7.18-7.67
1
3
(
m, 8 H), 7.78 (s, 1 H), 8.13 (d, J ) 8 Hz, 1 H); C NMR (75
MHz) 25.1 (CH ), 29.1 (CH), 42.8 (CH ), 89.7 (C), 95.6 (C), 105.5
C), 115.9 (CH), 117.3 (CH), 118.2 (C), 121.5 (CH), 124.4 (CH),
3
3
cis-3-Acetyl-5-(m eth oxycar bon yl)-1-m eth yl-4-[[(1-m eth -
yl-2-in d olyl)ca r b on yl]m e t h yl]-1,2,3,4-t e t r a h yd r op yr i-
(
1
1
1
25.8 (CH), 128.0 (C, CH), 136.6 (C), 137.6 (C), 138.4 (CH),
38.8 (C), 144.4 (CH), 158.9 (C), 178.6 (C), 195.1 (C).
In ter a ction of Acetylin d ole 1g w ith P yr id in iu m Sa lt
4 a n d TCAA. Operating as above, from acetylindole 1g3
d in e (33a ): IR (NaCl) 1622, 1666, 1704; H NMR (300 MHz)
2.36 (s, 3 H), 2.90 (m, 4 H), 3.03 (s, 3 H), 3.42 (t, J ) 12.1 Hz,
1 H), 3.53 (s, 3 H), 3.90 (m, 1 H), 4.02 (s, 3 H), 7.12 (m, 1 H),
3a
13
2
7.21 (s, 1 H), 7.38 (m, 3 H), 7.68 (dm, J ) 8 Hz, 1 H); C NMR
(
5
0.75 g, 3 mmol) were isolated the following compounds.
-Acetyl-2-[[(1-Ben zyl-2-in dolyl)car bon yl]m eth yl]-1-m eth -
yl-3-(tr ich lor oa cetyl)-1,2-d ih yd r op yr id in e (27g): 110 mg
(75 MHz) 28.9 (CH), 30.2 (CH ), 32.1 (CH ), 42.8 (CH ), 43.6
3
3
3
2 2 3
(CH ), 44.5 (CH ), 48.5 (CH), 50.6 (CH ), 97.8 (C), 110.2 (CH),
110.9 (CH), 120.4 (CH), 122.8 (CH), 125.7 (C), 125.6 (CH),
134.9 (C), 140.0 (C), 145.9 (CH), 167.8 (C), 192.0 (C), 209.2
(C). Anal. Calcd for C H N O : C, 68.46; H, 6.57; N, 7.60.
1
(
3
5
7%); H NMR (300 MHz) 2.32 (s, 3 H), 2.94 (dd, J ) 14.4 and
.5 Hz, 1 H), 3.03 (s, 3 H), 3.20 (dd, J ) 14.4 and 7.6 Hz, 1 H),
.28 (m, 1 H), 5.72 and 5.82 (2 d, J ) 16 Hz, 2 H), 7.00-7.40
2
1
24
2
4
Found: C, 68.47; H, 6.57; N, 7.61.
(
7
m, 8 H), 7.45 (s, 1 H), 7.74 (d, J ) 8 Hz, 1 H), 7.82 (s, 1 H),
cis-3-(1-Hyd r oxyeth yl)-5-(m eth oxyca r bon yl)-1-m eth yl-
4-[[(1-m eth yl-2-in d olyl)ca r bon yl]m eth yl]-1,2,3,4-tetr a h y-
2
1
3
.99 (s, 1 H); C NMR (75 MHz) 24.6 (CH
), 48.0 (CH ), 56.4 (CH), 96.2 (C), 98.8 (C), 110.7 (CH),
13.9 (CH), 120.0 (C), 121.2 (CH), 123.1 (CH), 126.0 (C), 126.2
3 2
), 43.5 (CH ), 44.0
(
1
CH
3
2
d r op yr id in e (34a ): mp 58-60 °C (cyclohexane-Et O); IR
1
(KBr) 1620, 1660, 3400; H NMR (300 MHz, acetone-d ) 1.29
6
(
(
CH), 126.5 (CH), 126.9 (CH), 128.3 (CH), 133.8 (C), 134.6
CH), 137.9 (C), 140.3 (C), 155.0 (CH), 175.7 (C), 189.8 (C),
(d, J ) 6.1 Hz, 3 H), 1.82 (m, 1 H), 2.65 (dd, J ) 14.5 and 4
Hz, 1 H), 3.08 (masked, 2 H), 3.09 (s, 3 H), 3.35 (dd, J ) 14.5
and 5 Hz, 1 H), 3.40 (s, 3 H), 3.69 (m, 2 H), 4.07 (s, 3 H), 7.15
(m, 1 H), 7.34 (s, 1 H), 7.40 (m, 1 H), 7.55 (d, J ) 7.5 Hz, 1 H),
7.65 (s, 1 H), 7.67 (d, J ) 8 Hz, 1 H); 13C NMR (75 MHz,
acetone-d ) 22.6 (CH ), 29.4 (CH), 32.3 (CH ), 42.7 (CH ), 44.6
1
95.0 (C). 3-Acet yl-4-[[(1-b en zyl-2-in d olyl)ca r b on yl]-
m et h yl]-1-m et h yl-5-(t r ich lor oa cet yl)-1,4-d ih yd r op yr i-
d in e (25g): 230 mg (14%); mp 141 °C (Et O); IR (KBr) 1649;
2
1
H NMR (300 MHz) 2.21 (s, 3 H), 2.89 (dd, J ) 12.7 and 5.6
6
3
3
3
Hz, 1 H), 2.99 (dd, J ) 12.7 and 5.8 Hz, 1 H), 3.09 (s, 3 H),
(CH ), 45.8 (CH), 47.0 (CH ), 50.8 (CH ), 66.6 (CH), 98.3 (C),
2
2
3
4
6
7
(
1
.56 (t, J ) 5.7 Hz, 1 H), 5.71 and 5.77 (2 d, J ) 16.2 Hz, 2 H),
.86 (s, 1 H), 7.05-7.30 (m, 8 H), 7.54 (s, 1 H), 7.63 (s, 1 H),
111.2 (CH), 112.1 (CH), 121.0 (CH), 123.5 (CH), 126.0 (CH),
126.9 (C), 136.2 (C), 141.0 (C), 146.7 (CH), 167.9 (C), 195.3
(C). Anal. Calcd for C H N O : C, 68.09; H, 7.07; N, 7.56.
1
3
.75 (d, J ) 8 Hz, 1 H); C NMR (75 MHz) 24.9 (CH
), 45.0 (CH ), 48.0 (CH
10.7 (CH), 113.7 (CH), 119.0 (C), 120.7 (CH), 123.3 (CH),
3
), 29.9
2
1
26
2
4
CH), 42.2 (CH
3
2
2
), 96.0 (C), 105.2 (C),
Found: C, 67.92; H, 7.19; N, 7.46. In the presence of trace
amounts of acid, tetrahydropyridine 34a was rapidly converted
into enol ether 36a : 1H NMR (300 MHz, acetone-d
) 1.54 (d,
6
(
48) Gribble, G. W.; Barden, T. C.; J ohnson, D. A. Tetrahedron 1988,
J ) 6.6 Hz, 3 H), 2.10 (m, 1 H), 3.07 (s, 3 H), 3.16 (m, 2 H),
3.42 (dd, J ) 5.8 and 2 Hz, 1 H), 4.47 (qd, J ) 6.6 and 2 Hz,
4
4, 3195.

3
608 J . Org. Chem., Vol. 62, No. 11, 1997
Bennasar et al.
1
H), 5.28 (m, 1 H), 6.49 (s, 1 H), 7.04 (t, J ) 8 Hz, 1 H), 7.18
Et
2
O. Evaporation of the organic extracts followed by flash
(
t, J ) 8 Hz, 1 H), 7.38 (d, J ) 8 Hz, 1 H), 7.42 (s, 1 H), 7.53
chromatography (AcOEt) of the residue gave diol 37a : 46 mg
(75%); mp 155 °C (CH Cl ); IR (KBr) 1609, 1646, 3380; H
2 2
1
3
1
(d, J ) 8 Hz, 1 H); C NMR (75 MHz, acetone-d
6
) 18.4, 25.6,
3
1
1.6, 34.5, 42.6, 48.5, 50.3, 73.1, 96.7, 102.3, 106.3, 110.2, 120.1,
21.1, 122.5, 128.2, 137.7, 139.0, 141.0, 147.0, 168.3.
cis-5-Acetyl-3-(m eth oxycar bon yl)-1-m eth yl-4-[[(1-m eth -
NMR (300 MHz) 1.26 (d, J ) 6 Hz, 3 H), 1.82 (m, 2 H), 2.13
(m, 1 H), 2.55 (m, 2 H), 2.90 (m, 2 H), 3.20 (m, 1 H), 3.62 (s, 3
H), 3.70 (m, 1 H), 3.81 (s, 3 H), 5.10 (dd, J ) 9.9 and 4 Hz, 1
H), 6.44 (s, 1 H), 7.05 (t, J ) 8 Hz, 1 H), 7.17 (t, J ) 8 Hz, 1
H), 7.29 (d, J ) 8 Hz, 1 H), 7.36 (s, 1 H), 7.53 (d, J ) 8 Hz, 1
yl-2-in d olyl)ca r b on yl]m e t h yl]-1,2,3,4-t e t r a h yd r op yr i-
d in e (35a ): IR (NaCl): 1647, 1733; H NMR (300 MHz) 2.10
1
H); 13C NMR (75 MHz) 22.3 (CH
(CH ), 42.8 (CH ), 44.9 (CH), 46.6 (CH
), 27.1 (CH), 29.8 (CH
), 50.7 (CH ), 65.4 (CH),
(
s, 3 H), 2.89 (m, 3 H), 3.10 (s, 3 H), 3.25 (ddd, J ) 13.5, 4.7
3
3
), 39.4
and 1.6 Hz, 1 H), 3.54 (t, J ) 13.5 Hz, 1 H), 3.66 (s, 3 H), 4.02
2
3
2
3
(masked, 1 H), 4.02 (s, 3 H), 7.12 (m, 1 H), 7.24 (s, 1 H), 7.36
66.3 (CH), 98.1 (CH), 98.7 (C), 108.8 (CH), 118.9 (CH), 120.4
(CH), 121.1 (CH), 127.1 (C), 137.7 (C), 142.4 (C), 146.5 (CH),
169.6 (C). Anal. Calcd for C21
7.66; N, 7.34. Found: C, 65.81; H, 7.37; N, 7.17.
1
3
(
m, 2 H), 7.47 (s, 1 H), 7.70 (d, J ) 8 Hz, 1 H); C NMR (75
), 29.2 (CH), 32.0 (CH ), 40.9 (CH), 43.2 (CH ),
), 44.9 (CH ), 51.8 (CH ), 110.2 (CH), 111.1 (C), 111.5
CH), 120.5 (CH), 122.9 (CH), 125.4 (CH), 125.9 (C), 135.0 (C),
39.9 (C), 147.6 (CH), 172.4 (C), 191.7 (C), 192.4 (C). Anal.
Calcd for O: C, 65.27; H, 6.78; N, 7.25.
1
MHz) 23.8 (CH
3.7 (CH
3
3
3
H
28
N
2
O
4
‚ /
2
H
2
O: C, 66.12; H,
4
(
1
2
2
3
cis-4-[2-(1-Ben zyl-2-in d olyl)-2-h yd r oxyet h yl]-3-(1-h y-
d r oxyet h yl)-5-(m et h oxyca r b on yl)-1-m et h yl-1,2,3,4-t et -
r a h yd r op yr id in e (37g). Operating as above, from tetrahy-
dropyridine 34g (180 mg, 0,4 mmol) was obtained a residue
which was chromatographed (flash, 3:7 hexane-AcOEt) to give
diol 37g as a foam: 150 mg (83%); IR (KBr) 1600, 1658, 3300;
C
21
H
24
N
2
O
4
‚H
2
Found: C, 66.54; H, 6.57; N, 7.29.
Ca ta lytic Hyd r ogen a tion of Dih yd r op yr id in e 26g. A
solution of dihydropyridine 26g (0.44 g, 1 mmol) in MeOH (35
1
mL) or 1:1 MeOH-THF (50 mL) was hydrogenated over PtO
2
H NMR (300 MHz) 1.07 (d, J ) 6 Hz, 3 H), 1.70 (m, 4 H),
(90 mg) for 18 or 10 h. The catalyst was filtered off, the
1.90 (m, 1 H), 2.78 (m, 2 H), 2.94 (s, 3 H), 3.08 (m, 1 H), 3.24
solution was evaporated, and the residue was purified as
above. The results are given in Table 1.
tr a n s-3-Acetyl-4-[[(1-ben zyl-2-in dolyl)car bon yl]m eth yl]-
(m, 1 H), 5.00 (dd, J ) 10.2 and 2.5 Hz, 1 H), 5.54 (s, 2 H),
1
3
6.53 (s, 1 H), 6.98-7.30 (m, 9 H), 7.58 (dm, J ) 8 Hz, 1 H);
C
NMR (75 MHz) 22.6 (CH
3
), 27.6 (CH), 41.0 (CH
2 3
), 42.8 (CH ),
5
-(m et h oxyca r b on yl)-1-m et h yl-1,2,3,4-t et r a h yd r op yr i-
44.5 (CH), 46.3 (CH ), 46.6 (CH
2
2
), 50.8 (CH ), 65.8 (CH), 66.1
3
d in e (32g): mp 58 °C (Et O); IR (KBr) 1624, 1650, 1668, 1710;
H NMR (300 MHz) 1.95 (s, 3 H), 2.38 (m, 1 H), 2.54 (dd, J )
2
(CH), 98.8 (CH), 99.5 (C), 109.5 (CH), 119.4 (CH), 120.6 (CH),
121.5 (CH), 127.6 (C), 138.8 (C), 143.1 (C), 145.8 (CH), 169.4
(C); HRMS calcd for C27H N O 448.2362, found 448.2353.
32 2 4
cis-3-Acet yl-4-[[(2-in d olyl)ca r b on yl]m et h yl]-5-(m et h -
oxyca r bon yl)-1-m eth yl-1,2,3,4-tetr a h yd r op yr id in e (33b).
1
1
4
4.6 and 11.3 Hz, 1 H), 3.00 (s, 3 H), 3.10 (dd, J ) 13.2 and
.1 Hz, 1 H), 3.30 (dm, J ) 13.2 Hz, 1 H), 3.57 (dd, J ) 14.6
and 3.3 Hz, 1 H), 3.68 (masked, 1 H), 3.69 (s, 3 H), 5.80 (d, J
)
16 Hz, 1 H), 5.92 (d, J ) 16 Hz, 1 H), 7.00-7.40 (m, 9 H),
Anhydrous AlCl
of tetrahydropyridine 33g (100 mg, 0.22 mmol) in anhydrous
(3 mL), and the resulting mixture was stirred at rt for 1
h. Additional anhydrous AlCl (120 mg, 0.9 mmol) was then
added, and stirring was continued for 2 h. The mixture was
3
poured into H O, basified with saturated aqueous NaHCO ,
3
(180 mg, 1.35 mmol) was added to a solution
1
3
7
.68 (s, 1 H), 7.78 (d, J ) 8 Hz, 1 H); C NMR (75 MHz) 26.8
CH ), 29.9 (CH), 42.8 (CH ), 43.0 (CH ), 46.4 (CH ), 46.8 (CH),
7.9 (CH ), 50.4 (CH ), 93.0 (C), 110.6 (CH), 113.6 (CH), 120.9
(
4
3
2
3
2
6 6
C H
2
3
3
(
1
C
CH), 123.3 (CH), 125.9 (CH), 126.1 (C), 133.9 (C), 140.1 (C),
46.6 (CH), 167.9 (C), 192.9 (C), 206.9 (C). Anal. Calcd for
: C, 72.95; H, 6.35; N, 6.30. Found: C, 72.88; H,
2
27
H
28
N
2
O
4
and extracted with AcOEt. The organic extracts were dried
and evaporated, and the residue was chromatographed (flash,
hexane-AcOEt, increasing polarity) to give tetrahydropyridine
6
.33; N, 6.33.
cis-3-Acetyl-4-[[(1-ben zyl-2-in d olyl)ca r bon yl]m eth yl]-
1
5
-(m et h oxyca r b on yl)-1-m et h yl-1,2,3,4-t et r a h yd r op yr i-
33b as a foam: 60 mg (75%); IR (KBr) 1595, 1658, 1715; H
1
d in e (33g): IR (KBr) 1620, 1665, 1703; H NMR (300 MHz)
NMR (300 MHz) 2.34 (s, 3 H), 2.89 (m, 4 H), 3.04 (s, 3 H),
2
1
5
.20 (s, 3 H), 2.90 (m, 4 H), 3.00 (s, 3 H), 3.39 (t, J ) 12.6 Hz,
H), 3.52 (s, 3 H), 3.93 (m, 1 H), 5.74 (d, J ) 16.2 Hz, 1 H),
.85 (d, J ) 16.2 Hz, 1 H), 7.05-7.30 (m, 8 H), 7.32 and 7.37
3.43 (t, J ) 12.6 Hz, 1 H), 3.54 (s, 3 H), 3.95 (m, 1 H), 7.12-
1
3
7.45 (m, 5 H), 7.67 (d, J ) 8 Hz, 1 H), 7.40 (s, 1 H); C NMR
(75 MHz) 28.9 (CH), 30.0 (CH
3 2 3
), 42.1 (CH ), 42.8 (CH ), 44.4
1
3
(
(
4
(
2 s, 2 H), 7.69 (d, J ) 8 Hz, 1 H); C NMR (75 MHz) 28.4
CH), 30.0 (CH ), 42.7 (CH ), 43.4 (CH ), 44.5 (CH ), 48.2 (CH ),
8.3 (CH), 50.5 (CH ), 97.7 (C), 110.8 (CH), 111.9 (CH), 120.8
CH), 122.9 (CH), 125.9 (CH), 126.1 (C), 134.3 (C), 139.8 (C),
45.9 (CH), 167.8 (C), 191.4 (C), 209.2 (C); HRMS calcd for
444.2049, found 444.2040.
cis-4-[[(1-Ben zyl-2-in d olyl)ca r b on yl]m et h yl]-3-(1-h y-
(CH ), 48.5 (CH), 50.6 (CH ), 97.6 (C), 109.0 (C), 112.1 (C),
2
3
3
3
2
2
2
120.6 (CH), 122.9 (CH), 125.9 (CH), 127.4 (C), 135.1 (C), 137.3
(C), 146.0 (CH), 167.8 (C), 199.9 (C), 209.0 (C); HRMS calcd
for C20H N O 354.1579, found 354.1577.
22 2 4
cis-3-(1-Hydr oxyeth yl)-4-[2-h ydr oxy-2-(2-in dolyl)eth yl]-
5-(m et h oxyca r b on yl)-1-m et h yl-1,2,3,4-t et r a h yd r op yr i-
d in e (37b). Operating as in the preparation of diols 37a and
37g, from tetrahydropyridine 33b (180 mg, 0.51 mmol) and
3
1
27 28 2 4
C H N O
d r oxyet h yl)-5-(m et h oxyca r b on yl)-1-m et h yl-1,2,3,4-t et -
r a h yd r op yr id in e (34g) was unstable and was immediately
used in the next reaction without further manipulation.
cis-5-Acetyl-4-[[(1-ben zyl-2-in d olyl)ca r bon yl]m eth yl]-
LiBEt
37b after flash chromatography (Et
polarity): 30 mg (72%); mp 88-90 °C (Et
3
H 1 M in THF (3.3 mL, 3.3 mmol) was obtained diol
O-DEA, increasing
O); IR (KBr) 1614,
2
2
1
3
-(m et h oxyca r b on yl)-1-m et h yl-1,2,3,4-t et r a h yd r op yr i-
d in e (35g): mp 108 °C (Et O-acetone); IR 1578, 1670, 1736;
H NMR (300 MHz) 2.09 (s, 3 H), 2.90 (m, 3 H), 3.06 (s, 3 H),
3290; H NMR (300 MHz) 1.21 (d, J ) 6.1 Hz, 3 H), 1.71 (m,
4 H), 2.03 (m, 1 H), 2.90 (m, 2 H), 2.98 (s, 3 H), 3.09 (m, 1 H),
3.65 (s, 3 H), 3.73 (m, 1 H), 5.13 (dd, J ) 7.7 and 6.2 Hz, 1 H),
6.33 (d, J ) 1 Hz, 1 H), 7.00-7.35 (m, 3 H), 7.32 (s, 1 H), 7.52
2
1
3
.19 (ddd, J ) 13.4, 4.6 and 1.6 Hz, 1 H), 3.45 (s, 3 H), 3.46 (t,
1
3
J ) 13.4 Hz, 1 H), 4.03 (m, 1 H), 5.69 (d, J ) 16.2 Hz, 1 H),
5
7
(d, J ) 8 Hz, 1 H), 9.40 (s, 1 H); C NMR (75 MHz) 22.4 (CH
26.7 (CH), 41.7 (CH ), 42.9 (CH ), 44.6 (CH), 46.7 (CH ), 50.8
(CH ), 66.4 (CH), 67.4 (CH), 96.9 (CH), 98.7 (C), 111.0 (CH),
119.3 (CH), 120.0 (CH), 121.0 (CH), 128.4 (C), 135.4 (C), 143.1
3
),
.89 (d, J ) 16.2 Hz, 1 H), 7.05-7.30 (m, 8 H), 7.22 (s, 1 H),
2
3
2
1
3
.57 (s, 1 H), 7.73 (d, J ) 8 Hz, 1 H); C NMR (75 MHz) 23.8
), 28.7 (CH), 40.8 (CH), 43.1 (CH ), 43.4 (CH ), 44.9 (CH ),
8.2 (CH ), 51.6 (CH ), 110.8 (CH), 111.0 (C), 112.4 (CH), 120.7
3
(CH
3
3
2
2
1
4
2
3
(C), 146.5 (CH), 169.7 (C). Anal. Calcd for C20
10O: C, 66.81; H, 7.90; N, 7.08; C, 66.49; H, 7.63; N, 6.91.
(4RS,4a SR,12a RS)-7-Ben zyl-6-h yd r oxy-4-(1-h yd r oxy-
26 2 4
H N O ‚ /
(
1
C
CH), 123.1 (CH), 125.8 (CH), 126.1 (C), 134.4 (C), 139.9 (C),
47.4 (CH), 172.4 (C), 191.8 (C), 191.9 (C). Anal. Calcd for
: C, 72.95; H, 6.35; N, 6.30. Found: C, 72.86; H,
2 4
C H
27
H
28
N
2
O
4
et h yl)-12a -(m et h oxyca r b on yl)-2-m et h yl-2,3,4,4a ,5,6,12,
12a -oct a h yd r o-1H -p yr id o[3′,4′:4,5]cycloh e p t a [1,2-b]-
in d ole (38g). A. N,N-Dimethylmethyleneiminium iodide
(Eschenmoser’s salt, 70 mg, 0.38 mmol) was added to a solution
6
.38; N, 6.29.
cis-3-(1-H yd r oxye t h yl)-4-[2-h yd r oxy-2-(1-m e t h yl-2-
in d olyl)eth yl]-5-(m eth oxyca r bon yl)-1-m eth yl-1,2,3,4-tet-
r a h yd r op yr id in e (37a ). A 1 M solution of LiBEt H in THF
Super-Hydride, 0.7 mL, 0.7 mmol) was added to a solution of
tetrahydropyridine 34a (61 mg, 0.17 mmol) in THF (4 mL) at
70 °C, and the mixture was stirred at -70 °C for 45 min.
The reaction mixture was poured into H O and extracted with
3
of diol 37g (75 mg, 0,17 mmol) in CH
was stirred at rt for 1 h. The mixture was poured into
saturated aqueous NaHCO and extracted with CH Cl . The
2 2
Cl , and the mixture
(
3
2
2
-
organic extracts were dried and evaporated to give crude II
(R ) Bn) as a foam.
2

Total Synthesis of Ervitsine and Ervatamine Alkaloids
J . Org. Chem., Vol. 62, No. 11, 1997 3609
B. MeI (26 µL, 0.42 mmol) was added to a solution of the
above residue in DMSO (2 mL), and the mixture was stirred
at rt for 30 min and at 70 °C for 4 h. After the mixture was
cooled at rt, a solution of NaCNBH (37 mg, 0.5 mmol) in
3
MeOH (3 mL) was added, and stirring was continued for 45
min. The solvent was evaporated, and the residue was
MHz) 1.58 (dd, J ) 6.78 and 1.86 Hz, 3 H), 2.24 (d, J ) 11.8
Hz, 1 H), 2.30 (s, 3 H), 2.44 (d, J ) 15.9 Hz, 1 H), 2.58 (br d,
J ) 12.1 Hz, 1 H), 2.88 (d, J ) 15.4 Hz, 1 H), 3.08 (dd, J )
15.9 and 11 Hz, 1 H), 3.10 (br d, J ) 12.1 Hz, 1 H), 3.44 (br d,
J ) 11.8 Hz, 1 H), 3.52 (d, J ) 11 Hz, 1 H), 3.59 (s, 3 H), 3.62
(d, J ) 15.4 Hz, 1 H), 5.42 (qd, J ) 6.78 and 1.4 Hz, 1 H), 7.12
1
3
partitioned between H
dried and evaporated, and the resulting residue was chro-
matographed (flash, 97:3 Et O-DEA) to give tetracycle 38g
as a foam: 31 mg (40%); IR (KBr) 1733 (CO), 3300; H NMR
2
O and Et
2
O. The organic extracts were
(t, J ) 8 Hz, 1 H), 7.40 (m, 2 H), 7.58 (d, J ) 8 Hz, 1 H);
NMR (75 MHz) 12.5 (CH ), 31.1 (CH ), 34.1 (CH), 44.0 (CH
45.9 (CH ), 49.1 (C), 52.4 (CH ), 61.2 (CH ), 61.8 (CH ), 112.3
C
3
2
2
),
2
3
3
2
2
1
(CH), 119.7 (C), 120.3 (CH), 120.7 (CH), 121.4 (CH), 126.6
(CH), 127.3 (C), 132.6 (C), 136.1 (C), 136.7 (C), 175.2 (C), 193.5
(C); HRMS calcd for C21H N O 352.1787, found 352.1772.
24 2 3
(
1
2
(
3
1
300 MHz) 1.21 (d, J ) 6 Hz, 3 H), 1.55 (t, J ) 11 Hz, 1 H),
.80-2.20 (m, 3 H), 1.95 (d, J ) 11.5 Hz, 1 H), 2.29 (s, 3 H),
.54 (dd, J ) 11 and 3 Hz, 1 H), 2.72 (d, J ) 16 Hz, 1 H), 3.11
(()-20-Ep ier va ta m in e (42). A. Alcohol 39 (20 mg, 0.054
mmol) was converted into the corresponding mesylate operat-
ing as above. LiCl (0.04 g, 0.94 mmol) was added to a solution
of this mesylate in acetone (1 mL), and the mixture was
refluxed for 1 h. The solvent was evaporated, and the resulting
residue was partitioned between H O and CH Cl . Evapora-
m, 1 H), 3.24 (d, J ) 16 Hz, 1 H), 3.38 (d, J ) 11.5 Hz, 1 H),
.63 (s, 3 H), 3.66 (m, 1 H), 5.02 (t, 1 H), 5.45 (d, J ) 16.7 Hz,
H), 5.75 (d, J ) 16.7 Hz, 1 H), 6.95-7.25 (m, 8 H), 7.40 (d,
1
3
J ) 8 Hz, 1 H); C NMR (75 MHz) 22.2 (CH
0.4 (CH), 30.5 (CH ), 45.3 (CH ), 46.5 (CH), 47.5 (CH
C), 52.4 (CH ), 54.6 (CH ), 60.8 (CH ), 66.7 (CH), 67.3 (CH),
3
), 27.3 (CH
2
),
3
(
2
3
2
), 51.4
2
2
2
3
2
2
tion of the organic extracts followed by flash chromatography
1
1
1
06.0 (C), 109.5 (CH), 117.8 (CH), 121.6 (2 CH), 126.2 (CH),
26.9 (CH), 128.5 (CH), 127.7 (C), 137.0 (C), 137.2 (C), 138.7
(AcOEt) gave chloride 40 as a foam: 15 mg (71%); H NMR
(300 MHz) 1.42 (d, J ) 6 Hz, 3 H), 1.67 (t, J ) 11.5 Hz, 1 H),
2.08 (d, J ) 12 Hz, 1 H), 2.10 (m, 1 H), 2.27 (s, 3 H), 2.36 (d,
J ) 15 Hz, 1 H), 2.51 (dd, J ) 15 and 10 Hz, 1 H), 2.65 (dd, J
) 11.5 and 3 Hz, 1 H), 2.78 (d, J ) 15.5 Hz, 1 H), 3.11 (dm, J
) 10 Hz, 1 H), 3.40 (d, J ) 12 Hz, 1 H), 3.48 (d, J ) 15.5 Hz,
1 H), 3.59 (s, 3 H), 3.93 (m, 1 H), 7.10 (t, J ) 8 Hz, 1 H), 7.15-
7.32 (m, 2 H), 7.49 (d, J ) 8 Hz, 1 H), 8.88 (s, 1 H); MS m/ z
34 2 4
(C), 176.0 (C); HRMS calcd for C28H N O 462.2518, found
4
62.2532.
(
()-19-Hyd r oxy-20-ep ier va ta m in e (39). Diol 37b (0.12
g, 0.34 mmol) was allowed to react with N,N-dimethylmeth-
yleneiminium iodide (0.15 g, 0.83 mmol) and then with MeI
(
42 µL, 0.67 mmol) and NaCNBH
described above. Crude 38b was dissolved in CHCl
and treated with MnO (0.22 g, 2.5 mmol) at rt for 1 h 30 min.
3
(74 mg, 1 mmol) as
+
3
(6 mL)
(rel intensity) 390 (M + 2, 20), 388 (M , 60), 353 (M - 35, 15),
2
352 (M - 36, 15), 329 (M - 59, 30).
The resulting mixture was filtered over Celite and evaporated.
Column chromatography (95:5 AcOEt-MeOH) of the residue
gave tetracycle 39 as a foam: 30 mg (25%); IR (KBr) 1637,
3
B. A solution of chloride 40 (15 mg, 0.039 mmol), n-Bu SnH
(
31 µL, 0.12 mmol), and AIBN (3 mg, 0.02 mmol) in benzene
(15 mL) was refluxed for 1 h. The resulting mixture was
1
1
1
1
718, 3395; H NMR (500 MHz, assignments aided by H- H
COSY and HMQC) 1.26 (d, J ) 6 Hz, 3 H, 18-H), 1.67 (t, J )
1.5 Hz, 1 H, 21-Hax), 1.75 (br s, 1 H, OH), 1.91 (m, 1 H, 20-
2 2
poured into H O and extracted with Et O. The organic
extracts were dried and evaporated, and the residue was
1
chromatographed (flash, 98:2 AcOEt-MeOH) to give 42 as a
H), 2.08 (d, J ) 12 Hz, 1 H, 5-H), 2.33 (s, 3 H, NMe), 2.52 (dd,
J ) 15.5 and 10 Hz, 1 H, 14-H), 2.62 (dd, J ) 11.5 and 3 Hz,
1
foam: 10 mg (73%); IR (KBr) 1625, 1725, 3300; H NMR (300
MHz) 0.87 (t, J ) 7.5 Hz, 3 H), 1.36 (m, 2 H), 1.59 (t, J ) 11.5
Hz, 1 H), 1.85 (m, 1 H), 2.08 (d, J ) 11.8 Hz, 1 H), 2.32 (s, 3
H), 2.53 (m, 2 H), 2.62 (d, J ) 15.9 Hz, 1 H), 2.65 (br d, J )
1
1
H, 21-Heq), 2.79 (d, J ) 15.5 Hz, 1 H, 14-H), 2.80 (d, J )
5.5 Hz, 1 H, 6-H), 3.01 (dd, J ) 10 and 4 Hz, 1 H, 15-H), 3.46
(
d, J ) 12 Hz, 1 H, 5-H), 3.47 (d, J ) 15.5 Hz, 1 H, 6-H), 3.65
1
1.5 Hz, 1 H), 2.80 (d, J ) 15.6 Hz, 1 H), 3.47 (br d, J ) 11.8
Hz, 1 H), 3.49 (d, J ) 15.6 Hz, 1 H), 3.63 (s, 3 H), 7.13 (t, J )
Hz, 1 H), 7.36 (m, 2 H), 7.55 (d, J ) 8 Hz, 1 H), 8.95 (s, 1 H);
(s, 3 H, OMe), 3.83 (m, 1 H, 19-H), 7.10 (t, J ) 8 Hz, 1 H,
1
1
0-H), 7.15-7.30 (m, 2 H, 11-H and 12-H), 7.49 (d, J ) 8 Hz,
13
8
H, 9-H), 9.10 (s, 1 H, NH); C NMR (75 MHz, assignments
13
C NMR (75 MHz) 11.4 (CH
CH), 36.6 (CH ), 39.0 (CH), 46.3 (CH
), 60.7 (CH ), 112.3 (CH), 119.5 (C), 120.1 (CH), 120.6
3
), 23.9 (CH
2
), 31.8 (CH
2
), 36.2
aided by HMQC) 22.5 (C-18), 31.7 (C-6), 33.8 (C-15), 37.3 (C-
(
5
2
3
), 49.3 (C), 52.5 (CH
3
),
1
2
9
4), 45.3 (NMe), 46.4 (C-20), 49.1 (C-16), 52.6 (OMe), 54.6 (C-
1), 60.2 (C-5), 66.4 (C-19), 112.4 (C-12), 119.2 (C-7), 119.6 (C-
), 120.4 (C-10), 125.9 (C-11), 127.0 (C-8), 132.7 (C-2), 136.6
7.5 (CH
2
2
(CH), 126.5 (CH), 127.4 (C), 132.7 (C), 136.6 (C), 175.5 (C),
1
94.1 (C); HRMS calcd for C21 354.1943, found 354.1943.
26 2 3
H N O
26 2 4
(C-13), 175.8 (CO), 194.3 (C-3); HRMS calcd for C21H N O
3
70.1893, found 370.1880.
()-19,20-Did eh yd r oer va ta m in e (41). A. MsCl (19 µL,
.24 mmol) and Et N (56 µL, 0.40 mmol) were added at 0 °C
Cl (2
mL), and the resulting solution was stirred at 0 °C for 1 h.
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
Grants GRQ93-1059 and SGR95-428, and for a fellow-
ship to B.V.
0
3
to a solution of 39 (30 mg, 0.08 mmol) in anhydrous CH
2
2
The solution was washed with aqueous NaHCO
evaporated to give a crude mesylate.
B. DBU (72 µL, 0.49 mmol) was added to a solution of the
above mesylate in DMSO (2 mL) and toluene (2 mL), and the
mixture was heated at 80 °C for 3 h. Then, additional DBU
3
, dried, and
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 16c, 17a , 17b, 33b, 37g, 38g, 39,
1, and 42 (18 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(
36 µL, 0.24 mmol) was added, and the mixture was heated at
00 °C for 1 h. The mixture was poured into H O and
extracted with AcOEt. The organic extracts were washed with
O, dried, and evaporated. Flash chromatography of the
4
1
2
H
2
residue (hexane-AcOEt, increasing polarity) gave 41 as a
foam: 20 mg (70%); IR (KBr) 1631, 1729, 3313; H NMR (300
1
J O9623301