Nucleophilic Addition of 1-Acetylindole Enolates to Pyridinium Salts. Stereoselective Formal Synthesis of (±)-Geissoschizine and (±)-Akagerine via 1,4-Dihydropyridines

Article abstract of DOI:10.1021/jo9911894

Addition of the enolate derived from 1-acetylindole (3) to pyridinium salt 4b followed by acid-induced cyclization of the resulting 1,4-dihydropyridine 5b in the presence of lithium iodide gives tetracyclic 3,7-methano[1,4]diazonino[1,2-a]indole 6b, which has subsequently been elaborated into the (E)-ethylidene derivative 7b. From this compound is reported a stereocontrolled route to (±)-geissoschizine, involving closure of C ring by Pummerer reaction, methanolysis of the resulting pentacyclic lactam 12, and desulfurization. A similar synthetic sequence starting from the enolate of 3 and 2-fluoropyridinium salt 15b gives access to the pentacyclic dilactam 2, which had previously been converted to (±)-akagerine through opening of the piperidone (D) ring.

Full text of DOI:10.1021/jo9911894

J . Org. Chem. 1999, 64, 9605-9612
9605
Nu cleop h ilic Ad d ition of 1-Acetylin d ole En ola tes to P yr id in iu m
Sa lts. Ster eoselective F or m a l Syn th esis of (()-Geissosch izin e a n d
(()-Ak a ger in e via 1,4-Dih yd r op yr id in es
M.-Llu¨ısa Bennasar,* J uan-Miguel J ime´nez, Bernat Vidal, Bilal A. Sufi, and J oan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
Received J uly 29, 1999
Addition of the enolate derived from 1-acetylindole (3) to pyridinium salt 4b followed by acid-
induced cyclization of the resulting 1,4-dihydropyridine 5b in the presence of lithium iodide gives
tetracyclic 3,7-methano[1,4]diazonino[1,2-a]indole 6b, which has subsequently been elaborated into
the (E)-ethylidene derivative 7b. From this compound is reported a stereocontrolled route to (()-
geissoschizine, involving closure of C ring by Pummerer reaction, methanolysis of the resulting
pentacyclic lactam 12, and desulfurization. A similar synthetic sequence starting from the enolate
of 3 and 2-fluoropyridinium salt 15b gives access to the pentacyclic dilactam 2, which had previously
been converted to (()-akagerine through opening of the piperidone (D) ring.
The nucleophilic addition of indole-containing enolates
to N-alkylpyridinium salts to give 1,4-dihydropyridines
constitutes a general and versatile method for the
synthesis of indole alkaloids.1 Taking advantage of the
high reactivity of both the dihydropyridine and indole
rings, it is possible to build complex polycyclic structures,
thus providing access to a variety of alkaloids belonging
to different structural types. Starting from the enolates
derived from 1-, 2-, and 3-indoleacetates, we have syn-
thesized indole alkaloids of the C-mavacurine2 and
Strychnos3 groups, as well as tetracyclic akuammiline-
type substructures,4 respectively. Similarly, starting from
2-acetylindole enolates, we have completed total synthe-
ses of bridged (ervitsine) and fused 2-acylindole alkaloids
of the ervatamine and silicine groups.5
In this paper, we report the extension of this methodol-
ogy, using the enolate derived from 1-acetylindole as the
nucleophilic partner. Successive formation of C-15/C-16
and C-2/C-3 (biogenetic numbering)6 bonds, the former
by nucleophilic attack of 1-acetylindole enolate to the
γ-position of a pyridinium salt and the latter by acid-
promoted cyclization of the resulting 1,4-dihydropyridine
on the indole ring, affords tetracyclic 1-acylindole deriva-
tives (A), from which we present short stereocontrolled
synthetic routes to the alkaloids geissoschizine7 and
akagerine.8
attention from the synthetic standpoint,9 although most
of the reported syntheses suffer from some stereochemical
problems, as they usually lead to C-3/C-15 trans deriva-
tives and/or to the unnatural Z configuration (or Z/E
mixtures) for the ethylidene double bond. Consequently,
additional steps to promote epimerization at C-3 and/or
Z-E isomerization are required. Akagerine, a tetracyclic
indole alkaloid isolated in 1975 from Strychnos usamba-
rensis10 and later from several Strychnos species,11 has
a peculiar skeleton related to that of geissoschizine, but
lacking the characteristic piperidine (D) ring and con-
taining an additional link between N-1 and C-17; con-
sequently, it incorporates a perhydroazepine ring fused
to a tetrahydro-â-carboline unit. This alkaloid has at-
tracted much less synthetic attention: only one total
synthesis in the racemic series via dilactam 2 (Scheme
1)12 and one enantioselective synthesis of (-)-akagerine13
have been reported to date.
Resu lts a n d Discu ssion
Scheme 1 outlines the unified strategy for the synthesis
of (()-geissoschizine and (()-akagerine. It consists of
(9) (a) Yamada, K.; Aoki, K.; Kato, T.; Uemura, D.; van Tamelen,
E. E. J . Chem. Soc., Chem. Commun. 1974, 908. (b) Hachmeister, B.;
Thielke, D.; Winterfeldt, E. Chem. Ber. 1976, 109, 3825. (c) Benson,
W.; Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1979, 18, 862. (d)
Wenkert, E.; Vankar, Y. D.; Yadav, J . S. J . Am. Chem. Soc. 1980, 102,
7971. (e) Banks, B. J .; Calverley, M. J .; Edwards, P. D.; Harley-Mason,
J . Tetrahedron Lett. 1981, 22, 1631. (f) Bohlmann, C.; Bohlmann, R.;
Rivera, E. G.; Vogel, C.; Manandhar, M. D.; Winterfeldt, E. Liebigs
Ann. Chem. 1985, 1752. (g) Wenkert, E.; Guo, M.; Pestchanker, M. J .;
Shi, Y.-J .; Vankar, Y. D. J . Org. Chem. 1989, 54, 1166. (h) Overman,
L. E.; Robichaud, A. J . J . Am. Chem. Soc. 1989, 111, 300. (i) Martin,
S. F.; Benage, B.; Geraci, L. S.; Hunter, J . E.; Mortimore, M. J . Am.
Chem. Soc. 1991, 113, 6161. (j) Lounasmaa, M.; J okela, R.; Miettinen,
J .; Halonen, M. Heterocycles 1992, 34, 1497. (k) Lounasmaa, M.; J okela,
R.; Anttila, U.; Hanhinen, P.; Laine, C. Tetrahedron 1996, 52, 6803.
(l) Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi, N. Tetrahedron
Lett. 1997, 38, 5307. (m) Martin, S. F.; Chen, K. X.; Eary, C. T. Org.
Lett. 1999, 1, 79. (n) See also: Birman, V. B.; Rawal, V. H. Tetrahedron
Lett. 1998, 39, 7219.
Geissoschizine is a pivotal early intermediate in indole
alkaloid biosynthesis that has received considerable
(1) For a review, see: Bosch, J .; Bennasar, M.-L. Synlett 1995, 587.
(2) (a) Bennasar, M.-L.; Alvarez, M.; Lavilla, R.; Zulaica, E.; Bosch,
J . J . Org. Chem. 1990, 55, 1156. (b) Bennasar, M.-L.; Zulaica, E.;
J ime´nez, J .-M.; Bosch, J . J . Org. Chem. 1993, 58, 7756.
(3) (a) Alvarez, M.; Salas, M.; de Veciana, A.; Lavilla, R.; Bosch, J .
Tetrahedron Lett. 1990, 31, 5089. (b) Amat, M.; Linares, A.; Bosch, J .
J . Org. Chem. 1990, 55, 6299.
(4) (a) Bennasar, M.-L.; Zulaica, E.; Ram´ırez, A.; Bosch, J . J . Org.
Chem. 1996, 61, 1239. (b) Bennasar, M.-L.; Zulaica, E.; Ram´ırez, A.;
Bosch, J . Tetrahedron 1999, 55, 3117.
(5) (a) Bennasar, M.-L.; Vidal, B.; Bosch, J . Chem. Commun. 1996,
2755. (b) Bennasar, M.-L.; Vidal, B.; Bosch, J . J . Org. Chem. 1997, 62,
3597.
(6) Le Men, J .; Taylor, W. Experientia 1965, 21, 508.
(7) For a preliminary account of this part of the work, see: Benna-
sar, M.-L.; J ime´nez, J .-M.; Sufi, B. A.; Bosch, J . Tetrahedron Lett. 1996,
37, 9105.
(10) Angenot, L.; Dideberg, O.; Dupont, L. Tetrahedron Lett. 1975,
1357.
(11) Massiot, G.; Delaude, C. The Alkaloids; Brossi, A., Ed.; Aca-
demic Press: San Diego, 1988; Vol. 34, pp 211-329.
(12) Benson, W.; Winterfeldt, E. Heterocycles 1981, 15, 935.
(13) Danieli, B.; Lesma, G.; Mauro, M.; Palmisano G.; Passarella,
D. J . Org. Chem. 1995, 60, 2506.
(8) For a preliminary account of this part of the work, see: Benna-
sar, M.-L.; Vidal, B.; Sufi, B. A.; Bosch, J . Chem. Commun. 1998, 2639.
10.1021/jo9911894 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/03/1999

9606 J . Org. Chem., Vol. 64, No. 26, 1999
Bennasar et al.
Sch em e 1. Syn th etic Str a tegy
Sch em e 2a
a
Reagents and conditions: (i) LDA, THF, -30 °C, 1.5 h; (ii)
TsOH-C6H6, LiI, THF, rt, 1.5 h; (iii) 2.5 N HCl, MeOH, reflux, 2
h, then NaBH4, MeOH, 0 °C, 1 h.
the (E)-ethylidenepiperidine 7a by the known17 one-pot
sequence consisting of treatment with refluxing aqueous
HCl and subsequent sodium borohydride reduction.
However, preliminary experimentation revealed that
debenzylation of 7a by hydrogenolysis [(Pd(OH)2, MeOH]
took place with simultaneous hydrogenation of the eth-
ylidene substituent. Therefore, we turned our attention
to tetracycles 6b and 7b, which incorporate a 2-(phenyl-
sulfanyl)ethyl group on the piperidine nitrogen able to
induce closure of the C ring by electrophilic cyclization
of a thionium ion generated by Pummerer rearrange-
ment.18 The nucleophilic addition-cyclization sequence
from 1-acetylindole (3) was then extended to pyridinium
bromide 4b: in this way, tetracycle 6b (a vinylogous
urethane) was obtained (40%) through 1,4-dihydropyri-
dine 5b (20%) and then chemoselectively oxidized at the
sulfur atom with m-CPBA to provide sulfoxide 8 as a
mixture of stereoisomers (evident by NMR) in 89% yield
(Scheme 3). Pummerer cyclization of these amino sul-
foxides 8 was satisfactorily accomplished with trimeth-
ylsilyl triflate (TMSOTf) in the presence of diisopropyl-
ethylamine (DIPEA)19 to give (60% yield) an epimeric
mixture (NMR) of pentacyclic sulfides 9, which were
converted (80% yield) to pentacycle 10 by desulfurization
with Ph3SnH-AIBN in C6H6. Unfortunately, this pen-
tacycle could not be converted into the desired lactam 1
since the application of the acid hydrolysis-decarboxy-
lation-reduction sequence in order to transform the
acrylate moiety into the (E)-ethylidene group resulted in
decomposition, probably due to the opening of the seven-
membered lactam ring.
three well-differentiated phases: (i) construction of the
tetracyclic partially reduced 3,7-methano[1,4]diazonino-
[1,2-a]indole system A (rings ABDE) using the above-
mentioned nucleophilic addition-cyclization methodol-
ogy; (ii) closure of the tryptamine bridge (C ring) by
cyclization of the functionalized two-carbon N-4 substitu-
ent on the indole 3-position to give the apogeissoschizine-
type14,15 pentacyclic derivatives 1 or 2; and (iii) opening
of either the seven-membered lactam (E) ring or the
piperidine (D) ring to give geissoschizine or akagerine,
respectively. In the former case, we anticipated that the
opening of E ring would easily occur to relieve the strain
associated with the pentacyclic derivative 1 and that the
bridgehead character of C-3 and C-15 in 1 would ensure
the required C-3/C-15 cis relationship of geissoschizine.
In the latter case, the opening of the piperidine ring has
previously been effected from 2,12 taking advantage of
the 2-piperidone moiety, so the preparation of this
pentacyclic dilactam constitutes a formal total synthesis
of akagerine. The oxo group at C-21 in 2 would be
introduced either by oxidation of the piperidine ring of 1
(or a suitable tetracyclic precursor) or by substitution of
a fluorine atom, which would be present in the starting
pyridinium salt (Z ) F), by a hydroxy group, taking
advantage of the R-fluoro enamine moiety of A.
To make use of tetracyclic substrates bearing different
functionalized two-carbon N-4 substituents, we initially
planned to prepare tetracycle 7a , which incorporates an
easily removable N-benzyl group (Scheme 2). Thus,
reaction of the enolate derived from 1-acetylindole (3)
with pyridinium salt 4a gave 1,4-dihydropyridine 5a in
22% yield. Acid-induced (TsOH, C6H6) cyclization in the
presence of lithium iodide16 gave tetracycle 6a (50%),
which was stereoselectively elaborated in 33% yield into
For this reason, we decided to reverse the order of the
steps in the above sequence and to elaborate the (E)-
(16) For the use of this procedure to the synthesis of (E)-ethylidene-
bearing indole alkaloids, see: Besselie`vre, R.; Cosson, J .-P.; Das, B.
C.; Husson, H.-P. Tetrahedron Lett. 1980, 21, 63. See also refs 2, 3a,
4a, 5b, and 9d,g.
(17) For a discussion on the effect of lithium iodide in the acid-
induced cyclization of these kind of dihydropyridines, see: Bennasar,
M.-L.; J ime´nez, J .-M.; Sufi, B. A.; Bosch, J . Tetrahedron Lett. 1996,
37, 7653.
(18) (a) For a review, see: Padwa, A.; Gunn, D. E., J r.; Osterhout,
M. H. Synthesis 1997, 1353. (b) For closure of the C ring of indolo-
[2,3-a]quinolizidines by the Pummerer reaction, see: Amat, M.;
Hadida, S.; Pshenichnyi, G.; Bosch, J . J . Org. Chem. 1997, 62, 3158.
(19) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1992, 48,
7803.
(14) (a) This pentacyclic system is present in the alkaloid 2,7-
dihydroxyapogeissoschizine: Quetin-Leclercq, J .; Dive, G.; Delaude,
C.; Warin, R.; Bassleer, R.; Angenot, L. Phytochemistry 1994, 35, 533.
For previous synthetic approaches, see: (b) Bennasar, M.-L.; Zulaica,
E.; Sufi, B. A.; Bosch, J . Tetrahedron 1996, 52, 8601. (c) Birman, V.
B.; Rawal, V. H. J . Org. Chem. 1998, 63, 9146.
(15) Dilactam
2 also constitutes an intermediate in an early
synthesis of (()-geissoschizine. See ref 9c.

Synthesis of (()-Geissoschizine and (()-Akagerine
J . Org. Chem., Vol. 64, No. 26, 1999 9607
Sch em e 3a
Sch em e 5
a
Reagents and conditions: (i) m-CPBA, CH2Cl2, -78 °C, 30 min;
(ii) TMSOTf, DIPEA, CH2Cl2, rt, 1.5 h; (iii) Ph3SnH, AIBN, C6H6,
reflux, 1 h.
rendering the pentacyclic sulfide 12 (mixture of C-6
stereoisomers) in 64% yield. In contrast, when the
rearrangement was induced with TFA-TFAA in reflux-
ing dichloromethane,20 no cyclization was observed and
a nearly equimolecular mixture of tetracyclic sulfides 7b
and 14 was unexpectedly obtained. Formation of sulfide
14 can be rationalized as depicted in Scheme 5, by
considering the nucleophilic displacement of the acyloxy
group by the indole ring in the initially formed (acyloxy)-
sulfonium intermediate 11a to give a pentacyclic sulfo-
nium salt (11b), which undergoes a subsequent ring
cleavage due to an external nucleophilic attack on the
R-carbon.21 On the other hand, reaction of sulfurane 11c
with TFA accounts for the formation of sulfide 7b.22
As expected, the opening of the seven-membered lac-
tam ring of pentacycle 12 occurred smoothly on treatment
with methanolic sodium methoxide. A subsequent radical
desulfurization using n-Bu3SnH-AIBN gave methyl gei-
ssoschizoate 13 in 52% overall yield. Since 13 had
previously been transformed into the alkaloid geissos-
chizine by formylation,9a the above synthesis constitutes
a stereocontrolled formal synthesis of this alkaloid. It is
worth mentioning that attempts to induce desulfurization
before the opening of ring E resulted in failure. Thus,
treatment of 12 with Raney nickel or nickel boride gave
complex mixtures due to the lactam ring opening and/or
reduction of the ethylidene group, whereas the use of
radical conditions [n-Bu3SnH (or Ph3SnH)-AIBN in
boiling benzene] caused concomitant isomerization of the
exocyclic double bond.
Sch em e 4a
a
Reagents and conditions: (i) TFA, CH2Cl2, 0 °C, 30 min, then
(20) (a) Takano, S.; Iida, H.; Inomata, K.; Ogasawara, K. Heterocycles
1993, 35, 47. (b) Bonjoch, J .; Catena, J .-L.; Valls, N. J . Org. Chem.
1996, 61, 7106.
m-CPBA, CH2Cl2, -78 °C, 30 min; (ii) TMSOTf, DIPEA, CH2Cl2,
rt, 1.5 h; (iii) MeONa, 4:1 MeOH-THF, rt, 3 h; (iv) n-Bu3SnH,
AIBN, C6H6, reflux, 4 h.
(21) For precedents of this abnormal Pummerer reaction, see: (a)
Pyne, S. G.; Hajipour, A. R. Tetrahedron 1994, 50, 13501. (b) Amat,
M.; Bennasar, M.-L.; Hadida, S.; Sufi, B. A.; Zulaica, E.; Bosch, J .
Tetrahedron Lett. 1996, 37, 5217.(c) Shinohara, T.; Takeda, A.; Toda,
J .; Ueda, Y.; Kohno, M. Sano, T. Chem. Pharm. Bull. 1998, 46, 918.
For related processes, see: (d) Kaneko, T. J . Am. Chem. Soc. 1985,
107, 5490. (e) Terauchi, H.; Tanitame, A.; Tada, K.; Nishikawa, Y.
Heterocycles 1996, 43, 1719. (f) Arnone, A.; Bravo, P.; Capelli, S.;
Fronza, G.; Meille, S. V.; Zanda, M.; Cavicchio, G.; Crucianelli, M. J .
Org. Chem. 1996, 61, 3375. (g) Volonterio, A.; Zanda, M.; Bravo, P.;
Fronza, G.; Cavicchio, G.; Crucianelli, M. J . Org. Chem. 1997, 62, 8031.
ethylidene substituent from a less strained tetracyclic
derivative, prior to the construction of the fifth ring.
Accordingly, the (E)-ethylidenepiperidine 7b was stereo-
selectively prepared (30%) in the usual way from tetra-
cycle 6b and then chemoselectively converted (80%) to
sulfoxide 11 (mixture of stereoisomers at the sulfur atom)
by sequential treatment with TFA (in order to protect
the piperidine nitrogen) and m-CPBA (Scheme 4). Ap-
plication of the above Pummerer reaction conditions
(TMSOTf-DIPEA) to sulfoxide 11 worked equally well,
(22) For
a similar reduction, see: (a) Cardwell, J .; Hewitt, B.;
Ladlow, M.; Magnus, P. J . Am. Chem. Soc. 1988, 110, 2242. See also:
(b) Kawasaki, T.; Suzuki, H.; Sakata, I.; Nakanishi, H.; Sakamoto, M.
Tetrahedron Lett. 1997, 38, 3251.

9608 J . Org. Chem., Vol. 64, No. 26, 1999
Bennasar et al.
Sch em e 6a
The access to the pentacyclic dilactam 2, a known
precursor of the indole alkaloid akagerine, required the
chemoselective oxidation of C-21 in the above tetracyclic
or pentacyclic intermediates. For this purpose, we chose
the model tetracycle 7a and pentacycle 12. However, only
complex mixtures were obtained when these compounds
were exposed to oxidizing reagents such as benzenese-
leninic anhydride (BSA)23 or ruthenium oxide.24 Because
of this failure, we altered our initial synthetic plan to
include a fluorine atom at the R-position of the starting
pyridinium salt in the nucleophilic addition-cyclization
sequence; in this manner, taking into account the easy
hydrolysis of the C-F bond in 2-fluoropyridines,25 we
thought that we would be able to gain access to tetracyclic
3,7-methano[1,4]diazonino[1,2-a]indole systems embody-
ing the required 2-piperidone moiety present in 2.
We set out to explore the feasibility of this sequence
using N-methylpyridinium salt 15a as a model substrate
(Scheme 6). Knowing that alkylation of 2-halopyridines
with alkyl halides or tosylates is a difficult process,26 we
prepared this compound in good yield by alkylation of
3-acetyl-2-fluoropyridine27 with methyl triflate. Exposure
of pyridinium triflate 15a to the enolate derived from
1-acetylindole (3) gave 1,4-dihydro-2-fluoropyridine 16a
1
in 25% yield. Its formation was evident in the H NMR
spectrum since the typical 1,4-dihydropyridine pattern
was complicated by the 1H-19F coupling. As expected,
treatment of a methanolic solution of 1,4-dihydropyridine
16a with TsOH in the presence of lithium iodide brought
about both cyclization upon the indole 2-position and
concomitant cleavage of the C-F bond to give (50% yield)
the tetracyclic lactam 17a . Its spectroscopic data clearly
showed that the acetyl group was in the enol form,
presumably with a Z double bond configuration.
The next step in the synthesis was the stereoselective
conversion of the acetyl group into the (E)-ethylidene
substituent. This was initially planned through an
elimination reaction, which would be effected upon the
alcohol resulting from the chemoselective reduction of the
enolized C-19 carbonyl group of 17a . Thus, controlled
NaBH4 reduction of 17a gave the corresponding alcohol
(mixture of stereoisomers), which was treated with
Martin Sulfurane to give the desired (E)-ethylidene
derivative 19a in moderate yield (30%). Less satisfacto-
rily, a DBU-induced elimination of the mesylate derived
from the above alcohol (19,20-dihydro-17) gave a 2:1
mixture of 19a and the corresponding Z isomer in lower
yield (21%).
a
Reagents and conditions: (i) LDA, THF, -30 °C, 1.5 h; (ii)
TsOH-C6H6, LiI, MeOH, rt, 2 h; (iii) Tf2O, 1,8-bis(dimethylami-
no)naphthalene, -40 to 0 °C (to -10 °C from 17b), 1 h; (iv)
n-Bu3SnH, Pd(PPh3)4, LiCl, THF, reflux, 1 h; (v) m-CPBA, CH2Cl2,
-78 °C, 30 min; (vi) TFAA, 2,6-di(tert-butyl)pyridine, CH2Cl2, rt,
30 min, then reflux, 1.5 h; (vii) n-Bu3SnH, AIBN, C6H6, reflux,
1 h.
triflate 18a ,28 which was satisfactorily prepared (90%)
by treatment of enol 17a with triflic anhydride in the
presence of 1,8-bis(dimethylamino)naphthalene. To our
delight, reduction of 18a with n-Bu3SnH in the presence
of Pd(Ph3P)4 and LiCl stereoselectively gave 19a in 76%
overall yield from 17a .
With a method in hand for the construction of the
tetracyclic 4(E)-ethylidene-1,5-dioxo-3,7-methano[1,4]-
diazonino[1,2-a]indole system, the development of an
analogous synthetic sequence from 2-fluoro-1-[2-(phenyl-
sulfanyl)ethyl]pyridinium triflate 15b should allow the
access to the target pentacyclic dilactam 2 after closure
of the C ring by Pummerer cyclization. The required
pyridinium salt 15b was prepared by alkylation of
3-acetyl-2-fluoropyridine with 2-(phenylsulfanyl)ethyl tri-
flate. As in the above N-methyl series, this salt was
allowed to react with the enolate of 1-acetylindole (3)
to give 1,4-dihydropyridine 16b (23%), which was then
cyclized to the tetracyclic enolic dilactam 17b (58%).
Subsequent Pd0-catalyzed reduction of the corresponding
triflate 18b with n-Bu3SnH stereoselectively afforded the
(E)-ethylidene derivative 19b in 42% overall yield from
With the aim of improving both the yield and the
stereoselectivity of the above transformation, we decided
to evaluate if the (E)-ethylidene substituent could be
generated by Pd0-catalyzed reduction of the (Z)-vinyl
(23) (a) Back, T. G. J . Org. Chem. 1981, 46, 1442. See also: (b)
Danieli, B.; Lesma, G.; Palmisano, G.; Passarella, D.; Silavani, A.
Tetrahedron 1994, 50, 6941.
(24) (a) Bettoni, G.; Franchini, C.; Morlacchi, F.; Tangari, N.;
Tortorella, V. J . Org. Chem. 1976, 41, 2780. (b) Miller, R. A.; Li. W.;
Humphrey, G. R. Tetrahedron Lett. 1996, 37, 3429.
(25) (a) Marsais, F.; Pineau, Ph.; Nivolliers, F.; Mallet, M.; Turck,
A.; Godard, A.; Queguiner, G. J . Org. Chem. 1992, 57, 565. (b) Rocca,
P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.; Mallet, M.;
Godard, A.; Queguiner, G. J . Org. Chem. 1993, 58, 7832. (c) Comins,
D. L.; Saha, J . K. Tetrahedron Lett. 1995, 36, 7995.
(26) (a) Dodd, R. H.; Poissonet, G.; Potier, P. Heterocycles 1989, 29,
365. (b) Dobbs, A. P.; J ones, K.; Veal, K. T. Tetrahedron Lett. 1997,
38, 5833. See also: (c) Vega, J . A.; Vaquero, J . J .; Alvarez-Builla, J .;
Ezquerra, J .; Hamdouchi, C. Tetrahedron 1999, 55, 2317.
(27) Gu¨ngo¨r, T.; Marsais, F.; Queguiner, G. J . Organomet. Chem.
1981, 215, 139.
(28) Ritter, K. Synthesis 1993, 735.

Synthesis of (()-Geissoschizine and (()-Akagerine
J . Org. Chem., Vol. 64, No. 26, 1999 9609
3-(3-pyridyl)acrylate (1.6 g, 9.6 mmol) and 2-(phenylsulfanyl)-
ethyl bromide30 (2.5 g, 11.5 mmol) was heated at 90-100 °C
for 1 h. The reaction mixture was diluted with Et2O, and the
resulting precipitate was filtered to give pyridinium bromide
17b. m-CPBA oxidation of sulfide 19b gave sulfoxide 20
(90%, mixture of stereoisomers), which smoothly under-
went Pummerer rearrangement at room temperature by
treatment with TFAA in dichloromethane in the presence
of 2,6-di(tert-butyl)pyridine.22a When the presumed acy-
loxy sulfide intermediate was refluxed in dichloromethane,
the desired pentacyclic sulfide 21 (a single stereoisomer,
undetermined configuration at C-6) was obtained in 71%
yield. Finally, desulfurization of 21 with n-Bu3SnH-
AIBN gave the target pentacyclic dilactam 2 (72%). The
1H NMR data of 2 are in agreement with those previously
reported.9c,12 Taking into account the previous work by
Winterfeldt,12 the synthesis of 2 represents a stereose-
lective formal total synthesis of (()-akagerine.
In summary, the results here presented significantly
expand the scope and potential of the methodology for
indole alkaloid synthesis based on the reactivity of
N-alkylpyridinium salts with indole-containing enolates.
For the first time, 1-acetylindole enolates are used as
nucleophilic partners in this methodology: the formation
of three crucial C-C bonds (1, C-15/C-16; 2, C-2/C-3; 3,
C-6/C-7) and subsequent opening of either the seven-
membered lactam E ring or the 2-piperidone D ring give
access to two structurally different tetracyclic alkaloids,
geissoschizine and akagerine, respectively. On the other
hand, for the first time a 2-fluoropyridinium salt is used
as the electrophilic partner in the above methodology, to
ultimately generate a 2-piperidone moiety.
1
4b: 3.1 g (86%); mp 124-125 °C (acetone-MeOH); H NMR
(DMSO-d6) 3.71 (t, J ) 6.4 Hz, 2H), 3.78 (s, 3H), 4.80 (t, J )
6.4 Hz, 2H), 7.02 (d, J ) 16 Hz, 1H), 7.15-7.40 (m, 5H), 7.72
(d, J ) 16 Hz, 1H), 8.14 (dd, J ) 7.9 and 6 Hz, 1H), 8.86 (d, J
) 7.9 Hz, 1H), 9.00 (d, J ) 6 Hz, 1H), 9.44 (s, 1H). Anal. Calcd
for C17H18NO2BrS: C, 53.82; H, 4.79; N, 3.69; S, 8.44. Found:
C, 53.56; H, 4.83; N, 3.72; S, 8.34.
Meth yl 4-[2-(1-In d olyl)-2-oxoeth yl]-1-[2-(p h en ylsu lfa -
n yl)eth yl]-1,4-d ih yd r o-p yr id in e-3(E)-a cr yla te (5b). Oper-
ating as in the preparation of dihydropyridine 5a , from
acetylindole 3 (0.5 g, 3.14 mmol) and pyridinium bromide 4b
(1.2 g, 3.14 mmol) was obtained dihydropyridine 5b after flash
chromatography (Et2O): 0.28 g (20%); mp 89-90 °C (hexanes-
Et2O); IR (film) 1576, 1607, 1664, 1700; 1H NMR 2.99 (m, 3H),
3.10 (dd, J ) 16, 3.2 Hz, 1H), 3.30 (t, J ) 7 Hz, 2H), 3.68 (s,
3H), 4.05 (m, 1H), 5.01 (dd, J ) 7.7, 5 Hz, 1H), 5.64 (d, J )
15.5 Hz, 1H), 5.78 (d, J ) 7.7 Hz, 1H), 6.30 (s, 1H), 6.57 (d, J
) 3.8 Hz, 1H), 7.20-7.35 (m, 9H), 7.53 (d, J ) 7.7 Hz, 1H),
8.47 (d, J ) 8.2 Hz, 1H); 13C NMR 29.2 (CH), 34.0 (CH2), 42.3
(CH2), 51.0 (CH3), 52.8 (CH2), 105.4 (CH), 107.3 (CH), 108.4
(C), 108.7 (CH), 116.5 (CH), 120.6 (CH), 123.5 (CH), 124.8
(CH), 124.9 (CH), 126.7 (CH), 128.3 (CH), 129.1 (CH), 129.8
(CH), 130.2 (C), 134.3 (C), 135.4 (C), 139.5 (CH), 145.2 (CH),
168.4 (C), 169.5 (C). Anal. Calcd for C27H26N2O3S: C, 70.71;
H, 5.71; N, 6.10; S, 6.99. Found: C, 70.67; H, 5.70; N, 6.11; S,
6.91.
Meth yl 6-Ben zyl-1-oxo-2,3,6,7-tetr a h yd r o-1H-3,7-m eth -
a n o[1,4]d ia zon in o[1,2-a ]in d ole-4(E)-a cr yla te (6a ). A solu-
tion of dihydropyridine 5a (0.12 g, 0.29 mmol) and LiI (68 mg,
0.51 mmol) in THF (20 mL) cooled at -30 °C was treated with
enough of a saturated C6H6 solution of dry TsOH to bring the
pH to 3.5-4, and the reaction mixture was stirred at room
temperature for 1 h 30 min. The mixture was poured into a
saturated aqueous Na2CO3 solution and extracted with AcOEt.
Concentration of the organic extracts gave a crude residue,
which was chromatographed (98:2 CHCl3-MeOH) to give 6a :
60 mg (50%); IR (film) 1584, 1697; 1H NMR 2.37 (m, 2H), 2.85
(dd, J ) 13.9, 2.4 Hz, 1H), 3.03 (m, 1H), 3.49 (dd, J ) 13.9, 6
Hz, 1H), 3.73 (s, 3H), 4.08 (s, 2H), 4.54 (br s, 1H), 5.52 (d, J )
15.3 Hz, 1H), 6.44 (s, 1H), 6.61 (s, 1H), 7.15-7.40 (m, 8H),
7.71 (d, J ) 7.1 Hz, 1H), 8.19 (d, J ) 8.2 Hz, 1H); 13C NMR
25.5 (CH), 31.5 (CH2), 45.5 (CH2), 51.0 (CH3), 52.4 (CH), 56.2
(CH2), 104.5 (CH), 106.1 (C), 111.8 (CH), 115.8 (CH), 120.4
(CH), 123.4 (CH), 125.6 (CH), 127.0 (C), 127.4 (CH), 128.1
(CH), 128.9 (CH), 134.2 (C), 136.2 (C), 138.6 (C), 143.4 (CH),
145.7 (CH), 168.8 (C), 172.2 (C); HRMS calcd for C26H24N2O3
412.1786, found 412.1786.
Exp er im en ta l Section
Melting points are uncorrected. Unless otherwise noted,
NMR spectra were recorded in CDCl3 solution at 300 (1H) or
75 MHz (13C). Only noteworthy IR absorptions (cm-1) are
listed. TLC was carried out on SiO2 (silica gel 60 F254, Merck,
0.063-0.200 mm). Flash chromatography was carried out on
SiO2 (silica gel 60, SDS, 0.04-0.06 mm). Drying of organic
extracts during the workup of reactions was performed over
anhydrous Na2SO4. Evaporation of the solvents was accom-
plished under reduced pressure with a rotatory evaporator.
All nonaqueous reactions were performed under an argon
atmosphere. Microanalyses and HRMS were performed by
Centro de Investigacio´n y Desarrollo (CSIC), Barcelona. All
compounds were synthesized in the racemic series.
Meth yl 1-Ben zyl-4-[2-(1-in d olyl)-2-oxoeth yl]-1,4-d ih y-
d r op yr id in e-3(E)-a cr yla te (5a ). LDA (10.7 mmol) was added
to a solution of acetylindole 329 (1 g, 6.29 mmol) in THF (75
mL) cooled at -78 °C, and the resulting solution was stirred
at -78 °C for 30 min. Then, pyridinium chloride 4a 2b (1.8 g,
6.29 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. The reaction mixture was partitioned between H2O
and Et2O and extracted with Et2O. Concentration of the
organic extracts followed by flash chromatography (3:7 hex-
anes-Et2O) gave dihydropyridine 5a : 0.57 g (22%); IR (film)
Met h yl 1-Oxo-6-[2-(p h en ylsu lfa n yl)et h yl]-2,3,6,7-t et -
r ah ydr o-1H-3,7-m eth an o[1,4]diazon in o[1,2-a ]in dole-4(E)-
a cr yla te (6b). Operating as above, from dihydropyridine 5b
(0.25 g, 0.54 mmol), tetracycle 6b was obtained after flash
chromtography (4:6 hexanes-Et2O): 0.1 g (40%); mp 210 °C
1
(Et2O); IR (film) 1580, 1690; H NMR 2.25 (dm, J ) 13.5 Hz,
1H), 2.35 (dt, J ) 13.5, 1.7 Hz, 1H), 2.90 (m, 5H), 3.27 (m,
1H), 3.46 (m, 1H), 3.74 (s, 3H), 4.62 (dt, J ) 4.9, 1.4 Hz, 1H),
5.50 (d, J ) 15.2 Hz, 1H), 6.30 (s, 1H), 6.40 (s, 1H), 7.20-7.45
1
1575, 1620, 1680, 1700; H NMR 2.98 (dd, J ) 14 and 10 Hz,
1H), 3.15 (dd, J ) 14, 3 Hz, 1H), 3.68 (s, 3H), 4.15 (m, 1H),
4.34 (s, 2H), 5.06 (dd, J ) 7.9, 5.2 Hz, 1H), 5.65 (d, J ) 15.4
Hz, 1H), 5.91 (dd, J ) 7.9, 1.5 Hz, 1H), 6.47 (d, J ) 1 Hz, 1H),
6.60 (dd, J ) 3.7, 0.7 Hz, 1H), 7.16 (m, 2H), 7.20-7.38 (m,
7H), 7.55 (dm, J ) 7 Hz, 1H), 8.47 (d, J ) 8 Hz, 1H); 13C NMR
29.3 (CH), 42.5 (CH2), 51.0 (CH3), 57.2 (CH2), 105.4 (CH), 107.3
(CH), 108.6 (C), 108.8 (CH), 116.5 (CH), 120.6 (CH), 123.5
(CH), 124.7 (CH), 124.8 (CH), 126.9 (CH), 127.8 (CH), 128.7
(CH), 128.9 (CH), 130.2 (C), 135.4 (C), 136.6 (C), 140.0 (CH),
145.3 (CH), 168.4 (C), 169.5 (C); HRMS calcd for C26H24N2O3
412.1786, found 412.1785.
(m, 8H), 7.45 (d, J ) 7.6 Hz, 1H), 8.15 (d, J ) 8.2 Hz, 1H); 13
C
NMR 25.5 (CH), 31.3 (CH2), 33.1 (CH2), 45.5 (CH2), 51.2 (CH3),
51.4 (CH2), 53.9 (CH), 104.6 (CH), 106.5 (C), 111.4 (CH), 115.7
(CH), 120.4 (CH), 123.5 (CH), 125.6 (CH), 127.0 (CH), 127.6
(C), 129.2 (CH), 130.4 (CH), 134.5, (C), 134.9 (C), 138.5 (C),
142.5 (CH), 145.5 (CH), 168.8 (C), 172.0 (C). Anal. Calcd for
C
27H26N2O3S‚1/4H2O: C, 70.03; H, 5.77; N, 6.05; S, 6.92.
Found: C, 69.90; H, 5.64; N, 6.06; S, 6.71.
6-Ben zyl-4(E)-eth ylid en e-1-oxo-2,3,4,5,6,7-h exa h yd r o-
1H-3,7-m eth a n o[1,4]d ia zon in o[1,2-a ]in d ole (7a ). A sus-
pension of tetracycle 6a (148 mg, 0.36 mmol) in MeOH (8.5
3-[(E)-2-(Meth oxyca r bon yl)vin yl]-1-[2-(p h en ylsu lfa n yl-
)eth yl]p yr id in iu m Br om id e (4b). A mixture of methyl (E)-
(30) Yamamoto, T.; Kakimoto, M.; Okawara, M. Bull. Chem. Soc.
J pn. 1979, 52, 841.
(29) Illi, V. O. Synthesis 1979, 387.

9610 J . Org. Chem., Vol. 64, No. 26, 1999
Bennasar et al.
1
mL) and 2.5 N aqueous HCl (17 mL) was refluxed for 2 h and
then concentrated. The residue was dissolved in MeOH (20
mL), treated with NaBH4 (0.1 g, excess) at 0 °C, and stirred
at this temperature for 1 h. The solvent was evaporated, and
the residue was partitioned between H2O and Et2O and
extracted with Et2O. The organic extracts were dried and
concentrated, and the residue was chromatographed (flash,
1583, 1690; H NMR 2.33 (dm, J ) 14.3 Hz, 1H), 2.47 (dd, J
) 14.3, 3.3 Hz, 1H), 2.82 (m, 2H), 2.98 (d, J ) 17.6 Hz, 1H),
3.03 (m, 1H), 3.23 (dd, J ) 17.6, 8.8 Hz, 1H), 3.58 (m, 1H),
3.66 (s, 3H), 3.80 (m, 1H), 4.54 (br s, 1H), 5.32 (d, J ) 15.7
Hz, 1H), 6.41 (s, 1H), 7.09 (d, J ) 15.7 Hz, 1H), 7.30 (m, 3H),
8.07 (dm, J ) 7 Hz, 1H); 13C NMR 20.9 (CH2), 23.7 (CH), 27.5
(CH2), 45.4 (CH2), 49.8 (CH2), 51.0 (CH3), 52.3 (CH), 107.2
(CH), 113.3 (C), 115.0 (CH), 117.4 (CH), 117.6 (C), 123.6 (CH),
124.9 (CH), 128.8 (C), 135.4 (C), 136.4 (C), 146.0 (CH), 146.9
(CH), 168.2 (C), 172.5 (C). Anal. Calcd for C21H20N2O3: C,
72.40; H, 5.79; N, 8.04. Found: C, 72.45; H, 5.80; N, 8.01.
P u m m er er Rear r an gem en t of Su lfoxides 11. TFA (0.022
mL, 0.25 mmol) was slowly added to a solution of sulfide 7b
(90 mg, 0.22 mmol) in CH2Cl2 (5 mL) at 0 °C, and the resulting
solution was stirred at 0 °C for 30 min. m-CPBA (45 mg, 0.25
mmol) in CH2Cl2 (1 mL) was slowly added at -78 °C, and the
stirring was continued for 15 min. The reaction was quenched
with solid K2CO3 (excess), and the mixture was stirred at -78
°C for 10 min, diluted with CH2Cl2, and washed with H2O.
The organic solution was concentrated, and the residue was
chromatographed (flash, 98:2 AcOEt-DEA) to give sulfoxide
11 as a 1:1 mixture of stereoisomers: 74 mg (80%).
1
Et2O) to give 7a : 42 mg (33%); IR (film) 1693; H NMR 1.68
(d, J ) 6.8 Hz, 3H), 2.18 (dt, J ) 13.5, 2.2 Hz, 1H), 2.41 (m,
1H), 3.06 (m, 4H), 3.24 (masked, 1H), 3.22 and 3.36 (2d, J )
13.9 Hz, 2H), 4.26 (dd, J ) 5.2, 2.2 Hz, 1H), 5.39 (q, J ) 6.8
Hz, 1H), 6.31 (s, 1H), 7.20-7.30 (m, 7H), 7.53 (d, J ) 7 Hz,
1H), 8.29 (d, J ) 8 Hz, 1H); 13C NMR 12.3 (CH3), 29.4 (CH),
34.8 (CH2), 47.2 (CH2), 54.0 (CH2), 56.0 (CH), 58.8 (CH2), 112.0
(CH), 115.9 (CH), 120.0 (CH), 120.4 (CH), 123.3 (CH), 124.6
(CH), 126.9 (CH), 128.0 (C), 128.3 (CH), 128.6 (CH), 135.0 (C),
135.3 (C), 137.9 (C), 138.5 (C), 174.2 (C); HRMS calcd for
C24H24N2O 356.1888, found 356.1886.
4(E )-E t h ylid e n e -1-oxo-6-[2-(p h e n ylsu lfa n yl)e t h yl]-
2,3,4,5,6,7-h exa h yd r o-1H-3,7-m eth a n o[1,4]d ia zon in o[1,2-
a ]in d ole (7b). Operating as above, from tetracycle 6b (0.5 g,
1.1 mmol) was obtained the ethylidene derivative 7b after flash
chromatography: 132 mg (30%); mp 142 °C (hexanes-AcOEt);
1H NMR 1.67 (dd, J ) 6.9, 1.1 Hz, 3H), 2.18 (dt, J ) 13.4, 2.2
Hz, 1H), 2.30 (m, 2H), 2.55 (m, 1H), 3.05 (m, 6H), 3.22 (br s,
1H), 4.25 (dd, J ) 5.4, 2.4 Hz, 1H), 5.48 (q, J ) 6.9 Hz, 1H),
6.30 (s, 1H), 7.20-7.35 (m, 7H), 7.47 (dm, J ) 7.2 Hz, 1H),
8.25 (dd, J ) 8.2, 0.8 Hz, 1H); 13C NMR 12.3 (CH3), 29.2 (CH),
31.7 (CH2), 34.6 (CH2), 47.0 (CH2), 53.6 (CH2), 54.0 (CH2), 56.2
(CH), 111.8 (CH), 115.8 (CH), 120.1 (CH), 120.8 (CH), 123.3
(CH), 124.7 (CH), 125.9 (CH), 128.2 (C), 128.8 (CH), 129.3
(CH), 134.6 (C), 135.2 (C), 136.3 (C), 137.8 (C), 174.0 (C). Anal.
Calcd for C25H26N2OS: C, 74.59; H, 6.51; N, 6.96; S, 7.96.
Found: C, 74.35; H, 6.60; N, 6.70; S, 7.60.
Meth yl 13-Oxo-7-(p h en ylsu lfa n yl)-1,2,5,6,7,12a -h exa h y-
dr o-2,12-eth an oin dolo[2,3-a ]qu in olizin e-3(E)-acr ylate (9).
m-CPBA (22 mg, 0.12 mmol) in CH2Cl2 (1 mL) was slowly
added to a solution of sulfide 6b (50 mg, 0.10 mmol) in CH2-
Cl2 (2 mL) at -78 °C, and the resulting mixture was stirred
at -78 °C for 30 min. The reaction was quenched with solid
K2CO3 (excess), and the stirring was continued at -78 °C for
10 min. The resulting mixture was diluted with CH2Cl2 and
washed with H2O. The organic solution was concentrated, and
the residue was chromatographed (flash, AcOEt) to give
sulfoxide 8 as a 1:1 mixture of stereoisomers: 46 mg (89%).
A solution of the above sulfoxides 8 (30 mg, 0.063 mmol) in
dry CH2Cl2 (5 mL) containing diisopropylethylamine (0.045
mL, 0.25 mmol) at 0 °C was treated with trimethylsilyl triflate
(0.045 mL, 0.25 mmol), and the mixture was stirred at room
temperature for 1.5 h. The mixture was poured into 10%
aqueous Na2CO3 and extracted with CH2Cl2. After concentra-
tion of the extracts and flash chromatography (6:4 hexanes-
AcOEt) of the residue, pentacycle 9 was obtained as a 3:1
mixture of stereoisomers: 17 mg (60%); IR (KBr) 1583, 1703;
1H NMR (major isomer) 2.25 (dm, J ) 14.3 Hz, 1H), 2.48 (dd,
J ) 14.3, 3.6 Hz, 1H), 2.81 (br d, J ) 17 Hz, 1H), 2.84 (m,
1H), 3.30 (dd, J ) 17, 10 Hz, 1H), 3.69 (s, 3H), 3.82 (d, J )
14.8 Hz, 1H), 4.03 (dd, J ) 14.8, 5.5 Hz, 1 H), 4.51 (br s, 1H),
4.62 (dd, J ) 5.5, 1.8 Hz, 1H), 5.28 (d, J ) 15.4 Hz, 1H), 6.58
(s, 1H), 7.10 (d, J ) 15.4 Hz, 1H), 7.33 (m, 5H), 7.43 (m, 2H),
7.81 (dm, J ) 7 Hz, 1H), 7.93 (dm, J ) 8 Hz, 1H); 13C NMR
23.2 (CH), 27.2 (CH2), 41.8 (CH), 46.6 (CH2), 51.5 (CH3), 52.7
(CH), 57.2 (CH2), 107.5 (CH), 113.0 (C), 114.5 (CH), 117.4 (C),
119.7 (CH), 123.6 (CH), 125.3 (CH), 127.8 (CH), 127.9 (C),
129.5 (CH), 131.9 (CH), 134.5 (C), 136.2 (C), 136.7 (C), 145.5
(CH), 146.3 (CH), 168.2 (C), 172.9 (C). Anal. Calcd for
Meth od A. TFA (0.030 mL, 0.38 mmol) and TFAA (0.053
mL, 0.38 mmol) were added at room temperature to a solution
of sulfoxides 11 (40 mg, 0.096 mmol) in CH2Cl2 (4 mL). After
being refluxed for 5 h, the mixture was cooled, poured into
10% aqueous Na2CO3, and extracted with CH2Cl2. The organic
extracts were dried and concentrated, and the residue was
chromatographed (flash, hexanes-AcOEt and ACOEt). The
initial elution gave sulfide 7b: 10 mg (26%). Further elution
gave 4(E)-eth ylid en e-6-(2-h yd r oxyeth yl)-1-oxo-8-(p h en yl-
su lfa n yl)-2,3,4,5,6,7-h e xa h yd r o-1H -3,7-m e t h a n o[1,4]-
d ia zon in o[1,2-a ]in d ole (14): 11 mg (28%); IR (film) 1690; 1H
NMR 1.71 (dd, J ) 6.8, 1.3 Hz, 3H), 2.12 (m, 2H), 2.43 and
2.64 (2m, 2H), 3.06 (m, 4H, 16-H), 3.28 (br s, 1H), 3.42 and
3.51 (2m, 2H), 5.01 (dd, J ) 5.5, 2.1 Hz, 1H), 5.51 (q, J ) 6.8
Hz, 1H), 7.05-7.40 (m, 7H), 7.50 (dm, J ) 7.7 Hz, 1H), 8.24
(dm, J ) 8.3 Hz, 1H); 13C NMR 12.3 (CH3), 29.7 (CH), 34.5
(CH2), 47.2 (CH2), 53.3 (CH), 53.4 (CH2), 55.3 (CH2), 57.8 (CH2),
115.6 (CH), 120.0 (CH), 121.3 (CH), 123.9 (CH), 125.4 (CH),
125.8 (CH), 126.1 (CH), 128.8 (C), 128.9 (CH), 129.3 (C), 134.2
(C), 136.8 (C), 136.9 (C), 140.0 (C), 174.2 (C).
Meth od B. Sulfoxides 11 (100 mg, 0.24 mmol) in dry CH2-
Cl2 (10 mL) containing diisopropylethylamine (0,17 mL, 0.96
mmol) at 0 °C were treated with trimethylsilyl triflate (0,17
mL, 0.96 mmol), and the mixture was stirred at room tem-
perature for 1.5 h. The mixture was poured into 10% aqueous
Na2CO3 and extracted with CH2Cl2. The organic extracts were
dried and concentrated to give 3(E)-eth ylid en e-13-oxo-7-
(p h en ylsu lfa n yl)-2,12-eth a n oin d olo[2,3-a ]qu in olizid in e
(12, 62 mg, 64%, 3:1 epimeric mixture). Flash chromatography
(AcOEt) allowed the isolation of major epimer: IR (KBr) 1720;
1H NMR (300 MHz, biogenetic numbering, assignments aided
by H-1H COSY and HMQC) 1.60 (dd, J ) 6.8, 2 Hz, 3H, 18-
1
H), 2.11 (dt, J ) 14.3, 4.2 Hz, 1H, 14-H), 2.39 (dd, J ) 14.5,
4.4 Hz, 1H, 16-H), 2.53 (dt, J ) 14.3, 2.7 Hz, 1H, 14-H), 3.07
(dd, J ) 14.5, 11.6 Hz, 1H, 16-H), 3.10 (d, J ) 13.2 Hz, 1H,
21-H), 3.39 (m, 1H, 15-H), 3.50 (d, J ) 15.0 Hz, 1H, 5-H), 4.03
(br d, J ) 13.2 Hz, 1H, 21-H), 4.25 (br s, 1H, 3-H), 4.55 (dd, J
) 6.5, 2.2 Hz, 1H, 6-H), 5.40 (q, J ) 6.8 Hz, 1H, 19-H), 7.25-
7.40 (m, 5H, Ar), 7.50 (m, 2H, Ar), 7.81 (dm, J ) 7.1 Hz, 1H,
9-H), 7.93 (dm, J ) 7.9 Hz, 1H, 12-H); 13C NMR 12.5 (C-18),
25.9 (C-15), 30.5 (C-14), 39.8 (C-6), 45.4 (C-16), 51.9 (C-21),
53.6 (C-3), 58.0 (C-5), 114.2 (C-12), 117.9 (C-7), 120.0 (C-9),
120.9 (C-19), 123.3 (C-10), 124.9 (C-11), 127.0 (Ph), 128.5 (C-
8), 129.3, 131.1 (Ph), 136.0, 136.2, 136.2 (Ph, C-2, C-20), 137.4
(C-13), 174.1 (CO).
C
27H24N2O3S: C, 71.03; H, 5.30; N, 6.14. Found: C, 69.92; H,
5.31; N, 5.86.
Meth yl (2RS, 12bSR)-3(E)-Eth yliden ein dolo[2,3-a ]qu in -
olizid in e-2-a ceta te [Meth yl Geissosch izoa te (13)].9h Me-
ONa (5.3 mg, 0.097 mmol) was added to a solution of
pentacycle 12 (26 mg, 0.065 mmol) in MeOH (2 mL) and THF
(0.5 mL), and the resulting mixture was stirred at room
temperature for 3 h. The reaction mixture was poured into
aqueous NH4Cl and extracted with AcOEt. The organic
extracts were dried and concentrated. The residue was dis-
Meth yl 13-Oxo-1,2,5,6,7,12a -h exa h yd r o-2,12-eth a n oin -
d olo[2,3-a ]qu in olizin e-3(E)-a cr yla te (10). A solution of
sulfide 9 (160 mg, 0.35 mmol), Ph3SnH (0.24 g, 0.70 mmol),
and AIBN (5 mg) in C6H6 (12 mL) was refluxed for 1 h. The
mixture was concentrated, and the residue was chromato-
graphed (hexanes-AcOEt, increasing polarity) to give penta-
cycle 10: 97 mg (80%); mp 206 °C (acetone-Et2O); IR (KBr)

Synthesis of (()-Geissoschizine and (()-Akagerine
J . Org. Chem., Vol. 64, No. 26, 1999 9611
solved in C6H6 (4 mL), and the resulting solution was treated
with n-Bu3SnH (32 mL, 0.12 mmol) and AIBN (2 mg) at reflux
temperature for 4 h. The mixture was concentrated, and the
residue was chromatographed (hexanes-AcOEt, increasing
chromatography gave 19a : 14 mg (30%); IR (film) 1608, 1660,
1698; 1H NMR 1.90 (d, J ) 7.3 Hz, 3H), 2.39 (dt, J ) 13.4, 2.4
Hz, 1H), 2.58 (dt, J ) 13.4, 5 Hz, 1H), 2.92 (s, 3H), 3.05 (dd,
J ) 13.8, 4.2 Hz, 1H), 3.16 (dd, J ) 13.8, 6.8 Hz, 1H), 3.49 (m,
1H), 4.75 (dd, J ) 5, 1.4 Hz, 1H), 6.64 (s, 1H), 7.14 (q, J ) 7.3
Hz, 1H), 7.28 (m, 2H), 7.52 (d, J ) 7 Hz, 1H), 8.20 (d, J ) 8.3
Hz, 1H); 13C NMR 13.8 (CH3), 28.9 (CH), 32.1 (CH2), 32.2
(CH3), 46.0 (CH2), 57.1 (CH), 112.9 (CH), 115.6 (CH), 120.5
(CH), 123.7 (CH), 125.7 (CH), 127.8 (C), 130.0 (C), 135.1 (C),
136.3 (CH), 138.3 (C), 163.0 (C), 171.0 (C); HRMS calcd for
1
polarity) to give 13: 11 mg (52%); H NMR (300 MHz) 1.65
(dd, J ) 6.8, 1.5 Hz, 3H), 2.17 (m, 3H), 2.31 (dt, J ) 14.2, 3.5
Hz, 1H), 2.64 (m, 1H), 2.94 (d, J ) 12.4 Hz, 1H), 2.98-3.20
(m, 3H), 3.27 (ddd, J ) 13, 6.1, 1.3 Hz, 1H), 3.55 (br d, J )
12.4 Hz, 1H), 3.69 (s, 3H), 4.27 (br s, 1H), 5.47 (q, J ) 6.8 Hz,
1H), 7.12 (m, 2H), 7.35 (d, J ) 7.9 Hz, 1H), 7.48 (d, J ) 7.7
Hz, 1H), 8.57 (br s, 1H); 13C NMR 12.6 (CH3), 17.9 (CH2), 30.5
(CH2), 31.1 (CH), 37.2 (CH2), 51.4 (CH2), 51.8 (CH3), 52.7 (CH),
53.2 (CH2), 107.6 (C), 111.1 (CH), 118.0 (CH), 119.4 (CH), 120.5
(CH), 121.4 (CH), 127.9 (C), 133.9 (C), 135.9 (C), 136.1 (C),
174.0 (C).
C
18H18N2O2 294.1368, found 294.1369. When the above alcohol
was converted into the corresponding mesylate by treatment
with mesyl chloride (0.039 mL, 0.45 mmol) and Et3N (0.08 mL,
0.56 mmol) at 0 °C for 1.5 h and then treated with DBU (0.14
mL, 0.96 mmol) in 1:1 DMSO-toluene (4 mL) at 40 °C for 3
h, a 2:1 mixture of 19a and the corresponding Z isomer was
obtained: 10 mg (21%). Z isomer: IR (film) 1615, 1659, 1699;
1H NMR 2.22 (d, J ) 7.2 Hz, 3H), 2.36 (dm, J ) 13.5 Hz, 1H),
2.50 (dm, J ) 13.5 Hz, 1H), 2.96 (s, 3H), 3.10 (m, 3H), 4.76 (d,
J ) 6.2 Hz, 1H), 6.13 (q, J ) 7.2 Hz, 1H), 6.64 (s, 1H), 7.28
(m, 2H), 7.52 (dd, J ) 7, 1 Hz, 1H), 8.24 (d, J ) 8.2 Hz, 1H);
13C NMR 15.9 (CH3), 32.0 (CH2), 32.3 (CH3), 36.5 (CH), 46.7
(CH2), 56.4 (CH), 112.8 (CH), 115.7 (CH), 120.5 (CH), 123.7
(CH), 125.7 (CH), 127.9 (C), 130.5 (C), 135.6 (C), 137.8 (C),
138.9 (CH), 163.7 (C), 171.0 (C); HRMS calcd for C18H18N2O2
294.1368, found 294.1360.
3-Acetyl-2-fluoro-1-methylpyridinium Trifluoromethane-
su lfon a te (15a ). Methyl trifluoromethanesulfonate (2.4 mL,
21.7 mmol) was added to 3-acetyl-2-fluoropyridine27 (2 g, 14.4
mmol). The resulting mixture was diluted with anhydrous CH2-
Cl2 (2 mL) and stirred at room temperature for 15 min. The
precipitate was filtered and washed with anhydrous Et2O to
give pyridinium triflate 15a (3.92 g, 90%), which was im-
mediately used in the next step without further purification.
3-Acetyl-2-flu or o-4-[2-(1-in d olyl)-2-oxoeth yl]-1-m eth yl-
1,4-d ih yd r op yr id in e (16a ). Operating as in the preparation
of 1,4-dihydropyridines 5, from acetylindole 2 (0.5 g, 3.14
mmol) and pyridinium triflate 15a (0.95 g, 3.14 mmol) was
obtained 1,4-dihydropyridine 16a (245 mg, 25%) after flash
chromatography (95:3:2 Et2O-acetone-DEA): mp 138 °C
Meth od B. Tf2O (0.035 mL, 0.21 mmol) was slowly added
to a stirred solution of tetracycle 17a (60 mg, 0.19 mmol) and
1,8-bis(dimethylamino)naphthalene (46 mg, 0.21 mmol) in
CH2Cl2 (2 mL) at -40 °C. The mixture was allowed to rise to
0 °C in a period of 1 h. The solvent was evaporated, and the
resulting residue was directly purified by flash chromatogra-
phy (hexane-AcOEt, increasing polarity) to give triflate 18a :
1
(Et2O-hexanes); IR (KBr) 1690; H NMR 2.37 (d, J ) 7 Hz,
3H), 2.71 (dd, J ) 13.5, 10 Hz, 1H), 3.06 (d, J ) 2.5 Hz, 3H),
3.28 (dd, J ) 13.5, 3.2 Hz, 1H), 4.16 (m, 1H), 5.09 (m, 1H),
5.80 (dd, J ) 7.6, 5.1 Hz, 1H), 6.63 (d, J ) 3.8 Hz, 1H), 7.28
(m, 2H), 7.55 (dm, J ) 7 Hz, 1H), 7.94 (d, J ) 3.8 Hz, 1H),
8.48 (d, J ) 8 Hz, 1H); 13C NMR 30.5 (CH3), 33.7 (CH), 34.3
(CH3), 44.4 (CH2), 91.8 (C), 108.3 (CH), 108.9 (CH), 116.6 (CH),
120.6 (CH), 123.5 (CH), 124.7 (CH), 126.1 (CH), 128.5 (CH),
130.5 (C), 135.5 (C), 160.4 (C, J ) 266.8 Hz), 169.5 (C), 193.3
(C). Anal. Calcd for C18H17N2O2F: C, 69.22; H, 5.48; N, 8.97.
Found: C, 69.20; H, 5.44; N, 8.98.
1
77 mg (90%); H NMR (300 MHz) 2.22 (s, 3H), 2.45 (dm, J )
14.1 Hz, 1H), 2.62 (ddd, J ) 14.1, 6.1, 2.8 Hz, 1H), 3.01 (s,
3H), 3.11 (m, 2H), 3.43 (m, 1H), 4.84 (d, J ) 6.1 Hz, 1H), 6.69
(s, 1H), 7.25-7.36 (m, 2H), 7.52 (d, J ) 7.5 Hz, 1H), 8.25 (d, J
) 8.2 Hz, 1H); 13C NMR 18.7 (CH3), 31.6 (CH), 31.9 (CH2),
33.5 (CH3), 44.0 (CH2), 56.4 (CH), 114.4 (CH), 116.4 (CH), 121.3
(CH), 124.6 (CH), 126.6 (CH), 128.4 (C), 135.1 (C), 138.3 (C),
149.4 (C), 160.3 (C), 169.9 (C). LiCl (22 mg, 0.5 mmol) and
Pd(PPh3)4 (4 mg, 0.003 mmol) were added to a solution of
triflate 18a (77 mg, 0.17 mmol) in THF (2 mL) at room
temperature. n-Bu3SnH (99 mg, 0.091 mL, 0.33 mmol) was
slowly added, and the resulting mixture was refluxed for 1 h.
Additional LiCl (22 mg, 0.5 mmol) and Pd(PPh3)4 (4 mg, 0.003
mmol) were added, and the mixture was refluxed for an
additional period of 2 h. The mixture was concentrated, and
the residue was purified by flash chromatography (hexanes-
AcOEt, increasing polarity) to give 19a : 44 mg (85%).
3-Acetyl-2-flu or o-1-[(2-p h en ylsu lfa n yl)eth yl] Tr iflu o-
r om eth a n esu lfon a te (15b). Tf2O (0.67 g, 0.4 mL, 2,4 mmol)
was added to a solution of 2-(phenylsulfanyl)ethanol (0.30 g,
0.27 mL, 2 mmol) and triethylamine (0.26 g, 0.37 mL, 2.4
mmol) in anhydrous CH2Cl2 (1 mL) at 0 °C, and the mixture
was stirred at 0 °C for 2 h. The solvent was removed to give
crude 2-(phenylsulfanyl)ethyl trifluoromethanesulfonate (mois-
ture sensitive). A mixture of the above triflate and 3-acetyl-
2-fluoropyridine27 (0.14 g, 1 mmol) was stirred at room
temperature for 12 h. The resulting oil was washed with
anhydrous Et2O to give pyridinium triflate 15b (0.35 g, 90%),
which was immediately used in the next step without further
purification.
4-Acetyl-6-m eth yl-1,5-d ioxo-2,3,4,5,6,7-h exa h yd r o-1H-
3,7-m eth a n o[1,4]d ia zon in o[1,2-a ]in d ole (17a ). A solution
of dihydropyridine 16a (0.38 g, 1.21 mmol) and LiI (0.27 g, 2
mmol) in MeOH (20 mL) cooled at -40 °C was treated with
enough of a saturated C6H6 solution of anhydrous TsOH to
bring the pH to 2-3, and the mixture was stirred at room
temperature for 2 h. The solvent was evaporated, and the
residue was directly purified by flash chromatography (95:5
Et2O-DEA) to give tetracycle 17a : 188 mg (50%); mp 161 °C
(Et2O); IR (KBr) 1596, 1627, 1698; 1H NMR 2.10 (s, 3H), 2.40
(dt, J ) 13.5, 2.2 Hz, 1H), 2.54 (m, 1H), 2.83 (s, 3H), 3.02 (dd,
J ) 13.3, 2.5 Hz, 1H), 3.21 (ddd, J ) 13.3, 6.5, 1.6 Hz, 1H),
3.25 (m, 1H), 4.71 (dm, J ) 4.8 Hz, 1H), 6.63 (s, 1H), 7.22-
7.36 (m, 2H), 7.51 (dm, J ) 7.7 Hz, 1H), 8.17 (d, J ) 8 Hz,
1H), 15.21 (s, 1H); 13C NMR 18.4 (CH3), 29.4 (CH), 32.1 (CH3),
32.4 (CH2), 47.7 (CH2), 57.5 (CH), 96.7 (C), 112.6 (CH), 115.5
(CH), 120.5 (CH), 123.6 (CH), 125.8 (CH), 127.7 (C), 134.7 (C),
138.5 (C), 168.9 (C), 171.7 (C), 172.1 (C). Anal. Calcd for
C
18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.56; H,
5.86; N, 9.03.
4(E)-Eth ylid en e-6-m eth yl-1,5-d ioxo-2,3,4,5,6,7-h exa h y-
d r o-1H -3,7-m et h a n o[1,4]d ia zon in o[1,2-a ]in d ole (19a ).
Meth od A. NaBH4 (12.2 mg, 0.32 mmol) was added to a cooled
(0 °C) solution of tetracycle 17 (50 mg, 0.16 mmol) in 5:2:1
EtOH-MeOH-H2O (4 mL), and the resulting mixture was
stirred at 0 °C for 4 h. The solvents were removed, and the
residue was partitioned between H2O and AcOEt and extracted
with AcOEt. Evaporation of the organic extracts gave a crude
alcohol (mixture of stereoisomers). A solution of Martin
Sulfurane (320 mg, 0.48 mmol) in CH2Cl2 (1.5 mL) was slowly
added to a solution of the above alcohol in CH2Cl2 (2 mL) cooled
at -78 °C, and the mixture was allowed to rise to room
temperature with stirring. The mixture was poured into a
saturated aqueous Na2CO3 solution and extracted with CH2-
Cl2. Evaporation of the organic extracts followed by flash
3-Acetyl-2-flu or o-4-[2-(1-in d olyl)-2-oxoeth yl]-1-[2-(p h e-
n ylsu lfa n yl)eth yl]-1,4-d ih yd r op yr id in e (16b). Operating
as in the preparation of 1,4-dihydropyridines 5 and 16a , from
acetylindole 2 (0.14 g, 0.89 mmol) and pyridinium triflate 15b
(0.35 g, 0.89 mmol) was obtained 1,4-dihydropyridine 16b (90
mg, 23%) after flash chromatography (hexanes-Et2O, increas-
ing polarity); IR (KBr) 1582, 1681, 1698; 1H NMR 2.36 (d, J )
7.1 Hz, 3H), 2.77 (dd, J ) 13.9, 9.8 Hz, 1H), 3.08 (m, 2H), 3.22
(dd, J ) 13.9, 3.1 Hz, 1H), 3.43 and 3.61 (2m, 2H), 4.11 (m,
1H), 5.11 (m, 1H), 5.76 (dd, J ) 7.6, 4.9 Hz, 1H), 6.63 (d, J )
3.8 Hz, 1H), 7.20-7.40 (m, 7H), 7.55 (d, J ) 7.4 Hz, 1H), 7.86
(d, J ) 3.8 Hz, 1H), 8.48 (d, J ) 8 Hz, 1H); 13C NMR 30.7

9612 J . Org. Chem., Vol. 64, No. 26, 1999
Bennasar et al.
(CH3), 33.0 (CH), 33.3 (CH2), 43.9 (CH2), 46.8 (CH2), 92.3 (C),
108.9 (CH), 108.9 (CH), 116.6 (CH), 120.6 (CH), 123.6 (CH),
124.8 (CH), 126.0 (CH), 127.0 (CH), 127.4 (CH), 129.2 (CH),
130.0 (CH), 130.5 (C), 134.0 (C), 135.5 (C), 159.9 (C, J ) 266.8
Hz), 169.5 (C), 193.4 (C); HRMS calcd for C25H23N2O2FS
434.1464, found 434.1468. Anal. Calcd for C25H23N2O2FS: C,
69.10; H, 5.34; N, 6.45; S, 7.38. Found: C, 68.83; H, 5.50; N,
6.33; S, 7.41.
3(E)-Eth yliden e-4,13-dioxo-7-(ph en ylsu lfan yl)-2,12-eth -
a n oin d olo[2,3-a ]qu in olizid in e (21). Sulfide 19b (25 mg,
0.06 mmol) was allowed to react with m-CPBA (13.4 mg, 0.06
mmol) in dry CH2Cl2 (4 mL) as described for the preparation
of sulfoxide 8. After workup and flash chromatography (95:5
AcOEt-DEA), sulfoxide 20 was obtained as a 1:1 mixture of
stereoisomers: 24 mg (90%).
TFAA (49 mg, 0.033 mL, 0.23 mmol) was slowly added to a
solution of sulfoxides 20 (23 mg, 0.058 mmol) and 2,6-di(tert-
butyl)pyridine (44 mg, 0.052 mL, 0.23 mmol) in dry CH2Cl2 (2
mL) cooled at 0 °C. After being stirred at room temperature
for 30 min, the mixture was refluxed for 1 h 30 min. The
solvent was evaporated, and the residue was chromatographed
(1:1 hexanes-AcOEt) to give pentacycle 21: 17 mg (71%); 1H
NMR (300 MHz) 1.77 (d, J ) 7.4 Hz, 3H), 2.37 (dd, J ) 14.6,
5.3 Hz, 1H), 2.39 (dt, J ) 14.5, 4.3 Hz, 1H), 2.62 (dt, J ) 14.5,
2.7 Hz, 1H), 3.20 (dd, J ) 14.6, 10.7 Hz, 1H), 3.55 (br, 1H),
3.60 (dd, J ) 14.1, 6.2 Hz, 1H), 4.62 (dm, J ) 6.2 Hz, 1H),
4.68 (br s, 1H), 5.07 (dd, J ) 14.1, 2.1 Hz, 1H), 7.09 (q, J ) 7.4
Hz, 1H), 7.26-7.35 (m, 5H), 7.64 (m, 2H), 7.90 (m, 2H); 13C
NMR 14.0 (CH3), 26.8 (CH2), 27.2 (CH), 43.5 (CH), 46.7 (CH2),
49.5 (CH2), 51.8 (CH), 114.6 (CH), 120.3 (C), 120.4 (CH), 123.9
(CH), 125.6 (CH), 127.9 (CH), 128.8 (C), 129.1 (CH), 133.0 (C),
133.5 (CH), 136.9 (C), 137.3 (C), 137.8 (C), 137.8 (CH), 164.6
(CO), 172.8 (CO).
3(E)-E t h ylid en e-4,13-d ioxo-2,12-et h a n oin d olo[2,3-a ]-
qu in olizid in e (2).9c,12 AIBN (catalytic amount) and n-Bu3SnH
(0.020 mL, 0.072 mmol) were added to a solution of pentacycle
21 (15 mg, 0.036 mmol) in dry C6H6 (0.8 mL) at room
temperature. The reaction vessel was then placed in a pre-
heated (100 °C) oil bath, and the mixture was refluxed for 1
h. Evaporation of the solvent followed by flash chromatography
of the residue gave pentacyclic dilactam 2: 8 mg (72%); 1H
NMR 1.77 (d, J ) 7.3 Hz, 3H), 2.51 (dt, J ) 14.4, 5.1 Hz, 1H),
2.60 (dt, J ) 14.4, 2.6 Hz, 1H), 2.67 (ddd, J ) 16.1, 3.9, 0.9
Hz, 1H), 2.77 (m, 1H), 3.24 (m, 1H), 3.29 (dd, J ) 16.1, 9.5
Hz, 1H), 3.44 (m, 1H), 3.49 (br, 1H), 4.67 (m, 1H), 4.73 (m,
1H), 7.05 (qd, J ) 7.3, 1.3 Hz, 1H), 7.25-7.34 (m, 2H), 7.40
(dm, J ) 7.5 Hz, 1H), 8.04 (dm, J ) 8 Hz, 1H); 13C NMR 14.3
(CH3), 20.0 (CH2), 27.3 (CH2), 27.6 (CH), 42.4 (CH2), 47.0 (CH2),
51.9 (CH), 115.2 (CH), 117.8 (CH), 120.1 (C), 123.9 (CH), 125.2
(CH), 129.3 (C), 132.6 (C), 135.8 (C), 136.8 (C), 138.1 (CH),
166.1 (C), 172.1 (C); HRMS calcd for C19H18N2O2 306.1368,
found 306.1375.
4-Acetyl-1,5-dioxo-6-[(2-ph en ylsu lfan yl)eth yl]-2,3,4,5,6,7-
h exa h yd r o-1H -3,7-m et h a n o[1,4]d ia zon in o[1,2-a ]in d ole
(17b). Dihydropyridine 16b (0.1 g, 0.23 mmol) in dry MeOH
(12 mL) was allowed to react with a saturated C6H6 solution
of anhydrous TsOH and LiI (52 mg, 0.39 mmol) and worked
up as described for the preparation of tetracycle 17a . After
flash chromatography (hexanes-AcOEt, increasing polarity),
tetracycle 17b was obtained: 58 mg (58%); IR (film) 1594,
1
1626, 1701; H NMR 2.09 (s, 3H), 2.32 (dm, J ) 14 Hz, 1H),
2.44 (m, 1H), 2.81 (m, 1H), 2.96 (br d, J ) 12.8 Hz, 1H), 3.15
(m, 4H), 3.60 (m, 1H), 4.80 (d, J ) 5.1 Hz, 1H), 6.16 (s, 1H),
7.26-7.33 (m, 7H), 7.42 (d, J ) 7.6 Hz, 1H), 8.13 (d, J ) 8.2
Hz, 1H); 13C NMR 18.4 (CH3), 29.3 (CH), 30.7 (CH2), 32.3
(CH2), 44.4 (CH2), 47.7 (CH2), 56.9 (CH), 96.7 (C), 112.5 (CH),
115.5 (CH), 120.6 (CH), 123.7 (CH), 125.8 (CH), 126.3 (CH),
129.2 (CH), 129.2 (CH), 129.3 (C), 135.0 (C), 135.2 (C), 138.4
(C), 168.9 (C), 171.7 (C), 172.7 (C); HRMS calcd for C25
H24N2O3S 432.1507, found 432.1505.
-
4(E)-Eth ylid en e-1,5-d ioxo-6-[2-(p h en ylsu lfa n yl)eth yl]-
2,3,4,5,6,7-h exa h yd r o-1H-3,7-m eth a n o[1,4]d ia zon in o[1,2-
a ]in d ole (19b). To a solution of tetracycle 17b (60 mg, 0.13
mmol) and 1,8-bis(dimethylamino)naphthalene (38 mg, 0.18
mmol) in CH2Cl2 (2 mL) cooled at -40 °C was added a solution
of Tf2O (0.030 mL, 0.18 mmol) in CH2Cl2 (120 mL) in four
portions, at 15 min intervals. The temperature of the mixture
was allowed to rise to -10 °C over a period of 1 h. The reaction
mixture was concentrated, and the residue was directly
purified by flash chromatography (hexanes-AcOEt, increasing
polarity) to give the vinyl triflate 18b (32 mg, 50%), along with
recovered starting material (20 mg). LiCl (22 mg, 0.5 mmol)
and Pd(PPh3)4 (8 mg, 0.007 mmol) were added to a solution of
the above triflate (3 × 32 mg, 0.17 mmol) in THF (4 mL) at
room temperature. n-Bu3SnH (99 mg, 0.091 mL, 0.33 mmol)
was slowly added, and the resulting mixture was refluxed for
1 h. The solvent was removed, and the resulting residue was
purified by flash chromatography (hexanes-AcOEt, increeas-
ing polarity) to give the (E)-ethylidene derivative 19b: 60 mg
(85%); IR (film) 1614, 1661, 1699; 1H NMR 1.91 (d, J ) 7.3
Hz, 3H), 2.33 (br d, J ) 13.6 Hz, 1H), 2.50 (dm, J ) 13.6 Hz,
1H), 2.87 (m, 1H), 3.01 (dd, J ) 13.8, 3.9 Hz, 1H), 3.22 (m,
3H), 3.44 (m, 1H), 3.68 (m, 1H), 4.86 (d, J ) 5.5 Hz, 1H), 6.17
(s, 1H), 7.17 (q, J ) 7.3 Hz, 1H), 7.24-7.35 (m, 7H), 7.42 (d, J
) 7.7 Hz, 1H), 8.15 (d, J ) 8.1 Hz, 1H); 13C NMR 13.8 (CH3),
28.8 (CH), 30.3 (CH2), 32.0 (CH2), 45.4 (CH2), 46.1 (CH2), 56.6
(CH), 112.7 (CH), 115.6 (CH), 120.5 (CH), 123.7 (CH), 125.8
(CH), 126.2 (CH), 127.7 (C), 129.1 (CH), 129.1 (CH), 129.8 (C),
135.3 (C), 135.4 (C), 136.9 (CH), 138.3 (C), 162.9 (C), 171.0
(C); HRMS calcd for C25H24N2O2S 416.1558, found 416.1563.
Ack n ow led gm en t. Financial support from the DGI-
CYT, Spain (project PB94-0214), is gratefully acknowl-
edged. Thanks are also due to the Comissionat per a
Universitats i Recerca, Generalitat de Catalunya, for
Grant No. 1997SGR-0018.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 2, 5a , 6a , 7a , 12-14, 17b, 19a ,b,
and 21. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9911894