Total synthesis of (±)-deethylibophyllidine: Studies of a Fischer indolization route and a successful approach via a Pummerer rearrangement/thionium ion-mediated indole cyclization

Article abstract of DOI:10.1021/jo960848z

The total synthesis of (±)-deethylibophyllidine is described, proceeding in eight steps from 4-(methoxyphenyl)ethylamine in 5% overall yield (Scheme 6). In terms of sequential annulation, the strategy involves the following operations: E → DE → ABDE → ABCDE (Scheme 1). The key steps in the synthesis are the stereoselective formation of octahydroindol-6-ones by acid treatment of dihydroanisole derivatives, the regioselective Fischer indolization to obtain octahydropyrrolo[3,2-c]carbazoles, and the tandem process consisting of Pummerer rearrangement upon a β-amino sulfoxide and thionium ion cyclization upon a β-indole position of a 2,3-disubstituted indole to generate the quaternary spiro center. Attempts to effect the construction of the pentacyclic framework by means of Fischer indolization of the octahydropyrrolo[3,2,1-hi]indol-6-one resulted in failure (Scheme 2).

Full text of DOI:10.1021/jo960848z

7106
J . Org. Chem. 1996, 61, 7106-7115
Tota l Syn th esis of (()-Deeth ylibop h yllid in e: Stu d ies of a F isch er
In d oliza tion Rou te a n d a Su ccessfu l Ap p r oa ch via a P u m m er er
Rea r r a n gem en t/Th ion iu m Ion -Med ia ted In d ole Cycliza tion
J osep Bonjoch,* J uanlo Catena, and Nativitat Valls
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain
Received May 8, 1996X
The total synthesis of (()-deethylibophyllidine is described, proceeding in eight steps from
4-(methoxyphenyl)ethylamine in 5% overall yield (Scheme 6). In terms of sequential annulation,
the strategy involves the following operations: E f DE f ABDE f ABCDE (Scheme 1). The key
steps in the synthesis are the stereoselective formation of octahydroindol-6-ones by acid treatment
of dihydroanisole derivatives, the regioselective Fischer indolization to obtain octahydropyrrolo-
[3,2-c]carbazoles, and the tandem process consisting of Pummerer rearrangement upon a â-amino
sulfoxide and thionium ion cyclization upon a â-indole position of a 2,3-disubstituted indole to
generate the quaternary spiro center. Attempts to effect the construction of the pentacyclic
framework by means of Fischer indolization of the octahydropyrrolo[3,2,1-hi]indol-6-one resulted
in failure (Scheme 2).
Sch em e 1. Retr osyn th etic P la n for th e Syn th esis
of Deeth ylibop h yllid in e
In tr od u ction
The pentacyclic system of pyrrolizino[1,7-cd]carbazole
constitutes the core of ibophyllidine alkaloids.1 Among
the great variety of skeletal types of monoterpenoid
indole alkaloids, the ibophyllidine alkaloids are charac-
terized structurally by the presence of a 2,3,3-trisubsti-
tuted indole, incorporating the unit of pyrrolo[2,3-d]-
carbazole (ABCE rings), and the lack of the C-21 biogenetic
carbon,2 which implies a pyrrolidine D ring instead of
the piperidine ring usually found in the related alkaloids.
Much research has been devoted to the synthesis of
alkaloids with the former feature, typified by the Aspi-
dosperma3 and Strychnos4 alkaloids, but far less attention
has been given to ibophyllidine alkaloids.5 We therefore
set out to explore some novel synthetic routes to this type
of alkaloid and chose deethylibophyllidine (I) as the
synthetic target.6
II and pyrrolo[3,2-c]carbazole8 III types, which embody
three and four of the rings of target I, respectively, in
order to study the elaboration of the desired pentacyclic
skeleton by Fischer indolization or else, by ring closure
upon the â-position of a 2,3-disubstituted indole, respec-
tively. In our project, we envisaged that both heterocyclic
systems II and III might arise from octahydroindol-6-
ones derivatives IV.
A retrosynthetic analysis of the pentacyclic structure
target I is diagrammed in Scheme 1. We are interested
in the development of synthetic routes to the scarcely
described heterocyclic systems of pyrrolo[3,2,1-hi]indole7
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) For leading references regarding isolation, characterization, and
biosynthesis of ibophyllidine alkaloids, see: (a) Khuong-Huu, F.;
Cesario, M.; Guilhem, J .; Goutarel, R. Tetrahedron 1976, 32, 2539. (b)
Kan, C.; Husson, H.-P.; J acquemin, H.; Kan, S.-K.; Lounasmaa, M.
Tetrahedron Lett. 1980, 21, 55. (c) Kan, C.; Husson, H.-P.; Kan, S.-K.;
Lounasmaa, M. Tetrahedron Lett. 1980, 21, 3363. (d) Kuehne, M. E.;
Pitner, J . B. J . Org. Chem. 1989, 54, 4553. (e) Saxton, J . E. The
Ibogamine-Catharanthine Group. In Monoterpenoid Indole Alkaloids,
supplement to part 4, Saxton, J . E., Ed. in The Chemistry of
Heterocyclic Compounds, Taylor, E. C., Ed.; J ohn Wiley: Chichester,
1994; Vol. 25, pp 487-521.
Resu lts a n d Discu ssion
Th e F ir st Ap p r oa ch (Rou te IV f II f I). According
to our initial synthetic plan, azatricyclo II, which pos-
sesses rings C, D, and E of ibophyllidine alkaloids, was
chosen as the key intermediate since it was expected that
further indolization would give rise to the pentacyclic
framework of these alkaloids.
(2) The biogenetic numbering (Le Men, J .; Taylor, W. I. Experientia
1965, 21, 508) is used throughout this paper only for pentacyclic
compounds.
(3) Desmae¨le, D.; d’Angelo, J . J . Org. Chem. 1994, 59, 2292 and
references cited therein.
(6) (a) Prior syntheses of (()-deethylibophyllidine: refs 1d, 5a, and
5c. (b) Preliminary communication: Catena, J .; Valls, N.; Bosch, J .;
Bonjoch, J . Tetrahedron Lett. 1994, 35, 4433. (c) Recently, we have
described another synthetic approach to this target: Ferna`ndez, J .-
C.; Valls. N.; Bosch, J .; Bonjoch, J . J . Chem. Soc., Chem. Commun.
1995, 2317.
(4) (a) Bosch, J .; Bonjoch, J . Pentacyclic Strychnos Indole Alkaloids.
In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1988; Vol. 1, pp 31-88. (b) Bosch, J .; Bonjoch,
J .; Amat, M. Strychnos Alkaloids. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1996; Vol. 48, pp 75-189.
(5) (a) Kuehne, M. E.; Matsko, T. H.; Bohnert, J . C.; Motyka, L.;
Oliver-Smith, D. J . Org. Chem. 1981, 46, 2002. (b) Kuehne, M. E.;
Bohnert, J . C. J . Org. Chem. 1981, 46, 3443. (c) Barsi, M.-C.; Das, B.
C.; Fourrey, J .-L.; Sundaramoorthi, R. J . Chem. Soc., Chem. Commun.
1985, 88. (d) J egham, S.; Fourrey, J .-L.; Das, B. C. Tetrahedron Lett.
1989, 30, 1959.
(7) For the previous synthesis of perhydropyrrolo[3,2,1-h,i]indoles
functionalized at the carbocyclic ring, see: (a) Lathbury, D. C.; Parsons,
P. J .; Pinto, I. J . Chem. Soc., Chem. Commun. 1988, 81. (b) Valls, N.;
Bonjoch, J .; Bosch, J . J . Org. Chem. 1992, 57, 2508.
(8) For the only previously described synthetic strategy, see: Mag-
nus, P. D.; Exon, C.; Sear, N. L. Tetrahedron 1983, 39, 3725.
S0022-3263(96)00848-1 CCC: $12.00 © 1996 American Chemical Society

Total Synthesis of (()-Deethylibophyllidine
J . Org. Chem., Vol. 61, No. 20, 1996 7107
Sch em e 2. Attem p ts to Syn th esize th e F r a m ew or k of Ibop h yllid in e Alk a loid s by F isch er In d oliza tion
Our synthetic approach to azatricyclo 8 requires the
intramolecular alkylation of a suitably 1-substituted octa-
hydroindol-6-one (Scheme 2). In contrast to the prepara-
tion of the 3a-aryloctahydroindol-6-ones, for which many
routes have been described since this unit is present in
mesembrine and related Amaryllidaceae alkaloids,9 only
a few approaches for 3a-unsubstituted derivatives of type
IV (i.e. 2) have been reported. Usually, the procedures
for the synthesis of cis-octahydroindol-6-ones take ad-
vantage of the presence of the â-amino ketone moiety for
the formation of the last bond in the synthetic step.
Thus, either the intramolecular 1,4-addition of an amino
group upon an R,â-unsaturated ketone10,11 or a Mannich
process from an adequate pyrroline derivative12 have
allowed access to the target unit.13
The octahydroindolone 214 was prepared in two steps
from commercially available O-methyltyramine in 80%
overall yield.15 The synthesis includes a Birch reduction16
which allows the formation of dihydrobenzene 1 in
excellent yield using lithium in ammonia and ethanol17
and later acylation with chloroacetyl chloride in the
presence of triethylamine in anhydrous medium. Inter-
estingly, the acylation, the conversion of the enol ether
into the ketone, the double bond isomerization, and the
last 1,4 addition of an amide group into the R,â-unsatur-
ated ketone occurs in a single operation step.18 The
process is stereoselective, the cis isomer of the octahy-
droindole ring being formed exclusively (a through-space
correlation between the H-3a and H-7a is observed in the
ROESY spectrum of 2). Unoptimized attempts to apply
the same tandem process using trichloroacetyl chloride
with 1 furnished a mixture of enones (4a , 4b) and the
cyclized product 5.
The closure of the C ring was accomplished in moderate
yield by treatment of N-(chloroacyl)octahydroindolone 2
with KtBuO. An analogous cyclization in the Aspi-
dosperma field (starting from a decahydroquinolone)
proceeds with good yield19 but in the Strychnos series
(starting from an azabicyclo[3.3.1]nonanone) was unsuc-
cessful.20 The different behavior in this cyclization type
seems to be related to the tension associated with the
carbonyl lactam group in the cyclized product.
To achieve the target tricyclic ketone 8, keto amide 6
was subjected to LAH reduction followed by J ones
oxidation of the resulting mixture of epimeric alcohols
7. The relative all-cis configuration of these perhydro-
pyrrolo[3,2,1-hi]indoles was deduced from the multiplicity
(9) For reviews: (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1987; Vol. 30, pp 251-376. (b) Lewis, J .
R. Nat. Prod. Rep. 1992, 9, 183.
(10) By Birch reduction of 4-methoxyphenethylamines: (a) Ueda,
N.; Tokuyama, T.; Sakan, T. Bull. Chem. Soc. J pn. 1966, 39, 2012. (b)
Sawlewicz, P.; Smulkowski, M.; Sowinski, P.; Borowski, E. Pol. J .
Chem. 1978, 52, 219.
(11) By alkylation of Fe(CO)3 complex of a 2-methoxycyclohexadiene
cation: Bo¨s, M.; Burkard, W. P.; Moreau, J .-L.; Scho¨nholzer, P. Helv.
Chim. Acta 1990, 73, 932.
(12) By intramolecular photocycloaddition and retro-Mannich frag-
mentation of acyclic tertiary vinylogous amides: Winkler, J . D.; Muller,
C. L.; Scott, R. D. J . Am. Chem. Soc. 1988, 110, 4831.
(13) For approaches leading to 1,2,3,3a,4,5-hexahydroindol-6-ones,
see: (a) from 1,3-cyclohexanedione, Bryson, T. A.; Gammill, R. B.
Tetrahedron Lett. 1974, 3963. (b) From 6-methoxyindoline, Iida, H.;
Aoyagi, S.; Kibayashi J . Chem. Soc., Perkin Trans. 1 1975, 2502. Iida,
H.; Yuasa, Y.; Kibayashi, C. Synthesis 1977, 879. (c) From pyrrolidine-
2-thiones, Michael, J . P.; Howard, A. S.; Katz, R. B.; Zwane, M. I.
Tetrahedron Lett. 1992, 33, 4751. Michael, J . P.; Zwane, M. I.
Tetrahedron Lett. 1992, 33, 4755. For the reduction to octa-
hydroderivatives: Higashiyama, H.; Honda, T.; Otomasu, H.; Kamet-
ani, T. Planta Med. 1983, 48, 268. Ito, K.; Naruma, M.; Furukawa,
H. J . Chem. Soc., Chem. Commun. 1975, 681.
(14) All synthetic compounds are racemic. The schemes depict only
the enantiomer bearing the natural configuration at C-14.
(15) The synthesis of octahydroindolones by acid treatment of
dihydroanisoles derived from tyramine derivatives has been prece-
dented but without experimental details10b or else with moderate
yields.10a For the synthesis of hexahydroindol-6-ones by hypervalent
iodine oxidation of tyramine derivatives, see: (a) Kita, Y.; Tohma, H.;
Kikuchi, K.; Inagaki, M.; Yakura, T. J . Org. Chem. 1991, 56, 435. (b)
Goldstein, D. M.; Wipf, P. Tetrahedron Lett. 1996, 37, 739.
(16) (a) Hook, J . M.; Mander, L. N. Nat. Prod. Rep. 1986, 35-85.
(b) Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334.
(17) For the synthesis of 1, using sodium as reducing agent, see:
Clarke, C. B.; Pinder, A. R. J . Chem. Soc. 1958, 1967.
1
and coupling constants of H-8b in the H NMR spectra.
In all cases the signal attributable to this proton appears
as a triplet with a J value between 4.5 and 7.5 Hz, which
implies a non-trans diaxial relationship with any proton
at C-5a or C-8a.
The last step of the synthesis was the Fischer indoliza-
tion with azatricyclo 8 as the ketonic moiety. It is well-
known that, in the Fischer indole synthesis of phenyl-
hydrazones derived from unsymmetrical ketones, the use
of weak acids promotes cyclization toward the more
branched R-carbon atom.21 However, unfortunately,
when 8 phenhylhydrazone was treated with glacial acetic
acid, only the nondesired indole 9 coming from cyclization
upon the methylene group was obtained. The structure
of 9 was ascertained from the NMR spectra, which
showed a typical indole pattern, instead of the indolenine
(18) On the contrary, when the acylation was carried out in the
Schotten-Baumann conditions, acylated but not cyclized compound 3
was isolated (see Experimental Section).
(19) (a) Wu, P.-L.; Chu, M.; Fowler, F. W. J . Org. Chem. 1988, 53,
963. (b) Meyers, A. I.; Berney, D. J . Org. Chem. 1989, 54, 4673.
(20) Bonjoch, J .; Casamitjana, N.; Quirante, J .; Rodr´ıguez, M.;
Bosch, J . J . Org. Chem. 1987, 52, 267.
(21) (a) Miller, F. M.; Schinske, W. N. J . Org. Chem. 1978, 43, 3384.
(b) Hugues, D. L.; Zhao, D. J . Org. Chem. 1993, 58, 228.

7108 J . Org. Chem., Vol. 61, No. 20, 1996
Ta ble 1. 13C NMR Da ta (δ) of Octa h yd r oin d ol-6-on esa
Bonjoch et al.
other
C-2
C-3
C-3a
C-4
C-5
C-6
C-7
C-7a
2 (Z)
2 (E)
5
12
15
45.7
45.1
43.4
52.8
173.9
53.2
52.6
29.3
25.8
30.7
29.2
36.7
29.3
29.3
34.8
36.8
37.1
35.0
28.6
35.2
35.2
23.9
23.6
24.4
26.2
26.4
26.2
26.2
36.5
35.7
34.7
35.8
36.7
36.3
36.1
210.0
208.5
209.2
212.4
209.4
212.1
212.3
41.8
43.5
40.9
41.5
41.2
41.5
41.5
56.3
57.4
59.4
61.2
55.0
62.8
62.0
41.2/164.8
41.0/164.6
/158.6
57.5b
44.0c
30a
30b
46.3/56.7d
46.5/56.3d
a
b
In CDCl3 (50.3 MHz). Values for compounds 2 and 12 were assigned on the basis of HMQC spectra. Phenyl ring carbons were
found at 138.9, 128.7, 128.0, and 126.7. c Phenyl ring carbons were found at 135.7, 128.7, 128.0, and 127.7. Values for the benzene
d
nucleus: 143.8 ((0.3), 130.9 ((0.1), 129.1 and 124.0 ((0.1).
one.22 Additionally, Fischer indolization of amido ketone
6 gives pentacyclic derivative 10 which upon reduction
leads to the same pyrrolizinocarbazole 9. The pentacyclic
framework of 9 and 10 constitutes a new type of hetero-
cyclic ring system.
the conformational preference of cis-octahydroindolone
12.27 This compound appears to adopt a preferred
conformation which locates the bond C-3a/C-3 axially
with respect to the carbocyclic ring (The ROESY experi-
ment for 12 shows, inter alia (see Figure 1), interrelations
between H-3R and H-5ax as well as H-2â and H-3a, which
corroborates this fact). Interestingly, the coupling con-
stants of H-7a with H-3a (9 Hz) and H-7 (4.5 Hz with
both protons) suggest that the carbocyclic ring does not
adopt a chair conformation. This feature seems to be
common for all bicyclic octahydroindol-6-one derivatives
synthesized in this work as reflected by their similar 13C
NMR data (see Table 1).
The synthesis of lactam 15 was achieved by means of
alkylation of an enol ether of 1,3-cyclohexanedione with
N-benzyliodoacetamide28 and further reduction of com-
pound 13 with sodium borohydride and later treatment
of the resulting enone 14 in acid medium. When the
reduction was carried out with lithium aluminum hy-
dride, the benzyl derivative 12 was formed after the final
acid treatment.
The reason for the different behavior in the indoliza-
tion step of our ibophyllidine series with respect to the
results described in the Aspidosperma field23,24 is not
clear. Nevertheless, what is remarkable is the different
conformation of the azatricyclic unit in 8 in which the
fusion of rings CD is cis, as is usual in pyrrolizidine
framework,25 instead of the trans conformation preferred
for the indolizidine unit present in the pyrroloquino-
lone derivatives used in the Aspidosperma synthesis.
The different conformation for compound 8 and the
D-homo derivatives was inferred from the chemical shift
of the methine proton adjacent to the nitrogen atom.
This proton resonates a δ 3.92 when it is located syn to
the lone pair of nitrogen as occurs in 8, whereas it
appears at a chemical shift lower than δ 3.2 when it is
located anti, as occurs in the pyrroloquinolone deriv-
atives.23e,f It seems reasonable to assume that the dif-
ferent conformational arrangement of the tricyclic ke-
tones in both series is also present in the corresponding
hydrazones. This feature could be the cause of the
different regioselectivity observed in the enehydrazine
formation-step and consequently in the isolation of in-
dole 9.26
The different course of the indolization of ketones 2,
5, 12, and 15 is depicted in Scheme 3. From ketone 2,
operating with AcOH, a mixture of indoles 16 and 17 was
isolated in 43% yield.29 The constitution of isomers 16
and 17 was assigned on the basis of the coupling pattern/
chemical shift observed for the methine proton adjacent
1
to the nitrogen atom: the H spectrum of [3,2-c] fused
Syn th esis of P yr r olo[3,2-c]ca r ba zoles. At this
point we decided to examine the sequence in reverse
involving the initial formation of the indole nucleus (III)
starting from an octahydroindol-6-one (IV) and then the
construction of the pyrrolidine C ring in the key step
(Scheme 1). In this context, we explored the Fischer
indolization of several types of octahydroindol-6-ones
bearing different functionality at the nitrogen atom. The
regioselectivity (C-5 vs C-7) in the indolization of amides
2 and 5, the amine 12, and the lactam 15 were checked.
The required amides 2 and 5 are the same as those
we synthesized in our first approach (Scheme 2). The
N-benzyl derivative 12 was synthesized by sodium boro-
hydride reduction of the imine from amine 1 and ben-
zaldehyde followed by acid treatment of the resulting
dihydroanisole 11 in an efficient manner.
compound 16 displays a δ (J ) 6.5 Hz) at 5.40 ppm for
H-10c, while the [2,3-b] fused compound 17 shows a
multiplet at 4.34 ppm for the H-10a hydrogen in the
major Z rotamer. From amide 5 and lactam 15, pyrrolo-
[2,3-b]carbazoles were isolated. Only when the nitrogen
atom adopts a sp3 hybridization does the geometry of the
molecule favor the formation of the enehydrazine toward
(24) For the same regioselectivity in the Aspidosperma series, see:
Akagi, M.; Oishi, T.; Ban, Y. Tetrahedron Lett. 1969, 2063.
(25) Crabb, T. A.; Newton, R. F.; J ackson, D. Chem. Rev. 1971, 71,
109.
(26) (a) For interesting mechanistic aspects on the Fischer indoliza-
tion upon â-amino ketones in this field, see: Ban, Y.; Iijima, I.
Tetrahedron Lett. 1969, 2523. See also ref 23e. (b) For a discussion
about the stereochemical factors influencing the regiochemical course
of Fischer indole synthesis, see: Freter, K.; Fuchs, V.; Pitner, T. P. J .
Org. Chem. 1983, 48, 4593.
(27) For conformational analysis of the cis-octahydroindole, see:
Mokotoff, M.; Hill, S. T. J . Heterocycl. Chem. 1988, 25, 65. For the
conformational preference in 3a-aryloctahydroindol-6-ones (i.e. mesem-
brine), see: J effs, P. W.; Hawks, R. L.; Farrier, D. S. J . Am. Chem.
Soc. 1969, 91, 3831. Sa´nchez, I. H.; Larraza, M.-I.; Flores, H. J .; D´ıaz,
E. Heterocycles 1985, 23, 593.
(28) N-Benzyliodoacetamide was prepared from benzylamine and
chloroacetyl chloride and later treatment of the resulting chloroceta-
mide with sodium iodide in 2-butanone according to Dufour, M.;
Gramain, J .-C.; Husson, H.-P.; Sinibaldi, M.-E.; Troin, Y. J . Org. Chem.
1990, 55, 5483.
Studies using NMR spectroscopy (500 MHz, COSY,
HMQC, ROESY experiments) have allowed us to assign
(22) Schripsema, J .; Verpoorte, R. Stud. Nat. Prod. Chem. 1991, 9,
163-199.
(23) For indolization upon the methine carbon in the Aspidosperma
series, see: (a) Stork. G.; Dolfini, J . E. J . Am. Chem. Soc. 1963, 85,
2872. (b) Ban, Y.; Sato, Y.; Inoue, I.; Nagai, M.; Oishi, T.; Terashima,
M.; Yonemitsu, O.; Kanaoka, Y. Tetrahedron Lett. 1965, 2261. (c) Inoue,
I.; Ban, Y. J . Chem. Soc (C) 1970, 602. (d) Klioze, S. S.; Darmory, F.
P. J . Org. Chem. 1975, 40, 1588. (e) Lawton, G.; Saxton, J . E.; Smith,
A. J . Tetrahedron 1977, 33, 1641. (f) Pearson, A. J .; Rees, D. C. J .
Chem. Soc., Perkin Trans. 1 1982, 2467.
(29) Operating with AcOH/NaOAc or EtOH/HCl instead of AcOH
neat, the ratio of indole 17 increases and is the major product in the
indolization.

Total Synthesis of (()-Deethylibophyllidine
J . Org. Chem., Vol. 61, No. 20, 1996 7109
Sch em e 3. Syn th esis a n d F isch er In d oliza tion of
Hyd r oin d olon e Der iva tives
ibophyllidine alkaloids by means of photocyclization
(CH3CN-H2O, hν 125 W, 45 min) of N-chloroacetyl
derivative 16 through coupling of the initially formed
diradical cation failed33 and led instead to an azepi-
none34,35 (Scheme 4).
We therefore decided on the formation of the required
2,3,3-trisubstituted indole unit by means of a thionium
ion-mediated cyclization. The advanced key thionium ion
intermediate III (Scheme 1) would arise via Pummerer
rearrangement36 of sulfoxide 25 or else by formation from
dithioacetal 28 by dimethyl(methylthio)sulfonium tet-
rafluoroborate (DMTSF) treatment.37
Compound 25 is available from the N-benzyl derivative
19 through methoxycarbonylation of the indole nitrogen38
(ClCO2Me, NaOH), N-debenzylation with Pearlman’s
catalyst,39 and addition of phenyl vinyl sulfoxide40 to the
secondary amine 24.
The good results obtained in the elaboration of the
pentacyclic skeleton from the sulfoxide 25 (vide infra)
induced us to abandon the path which involves dithio-
acetal 28, which had been prepared in an unoptimized
manner from the benzyl derivative 19.
Taking into account that in the overall sequence for
the synthesis of the key intermediate 25 the benzyl group
is introduced (1 to 11) and removed (23 to 24), we decided
to carry out a shorter synthesis of 25 taking advantage
of our results in the synthesis of octahydroindol-6-ones
and their Fischer indolization (see above). Thus, addition
of 1 to phenyl vinyl sulfoxide40 yielded â-aminoethyl
sulfoxide 29 which, without further purification, was
treated with 2 N HCl at 90 °C for 3 h. After basification
with sodium hydroxide and flash chromatography on
silica gel (EtOAc), cis-octahydroindolone 3041 was ob-
tained in a stereoselective manner in 54% overall yield
for the three steps.
C6-C7 and consequently the regioselectivity is in line
with the desired structure, the pyrrolocarbazole 19 being
the only indole derivative isolated (60% yield).30
Interestingly, the pyrrolocarbazoles 16 and 19 show
different conformational behavior. The unit of cis-
octahydroindole can exist in two chair conformations,
namely c1 and c2, which refer to the N-outside and
N-inside conformer, respectively. Whereas amide 16
exhibited c1 as a preferred conformation, pyrrolocarbazole
19, as well as all derivatives with an amine nitrogen,
showed the c2 conformation as preferred31 (see Table 2
for 13C NMR data). In order to obtain additional data
about the conformational change of pyrrolocarbazoles
when functionality on N(1) varies, we prepared the N-Boc
derivative 21.32 The 13C NMR spectrum reflects the
conformational inversion of the hydroindole ring, which
adopts a c1 conformation as did amide 16, as shown by
the shielding in the C-3, C-4, and C-5 carbon atoms.
Syn th esis of Deeth ylibop h yllid in e (Rou te IV f III
f I). With an efficient procedure for the elaboration of
the ABDE tetracyclic framework of ibophyllidine alka-
loids, we investigated the synthesis of (()-deethylibo-
phyllidine by formation of the C ring (Scheme 1). Ini-
tial attempts to obtain the pentacyclic framework of
(33) For a successful formation of C-6/C-7 bond by this coupling-
type in â-unsubstituted indoles, see: Bennasar, M.-L.; Zulaica, E.;
J ime´nez, J .-M.; Bosch, J . J . Org. Chem. 1993, 58, 7756.
(34) The single product isolated (12%), coming from cyclization upon
C-4 indole atom, was identified as the 1,2,3,3a,3,5,6,10c-octahydro-1,-
10-ethanopyrrolo[3,2-c]carbazol-12-one (22): 1H NMR (300 MHz,
CDCl3, COSY): 1.69 (m, H-3), 1.80 (m, H-3), 1.96 (m, H-4), 2.10 (m,
H-4), 2.62-2.66 (m, 2H, H-5), 2.78 (m, H-3a), 3.35 (ddd, J ) 10.5, 10,
6, 1H, H-2), 3.59 (d, J ) 13.2, 1H, H-11), 3.74 (ddd, J ) 10, 9, 1.5, 1H,
H-2), 4.48 (d, J ) 13.2, 1H, H-11), 5.24 (d, J ) 6.3, H-10c), 6.81 (d, J )
7.2, H-9), 6.96 (t, J ) 7.6, H-8), 7.06 (d, J ) 8, H-7), 7.69 (br s, NH);
13C NMR (75 MHz, CDCl3, HMQC) 18.4 (C-4), 23.6 (C-5), 26.4 (C-3),
29.7 (C-11), 36.7 (C-3a), 46.4 (C-2), 54.8 (C-10c), 109.6 (C-7), 110.0
(C-10b), 119.0 (C-9), 122.7 (C-8), 124.3 (C-10a), 126.2 (C-10), 131.2
(C-5a), 135.2 (C-6a), 170.4 (C-12).
(35) A similar result has been observed in the Strychnos series:
Bosch, J .; Amat, M.; Sanfeliu, E.; Miranda, M.-A. Tetrahedron 1985,
41, 2557.
(36) The Pummerer rearrangement has emerged as a versatile and
effective method for the generation of cationic reactive intermediates
from sulfoxide precursors. For recent reviews, see: (a) Grierson, D.
S.; Husson, H.-P. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991; Vol. 6, pp 909-947. (b) Kennedy, M.;
McKervey, M. A. Ibid. Vol. 7, pp 193-216. (c) De Lucchi, O.; Miotti,
U.; Modena, G. Org. React. 1991, 40, 157-405.
(37) (a) Amat, M.; Alvarez, M.; Bonjoch, J .; Casamitjana, N.; Gra`cia,
J .; Lavilla, R.; Garc´ıas, X.; Bosch, J . Tetrahedron Lett. 1990, 31, 3453.
(b) Amat, M.; Linares, A.; Bosch, J . J . Org. Chem. 1990, 55, 6299. (c)
Gra`cia, J .; Casamitjana, N.; Bonjoch, J .; Bosch, J . J . Org. Chem. 1994,
59, 3939.
(38) Illi, V. O. Synthesis 1979, 136.
(39) Yoshida, K.; Nakajima, S.; Wakamatsu, T.; Ban, Y.; Shibasaki,
M. Heterocycles 1988, 27, 1167.
(30) For studies on the regioselectivity in the Fischer indolization
of â-amino ketones, see: Bonjoch, J .; Casamitjana, N.; Gra`cia, J .;
UÄ beda, M.-C.; Bosch, J . Tetrahedron Lett. 1990, 31, 2449.
(31) The influence of the A 1,3 strain (J ohnson, F. Chem. Rev. 1968,
68, 375) caused by the amide linkage in this conformational change
was suggested by a reviewer. Also the difference in regioselectivity in
the Fischer indole synthesis of hydroindolones could be accounted for
considering that it occurs through the enehydrazine that minimizes
the A 1,3 strain.
(32) Compound 21 was prepared by hydrogenation of benzyl deriva-
tive 19 followed by in situ tert-butyloxycarbonylation (H2, Pd(OH)2,
Boc2O, 87% yield): 1H NMR (300 MHz, CDCl3): 1.54-1.61 (m, 9H),
1.87 (m, 2H), 2.05 (m, 2H), 2.68 (m, 2H), 2.80 (m, 1H), 3.20 (m, 1H),
3.50 (m, 1H), 5.32 (br s, 1H), 7.06 (t, J ) 7.5, 1H), 7.12 (t, J ) 7.5, 1H),
7.25 (d, J ) 7.5, 1H), 7.80 (br s, 1H), 8,05 (br s amp, 1H); 13C NMR,
see Table 2.
(40) For conjugate addition of secondary40a,b or primary amines40c,d
upon phenyl vinyl sulfoxide, see: (a) Abbott, D. J .; Colonna, S.; Stirling,
C. J . M. J . Chem. Soc., Perkin Trans. 1 1976, 492. (b) Maignan, C.;
Guessous, A.; Rouessac, F. Tetrahedron Lett. 1986, 27, 2603. (c) Lee,
A. W. M.; Chan, W. H.; Chan, E. T. T. J . Chem. Soc., Perkin Trans. 1
1992, 309. (d) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron
1992, 48, 7803.
(41) Compound 30 was a diastereomeric mixture at sulfur, which
could not be separated at this stage.

7110 J . Org. Chem., Vol. 61, No. 20, 1996
Ta ble 2. 13C NMR Da ta (δ) of Octa h yd r op yr r olo[3,2-c]ca r ba zole Der iva tivesa
Bonjoch et al.
C-2
C-3
C-3a
C-4
C-5
C-5a
C-6a
C-7
C-8
C-9
C-10
C-10a C-10b C-10c N(1)C other
16b
19b
21
23
24
44.8 25.6
52.4 28.8
45.1 25.7
52.1 28.4
45.8 30.7
36.1
37.3
36.8
36.4
36.9
36.4
36.1
37.8
36.6
36.4
37.1
37.0
22.7 18.1 134.9 136.0 110.5 120.6 118.4 120.1
27.9 23.0 135.9 136.6 110.6 120.9 119.4 118.5
22.8 18.3 133.6 135.8 110.1 121.1 119.3 120.0
27.7 25.1 135.9 138.3 115.5 123.4 122.8 118.6
26.0 23.9 135.5 136.7 115.1 123.5 122.7 118.4
27.3 25.2 135.7 138.0 115.3 123.4 122.8 117.9
27.1 24.7 136.8 138.0 115.5 123.4 123.2 118.4
25.7 21.6 135.7 135.7 110.4 120.8 119.0 117.8
27.4 22.3 135.9 136.8 110.6 120.4 119.0 118.1
28.2 24.1 135.9 136.8 110.5 120.4 119.0 118.1
27.7 22.8 136.1 137.0 110.9 120.2 118.8 117.6
27.7 22.8 136.1 137.1 111.0 120.3 118.7 118.0
126.7
128.4
127.1
130.2
129.1
129.8
129.8
127.0
128.1
128.1
128.0
128.1
108.3
109.7
110.2
116.5
117.2
115.5
115.7
109.1
108.4
108.4
107.5
107.6
54.0
61.1
54.0
60.3
54.4
60.0
60.7
54.4
61.4
58.9
60.7
61.2
165.1
59.8
155.3
59.8
c
d
e
d,f
f
25a b 51.9 28.5
56.6
57.3
f,g
f,g
25b
26h
27
28
31a
51.6 28.2
45.3 30.8
53.0 29.2
51.6 32.7
51.7 28.7
57.7
57.9
55.9
55.5
i
j
g
g
31bb 51.8 28.6
a
b
d
In CDCl3 (50.3 MHz). Assignments were aided by HMQC spectrum. c CH2Cl: δ 43.3. Phenyl ring carbons were found at δ 140.4;
128.6, 128.0, and 126.5. e C(CH3)3: δ 78.9, 28.6. f CO2Me: δ 152.3 ((0.1), 53.2 ((0.2). CH2SOAr: δ 48.3 ((0.1) for 25 and 47.4 ((0.1) for
g
h
i
31,124.1 ((0.1), 128.6 ((0.2), 130.5 ((0.2), and 142.4 (25a ), 144.1 (25b), 143.7 (31a ), and 144.7 (31b). In CDCl3 + CD3OD. CH(OEt)2:
j
δ 101.8, 61.1, 15.3, 15.1. CH(SMe)2: δ 44.7, 11.3, 11.1.
Sch em e 5. Syn th esis of P yr r olo[3,2-c]ca r ba zole
P r ecu r sor s of th e Key Th ion iu m Ion III
F igu r e 1. Conformational behavior of hydroindole unit.
Sch em e 4. P h otocycliza tion of Ch lor oa ceta m id e
16
derivative. This methoxycarbonylation was initially
The Fischer indolization from the phenylhydrazone of
ketone 30 took place regioselectively when AcOH was
used as an acid catalyst to afford the key tetracyclic
derivative 31 (60% yield). The sequence of four steps
from O-methyltyramine developed here to obtain the
pyrrolo[3,2-c]carbazole framework, exemplified with the
synthesis of compound 19 as well as 31, constitutes an
efficient new entry to this tetracyclic skeleton.8 It is
noteworthy that the sulfoxide group did not undergo
Pummerer rearrangement under the acidic conditions
required for both the hydrolytic cleavage of the enol ether
and the Fischer indolization. The stability of the â-amino
sulfoxide moiety is in contrast with the higher reactivity
of sulfoxides with an electron-withdrawing substituent
at the R-position34 and constitutes an advantage from the
synthetic point of view because the sulfoxide group can
be incorporated in an early stage of the synthesis with
the required oxidation level at the methylene carbon
adjacent to the nitrogen atom.
troublesome since the use of several standard procedures
(LDA, ClCO2Me, or dimethylcarbonic anhydride; (CO2-
Me)2O, CH3CN, DMAP; or NaOH aq, TBAB, ClCO2Me)
caused the partial or total formation of carbazole deriva-
tives by way of an additional methoxycarbonylation at
N(1) and further gramine-type cleavage.43 The exclusive
formation of the required protected indole 25 was achieved
in good yield (76%) using LDA as a base and methyl
cyanoformate as the acylating agent. The methoxycar-
bonyl group not only ensures the stability of the cyclized
product but also allows for the elaboration of the anili-
noacrylate moiety in the last step of the synthesis. The
best results for the tandem Pummerer rearrangement-
cyclization were obtained when a mixture of sulfoxides
25 was treated with an equimolecular mixture of TFA
(42) (a) Scarce tandem Pummerer rearrangement-cyclization pro-
cesses using â-amino sulfoxides have been reported so far: upon the
indole 3-position in 2,3-disubstituted indoles,42b in 3-unsubstituted
indoles,42c upon the benzene ring.42d (b) Amat, M.; Bosch, J . J . Org.
Chem. 1992, 57, 5792. (c) Amat, M.; Hadida, S.; Sathyanarayana, S.;
Bosch, J . Tetrahedron Lett. 1996, 37, 3071. (d) Takano, S.; Iida, H.;
Inomata, K.; Ogasawara, K. Heterocycles 1993, 35, 47.
(43) Besselie`vre, R.; Husson, H.-P. Tetrahedron 1981, 37, Suppl. No.
1, 241.
A limited number of examples of Pummerer reactions
from â-amino sulfoxides have been reported so far.42 In
order to carry out the tandem process, the indole nitrogen
of 31 was first protected as a N(6)-methoxycarbonyl

Total Synthesis of (()-Deethylibophyllidine
J . Org. Chem., Vol. 61, No. 20, 1996 7111
Sch em e 6. Syn th esis of (()-Deeth ylibop h yllid in e by P u m m er er Rea r r a n gem en t-In d u ced Cycliza tion
and TFAA (3 equiv) at 80 °C for 2 h. Under these
experimental conditions the crucial quaternary center at
C-72 was formed in a satisfactory manner44 and the
pentacyclic derivative 32 was obtained in 63% yield as
an epimeric mixture at C-62 (both epimers gave 33 on
desulfurization). Similar results were obtained from the
separate epimers 25a or 25b.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, 1H and 13C NMR spectra
were recorded in CDCl3 solution at 200 and 50.3 MHz,
respectively, using Me4Si as internal standard. Chemical
shifts are reported in ppm downfield (δ) from Me4Si, and
coupling constants are expressed in hertz. The 13C NMR
spectra, when an unambiguous assignment was not available,
are reported as follows: chemical shift (multiplicity determined
The final stages in the synthesis involved (i) reductive
removal of the sulfur function and (ii) rearrangement of
the methoxycarbonyl group. The N-(methoxycarbonyl)-
enamine function present in 32 allowed us to effect both
the chemoselective hydrogenolysis of the phenylthio
substituent without affecting the double bond at C-2 and
the photochemical rearrangement45 to the vinylogous
carbamate moiety present in the ibophyllidine alkaloids.
Thus, desulfurization of 32 using Raney nickel (W-2) in
ethanol gave 33 (63% yield), which was then irradiated
with a medium-pressure mercury lamp to give (()-
deethylibophyllidine in 50% yield. Our synthetic mate-
from DEPT spectra). Only noteworthy IR absorptions (cm-1
)
are listed. Melting points were determined in a capillary tube
and are uncorrected. TLC was carried out on SiO2 (silica gel
60 F254, Merck), and the spots were located with iodoplatinate
reagent. Chromatography refers to flash chromatography and
was carried out on SiO2 (silica gel 60, SDS, 230-400 mesh
ASTM). Drying of organic extracts during workup of reactions
was performed over anhydrous Na2SO4. Evaporation of sol-
vents was accomplished with a rotatory evaporator. Mi-
croanalyses were performed by Centro de Investigacio´n y
Desarrollo (CSIC), Barcelona.
2-(4-Meth oxy-2,5-d ih yd r op h en yl)eth yla m in e (1). To a
solution of O-methyltyramine (32 mL, 0.218 mmol) in dry
EtOH (150 mL) under argon was added at -78 °C ammonia
(200 mL) that was passed through solid NaOH. Lithium (11.1
g, 1.6 g-atom) as small chips was added (ca. 3 h) until the
solution was a persistent deep blue for 15 min. Then, the
cooling bath was removed, the ammonia was allowed to
evaporate overnight, and the reaction mixture was evaporated.
Brine (200 mL) was added to the residue, and the mixture was
extracted with Et2O (4 × 150 mL). The dried extract was
evaporated to give 117 (31.4 g, 94% yield) as a yellowish thick
oil that was deemed suitably pure to carry through to
subsequent steps without purification: IR (film) 3364, 1696,
1665; 1H NMR 1.71 (s, 2H), 2.15 (t, J ) 6.7, 2H), 2.72 and
2.73 (2s, 2H each), 2.78 (t, J ) 6.7, 2H), 3.54 (s, 3H), 4.62 (s,
1H), 5.44 (s, 1H); 13C NMR 28.7(two t), 39.4 (t), 40.3 (t), 53.5
(q), 90.1 (d), 119.2 (d), 132.7 (d), 152.9 (d).
1-(Ch lor oa cetyl)octa h yd r oin d ol-6-on e (2). To a solution
of crude amine 1 (6 g, 39 mmol) in anhydrous CH2Cl2 (18 mL)
was added triethylamine (4.8 mL, 42 mmol). A solution of
chloroacetyl chloride (4.3 mL, 51 mmol) in CH2Cl2 (6 mL) was
added dropwise (exothermic), and the solution was stirred
for 3 h. The solution was evaporated to dryness, brine was
added (40 mL), and the mixture was extracted with CH2Cl2
(4 × 50 mL). Chromatography (hexanes-CH2Cl2-EtOAc, 1:1:
1) of the dried and evaporated organic extract gave chloro-
acetamide 2 (7.1 g, 85%) as a yellowish oil: IR (film) 1713,
1650; 1H NMR (500 MHz, COSY) (Z isomer) 1.86 (dddd,
J ) 11, 10, 7, 7, 1H, H-4ax), 2.01 (m, H-3), 2.10 (m, H-4eq), 2.17
(m, H-3), 2.22 (ddd, J ) 16.5, 8.5, 3, H-5ax), 2.29 (dd, J ) 15.5,
9, H-7ax), 2.39 (ddd, J ) 16, 8, 6.5, H-5eq), 2.53 (sext, J ) 8,
H-3a), 2.99 (dd, J ) 15.5, 6, H-7eq), 3.60 (ddd, J ) 10, 8, 8
H-2R), 3,69 (ddd, J ) 10, 8, 4, H-2â), 3.97 (s, CH2Cl), 4.42 (ddd,
J ) 9, 8.5, 6, H-7a); 13C NMR, Table 1. Anal. Calcd for
C10H14ClNO2: C, 55.69; H, 6.54; N, 6.49. Found: C, 55.38; H,
6.51; N, 6.38.
1
rial was identified by comparing its H NMR spectrum
(500 MHz) with that of the natural product.1b Its 13C
NMR spectrum is reported for the first time, and unam-
biguous assignment, aided by an HMQC spectrum, has
been effected. The good yield in the formation of the
anilinoacrylate unit in this series contrasts with the
moderate yields obtained in analogous photochemical
rearrangements in the Strychnos series,46 probably due
to the greater coplanarity of the N-C(2)-C(16) unit in
the ibophyllidine derivatives.
In summary, a synthesis of (()-deethylibophyllidine
has been achieved. The route requires eight steps from
O-methyltyramine and proceeds with 5.5% overall yield.
The key steps involve stereoselective formation of the
octahydroindol-6-one bicyclic system, regioselective Fis-
cher indolization to a tetracyclic ring system, tandem
Pummerer rearrangement-thionium ion cyclization op-
erating from a â-aminosulfoxide, in acidic medium, in the
three anelation processes, and finally a photo Fries
rearrangement for generation of the aminoacrylate func-
tion of deethylibophyllidine.
(44) The intramolecular Pummerer reaction has been used to close
the crucial C6-C7 bond in the synthesis of Aspidosperma alkaloids,
but using either an exocyclic or an endocyclic amide as the substrate:
Gallagher, T.; Magnus, P.; Huffman, J . C. J . Am. Chem. Soc. 1983,
105, 4750. See also, Magnus, P.; Sear, N. L.; Kim, C. S.; Vicker, N. J .
Org. Chem. 1992, 57, 70 and references cited therein.
(45) (a) Wenkert, E.; Orito, K.; Simmons, D. P.; Kunesh, N.;
Ardisson, J .; Poisson, J . Tetrahedron 1983, 39, 3719. (b) Wenkert, E.;
Porter, B.; Simmons, D. P. J . Org. Chem. 1984, 49, 3733.
(46) Sole´, D.; Bonjoch, J .; Bosch, J . J . Org. Chem. 1996, 61, 4194.
See also ref 37b, 37c.

7112 J . Org. Chem., Vol. 61, No. 20, 1996
Bonjoch et al.
When the chloroacetylation was carried out as above but
with additional water (1.1 equiv), the acylated dihydroanisole
3 was obtained as a brown solid: IR (film) 3316, 1697, 1664,
(5a RS,11bSR,11cSR)-1,2,4,5,5a ,6,11b,11c-Octa h yd r op y-
r r olizin o[1,7-a b] ca r ba zole (9). To a solution of ketone 8
(100 mg, 0.6 mmol) in EtOH (6 mL) were added phenylhydra-
zine hydrochloride (100 mg, 0.7 mmol) and Na2CO3 (76 mg,
0.72 mmol). The mixture was heated at reflux for 1.5 h,
filtered, and evaporated. The crude hydrazone was dissolved
in glacial AcOH (10 mL) and heated at 95 °C for 1 h. The
acid was removed, and the residue was dissolved in CH2Cl2
and washed with aqueous Na2CO3. Chromatography (CHCl3-
MeOH) gave pentacycle 9 (20 mg, 25%); mp 165 °C dec; 1H
NMR 1.75-1.92 (m, 2H), 2.06 (td, J ) 13, 7.2, 1H), 2.30-2.41
(m, 1H), 2.50 (dd, J ) 15, 6.7, 1H), 2.56 (dd, J ) 11, 5.4, 1H),
2.60-2.66 (m, 1H), 2.70 (dt, J ) 10.5, 7.4, 1H), 2.99 (dd, J )
15.1, 6.2, 1H), 3.06 (dt, J ) 10, 5.2, 1H), 3.25 (ddd, J ) 10.5,
7.1, 5.2, 1H), 3.42 (dt, J ) 8, 5, 1H), 4.00 (dd, J ) 8.5, 6.1,
1H), 7.11 (td, J ) 7.1, 1.4, 1H); 7.16 (td, J ) 7.1,1.4 Hz, 1H),
7.32 (dd, J ) 7.4, 1.7, 1H); 7.50 (d, J ) 7.3, 1H), 8.41 (br s,
1H); 13C NMR 21.6 (C-6), 32.4 (C-4), 32.9 (C-1), 33.8 (C-5a),
36.0 (C-11b), 52.4 (C-2), 54.0 (C-4), 68.3 (C-11c), 107.1 (C-6a),
111.1 (C-10), 117.9 (C-7), 119.3 (C-8), 121.8 (C-9), 126.7
(C-6b), 132.2 (C-11a), 136.7 (C-10a). Anal. Calcd for C16H18N2‚
1/4H2O: C: 79.12; H: 7.51; N: 11.42. Found: C: 78.74; H:
7.55; N: 11.30.
(5a RS,11b SR,11cSR)-4,5,5a ,6,11b ,11c-H exa h yd r o-1H -
p yr r olizin o[1,7-a b] ca r ba zol-2-on e (10). Operating as
above, from ketone 6 (380 mg, 2.12 mmol), pentacycle 10 was
obtained (224 mg, 42%) after chromatography (Al2O3, CH2Cl2);
mp 249-250 °C (hexane-CHCl3). IR (KBr) 3394, 3253, 1667;
1H NMR 2.06-2.39 (m, 4H), 2.46 (d, J ) 16.4, 1H), 2.95 (dd,
J ) 15, 6, 1H), 3.18 (dd, J ) 16.4, 9.4, 1H), 3.21-3.27 (m, 1H),
3.63 (m, 2H), 4.35 (dd, J ) 7.5, 4.5, 1H), 7.07-7.13 (m, 2H),
7.24-7.28 (m, 1H), 7.43-7.48 (m), 8,2 (br s, 1H); 13C NMR
21.4 (C-6), 29.3 (C-5a), 33.2 (C-5), 34.0 (C-11b), 39.0 (C-1), 41.9
(C-4), 64.8 (C-11c), 108.6 (C-6a), 110.9 (C-10), 117.9 (C-7), 119.2
(C-8), 121.7 (C-9), 126.6 (C-6b), 133.6 (C-11a), 136.7 (C-10a),
172.2 (C-2). Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39;
N, 11.10. Found: C, 76.14; H, 6.36; N, 11.18.
1
1645; H NMR 2.24 (t, J ) 6.7, 2H), 2.74 (s, 4H), 3.39 (q, J )
6.7, 2H), 3.55 (s, 3H), 4.04 (s, 2H), 4.63 (s, 1H), 5.48 (s, 1H),
6,7 (br s, 1H); 13C NMR 28.7 (t), 28.8 (t), 35.8 (t), 37.2 (t), 42.4
(t), 53.7 (q), 89.9 (d), 120.2 (s), 132.0 (s), 152.8 (s), 165.9 (s).
HRMS calcd for C11H16ClNO2 229.0869, found 229.0861.
Treatment of 3 (100 mg, 0.45 mmol) in 2 N HCl (10 mL) at
room temperature for 24 h afforded after workup the cyclized
product 2 (70 mg, 60%).
cis-1-(Tr ich lor oa cetyl)octa h yd r oin d ol-6-on e (5). Op-
erating as above in the anhydrous form and starting from
dihydroanisole 1 (3 g, 19.5 mmol) and trichloroacetyl chloride
(3.75 mL, 33 mmol) was obtained octahydroindolone 5 (1.85
g, 34%). In this case, cyclohexenones 4b (700 mg, 13%) and
4a (800 mg, 14.5%) were also isolated in the purification step
(chromatography, CH2Cl2).
Compound 5: mp 118 °C (EtOAc); IR (KBr) 1709, 1668; 1H
NMR 1.9-2.6 (m, 8H), 3.09 (dd, J ) 15.4, 6.2, 1H), 3.91-4.16
(m, 2H); 4.53 (dd, J ) 15.4, 8.3, 1H); 13C NMR, Table 1. Anal.
Calcd for C10H12Cl3NO2: C, 42.20; H, 4.25; N, 4.92. Found:
C, 42.22; H, 4.30; N, 4.90. Compound 4b: IR (film) 3340, 1712,
1668; 1H NMR 1.54-1.67 (m, 4H), 1.96-1.99 (m, 3H), 2.20 (t,
J ) 6.2, 1H), 3.42 (t, J ) 6.7, 1H); 3,45 (t, J ) 6.7, 1H), 5.54
1
(m, 1H), Compound 4a : IR (film) 3375, 1698, 1673; H NMR
1.54-2.67 (m, 7H), 3.38-3.50 (m, 2H), 5.95 (dd, J ) 10, 2.4,
1H), 6.80 (d, J ) 10.2, 1H); 7,0 (br s, 1H); 13C NMR 28.1 (t),
33.4 (d), 33.4 (t), 36.4 (t), 38.8 (t), 92.4 (s), 129.2 (d), 153.8 (d),
169.1 (s), 199.5 (s).
(5a RS,8a SR,8bSR)-Octa h yd r op yr r olo[3,2,1-h i]in d ole-
2,8-d ion e (6). To a solution of chloroacetamide 3 (1 g, 4.63
mmol) in tert-butyl alcohol (40 mL) was added a solution of
potassium tert-butoxide in tert-butyl alcohol (1 M, 4.7 mL, 4.7
mmol) under Ar, and the reaction mixture was stirred at room
temperature for 1 h. The solvent was removed, and the
residue was partionated between aqueous NaHCO3 solution
(0.1 M, 25 mL) and CHCl3 (25 mL). The aqueous phase was
reextracted, and the combined organic extracts were dried and
chromatographed (Al2O3, CH2Cl2-EtOAc 1:1) to give amido
ketone 6 (330 mg, 40%) as a white solid: mp 126-127 °C
(EtOAc); IR (KBr) 1710, 1676; 1H NMR (500 MHz, COSY) 1.37
(qd, J ) 12.5, 3.5, H-6ax), 1.8-1.9 (m, H-6eq and H-5ax), 2.2-
2.4 (m, 4H), 2.8-2.9 (m, 3H), 3.07 (td, J ) 10.5, 1.5, H-4), 3.41
(ddd, J ) 11, 9, 8.5, H-4), 4.32 (br t, J ) 6, H-8b); 13C NMR
(HMQC), 24.2 (C-6), 32.1 (C-5), 34.3 (C-5a), 37.3 (C-7), 38.5
(C-1 and C-4), 43.2 (C-8a), 65.0 (C-8b), 172.0 (C-2), 209.9 (C-
8). Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.81.
Found: C, 67.00; H, 7.30; N, 7.87.
(5a RS,8a SR,8bRS)-Deca h yd r op yr r olo[3,2,1-h i]in d ol-6-
ol (7). To a solution of keto lactam 6 (100 mg, 0.55 mmol) in
anhydrous THF (15 mL) was added LiAlH4 (85.4 mg, 2.25
mmol) under N2. The mixture was heated to reflux for 6 h.
After the mixture was cooled, water and a saturated solution
of sodium potassium tartrate were slowly added. The aqueous
phase was separated and extracted with Et2O. Evaporation
of the combined dried organic extracts gave 7 as a mixture of
epimers in a nearly equimolecular ratio. IR (neat) 3350, 1063,
1039; 1H NMR 0.8-3.2 (m, 13H), 3.50 (t, J ) 8, 1H, compd
7a ), 3.60 (t, J ) 5, 1H, compd 7b), 3.88 and 3.90 (m, 1H), 4.60
(br s, 1H); 13C NMR alcohol 7a : 27.3 (t), 31.6 (t), 33.6 (t), 34.8
(d), 35.1 (t), 44.7 (d), 52.5 (t), 53.0 (t), 67.5 (d), 71.7 (d); alcohol
7b: 23.7 (t), 25.0 (t), 32.9 (t), 33.9 (t), 36.1 (d), 44.3 (d), 56.7
(t), 56.9 (t), 66.1 (d), 69.0 (d).
To a solution of 10 (100 mg, 0.4 mmol) in THF (12 mL) was
added LiAlH4 (60 mg, 1.6 mmol). The mixture was heated at
reflux for 10 h. After cooling, a satutared solution of sodium
potassium tartrate (15 mL) was added and the aqueous phase
was extracted with Et2O and EtOAc. Evaporation of the
combined dried organic phases, followed by chromatography
(Al2O3, 10% MeOH in EtOAc), gave 9 (65 mg, 70%) as an
amorphous solid.
N -B e n zy l-2-(4-Me t h o x y -2,5-d ih y d r o p h e n y l)e t h y l-
a m in e (11). To a solution of 1 (10.7 g, 70 mmol) in CH2Cl2
(50 mL) were added benzaldehyde (8 mL, 78 mmol) and
molecular sieves (4Å). The mixture was stirred at room
temperature for 4 h, filtered, and evaporated to give the crude
1
imine (>95% pure by NMR): IR (film) 1702, 1665, 1645; H
NMR 2.39 (t, J ) 7.5, 2H), 2.76 (m, 4H), 3.55 (s, 3H), 3.72 (td,
J ) 7.5, 1.3, 2H), 4.63 (t, J ) 2.8, 1H), 5.46 (t, J ) 3.0, 1H),
7.41 (m, 3H), 7.72 (m, 2H), 8.26 (s, 1H); 13C NMR 28.9 (t), 29.6
(t), 37.9 (t), 53.5 (q), 60.0 (t), 90.1 (d), 118.8 (d), 127.8 (d), 128.3
(d), 130.3 (d), 133.1 (s), 136.0 (s), 152.7 (s), 160.9 (d).
To a stirred solution of this imine (15.7 g) in MeOH (40 mL)
was slowly added NaBH4 (2.43 g, 64.2 mmol) at 0 °C. The
reaction mixture was stirred at room temperature for 2 h,
quenched by addition of H2O (100 mL) and then extracted with
CH2Cl2 (3 × 100 mL). The organic extract was dried and
evaporated to provide 11 (14.8 g, 95%), which was used directly
in the next step: IR (film) 3364,1697, 1665; 1H NMR 1.50 (br,
1H), 2.18 (t, J ) 7, 2H), 2.71 (t, J ) 7, 2H), 2.72 (s, 4H), 3.53
(s, 3H), 3.78 (s, 2H), 4,60 (br s, 1H), 5.43 (br s, 1H), 7.30 (s,
5H); 13C NMR 28.9 (two t), 36.8 (t), 46.7 (t), 53.6 (q), 53.7 (t),
90.1 (d), 118.8 (d), 126.6 (d), 127.9 (d), 128.1 (d), 133.0 (s), 140.2
(s), 152.7 (s).
cis-1-Ben zylocta h yd r oin d ol-6-on e (12). A solution of
crude benzyl derivative 11 (13.7 g, 56.3 mmol) in 6 N HCl (70
mL) was heated at reflux for 5 h. The reaction mixture was
basified with pellets of NaOH and extracted with CH2Cl2.
Purification of the dried organic extract by chromatography
(1:1 CH2Cl2-EtOAc) gave 12 (6.38 g, 50%): IR (film) 1716;
1H NMR (500 MHz, COSY) 1.47 (ddt, J ) 12, 10.5, 7.5, H-3R),
1.72 (dddd, J ) 13, 6.5, 6, 5, H-4eq), 1.91-1.98 (m, 2H, H-3â
(5a RS,8a SR,8bRS)-Octa h yd r op yr r olo[3,2,1-h i]in d ol-6-
on e (8). 1.23 M J ones reagent (1.02 mL, 1.27 mmol) was
added at 0 °C to a stirred solution of alcohols 7 (70 mg, 0.42
mmol) in acetone (2 mL), and the mixture was stirred at 25
°C for 45 min. Addition of 10% aqueous NaHSO3 solution (7.5
mL) and 4 N aqueous NaOH (6 mL), followed by extraction
with Et2O (4 × 25 mL), left an oil which was chromatographed
(Al2O3, CHCl3) to give ketone 8 (50 mg, 75%): IR (film) 1707;
1H NMR 1.5-3.8 (m, 14H), 3.92 (t, J ) 7.7, 1H); 13C NMR 24.8
(t), 29.3 (t), 31.7 (t), 35.8 (d), 36.8 (t), 45.7 (d), 52.8 (t), 53.3 (t),
67.6 (d), 213.1 (s). HRMS calcd for C10H15NO 165.1154, found
165.1147.

Total Synthesis of (()-Deethylibophyllidine
J . Org. Chem., Vol. 61, No. 20, 1996 7113
and H-4ax), 2.05 (td, J ) 9, 7, H-2â), 2.18 (ddd, J ) 18, 6, 4.5,
H-5eq), 2.45 (ddd, J ) 18, 10, 4.5, H-5ax), 2.47 (m, H-3a), 2.52
and 2.58 (2 dd, J ) 16, 4.5 each, H-7), 2.80 (dt, J ) 9, 4.5,
H-7a), 2.85 (t, J ) 8.5, H-2R), 3.09 and 3.95 (2 d, J ) 13 each
CH2Ar), 7.15-7.3 (m, 5H); 13C NMR, Table 1; HRMS calcd for
H-2â), 4.34 (s, CH2Cl), 5.40 (d, J ) 6.5, H-10c), 6.85 (t, J ) 8,
H-9), 6.96 (t, J ) 8, H-8), 7.21 (d, J ) 8, H-7), 7.65 (d, J ) 8,
H-10), 10.78 (s, NH); 13C NMR, Table 2. Anal. Calcd for
C16H17ClN2O: C, 66.55; H, 5.93; N, 9.70. Found: C, 66.46; H,
5.96; N, 9.61.
C15H19NO 229.1467, found 229.1478. Anal. Calcd for C15H19
-
cis-1-(Ch lor oa cetyl)-1,2,3,3a ,4,9,10,10a -octa h yd r op yr -
r olo[2,3-b]ca r ba zole (17): mp 197-198 °C (EtOH); IR (KBr)
NO: C, 78.56; H, 8.35; N, 6.10. Found: C, 78.58; H, 8.43; N,
6.12.
1
3232, 1649; H NMR (COSY, peaks of the major Z rotamer)
6-[(N-Ben zylcar bam oyl)m eth yl]-3-eth oxy-2-cycloh exen -
1-on e (13). To a stirred solution of diisopropylamine (2.5 mL,
18 mmol) in THF (15 mL) was added under nitrogen at -78
°C a 1.6 M solution of n-BuLi in hexane (10.6 mL, 17 mmol).
After the mixture was stirred for 25 min, a solution of 3-ethoxy-
2-cyclohexen-1-one47 (2 g, 14 mmol) in THF (10 mL) was added
slowly. After 30 min at -78 °C, the solution was cannulated
into a solution of N-benzyliodoacetamide27 (8.7 g, 28 mmol) in
THF (10 mL) stirring at -78 °C. The cold bath was removed
upon complete addition, and after a further 6 min, the reaction
was quenched by addition of H2O (15 mL). The aqueous layer
was extracted with Et2O. Combined organic layers were
washed with H2O (3 × 15 mL) and brine (3 × 15 mL). Workup
and chromatography (EtOAc-CH2Cl2) gave, in order of elution,
the starting materials, iodo derivative (2.4 g) and cyclohex-
enone (520 mg), and 13 (2.1 g, 67%, over consumed starting
material). A sample of 13, crystallized (hexane-CH2Cl2),
1.80 (m, H-3â), 2.04 (quint, J ) 10.5, H-3R), 2.49 (dd, J ) 17,
7.5, H-10ax), 2.56 (m, H-3a), 2.75 (d, J ) 17, H-4ax), 2.98 (dd,
J ) 17, 8, H-4eq), 3.25 (dd, J ) 17, 7.5, H-10eq), 3.52 (td, J )
10, 7.5, H-2â), 3.63 (td, J ) 9.5, 1.5, H-2R), 4.29 (s, CH2Cl),
4.34 (m, H-10a), 6.92 (t, J ) 7.5, H-6), 6.99 (t, J ) 7.5, H-7),
7.24 (d, J ) 7.5, H-8), 7.33 (d, J ) 7.5, H-5), 10.62 (s, NH); 13
C
NMR (DMSO-d6, HMQC) (Z): 21.1 (C-4), 24.7 (C-10), 29.6 (C-
3), 35.0 (C-3a), 42.9 (CH2Cl), 44.7 (C-2), 54.3 (C-10a), 105.0
(C-4a), 110.9 (C-8), 117.4 (C-5), 118.3 (C-6), 120.5 (C-7), 127.1
(C-4b), 131.1 (C-9a), 136.4 (C-8a), 164.2 (CO); (E): 21.3 (C-4),
25.5 (C-10), 27.2 (C-3), 36.8 (C-3a), 42.7 (CH2Cl), 44.6 (C-2),
54.8 (C-10a), 105.2 (C-4a), 110.9 (C-8), 117.4 (C-5), 118.3 (C-
6), 120.6 (C-7), 127.1 (C-4b), 130.6 (C-9a), 136.4 (C-8a), 163.9
(CO). Anal. Calcd for C16H17ClN2O: C, 66.55; H, 5.93; N, 9.70.
Found: C, 66.18; H, 5.92; N, 9.57.
cis-1-(Tr ich lor oa cet yl)-1,2,3,3a ,4,9,10,10a -oct a h yd r o-
p yr r olo[2,3-b]ca r ba zole (18). The same procedure described
above for indolization of ketone 2 was carried out with ketone
5 (140 mg, 0.49 mmol). Chromatography (CH2Cl2) afforded
50 mg (30%) of indole 18: IR (KBr) 3386, 1665; 1H NMR
(CDCl3 + CD3OD) 1.90-2.12 (m, 2H), 2.50-3.20 (m, 3H),
3.50-3.70 (m, 2H), 3.85-4.20 (m, 2H), 4.65 (dd, 1H), 7.08-
7.43 (m, 3H), 7.90 (s, 1H), 8.03 (d, J ) 7.5, 1H); 13C NMR 21.1
(C-4), 23.9 (C-10), 30.4 (C-3), 34.8 (C-3a), 48.2 (C-2), 58.4 (C-
10a), 105.9 (C-4a), 110.9 (C-8), 117.4 (C-5), 119.0 (C-6), 120.0
(C-7), 127.1 (C-4b), 129.8 (C-9a), 136.3 (C-8a), 159.2 (CO).
cis-1-Ben zyl-1,2,3,3a ,4,5,6,10c-octa h yd r op yr r olo[3,2-c]-
ca r ba zole (19). Reaction of 12 (6.3 g, 27.8 mmol) with
phenylhydrazine and then with AcOH (115 °C, 3 h), as
described for the indolization of 2, gave 19 (4.5 g, 54%) as a
solid after chromatography (2:1, CH2Cl2-EtOAc); mp 90-92
1
melted at 129-131 °C: IR (KBr) 3310, 1638, 1607; H NMR
1.37 (t, J ) 7, 3H), 2.1-2.8 (m, 7H), 3.92 (dq, J ) 7, 2, 2H),
4.43 (d, J ) 6, 2H), 6.5 (br, 1H), 7.25 (m, 5H); 13C NMR 13.8
(q), 27.3 (t), 28.8 (t), 36.7 (t), 42.6 (d), 43.2 (t), 64.3 (t), 101.9
(d), 127.1 (d), 127.5 (d), 128.4 (d), 138.6 (s), 172.0 (s), 177.9
(s), 200.7 (s). Anal. Calcd for C17H21NO3: C, 71.05; H, 7.37;
N, 4.87. Found: C, 70.88; H, 7.34; N, 4.88.
cis-1-Ben zylh exa h yd r oin d ole-2,6-d ion e (15). To a solu-
tion of 13 (700 mg, 2.6 mmol) in MeOH (25 mL) at 0 °C was
added NaBH4 (250 mg, 7 mmol) in five portions at 30 min
intervals each. The mixture was stirred for 24 h and then
quenched by aqueous 30% H2SO4, and the stirring was
maintained for 4 h at room temperature. The resulting
solution was neutralized with solid NaHCO3 and evaporated.
Digestion of the dryness residue with CHCl3 furnished a
mixture of amido enone 14 and 15 (443 mg, 71%). Compound
1
°C (EtOH); IR (film) 3420, 3382; H NMR (300 MHz, COSY)
1.49 (dddd, J ) 11, 8, 8, 2.5, H-3R), 1.74 (dddd, J ) 10, 5.5,
3.3, 3.3, H-4eq), 2.08 (dddd, J ) 12, 10.5, 2.7, 2.5, H-3â), 2.2
(m, H-4ax), 2.25 (m, H-2R), 2.3 (m, H-3a), 2.66 (ddd, J ) 16.5,
10.5, 5.5, H-5ax), 2.74 (ddd, J ) 16.5, 5.5, 3, H-5eq), 2.93 (td, J
) 9.1, 2.7, H-2â), 3.37 and 4.49 (2d, J ) 12.3 each, CH2Ar),
3.59 (d, J ) 4.4, H-10c), 7.06-7.08 (m, H-9, H-8), 7.15-7.29
(m, 5H), 7.65 (t, J ) 5, H-10), 7.91 (s, NH); 13C NMR, Table 2.
Anal. Calcd for C21H22N2: C, 83.40; H, 7.33; N, 9.26. Found:
C: 83.50; H: 7.42; N: 9.29.
cis-1-Ben zyl-1H-3,3a ,4,9,10,10a -h exa h yd r op yr r olo[2,3-
b]ca r ba zol-2-on e (20). The procedure described above for
the preparation of 16 was carried out with ketone 15 (222 mg,
0.92 mmol) to afford, after chromatography (CH2Cl2), 20 (73
mg, 27%): IR (KBr) 3407, 1667; 1H NMR 2.36 (dd, J ) 17, 8.5
Hz, 1H), 2.6-3.1 (m, 6H), 3.88 (dd, J ) 8, 5, 1H), 4.17 (d, J )
15, 1H), 4.90 (d, J ) 15, 1H), 7.1-7.4 (m, 9H), 7.7 (br s, 1H);
13C NMR 23.3 (t), 25.1 (t), 29.7 (t), 36.8 (d), 43.8 (t), 53.4 (d),
110.7 (d), 118.1 (d), 119.2 (d), 121.6 (d), 127.1 (d). 129.1 (d),
129.7 (d), 172.0 (s).
Meth yl cis-1-Ben zyl-1,2,3,3a,4,5,6,10c-octah ydr opyr r olo-
[3,2-c]ca r ba zole-6-ca r boxyla te (23). A 50% aqueous NaOH
solution (6.7 mL) was added to a suspension of indole 19 (500
mg, 1.65 mmol) and tetrabutylammonium hydrogen sulfate (10
mg) in toluene (20 mL). The resulting two-phase mixture was
vigorously stirred at room temperature for 15 min. Then, a
solution of methyl chloroformate (0.2 mL, 2.4 mmol) in toluene
(2 mL) was added dropwise. The mixture was stirred for 1 h
and additional methyl chloroformate (0.2 mL) in toluene was
added. After 15 min, H2O (40 mL) was added, and the aqueous
layer was extracted with EtOAc (3 × 100 mL). After workup
and chromatography (CH2Cl2), indole 23 (470 mg, 80%) was
isolated as a white solid: mp 86 °C (EtOH); IR (KBr) 1735;
1H NMR 1.48-1.60 (m, H-3R), 1.77-1.84 (ddd, J ) 12, 5.5, 1.6,
H-4eq), 2.04 (m, H-3â), 2.22 (dd, J ) 9.5, 4, H-2R), 2.25-2.31
(m, H-3a and H-4ax), 2.92 (dd, J ) 18.4, 3.2, H-5eq), 2.93 (td, J
) 9, 6, H-2â), 3.26 (ddd, J ) 18.4, 5, 4.5, H-5eq), 3.41 and 4.34
1
14: IR (KBr) 3282, 1678, 1637; H NMR 1.30-2.50 (m, 6H),
3.05 (m, 1H), 4.45 (d, J ) 5.8, 2H), 5.97 (dd, J ) 10.2, 2.5,
1H), 6.2 (br s, 1H), 6.86 (dt, J ) 10.2, 1.2, 1H), 7.27-7.32 (m,
5H); 13C NMR 28.3 (t), 33.1 (d), 36.4 (t), 40.6 (t), 43.7 (t), 127.6
(d), 127.7 (d),128.7 (d), 129.3 (d), 138.2 (s), 153.9 (d), 170.7 (s),
199.8 (s).
A solution of 14 (295 mg, 1.3 mmol) and TsOH (50 mg, 2.26
mmol) in benzene (25 mL) was heated at reflux for 6 h and
then concentrated to dryness. The residue was dissolved in
CH2Cl2 and washed with saturated aqueous Na2CO3. From
the organic extracts ketone 15 was isolated (250 mg, 85%); IR
(film) 1721, 1679; 1H NMR 1.4-2.9 (m, 9H), 3.80 (d, J ) 12.5,
1H), 3.84 (d, J ) 15, 1H), 4.98 (d, J ) 15, 1H), 7.1-7.4 (m,
5H); 13C NMR, see Table 1.
F isch er In d oliza tion of Keton e 2. To a solution of ketone
2 (1.02 g, 4.7 mmol) in EtOH (25 mL) were added phenylhy-
drazine hydrochloride (720 mg, 5 mmol) and anhydrous Na2-
CO3 (550 mg, 5.2 mmol). The mixture was heated at reflux
under Ar for 1.5 h and then filtered and evaporated to dryness.
A solution of the resulting crude phenylhydrazone (650 mg,
2.1 mmol) in glacial AcOH (20 mL) was heated at 95 °C for 2
h. The solvent was evaporated, saturated aqueous NaHCO3
(15 mL) was added, and then the mixture was extracted with
CH2Cl2 (4 × 25 mL). Evaporation of the dried extracts followed
by chromatography (CH2Cl2) gave indole 16 (150 mg, 23%) and
indole 17 (120 mg, 20%).
cis-1-(Ch lor oacetyl)-1,2,3,3a,4,5,6,10c-octah ydr opyr r olo-
[3,2-c]ca r ba zole (16): mp 179-180 °C (EtOH); IR (KBr)
3556, 3275, 1651; 1H NMR (500 MHz, DMSO-d6, COSY) 1.93
(ddd, J ) 11, 9, 5, 2H, H-3); 1.98 (dd, J ) 8.5, 3.5, 2H, H-4),
2.52 (m, H-3a), 2.66 (dt, J ) 17, 3.5, H-5eq), 2.78 (dt, J ) 17,
8.5, H-5ax), 3.34 (dt, J ) 10, 5, H-2R), 3.60 (ddd, J ) 10, 9, 9,
(47) (a) Stork, G.; Danheiser, R. L. J . Org. Chem. 1973, 38, 1775.
(b) Kende, A. S.; Fludzinski, P. Org. Synth. 1986, 64, 68.

7114 J . Org. Chem., Vol. 61, No. 20, 1996
Bonjoch et al.
(2d, J ) 12.5 each, CH2Ar), 3.64 (d, J ) 4.4, H-10c), 4.02 (s,
3H, CH3O), 7.20-7.28 (m, 7H). 7.65 (m, H-10), 8.13 (m, H-7);
13C NMR, Table 2. Anal. Calcd for C23H24N2O2: C, 76.64; H,
6.71; N, 7.77. Found: C, 76.66; H, 6.67; N, 7.64.
eth yla m in e (29), which was used directly. An aliquot was
chromatographed (CH2Cl2-EtOAc) and gave a pure 29 as a
1
yellowish oil: IR (film) 3303, 1696, 1664; H NMR 1.63 (br s,
1H), 2.19 (t, J ) 7, 2H), 2.71 (t, J ) 7, 2H), 2,73 (s, 4H), 2.90-
3.17 (m, 4H), 3.54 (s, 3H), 4.62 (s, 2H), 5.43 (s, 1H), 7.50-7.67
(m, 5H); 13C NMR 29.0 (two t), 36.7 (t), 42.8 (t), 47.3 (t), 53.4
(q), 57.4 (t), 90.1 (d), 119.1 (d), 123.7 (d), 129.1 (d), 130.8 (d),
132.8 (s), 143.8 (s), 152.8 (s).
The crude 29 was dissolved in 2 N HCl (100 mL) and
warmed at 90 °C for 2 h. The solution was allowed to cool to
room temperature and was carefully basified with NaOH
pellets. The resulting solution was extracted with CH2Cl2 (3
× 100 mL). The organic extracts after workup and chroma-
tography (EtOAc) furnished 5.72 g (63%) of 30 (mixture of
diastereomers at sulfur atom) as a yellow oil: IR (film) 1713;
1H NMR 1.50-3.30 (m, 16H); 7.48-7.64 (m, 5H).13C NMR,
Table 1. Anal. Calcd for C16H21NO2S‚1/4H2O: C, 64.94; H,
7.32; N, 4.73. Found: C, 64.81; H, 7.42; N, 4.58.
cis-1-[2-P h en ylsu lfin yl)eth yl]-1,2,3,3a ,4,5,6,10c-octa h y-
d r op yr r olo[3,2-c]ca r ba zole (31). The same procedure used
for the preparation of 19 from ketone 12 was carried out with
the ketone 30 (5.7 g, 19.55 mmol). The indolization step was
carried out at 120 °C for 1 h 30 min. Chromatography (Al2O3,
EtOAc) afforded 4.45 g (60%) of 31 as an epimeric mixture at
sulfur. The process allowed isolation of separate pure dia-
stereomers 31a and 31b.
31a (less polar isomer): mp 195 °C (EtOAc); IR (film) 3130;
1H NMR (500 MHz, DMSO-d6, COSY) 1.48 (dtd, J ) 13, 9,
1.5, H-3R), 1.70 (m, H-4â), 1.99 (qd, J ) 12, 6, H-4R), 2.08 (dtd,
J ) 12.5, 10, 3, H-3â), 2.15 (m, H-3a), 2.23 (td, J ) 9, 7.5, H-2â),
2.60 and 3.00 (2m, CH2S), 2.68 (ddd, J ) 16.5, 11, 5.5, H-5â),
2.75 (ddd, J ) 17, 5.5, 2.5, H-5R), 2.88 and 3.02 (2m, CH2N),
3.26 (td, J ) 9, 3, H-2R), 3.32 (d, J ) 5.5, H-10c), 6.83 (td, J )
7.5, 1, H-9), 6.96 (td, J ) 7.5, 1, H-8), 7.16 (t, J ) 7, 2H), 7.19
(d, J ) 7.5, H-10), 7.25 (d, J ) 7, 1H), 7.26 (d, J ) 7.5, H-7),
7.31 (dd, J ) 7, 1, 2H), 10.90 (s, H-6); 13C NMR, Table 2. Anal.
Calcd for C22H24N2OS: C, 72.49; H, 6.64; N, 7.68. Found: C,
72.34; H, 6.65; N, 7.66.
31b (more polar isomer): mp 205-207 °C (EtOAc); IR
(Nujol): 3189-3217; 1H NMR (500 MHz, DMSO-d6): 1.45 (ddt,
J ) 10, 7, 1.5, H-3R), 1.70 (m, H-4â), 1.98 (qd, J ) 11.5, 5.5,
H-4R), 2.04 (dtd, J ) 12, 9, 3, H-3â), 2.10 (t, J ) 8.5, H-2â),
2.14 (m, H-3a), 2.40 (ddd, J ) 11.5, 7.5, 5, 1H, CH2S), 2.66
(ddd, J ) 17, 11, 5.5, H-5â), 2.72 (ddd, J ) 17, 6, 3, H-5R), 2.91
(m, 2H, CH2N), 3.15 (td, J ) 9, 2, H-2R), 3.28 (d, J ) 6, H-10c),
3.42 (dt, J ) 12, 8, 1H, CH2S); 6,96 (td, J ) 7.5, 1, H-8), 7.00
(td, J ) 7.5, 1, H-9), 7.26 (d, J ) 7.5, H-7), 7.32 (d, J ) 7.5,
H-10), 7.50-7.58 (m, 5H), 10.88 (s, H-6); 13C NMR, Table 2.
Anal. Calcd for C22H24N2OS: C, 72.49; H, 6.64; N, 7.68.
Found: C: 72.46; H: 6.64; N: 7.77.
N-Meth oxyca r bon yla tion of In d ole 31. To a solution of
indoles 31 (630 mg, 1.66 mmol) in a 6:1 mixture of THF-
HMPA (10 mL) at -78 °C was added 1.6 M LDA in cyclohex-
ane (1.1 mL, 1.7 mmol). The mixture was stirred at this
temperature for 1 h. Then, methyl cyanoformate (0.25 mL,
3.15 mmol) was added and the ice bath was removed. The
temperature was raised to room temperature and stirring was
maintained for 2 h. The reaction was quenched with saturated
aqueous Na2CO3 (25 mL) and extracted with EtOAc (3 × 50
mL). The organic phase was washed with brine (10 × 50 mL),
dried, and evaporated to dryness. Crystallization of the
residue with EtOAc allowed isolation of separate pure dias-
tereomer 25a . From the mother liquors and by column
chromatography (EtOAc), the other carbamate 25b was iso-
lated in a pure form. The overall yield was 78% (550 mg) in
an equimolecular ratio of both carbamates.
Meth yl cis-1,2,3,3a ,4,5,6,10c-Octa h yd r op yr r olo[3,2-c]-
ca r ba zole-6-ca r boxyla te (24). A suspension of tetracycle 23
(1 g, 2.77 mmol) and activated39 Pd(OH)2 (100 mg) in MeOH
(25 mL) was hydrogenated until the disappearance of the
starting compound was observed by TLC (3 days). The catalyst
was removed by filtration through Celite, and the solvent was
evaporated to give indole 24 (970 mg) as a white solid, which
was used in the next step without further purification. A pure
sample was obtained by chromatography (1% diethylamine in
a 1:10 mixture MeOH-EtOAc): mp 98-100 °C (EtOH); IR
(film) 3297, 1720; 1H NMR 1.50-1.65 (m, 2H), 1.78-1.85 (ddd,
J ) 13.6, 9.1, 4.4, 1H), 2.02 (m, 1H), 2.31 (m, 1H), 2.52 (br s,
1H), 2.79 (ddd, J ) 18, 9.5, 5.8, 1H), 2.96-3.14 (m, 3H), 3.98
(s, 3H), 4.09 (d, J ) 5.9, 1H), 7.20-7.24 (m, 2H), 7.59-7.63
(m, 1H), 8.04-8.09 (m, 1H); 13C NMR, Table 2. HRMS calcd
for C16H18N2 270.1368, found 270.1364.
Met h yl cis-1-[2-(P h en ylsu lfin yl)et h yl]-1,2,3,3a ,4,5,6,-
10c-octa h yd r op yr r olo[3,2-c]ca r ba zole-6-ca r boxyla te (25).
To a solution of amine 24 (400 mg, 1.47 mmol) in MeOH (4
mL) was slowly added phenyl vinyl sulfoxide (0.25 mL, 45
mmol). The reaction mixture was heated to reflux for 18 h.
Following evaporation to dryness, chromatography (EtOAc)
afforded 25 (400 mg, 65%) as a mixture of diastereoisomers
at sulfur. For analytical data, vide infra.
cis-1,2,3,3a ,4,5,6,10c-Oct a h yd r op yr r olo[3,2-c]ca r b a -
zole (26). A suspension of tetracycle 19 (820 mg, 2.71 mmol)
and activated39 Pd(OH)2 (80 mg) in MeOH (80 mL) was
hydrogenated until the disappearance of the starting com-
pound was observed by TLC (3 days). The catalyst was
removed by filtration through Celite, and the solvent was
evaporated to give indole 26 (420 mg, 90%) as a white solid:
1
mp 157-159 °C (EtOH); IR (film) 3398; H NMR 1.53-2.20
(m, 4H), 2.42 (m, 1H), 2.71 (dd, J ) 7.2, 5, 2H), 2.96 (ddd, J )
11.2, 8.7, 6.1, 1H), 3.14 (ddd, J ) 11.3, 8.8, 6.2, 1H), 3.63 (s,
2H), 4.21 (d, J ) 9, 1H), 7.06-7.12 (m, 2H), 7.26-7.33 (m,
1H), 7.62-7.66 (m, 1H); 13C NMR, Table 2. HRMS calcd for
C14H16N2 212.1313, found 212.1304.
cis-1-[2,2-Bis(m et h ylt h io)et h yl]-1,2,3,3a ,4,5,6,10c-oc-
ta h yd r op yr r olo[3,2-c]ca r ba zole (28). A stirred mixture of
26 (212 mg, 1 mmol), bromoacetaldehyde diethyl acetal (0.25
mL, 1.5 mmol), and anhydrous K2CO3 (200 mg, 1.3 mmol) in
dioxane (15 mL) was heated at reflux for 20 h. Removal of
the solvent gave a residue which was taken up with CH2Cl2.
The resulting solution was washed with saturated aqueous
Na2CO3. After workup, the residue was chromatographed
(CH2Cl2-EtOAc) to yield acetal 27 (150 mg, 50%): IR (film)
3398; 1H NMR 0.96 (t, J ) 7, 3H), 1.10 (t, J ) 7, 3H), 1.50 (m,
1H), 1.60 (m, 1H), 1.90-2.11 (m, 2H), 2.15 (m, 1H), 2.38 (td,
J ) 9.2, 8, 1H), 2.45 (m, 1H), 2.56 (dd J ) 12.5, 5.5, 1H), 3.20-
3.35 (m, 3H), 3.39 (dq, J ) 10, 7, 2H), 3.51 (d, J ) 5.1, 1H),
3.57 (dq, J ) 9.5, 7, 2H), 4.57 (t, J ) 5.3, 1H), 6.96-7.03 (m,
2H), 7.14 (m, 1H), 7.52 (m, 1H), 8.06 (br s, 1H); 13C NMR, Table
2. A solution of 27 (150 mg, 0,46 mmol), BF3‚Et2O (0.9 mL,
6.9 mmol), and methanethiol (1 mL) in CH2Cl2 (10 mL) was
stirred at 0 °C in a sealed tube for 6 h. The mixture was
poured into 50% aqueous NaOH and extracted with CH2Cl2
(3 × 50 mL). After workup and chromatography (1:1, hexane-
CH2Cl2), thioacetal 28 (50 mg, 34%) was isolated: IR (film)
3398; 1H NMR 1.58-1.67 (m, 1H), 1.72-1.80 (m, 1H), 1.88 (s,
3H), 1.95 (s, 3H), 2.03-2.22 (m, 2H), 2.23 (m, 1H), 2.38 (td, J
) 9, 7, 1H), 2.67-2.72 (m, 2H), 2.85 (dd, J ) 12.2, 5.4, 1H),
3.32 (td, J ) 8.5, 3.5, 1H), 3.38 (dd, 1H, J ) 12.3, 9.8, 1H),
3.60 (d, J ) 4.4, 1H), 4.57 (dd, J ) 9.7, 5.3, 1H), 7.05-7.11
(m, 2H), 7.22-7.28 (m, 1H), 7.56-7.61 (m, 1H), 7.87 (br s, 1H);
13C NMR, Table 2. HRMS calcd for C18H24N2S2 332.1380,
found 332.1366.
Using the same procedure, the less polar diastereomer 31a
gave the related carbamate 25a , and the more polar diaste-
reomer 31b gave 25b.
cis-1-[2-P h en ylsu lfin yl)eth yl]octah ydr oin dol-6-on e (30).
To a solution of amine 1 (4.8 g, 31.3 mmol) in absolute EtOH
(15 mL) was slowly added phenyl vinyl sulfoxide (5.93 mL, 45
mmol) under nitrogen. The reaction mixture was stirred at
room temperature for 18 h. Concentration give a crude N-[2-
(p h en ylsu lfin yl)eth yl]-2-(4-m eth oxy-2,5-d ih yd r op h en yl)-
Met h yl cis-1-[2-(P h en ylsu lfin yl)et h yl]-1,2,3,3a ,4,5,6,-
10c-octah ydr opyr r olo[3,2-c]car bazole-6-car boxylate (25a):
mp 138-139 °C (EtOAc); IR (KBr) 1736; 1H NMR 1.62 (m, 1H),
1.80 (m, 1H), 1.99-2.20 (m, 3H), 2.23 (m, 1H), 2.60-3.00 (m,
4H), 3.17 (m, 1H), 3.27 (m, 1H), 3.40 (m, 1H), 3.41 (d, J ) 4,
1H), 4.04 (s, 3H), 6.90-7.30 (m, 8H), 8.10 (d, J ) 7.5, 1H); 13
C

Total Synthesis of (()-Deethylibophyllidine
J . Org. Chem., Vol. 61, No. 20, 1996 7115
NMR, Table 2. Anal. Calcd for C24H26N2O3S : C, 68.22; H,
6.20; N, 6.63. Found: C, 68.16; H, 6.20; N, 6.66.
(220 mg, 0.12 mmol) in absolute EtOH (6 mL) was added
freshly prepared Raney Ni (W-2, 6 spatulas), and the mixture
was heated at reflux for 4 h. The solids were removed by
filtration through Celite and washed with EtOH. Removal of
the solvent and purification of the residue by chromatography
(1% diethylamine in EtOAc) gave 33 as an oil (100 mg, 64%):
IR (film) 1717; 1H NMR 1,70 (ddd, J ) 12.4, 5.7, 2, H-6â), 1.75-
1.83 (m, H-15â), 1.82 (dt, J ) 11.5, 3.2, H-17R), 2.04 (td, J )
11.6, 5.1, H-17â), 2.10 (m, H-14), 2.18 (dd, J ) 11.4, 7, H-6R),
2.34 (dddd, J ) 14.3, 8.2, 5.2, 1, H-15R), 2.81 (m, H-20R). 2.87
(ddd, J ) 12.2, 7.5, 2, H-5R), 3.30 (t, J ) 8.5, H-20â), 3.32 (td,
J ) 12, 5.5, H-5â), 3.76 (d, J ) 6, H-3), 6.23 (dd, J ) 8, 3,
H-16), 7.07 (td, J ) 7.5, 1, H-11), 7.24 (td, J ) 7.5, 1, H-10),
7.34 (dd, J ) 7.5, 1, H-9), 7.81 (dd, J ) 7.5, 1, H-12); 13C NMR
27.8 (C-15), 32.1 (C-17), 38.2 (C-14), 40.1 (C-6), 52.1 (C-5), 52.8
(OCH3), 53.5 (C-7), 54.6 (C-20), 74.1 (C-3), 106.6 (C-16), 115.3
(C-12), 122.4 (C-10), 123.8 (C-9), 127.8 (C-11), 137.8 (C-8),
140.5 (C-2), 144.2 (C-13), 153.2 (CO). Anal. Calcd for
Met h yl cis-1-[2-(P h en ylsu lfin yl)et h yl]-1,2,3,3a ,4,5,6,-
10c-oct a h yd r op yr r olo[3,2-c]ca r b a zole -6-ca r b oxyla t e
(25b): 1H NMR 1.50-1.70 (m, 1H), 1.70-1.90 (m, 1H), 1.98-
2.10 (m, 3H), 2.24 (m, 1H), 2.44 (m, 1H), 2.70-3.00 (m, 3H),
3.10-3.30 (m, 2H), 3.45 (m, 1H), 3.58 (d, J ) 5.1, 1H), 4.02
(s, 3H), 7.23-7.50 (m, 8H), 8.10 (d, J ) 7.5, 1H); 13C NMR,
Table 2.
Met h yl 1-(P h en ylt h io)-2,4,5,5a ,6,7,8,12a -h exa h yd r o-
1H-p yr r olizin o[1,7-cd ]ca r ba zole-8-ca r boxyla te (32). To
a solution of sulfoxides 25 (300 mg, 0.71 mmol) in anhydrous
toluene (10 mL) was added at room temperature, in
a
sequential manner, TFAA (0.3 mL, 2.16 mmol) and TFA (0.18
mL, 2.16 mmol). The solution was warmed at 80 °C for 2 h.
The mixture was then cooled and the reaction quenched by
addition of aqueous saturated Na2CO3 (25 mL). The aqueous
mixture was extracted three times with 50 mL portions of
CH2Cl2. Purification of dried extracts by chromatography (4:
1, EtOAc-CH2Cl2) afforded 180 mg (63%) of pentacycle 32 as
an epimeric mixture at C-6, which could be separated partially
by a chromatography: IR (film) 1717.
.
C18H20N2O2 H2O: C, 68.77; H, 7.05; N, 8.91. Found: C, 68.65;
H, 6.98; N, 8.76.
(()-Deeth ylibop h yllid in e. A degassed solution of 33 (50
mg, 0.17 mmol) in MeOH (100 mL) was photolyzed under
argon with a 125-W medium-pressure mercury lamp in a
quartz immersion well reactor for 2.5 h. After evaporation of
the solvent, the residue was dissolved in CH2Cl2 and washed
with saturated aqueous Na2CO3. After workup and chroma-
tography (2% diethylamine in CH2Cl2), deethylibophyllidine
(25 mg, 50%) in amorphous form was isolated: mp 111-112
°C (reported5a mp 110 °C); IR (film) 3500, 1676, 1608; 1H NMR
(500 MHz, COSY) 1.68 (dd, J ) 12.5, 5, H-6â), 1.78 (dd, J )
12.5, 5.5, H-15R), 1.86 (dd, J ) 15.5, 12, H-17R), 2.02 (m, H-14),
2.05 (td, J ) 12.5, 5.5, H-6R), 2.14 (tt, J ) 12.5, 7, H-15â), 2,73
(m, H-20R), 2.78 (dd, J ) 15.5, 6, H-17â), 2.92 (dd, J ) 12.5, 7,
H-5R), 3.33 (t, J ) 8, H-20â), 3.38 (td, J ) 12.5, 5.5, H-5â), 3.75
(s, 3H), 3.79 (d, J ) 6, H-3), 6.82 (dd, J ) 7.5, 0.5, H-12), 6.88
(td, J ) 7.5, 1, H-10), 7.15 (td, J ) 7.5, 1, H-11), 7.33 (dd, J )
7.5, 0.5, H-9), 9.05 (s, NH); 13C NMR (HMQC) 26.2 (C-17), 31.8
(C-15), 38.7 (C-14), 38.9 (C-6), 51.0 (OCH3), 52.4 (C-5), 55.1
(C-20), 57.5 (C-7), 73.0 (C-3), 91.6 (C-16), 109.1 (C-12), 120.9
(C-10), 122.5 (C-9), 128.1 (C-11), 136.6 (C-8), 143.5 (C-13),
164.3 (C-2), 168.5 (CO).
Compound 32a (H-6â):2 1H NMR 1.76 (m, 2H, H-17), 1.94
(ddd, J ) 14.5, 11.5, 3, H-15â), 2.08-2.25 (m, H-14 and H-15R),
2.31-2.44 (m, H-20â), 2.77 (ddd J ) 14.5, 9, 5.5, H-20R), 3.18
(dd, J ) 12.5, 7.5, H-6), 3.29 (t, J ) 11.5, H-5R), 3.65 (dd, J )
12, 7.5, H-5â), 3.87 (s, 3H), 3.94 (d, J ) 6.5, H-3), 6.25 (dd,
J ) 7.5, 1, H-16), 7.10-7.40 (m, 8H), 7.83 (d, J ) 8, H-12);
13C NMR 30.6 (C-15), 31.6 (C-17), 38.3 (C-14), 53.1 (C-20), 52.6
(OCH3), 55.7 (C-6), 56.5 (C-7), 58,0 (C-5), 74.2 (C-3), 107.1
(C-16), 115.2 (C-12), 123.5 (C-9), 123.5 (p-Ar), 126.5 (C-10),
128.4 (C-11), 128.6 (o-Ar), 131.0 (m-Ar), 133.0 (ipso-Ar), 135.2
(C-8), 141.8 (C-2), 142.9 (C-13), 152.6 (CO).
Compound 32b (H-6R):2 1H NMR 1.91 (m, H-15â), 2.03 (m,
2H, H-17), 2.14 (m, H-14), 2.44 (td, J ) 11.3, 2.5, H-15R), 2,72
(t, J ) 10, H-5â), 3.03 (dt, J ) 11, 7, H-20â), 3.20 (m, H-20R),
3.59 (dd, J )10, 7, H-5R), 3.87 (d, J ) 7, H-3), 3.87 (s, 3H),
3.93 (dd, J ) 10, 7, H-6), 6.59 (dd, J ) 9, 1.5, H-16), 6.9-7.0
(m, 5H), 7.08 (td, J ) 7.5, 1.5, H-11), 7.20 (td, J ) 7.5,1.5,
H-10), 7.43 (dd, J ) 7.5, 1.5, H-9), 7.64 (d, J ) 7.5, H-12); 13
C
NMR 30.6 (C-15), 31.5 (C-17), 37.3 (C-14), 52.6 (C-20), 52.7
(OCH3), 55.2 (C-7), 62.9 (C-6), 63.0 (C-5), 75.4 (C-3), 113.0
(C-16), 115.2 (C-12), 121.8 (C-9), 123.7 (p-Ar), 126.0 (C-10),
128.0 (C-11), 128.5 (o-Ar), 129.9 (m-Ar), 135.3 (C-8), 137.1
(ipso-Ar), 140.9 (C-2), 141.7 (C-13), 153.2 (CO). HRMS calcd
for C24H24N2O2S 404.1558, found 404.1558.
Ack n ow led gm en t . Financial support from the
DGICYT, Spain (Project PB94-0858), is gratefully
acknowledged.
Met h yl 2,4,5,5a ,6,7,8,12a -Hexa h yd r o-1H-p yr r olizin o-
[1,7-cd ]ca r ba zole-8-ca r boxyla te (33). To a solution of 32
J O960848Z