Total syntheses of (±)-deethylibophyllidine using a crisscross annulation: Ring cleavage of octahydroindolo[2,3-α]quinolizines followed by tandem cyclizations of octahydroazecino[5,4-b]indoles

Article abstract of DOI:10.1021/jo980909o

The total synthesis of (±)-deethylibophyllidine (1) is described. Three different sequences provide this pentacyclic alkaloid using a common strategy involving a crisscross annulation. Key steps include (i) C/D ring cleavage of a 2-formyloctahydroindolo[2,3-a]quinolizine to obtain octahydroazecino[5,4-6]indoles, via either a chloroformate induced process or a quaternary ammonium salt formation followed by treatment with lithium, and (ii) a tandem process consisting of an intramolecular Pictet-Spengler double cyclization upon a /3-indole position of a 2,3-disubstituted indole to generate the quaternary spiro center of the pentacyclic skeleton of ibophyllidine alkaloids. Attempts to extend the procedure to the construction of the pentacyclic framework of (±)-ibophyllidine result in very low yield.

Full text of DOI:10.1021/jo980909o

7338
J . Org. Chem. 1998, 63, 7338-7347
Tota l Syn th eses of (()-Deeth ylibop h yllid in e Usin g a Cr isscr oss
An n u la tion : Rin g Clea va ge of Octa h yd r oin d olo[2,3-a ]qu in olizin es
F ollow ed by Ta n d em Cycliza tion s of
Octa h yd r oa zecin o[5,4-b]in d oles
J osep Bonjoch,* J oan-Carles Ferna`ndez, and Nativitat Valls
Laboratory of Organic Chemistry, Faculty of Pharmacy, Universitat de Barcelona,
08028-Barcelona, Spain
Received May 12, 1998
The total synthesis of (()-deethylibophyllidine (1) is described. Three different sequences provide
this pentacyclic alkaloid using a common strategy involving a crisscross annulation. Key steps
include (i) C/D ring cleavage of a 2-formyloctahydroindolo[2,3-a]quinolizine to obtain octahydroaze-
cino[5,4-b]indoles, via either a chloroformate induced process or a quaternary ammonium salt
formation followed by treatment with lithium, and (ii) a tandem process consisting of an
intramolecular Pictet-Spengler double cyclization upon a â-indole position of a 2,3-disubstituted
indole to generate the quaternary spiro center of the pentacyclic skeleton of ibophyllidine alkaloids.
Attempts to extend the procedure to the construction of the pentacyclic framework of (()-
ibophyllidine result in very low yield.
Sch em e 1. Syn th etic Str a tegies for th e Syn th esis
of Ibop h yllid in e Alk a loid s
In tr od u ction
The ibophyllidine alkaloids1 are a type of pentacyclic
monoterpenoid indole alkaloids belonging to the Ibogan
biogenetic class.2 They have been synthesized using the
strategies depicted in Scheme 1, in which the crucial step
is the formation of the spiro stereocenter at C-73 to
generate the characteristic 2,3,3-trisubstituted indoline
unit. Kuehne,4 and later Das,5 used an intramolecular
Diels-Alder process to form the strategic bonds. Later
Kuehne reported a modification of his first approach,
elaborating the D ring at the end of the synthesis by a
reductive amination.6 In the more recent example from
our laboratory,7 a Pummerer rearrangement/thionium
ion-mediated indole cyclization was employed to elabo-
rate the C ring in the key step.8 The ibophyllidine
alkaloids have a skeleton which lacks the C-21 biogenetic
carbon, implying the presence of a pyrrolidine D ring
instead of the piperidine ring found in the structurally
(1) Saxton, J . E. The Ibogamine-Catharanthine Group in Monoter-
penoid Indole Alkaloids; Saxton, J . E., Ed.; In The Chemistry of
Heterocyclic Compounds; Taylor, E. C. Ed.; Wiley: New York 1994;
Supplement to Vol. 25, Part 4, pp 487-521.
(2) (a) Kisaku¨rek, M. V.; Leeuwenberg, A. J . M.; Hesse, M. A. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1983; Vol. 1, pp 211-376. (b) Van Beek, T. A.;
Verpoorte, R.; Baerheim Svendsen, A.; Leeuwenberg, A. J . M.; Bisset,
N. G. J . Ethnopharmacol. 1984, 10, 1-156. (c) Van Beek, T. A.; Van
Gessel, M. A. J . T. Alkaloids of Tabernaemontana Species. In Alka-
loids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1988; Vol. 6, pp 75-226.
(3) The biogenetic numbering (Le Men, J .; Taylor, W. I. Experientia
1965, 21, 508-509) is used throughout this paper, but the systematic
nomenclature has been used in the tables and Experimental Section.
(4) (a) Kuehne, M. E.; Matsko, T. H.; Bohnert, J . C.; Motyka, L.;
Oliver-Smith, D. J . Org. Chem. 1981, 46, 2002-2009. (b) Kuehne, M.
E.; Bohnert, J . C. J . Org. Chem. 1981, 46, 3443-3447.
(5) (a) Barsi, M.-C.; Das, B. C.; Fourrey, J .-L.; Sundaramoorthi, R.
J . Chem. Soc., Chem. Commun. 1985, 88-89. (b) J egham, S.; Fourrey,
J .-L.; Das, B. C. Tetrahedron Lett. 1989, 30, 1959-1962.
related Aspidosperma and Strychnos alkaloids. Never-
theless, since all of them possess a pyrrolo[2,3-d]carbazole
moiety (ABCE rings) as a common structural feature, the
development of a new synthetic strategy to the ibophyl-
lidine alkaloids can also open new perspectives for the
synthesis of the aforementioned related alkaloid types.9
In this paper we describe a new, straightforward
synthetic entry to 2,3,3-trisubstituted indole alkaloids
embodying the pyrrolo[2,3-d]carbazole skeleton based on
the transannular Pictet-Spengler cyclization (bond formed
C-3/C-7) of an iminium ion generated intramolecularly
(8) For other synthetic approaches leading to derivatives with the
pyrrolizino[1,7-cd]carbazole skeleton, see: (a) Kuehne, M. E.; Oku-
niewicz, F. J .; Kirkemo, C. L.; Bohnert, J . C. J . Org. Chem. 1982, 47,
1335-1343. (b) Kuehne, M. E.; Wang, T.; Seaton, P. J . J . Org. Chem.
1996, 61, 6001-6008. (c) Kuehne, M. E.; Wang, T.; Seraphin, D. J .
Org. Chem. 1996, 61, 7873-7881.
(9) Syntheses of Aspidosperma and Strychnos alkaloids through
formation of E-,10 D-,11 and C-ring12 by the strategies shown in Scheme
1 have also been reported.
(6) (a) Kuehne, M. E.; Pitner, J . B. J . Org. Chem. 1989, 54, 4553-
4569. (b) Bornmann, W. G.; Kuehne, M. E. J . Org. Chem. 1992, 57,
1752-1760. (c) Kuehne, M. E.; Bandarage, U. K.; Hammach, A.; Li,
Y.-L.; Wang, T. J . Org. Chem. 1998, 63, 2172-2183. (d) Reference 4a.
(7) Bonjoch, J .; Catena, J .; Valls, N. J . Org. Chem. 1996, 61, 7106-
7115.
S0022-3263(98)00909-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/19/1998

Total Syntheses of (()-Deethylibophyllidine
J . Org. Chem., Vol. 63, No. 21, 1998 7339
Sch em e 2. Retr osyn th etic P la n for th e Syn th esis
of Deeth ylibop h yllid in e
most common procedure involves the use of chloroformate
esters.18,19 Less common procedures to the cleavage are
the reactions with cyanogen bromide20 or anhydrides.21
Other approaches have utilized the formation of a
quaternary ammonium salt, which is then treated with
an alkali metal22 or cyanide ions.23
With the aforementioned strategy to synthesize ibo-
phyllidine alkaloids, two different tactics can be envis-
aged to introduce the C-22 exocyclic carbon (Scheme 2).
Thus, the C-22 can be introduced before the double ring
closure, which would allow the pentacyclic skeleton of the
targets to be built (via a), taking advantage of the
functionalization present in C-16 when the ring cleavage
was conducted in solvolytic conditions. On the other
hand, the C-22 can be introduced later to the tandem
process (via b), taking advantage of the formation of the
known ene carbamate 24, which has been previously
converted to (()-deethylibophyllidine.7
Resu lts a n d Discu ssion
Tota l Syn th esis of (()-Deeth ylibop h yllid in e: Th e
F ir st Ap p r oa ch .24 According to our synthetic plan we
(bond formed C-3/N-4) from an appropriately substituted
azecino[5,4-b]indole. The usefulness of this strategy is
exemplified by the three routes developed for the syn-
thesis of the alkaloid deethylibophyllidine. Our approach
constitutes a crisscross-type annulation,13 in which the
key octahydro azecino[5,4-b]indole intermediate is pre-
pared by ring cleavage (bond cleaved N-4/C-16) of a
readily accessible 2-formyloctahydroindolo[2,3-a]quino-
lizine (Scheme 2). Beginning with the pioneering work
of Dolby and Sakai14 in 1964, a number of procedures
have been reported for the cleavage of zero bridged single
bonds in tetra- or pentacyclic indole compounds incor-
porating a tetrahydro-â-carboline unit (i.e. 6).15-17 The
(18) (a) Sakai, S.; Yamanaka, E.; Dolby, L. J . Heterocycles 1976, 4,
981-984. (b) Calverley, M. J .; Harley-Mason, J .; Quarrie, S. A.;
Edwards, P. D. Tetrahedron 1981, 37, 1547-1556. (c) Liu, C.; Sun, S.;
Yu, Q. J . Org. Chem. 1983, 48, 44-47. (d) Takayama, H.; Masubuchi,
K.; Kitajima, M.; Aimi, N.; Sakai, S. Tetrahedron 1989, 45, 1327-1336.
(e) Schill, G.; Priester, C. U.; Windho¨vel U. F.; Fritz, H. Tetrahedron
1990, 46, 1211-1220 and previous papers in this series. (f) Magnus,
P.; Mendoza, J . S.; Stamford, A.; Ladlow, M.; Willis, P. J . Am. Chem.
Soc. 1992, 114, 10232-10245. (g) Takayama, H.; Tominaga, Y.;
Kitajuma, M.; Aimi, N.; Sakai, S.-I. J . Org. Chem. 1994, 59, 4381-
4385 and previous papers in this series. (h) Mahboobi, S.; Wagner,
W.; Burgemeister, T.; Wiegrebe, S. Arch. Pharm. (Weinheim) 1994, 327,
463-465. Mahboobi, S.; Wagner, W.; Burgemeister, T. Arch. Pharm.
(Weinheim) 1995, 328, 371-376.
(19) (a) Calverley, M. J . J . Chem. Soc., Chem. Commun. 1981, 1209-
1210. (b) Calverley, M. J .; Harley-Mason, J . Tetrahedron Lett. 1981,
22, 1631-1634. (c) Calverley, M. J .; Banks, B. J .; Harley-Mason, J .
Tetrahedron Lett. 1981, 22, 1635-1638. (d) Calverley, M. J . J . Chem.
Res., Synop. 1983, 190-191; J . Chem. Res. Miniprint 1983, 1848-
1890.
(20) (a) Albright, J . D.; Goldman, L. J . Am. Chem. Soc. 1969, 91,
4317-4318. (b) Sakai, S; Shinma, N. Heterocycles 1976, 4, 985-988.
(c) Costa, G.; Riche, C.; Husson, H. P. Tetrahedron 1977, 33, 315-
320. (d) Kutney, J . P.; Eigendorf, G. K.; Matsue, H.; Murai, A.; Tanaka,
K.; Sung, W. L.; Wada, K.; Worth, B. R. J . Am. Chem. Soc. 1978, 100,
938-943. (e) Schill, G.; Lo¨wer, H.; Priester, C. U.; Windho¨vel, U. D.;
Fritz, H. Tetrahedron 1987, 43, 3729-3745. (f) Koike, T.; Takayama,
H.; Sakai, S. Chem. Pharm. Bull. 1991, 39, 1677-1681. See also ref
18b.
(21) (a) Dolby, L. J .; Sakai, S. Tetrahedron 1967, 23, 1-9. (b) Foster,
G. H.; Harley-Mason, J .; Waterfield, W. R. J . Chem. Soc., Chem.
Commun. 1967, 21. (c) Harley-Mason, J .; Atta-ur-Rahman. J . Chem.
Soc., Chem. Commun. 1967, 1048-1049. (d) Harley-Mason, J . Pure
Appl. Chem. 1975, 41, 167-174 and references therein. (e) Ponglux,
D.; Wongscripipatana, S. Subhadhirasakul, S.; Takayama, H.; Yokota,
M.; Ogata, K.; Phisalaphong, C.; Aimi, N.; Sakai, S. Tetrahedron 1988,
44, 5075-5093. See also ref 20e.
(10) (a) Kuehne, M. E.; Hafter, R. J . Org. Chem. 1978, 43, 3702-
3704. (b) Kuehne, D. A. Frasier and T. D. Spitzer, J . Org. Chem. 1991,
56, 2696-2700. Kuehne, M. E.; Brook, C. S.; Frasier, D. A. J . Org.
Chem. 1994, 59, 5977-5982.
(11) (a) Kalaus, G.; J uha´sz, I.; Greiner, I.; Kajta´r-Peredy, M.; Brlik,
J .; Szabo´, L.; Sza´ntay, C. J . Org. Chem. 1997, 62, 9188-9191. See also
ref 6b. (b) Nkiliza, J .; Vercauteren, J .; Le´ger, J .-M. Tetrahedron Lett.
1991, 32, 1787-1990. Kuehne, M. E.; Xu, F. J . Org. Chem. 1993, 58,
7490-7497.
(12) (a) Gallagher, T.; Magnus, P. J . Am. Chem. Soc. 1983, 105,
4750-4757. (b) Amat, M.; Linares, A.; Bosch, J . J . Org. Chem. 1990,
55, 6299-6312.
(13) This name was suggested by Prof. B. M. Trost, see: Ohnuma,
T.; Tabe, M.; Shiiya, K.; Ban, Y.; Date, T. Tetrahedron Lett. 1983, 24,
4249-4252.
(14) Dolby, L. J .; Sakai, S. J . Am. Chem. Soc. 1964, 86, 5362-5363.
(15) The most significant methods in this field are depicted in the
following figure.
(22) For ring cleavage of indolo[2,3-a]quinolizidine Nb-metho salts
by an alkali metal in ammonia, see: (a) Harley-Mason, J .; Atta-ur-
Rahman, Beisler, J . A. J . Chem. Soc., Chem. Commun. 1966, 743. (b)
Herbst, D.; Rees, R.; Hughes, G. A.; Smith, H. J . Med. Chem. 1966, 9,
864-868. (c) Dolby, L. J .; Gribble, G. W. J . Org. Chem. 1967, 32, 1391-
1398. For the same procedure with other heterocyclic related systems,
see (d) Wenkert, E.; Garratt, S.; Dave, K. G. Can. J . Chem. 1964, 42,
489-490. (e) Kutney, J . P.; Abdurahman, N.; Le Quesne, P.; Piers, E.;
Vlattas, I. J . Am. Chem. Soc. 1966, 88, 3656-3657. (f) Kutney, J . P.;
Beck, J .; Bylsma, F.; Cook, J .; Cretney, W. J .; Fuji, K.; Imhof, R.;
Treasurywala, A. M. Helv. Chim. Acta 1975, 58, 1690-1719 and
preceding paper. (g) Takano, S.; Hirama, M.; Ogasawara, K. Tetrahe-
dron Lett. 1982, 23, 881-884. (h) Node, M.; Nagasawa, H.; Fuji, K. J .
Org. Chem. 1990, 55, 517-521.
F igu r e 1.
(16) For a review on synthetic approaches to anticancer alkaloids,
using this type of cleavage, see: Atta-ur-Rahman, Iqbal, Z.; Nasir, H.
Stud. Nat. Prod. Chem. 1994, 14, 805-884.
(17) For reviews about the synthesis of medium sized rings by ring
expansion reactions, see: (a) Hesse, M. Ring Enlargement in Organic
Synthesis; VHC: Weinheim, 1991. (b) Roxburgh, C. J . Tetrahedron
1993, 49, 10749-10784.
(23) (a) Foster, G. H.; Harley-Mason, J . J . Chem. Soc., Chem.
Commun. 1968, 1440-1441 and references therein. (b) Bu¨chi, G. H.
Chimia 1975, 29, 172-173. (c) Kutney, J . P.; Chan, K. K.; Failli, A.;
Fromson, J . M.; Gletsos, C.; Leutwiler, A.; Nelson, V. R.; De Souza J .
P. Helv. Chim. Acta 1975, 58, 1648-1671.

7340 J . Org. Chem., Vol. 63, No. 21, 1998
Bonjoch et al.
while that of acetal 7b, as well as thioacetal 8b, was cis
(see Table 1 for 13C NMR data).31
Acetals 7a and 7b were independently submitted to
C/D ring cleavage with benzyl chloroformate and excess
18e
water in THF in the presence of Na2CO3 to stereospe-
cifically give the respective epimeric alcohols 10a (72%)
and 10b (40%). The stereochemical assignment for 10a
was based upon a comparison of its 13C NMR data with
those of a model compound lacking the substituent at
C-14 and possessing the same CBC conformation for the
azecino ring on the basis of the diagnostic 1H NMR
upfield shift of the proton H-15 (δ 0.55).32 The relative
configuration of 10a also agrees with mechanistic
considerations.18b
When the ring cleavage was effected with chlorofor-
mates other than benzyl, such as vinyl, p-nitrophenyl,
or R,R,R-trichloroacetyl, the yields were lower, the 54%
yield of carbamate 11a in the Sakai conditions (MgO,
TrocCl)18g being the most significant. Using other start-
ing materials for this cleavage, the seco derivative 12 was
isolated from thioacetal 8a in 30% yield, and azecinoin-
dole 13 was isolated operating from aldehyde 6 or enol
ether 9, in 10% and 40% yields, respectively. Clearly,
these results are lower than those observed in the acetal
series, and as a consequence acetal 10a was chosen as
the advanced intermediate for the final steps.
F igu r e 2.
needed as starting material the indoloquinolizine 6,
which was synthesized by a slight modification of the
protocol described by Massiot,25 who used the method
developed by J oule26 for the synthesis of octahydroindolo-
[2,3-a]quinolizines by means of acid isomerization of
tetrahydropyridine derivatives with an electron-with-
drawing substituent at C-4. Compound 6 is available
from the pyridinium salt 4 through NaBH4 reduction and
acetic acid treatment of the tetrahydropyridine 5. The
latter process brought about deprotection of the acetal
function, isomerization of the double bond, which gave
an enamine, and cyclization via an iminium ion. Alde-
hyde 6 was isolated as a 7:2 mixture of epimers and,
without purification, was protected as an ethylene acetal
using Amberlyst-1527 or BF3‚Et2O28 as the catalyst. The
resulting acetals 7a and 7b were separated by column
chromatography (the first in this reaction sequence).
Although this separation is not strictly necessary from
the synthetic standpoint, since C-16 (corresponding to
C-12b in the indolo[2,3-a]quinolizidine system) is not a
stereogenic center in the final product, it is convenient
from the practical point of view due to the slightly
different reactivity of both epimers (see below).
For the introduction of the additional carbon (C-22),
alcohol 10a was converted to the corresponding acetate
14a (92%) and then treated with NaCN in DMSO.33
A
nearly equimolecular mixture of epimeric nitriles 15
(88%) was obtained, thus suggesting that the SN1 process
is preponderant.34 Operating in a similar manner from
alcohol 10b, a mixture of nitriles 15 was also obtained,
although in lower overall yield (40%). Attempts to obtain
esters 18 from nitriles 15, via amides 17 (i, H2O2, NaOH;
ii, MeOH, Amberlyst-15), resulted in low yield. When
we attempted this conversion in acid medium,35 to our
pleasant surprise we found a transformation that ad-
ditionally overcomes the crucial difficulty of the synthe-
sis, involving the simultaneous formation of rings CDE
by an intramolecular Pictet-Spengler reaction. The
alkaloid deethylibophyllidine, which was identified by
comparison with a sample prepared by an alternative
route,7 was directly obtained. Thus, when the mixture
of nitriles 15 was treated with HCl in methanol, followed
by in situ acid hydrolysis, a double transannular cycliza-
tion took place satisfactorily leading to a 1:1 mixture of
1 and 19 in a combined yield of 60%. This expeditious
To test the following ring cleavage, thioacetals 8 and
enol ether 929 were also prepared (Figure 2). Interest-
ingly, the trans-indoloquinolizine 6b shows different
conformational behavior from 7b and 8b. The preferred
conformation of aldehyde 6b was trans (C/D juncture),
(30) Synthesized from either Sza´ntay or Kuehne protocol: (a)
Blasko´, G.; Honty, K.; Nova´k, L.; Sza´ntay, C. Acta Chim. Acad. Sci.
Hung. 1979, 99, 35-41. (b) Kuehne, M. E.; Muth, R. S. J . Org. Chem.
1991, 56, 2701-2712.
(31) For conformational analysis of 2-substituted octahydroindolo-
[2,3-a]quinolizines, see: Lounasmaa, M.; J okela, R. Tetrahedron 1989,
45, 3975-3991.
(32) The NMR spectra of all octahydroazecinoindoles synthesized
in this work are very complicated due to the conformational flexibility
of medium sized rings and the duplicity of signals caused by the
(24) (a) Prior syntheses of (()-deethylibophyllidine: refs 4a, 5a, 6a,
and 7. (b) For a preliminary account of this part of the work, see:
Ferna`ndez, J . C.; Valls, N.; Bosch, J .; Bonjoch, J . J . Chem. Soc., Chem.
Commun. 1995, 2317-2318.
restricted rotation of the carbamate bond. For
a conformational
analysis of simple octahydroazecino[5,4-b]indoles, see: Bonjoch, J .;
Ferna`ndez, J .-C.; Valls, N. Eur. J . Org. Chem., submitted to be
published.
(33) Dadson, B. A.; Harley-Mason, J . J . Chem. Soc., Chem. Commun.
1969, 665.
(34) In one run with longer reaction times (24 h), ketone 16 was
formed.
(35) For conversion of nitriles to methyl esters, via imidates, see:
(a) Mandal, A. N.; Raychaudhuri, S. R.; Chatterjee, A. Synthesis 1983,
727-729. (b) Brussee, J .; Loos, W. T.; Kruse, C. G.; Van Der Gen, A.
Tetrahedron 1990, 46, 979-986.
(25) Massiot, G.; Cherif, A. Bull. Soc. Chim. Fr. 1990, 648-655.
(26) Allen, M. S.; Gaskell, A. J .; J oule, J . A. J . Chem. Soc. 1971,
736-743.
(27) Stenberg, V. I.; Vesley, G. F.; Kubik, D. J . Org. Chem. 1971,
36, 6, 2550-2551.
(28) Fieser, L. F.; Steveson, R. J . Am. Chem. Soc. 1954, 76, 1728-
1733.
(29) Compound 9 was prepared from octahydroindolo[2,3-a]quino-
lizine-2-one30 by a Wittig-type process [(C6H5)2POCH2OCH3, LDA] as
described in the Supporting Information.

Total Syntheses of (()-Deethylibophyllidine
Ta ble 1. 13C NMR of Octa h yd r oin d olo[2,3-a ]qu in olizin es (δ p p m , CDCl3)a
C-3 C-4 C-6 C-7 C-7a C-7b C-8 C-9 C-10 C-11 C-11a C-12a C-12b other other
J . Org. Chem., Vol. 63, No. 21, 1998 7341
C-1
C-2
6a b
6bc
7a
7b
8a
8b
9
29.3
28.2
30.7
29.1
35.1
33.1
48.3 25.3 54.4 52.9 21.6 108.2 127.1 118.1 119.3 121.3 110.9 136.1 134.1
44.8 24.5 53.4 51.7 21.0
40.3 26.9 54.8 53.1 21.7 108.1 127.3 118.1 119.3 121.3 110.7 136.0 134.7
35.5 26.5 47.7 52.2 19.0 108.0 127.5 118.0 119.3 121.3 110.8 135.7 133.7
44.0 31.4 55.1 52.8 21.6 108.1 127.3 118.1 119.3 121.3 110.8 135.9 134.4
39.8 30.7 46.5 51.3 18.1 108.0 127.4 118.0 119.5 121.5 111.0 135.8 132.7
58.7
56.4
59.1
54.3
59.4
53.9
59.3
64.7
66.0
66.8
203.3
204.7
65.0
106.8
64.9d 105.8
38.4
38.4
59.4
58.0
59.5
29.3 113.4 29.3 56.2 52.9 21.4 107.9 127.1 117.9 119.0 121.0 111.7 135.9 134.6
140.3
64.9
25a -1e 30.7
25a -2f 22.6
32a -1g 31.3
35.9 20.2 64.2 51.7 17.6 101.0 125.0 117.9 119.7 122.7 111.6 136.4 129.0
37.3 20.6 62.3 61.4 17.5 104.2 125.9 118.6 119.6 122.2 111.9 136.6 127.9
35.7 23.0 76.4 45.9 17.3 102.0 125.0 118.2 119.7 122.5 111.7 136.1 129.6
104.0
64.7d 104.8
64.8
103.9
a
b
Values for compounds 6a , 7a , 7b, 8a , and 8b were assigned on the basis of HMQC spectra. See also ref 25. c Values taken from an
NMR spectrum of a mixture of 6a and 6b. d Two peaks. e In CDCl3 + CD3OD: NMe δ 49.9. f In DMSO-d6: NMe δ 37.4. g Et: δ 11.6, 24.6.
NMe: δ 47.4.
Sch em e 3. Syn th esis of (()-Deeth ylibop h yllid in e
one-pot transformation involves seven chemical pro-
cesses: formation of an imidate from the cyano group,
cleavage of the carbamate protecting group, hydrolysis
of the acetal, generation of an iminium salt, hydrolysis
of the imidate, and finally, cyclization upon the substi-
tuted indole â-position with isomerization of the resulting
indolenine double bond to give the R-anilinoacrylate
moiety. It is worth mentioning the isolation of the
pentacyclic imidate 19 (a vinylogous O-methylurea),
which could not be further hydrolyzed36 to deethylibo-
phyllidine, thus suggesting that hydrolysis of the imidate
occurs before cyclization.
A Differ en t Ta ctic. A Secon d Wa y to (()-Deeth -
ylibop h yllid in e. As we have mentioned in the Intro-
duction, a second tactic with a crisscross strategy (via b,
Scheme 2) to achieve the synthesis of (()-deethylibophyl-
lidine can also be envisaged. Although the reductive
cleavage of 7a (CbzCl, NaCNBH3)19d allowed us to obtain
the azecinoindole 21 in only 27% yield, this intermediate
was obtained in improved yield by reduction (NaCNBH3,
AcOH) of the hydroxy derivative 10a (Scheme 4).
The formation of the required protected indole 22 was
achieved in good yield (95%) using LDA as a base and
methyl cyanoformate as the acylating agent. The meth-
oxycarbonyl group not only ensures the stability of the
product in the cyclization step but will also allow the
elaboration of the anilinoacrylate moiety in the last stage
of the synthesis. On the contrary, the deactivation of the
nucleophilicity of the indole nucleus did not allow the
double ring closure (22 f 24) at room temperature in
the same conditions used in the first series (15 f 1). The
best results for the tandem intramolecular iminium salt
formation/Pictet-Spengler cyclization were obtained when
azecinoindole 2337 was treated with TFA at toluene reflux
synthesis of more complex alkaloids with the same
skeletal-type and bearing a C-20 substituent.3,38 At-
tempts to induce the C/D ring cleavage reaction with
benzyl chloroformate and excess water in tetrahydrofu-
ran in the presence of sodium carbonate on the mixture
of amino acetals 3139 were unsuccessful. The unreactiv-
ity of 31 is probably due to the fact that the nitrogen is
rather more hindered than in 7, probably by the steric
crowding on the nitrogen atom exerted by the adjacent
ethyl group. At this point, to obtain the required azecino-
[5,4-b]indole system, we chose a method that implied in
the first instance the irreversible formation of a carbon-
nitrogen bond instead of the reversible formation that
temperature. Under these experimental conditions the
crucial quaternary center at C-7 was formed in a satis-
factory manner and the pentacyclic derivative 24 was
obtained in high yield. The final stage in the synthesis
involving the rearrangement of the methoxycarbonyl
group to give (()-deethylibophyllidine has been previ-
ously described in our laboratory.7
Syn th etic Stu d ies tow a r d (()-Ibop h yllid in e. Af-
ter successful results in the deethyl series, we became
interested in developing, using the same strategy, the
(36) For an alkaloid related to 19 with the same stability under
hydrolysis, see: Nuzillard, J .-M.; The´penier, P.; J acquier, M.-J .;
Massiot, G.; Le Men-Olivier, L.; Delaude, C. Phytochemistry 1996, 43,
897-902.
(37) The removal of the benzyloxycarbonyl group in 22 by means of
hydrogenation was reluctant and the secondary amine 23 was only
isolated in 35% yield (no other reagents were tested to attempt this
decarbamation).
(38) Ibophyllidine and 20-epiibophyllidine: Husson, H.-P.; J ac-
quemin, H.; Kan, S.-K.; Lounasmaa, M. Tetrahedron Lett. 1980, 21,
55-58.
(39) Bonjoch, J .; Ferna`ndez, J .-C.; Terricabras, D.; Valls, N. Tetra-
hedron 1997, 53, 9407-9414.

7342 J . Org. Chem., Vol. 63, No. 21, 1998
Bonjoch et al.
Sch em e 4. Syn th esis of (()-Deeth ylibop h yllid in e
and 25a -2 were treated with Li in ammonia, the C/D ring
cleavage occurred satisfactorily,42 giving the azecinoin-
dole 26, from which we needed to remove the N-alkyl
substituent to pursue the synthesis. To ensure a greater
stability for the indole nucleus, the indole nitrogen of 26
was first protected as an N(1)-methoxycarbonyl deriva-
tive.43 Treatment of amine 28 with vinyl chloroformate
provided the carbamate 29a , which, by means of treat-
ment with hydrogen chloride and then methanol at
reflux, gave the secondary amine 23, which had been
converted into target compound 1, as shown in Scheme
4. The best results for the demethylation process of 28
and double ring closure were obtained working in a one-
pot sequence in which amine 28 was treated wirth
R-chloroethyl chloroformate, the resulting carbamate 29b
was heated at methanol reflux, and the secondary amine
23 was heated overnight with TFA-MeOH. This process
gave in 55% overall yield a mixture of pentacyclic
deivatives 24 and 30,44 the latter, under dehydration
conditions, quantitatively rendering the enecarbamate
24, which had been converted to deethylibohyllidine such
as has been indicated previously.
Sch em e 5. Stu d ies in th e Syn th esis of
(()-20-Ep iibop h yllid in e
With these good results, we attempted to repeat the
sequence starting from indoloquinolizidine 31a ,39,45 which
incorporates an ethyl substituent in the C-20 biogenetic
position. Treatment of 31a with methyl iodide furnished
a mixture of metho salts, 32a -1 being the major isomer
as can be inferred from NMR data (δ 3.26 and 47.4 for
the N-Me group), indicating that the N-methyl group and
the H-16 are in a cis relationship.40 Reduction of 32 with
Li in ammonia furnished a 5:1 mixture of 33a and 33b,
after the usual reoxidation step (see Experimental Sec-
tion). After N(1)-methoxycarbonylation as above, we
attempted the demethylation process. Both 34a and 34b
were considered a priori to be good substrates for conver-
sion into ibophyllidine alkaloids. However, the reluc-
tance shown by these tertiary amines toward demethy-
lation at N(4) made clear that the sequence would not
work.46 Under usual conditions, 34 failed to react with
chloroformates, due to the low nucleophilicity of the
nitrogen atom, or suffered decomposition processes. After
exhaustive attempts to induce demethylation in 34 using
several types of chloroformates, only R-chloroethyl chlo-
roformate gave a significant result operating without
solvent and with long reaction times. When the crude
35 thus obtained was heated at methanol reflux and then
treated with trifluoroacetic acid in toluene at reflux, we
could isolate in 8% overall yield a mixture of ibophylli-
(40) For the stereoselectivity in the preparation of indolo[2,3-a]-
quinolizidine Nb-metho salts and NMR data of these compounds, see:
Lounasmaa, M.; Tamminen, T. Heterocycles 1991, 32, 1527-1535.
(41) When the same reaction was carried out with 7b a mixture of
25b-1 and 25b-2 was obtained (6:1 ratio, 89% overall yield, see
Supporting Information).
(42) To obtain
a pure indolo derivative 26, the crude reaction
mixture, in which a dihydroindole derivative appeared, was kept in
an oxygen atmosphere in order to reoxidize the over-reduced product.
(43) Attempts to form the carbamate from the unprotected indole
26 operating with several chloroformates gave lower yields, the best
result being with phenyl chloroformate, which gave carbamate 27 in
36% yield.
(44) The same compound 30 was isolated in 33% overall yield when
allyl chloroformate 29c was treated initially with Pd(PPh3)4/AcOH, Bu3-
SnH/CH2Cl2, and then with 1 N aqeous HCl.
occurs in the carbamate path. Thus, we focused on the
reductive cleavage of a substrate possessing a quaternary
ammonium salt functionality.22 To test the feasibility of
this procedure, we initially carried out a model study in
the deethylibophyllidine series (Scheme 5).
Treatment of amine 7a with methyl iodide yielded in
nearly quantitative yield a mixture of epimers 25a -1 and
25a -2 in a 7:3 ratio.40,41 When the ammonium salts 25a -1
(45) Accompanied by a low percentatge of 31b and other isomers,
all of them synthetically useful.
(46) For some examples of steric hindrance in dealkylation processes
via carbamates, see: (a) Torisawa, Y.; Nakagawa, M.; Hosaka, T.;
Tanabe, K.; Lai, Z.; Ogata, K.; Nakata, T.; Oishi, T.; Hino, T. J . Org.
Chem. 1992, 57, 5741-5747. (b) Tidwell, J . H.; Buchwald, S. L. J . Am.
Chem. Soc. 1994, 116, 11797-11810.

Total Syntheses of (()-Deethylibophyllidine
J . Org. Chem., Vol. 63, No. 21, 1998 7343
2810, 2735, 1719, 1717. For the major isomer 6a : 1H NMR
(500 MHz, COSY) 1.60 (q, J ) 12.5 Hz, 1H, H-1ax), 1.77 (qd, J
) 12.5, 4.5 Hz, 1H, H-3ax), 2.03 (d, J ) 12.5 Hz, 1H, H-3eq),
2.36 (d, J ) 12.5 Hz, 1H, H-1eq), 2.44 (m, 1H, H-2ax), 2.49 (td,
J ) 12, 4.5 Hz, 1H, H-4ax), 2.67 (m, 1H, H-6ax), 2.74 (br d, J )
17 Hz, 1H, H-7eq), 2.98 (m, 1H, H-7ax), 3.11 (dd, J ) 10, 5 Hz,
1H, H-6eq), 3.16 (br d, J ) 12 Hz, 1H, H-4eq), 3.32 (br d, J )
10.5 Hz 1H, H-12b), 7.07 (td, J ) 7.5, 1 Hz, 1H, H-9), 7.13 (td,
J ) 7.5, 1 Hz, 1H, H-10), 7.30 (d, J ) 7.5 Hz, 1H, H-11), 7.44
(d, J ) 7.5 Hz, 1H, H-8), 7.90 (br s, 1H, NH), 9.64 (s, 1H, CHO).
Minor signals for the minor isomer 6b were also observed in
the 1H NMR spectrum: 3.43 (brd, J ) 10.5 Hz 1H, H-12b),
7.92 (brs, 1H, NH), 9.74 (s, 1H, CHO); 13C NMR, Table 1;
HRMS calcd for C16H18N2O 254.1419, found 254.1430.
cis- a n d tr a n s-2-[2-(1,3-Dioxola n yl)]-1,2,3,4,6,7,12,12b-
octa h yd r oin d olo[2,3-a ]qu in olizin e (7a a n d 7b). Meth od
A. A solution of crude 6 (254 mg, 1 mmol) in glacial AcOH
(6.5 mL) and ethylene glycol (0.45 mL, 8 mmol) was warmed
at 35-40 °C. Then, freshly distilled BF3‚Et2O (0.63 mL, 5
mmol) was added slowly. The mixture was stirred at room
temperature for 15 min. CHCl3 (30 mL) was added to the
resulting suspension, and the mixture was basified with 2 N
aqueous NaOH. The organic layer was separated off, and the
aqueous layer was extracted with CHCl3 (2 × 50 mL). The
combined organic layers were washed with brine, dried,
evaporated, and chromatographed (Al2O3). On elution with
EtOAc, 7a (146 mg, 48%) was obtained as a yellowish solid.
On elution with 5% MeOH in EtOAc, 7b (40 mg, 13%) was
isolated as a brown solid.
7a : mp 150-152 °C; Rf 0.7 (Al2O3, EtOAc); IR (KBr) 3400,
2809, 2747 (Bohlmann bands); 1H NMR (500 MHz, COSY) 1.39
(q, J ) 12.5 Hz, 1H, H-1ax), 1.59 (qd, J ) 12, 4 Hz, 1H, H-3ax),
1.75 (m, 1H, H-2ax), 1.78 (brd, J ) 12 Hz, 1H, H-3eq), 2.14 (qd,
J ) 12.5, 2.5 Hz, 1H, H-1eq), 2.34 (td, J ) 12, 2.5 Hz, 1H, H-4ax),
2.55 (td, J ) 11.5, 4.5 Hz, 1H, H-6ax), 2.65 (brd, J ) 15 Hz,
1H, H-7eq), 2.93 (m, 1H, H-7ax), 3.03 (m, 2H, H-6eq and H-4eq),
3.17 (brd, J ) 10.5 Hz, 1H, H-12b), 3.81-3.93 (m, OCH2), 4.59
(d, J ) 5.5 Hz, 1H, OCHO), 7.00 (td, J ) 7.5, 1 Hz, 1H, H-9),
7.05 (td, J ) 7.5, 1 Hz, 1H, H-10), 7.20 (d, J ) 7.5 Hz, 1H,
H-11), 7.39 (d, J ) 7.5 Hz, 1H, H-8), 7.80 (br s, 1H, NH); 13C
NMR, Table 1. HRMS calcd for C18H22N2O2 298.1681, found
298.1687. 7b: TLC Rf ) 0.2 (Al2O3, EtOAc); IR (KBr) 3407;
1H NMR (500 MHz, COSY) 1.68 (m, 1H, H-2ax), 1.70 (qd, J )
9, 3 Hz, 1H, H-3ax), 1.81 (m, 1H, H-3eq), 2.07 (dd, J ) 6, 5 Hz,
1H, H-1ax), 2.14 (qd, J ) 12.5, 2.5 Hz, 1H, H-1eq), 2.63 (d, J )
17 Hz, 1H, H-7ax), 2.73 (m, 1H, H-4ax), 2.81 (m, 1H, H-4eq),
3.01 (m, 2H, H-6ax and H-7eq), 3.01 (m, 1H,), 3.22 (dd, J ) 12,
6 Hz, 1H, H-6eq), 3.81-3.93 (m, OCH2), 4.18 (brd, J ) 10.5 Hz
1H, H-12b), 4.81 (d, J ) 5.5 Hz, 1H, OCHO), 7.07 (td, J ) 7.5,
1 Hz, 1H, H-9), 7.12 (td, J ) 7.5, 1 Hz, 1H, H-10), 7.31 (d, J )
7.5 Hz, 1H, H-11), 7.44 (d, J ) 7.5 Hz, 1H, H-8), 8.14 (br s,
1H, NH); 13C NMR, Table 1; HRMS calcd for C18H22N2O2
298.1681, found 298.1671.
dine-type pentacyclic derivatives 37a and 37b, in 9:1
ratio determined by GC-MS analysis.47 Unfortunately,
this process was erratic and did not give enough material
to complete the synthesis of 20-epiibophyllidine (3). At
this point, we decided not to pursue this line of research
any longer, concluding that the ring-opening/reclosure
strategy starting from octahydroindoloquinolizines does
not appear amenable for the synthesis of members of the
ibophyllidine family other than 1.48
In summary, total syntheses of (()-deethylibophylli-
dine (1) are described, proceeding in eight steps (Scheme
3) or nine steps (Scheme 5) from the dimethyl acetal of
4-pyridinecarbaldehyde with nearly 6% overall yield in
both cases, results similar to those derived from our first
approach.7 We were unable to extend our crisscross
annulation strategy to the synthesis of crowded com-
pounds leading to 20-substituted alkaloids.
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 300 and 50.3 MHz,
respectively, using Me4Si as internal standard. Chemical
shifts are reported in ppm downfield (δ) from Me4Si. NMR
peak assignments are given only when they are derived from
definitive two-dimensional NMR experiments. The 13C NMR
spectra, when an unambiguous assignation was not available,
are reported as follows: chemical shift (multiplicity determined
from DEPT spectra). Only noteworthy IR absorptions (cm-1
)
are listed. TLC plates were visualized with UV illumination
and then developed with iodoplatinate reagent. Chromatog-
raphy refers to flash chromatography and was carried out on
SiO2 (silica gel 60, SDS, 230-400 mesh ASTM) unless other-
wise noted. Drying of organic extracts during workup of
reactions was performed over anhydrous Na2SO4. Evaporation
of solvents was accomplished with a rotatory evaporator.
Microanalyses and HRMS were performed by the Centro de
Investigacio´n y Desarrollo (CSIC), Barcelona.
4-(Dim eth oxy)m eth yl-1-[2-(3-in d olyl)eth yl]-1,2,3,6-tet-
r a h yd r op yr id in e (5). To a solution of 4-(dimethoxy)methyl-
1-[2-(3-indolyl)ethyl]pyridinium bromide (4)39 (23.5 g, 65 mmol)
in MeOH (150 mL) was added NaBH4 (1.3 g, 32 mmol)
portionwise at room temperature. Additional NaBH4 (650 mg,
16 mmol) was added three times at 2 h intervals, and 30 min
after the last addition, the solvent was evaporated, H2O (100
mL) was added, and the aqueous basic solution was extracted
with CHCl3 (3 × 75 mL). The organic extracts were washed
with brine, dried, and concentrated to give, in a quantitative
form (19.2 g), the tetrahydropyridine 5, whose NMR data are
the same as those previously reported.39
cis- a n d tr a n s-1,2,3,4,6,7,12,12b-Octa h yd r oin d olo[2,3-
a ]qu in olizin e-2-ca r ba ld eh yd e (6a a n d 6b). A solution of
tetrahydropyridine 5 (19 g, 63 mmol) in 30% aqueous AcOH
(350 mL) was heated at reflux overnight and then concen-
trated. The residue was dissolved with CH2Cl2, and the
mixture was basified with 2 N aqueous NaOH in an ice bath.
The organic layer was separated off, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried, and evaporated to give 12.8 g (80%)
of crude 6 as a brown solid, which was used for the next
reaction without purification. An analytical sample of a
mixture of aldehydes 6a and 6b (3:1 ratio by 1H NMR analysis)
was obtained by chromatography (Florisil, EtOAc): Rf 0.45
(Al2O3, 1:1 hexane/EtOAc); mp 115-120 °C; IR (KBr) 3400,
Meth od B. To a solution of crude 6 (3 g, 11.8 mmol) in
ethylene glycol (20 mL) were added Amberlyst 15 (3 g;
activated previously under reduced pressure at 100 °C) and
anhydrous calcium chloride (2 g, 13 mmol; activated previously
under reduced pressure at 200 °C). The mixture was stirred
at 31 °C for 3 days. CH2Cl2 (50 mL) was added, and after
stirrring for 10 min the mixture was basified with 2 N aqueous
NaOH and filtered through cotton, washing copiously with
CH2Cl2 (10 × 75 mL). The two phases were separated, and
the organic phase was washed with brine, dried, and concen-
trated. The residue was chromatographed (Al2O3, CH2Cl2)
yielding 1.24 g (35%) of 7a and 328 mg (10%) of 7b (45% overall
yield).
(6RS,8RS)-3-Ben zyloxyca r bon yl-6-[2-(1,3-d ioxola n yl)]-
2,3,4,5,6,7,8,9-octah ydr o-1H-azecin o[5,4-b]in dol-8-ol (10a).
To a solution of 7a (260 mg, 0.9 mmol) in THF (20 mL) was
added Na2CO3 (462 mg, 4.4 mmol). The solution was cooled
to 0 °C, and benzyl chloroformate (0.4 mL, 2.75 mmol) was
introduced dropwise. The mixture was stirred for 1 h at 0 °C
and for 1 h at room temperature‚ H2O (2.2 mL, 120 mmol)
was added, and the mixture was warmed to 50 °C. Three
hours later, the addition of reagents was repeated in the same
(47) As occurs in the 20-epiibophyllidine syntheses,4b,5 the stereo-
selectivity observed in this cyclization can be ascribed to selective
addition of the indole to the iminium salt intermediate of the D ring
on the side which is not shielded by the ethyl substituent.
(48) It has been noted that our early strategy7 did not allow access
to these alkaloids either: Bonjoch, J .; Catena, J .; Terricabras, D.;
Ferna`ndez, J .-C.; Lo´pez-Canet, M.; Valls, N. Tetrahedron: Asymmetry
1997, 8, 3143-3151.

7344 J . Org. Chem., Vol. 63, No. 21, 1998
Ta ble 2. 13C NMR of Octa h yd r oa zecin o[5,4-b]in d oles (δ p p m , CDCl3)a
13 14a 14b 15a 15b 17a 18a 21 22 23 26
Bonjoch et al.
10a
10b
12a
28
29a
34a
34b
C-1
C-2
C-4
C-5
C-6
C-7
C-8
C-8a
C-9a
C-10
C-11
C-12
C-13
C-13a
C-13b
25.4 24.9 25.2 17.6 25.1 25.4 25.4 25.7 24.4 24.6 24.7 25.1 24.3 22.9 23.5 25.0 24.2 22.9
50.7 48.9 51.2 46,3 50.3 48.4 50.5 48.5 51.9 52.3 50.0 48.2 46.4 51.1 55.4 48.5 51.5 51.5
47.7 47.9 47.8 44.9 48.2 48.4 47.8 48.1 47.5 47.6 48.3 47.9 45.2 56.0 51.2 48.0 65.7 54.8
27.0 28.1 31.6 29.2 26.9 28.0 27.5 26.2 27.6 27.6 27.6 27.7 30.0 28.5 29.0 27.6 32.6 33.3
35.0 35.0 37.1 23.8 35.4 34.6 29.2 34.6 38.0 38.1 38.8 38.2 35.3 34.2 35.1 38.6 37.1 33.7
36.2 33.8 38.5 38.4 33.5 32.0 32.3 31.3 31.2 31.9 27.6 26.6 27.2 29.6 28.9 27.1 29.0 29.7
67.6 66.4 67.1 66.6 69.7 67.5 29.2 27.5 43.4 43.1 25.6 26.0 24.9 24.2 25.5 26.0 24.6 25.4
136.1 134.9 136.2 135.2 133.4 132.4 136.2 136.0 133.1 131.6 135.8 135.7 136.2 135.2 136.2 135.9 136.1 136.3
137.4 136.9 137.1 136.2 136.8 136.0 136.2 136.0 136.8 137.0 135.8 138.8 137.5 135.7 136.9 137.6 137.4 136.9
111.2 110.8 111.0 110.7 110.0 110.9 111.2 111.1 111.2 111.1 110.4 115.7 115.7 110.2 115.5 115.8 115.5 115.5
122.1 121.1 121.9 121.8 122.6 122.2 123.0 121.6 121.8 122.3 121.2 123.7 123.6 120.6 123.5 123.9 123.4 123.4
119.1 119.2 118.9 119.7 119.4 119.6 119.9 119.7 119.0 119.4 119.0 122.6 122.7 118.6 122.4 122.8 122.4 122.4
118.3 118.6 118.2 118.7 118.7 119.3 118.6 119.4 118.0 118.3 118.2 118.2 118.4 117.8 118.0 118.2 117.8 118.0
127.3 128.8 127.1 128.0 127.2 127.6 127.2 127.0 127.2 127.6 128.0 129.5 129.4 128.4 129.9 129.5 130.6 129.8
111.6 111.1 113.3 111.5 112.9 111.1 113.3 111.7 112.3 111.1 111.7 110.3 117.7 111.1 118.9 117.8 119.3 119.2
C-C(6) 106.2 106.1 59.1 201.2 106.4 105.6 105.7 105.1 106.0 106.6 106.6 106.6 107.8 108.3 108.4 106.9 108.3 108.8
other
b,c
b,c
b,d
b
b,c,e b,c,e b,c,f b,c,f b,c,g b,c,h b,c
b,c,i c,i
c,j
c,i,j
c,i,k c,i,l
c,i,m
a
Values for compounds 10a , 12a , 14a , 28, and 29a were assigned on the basis of HMQC spectra. All compounds, except 26, 28, and
b
34, show duplicate signals. In this table the values corresponding to the major rotamer have been indicated. CO2CH2Ar: δ 156.8 ((0.8),
66.8 ((0.7). c OCH2: δ 64.9 ((0.2). SCH2: 38.4. e OAc: δ 169.6 ((0.1), 21.0. f CN: δ 119.8. CONH2: δ 176.1. CO2Me: δ 174.4, 52.3.
d
g
h
i
j
k
l
m
NCO2Me: δ 152.3 ((0.1), 53.3 ((0.1). NMe: 43.6 ((0.2). CO2CHdCH2: δ 153.8, 142.4, 95.1. Et: δ 12.3, 22.3. NMe: δ 35.4. Et: δ
12.3, 20.6. NMe: δ 35.4.
quantities, and the stirring was maintained at 50 °C for 2 h.
The solvent was evaporated, CHCl3 was added, and the
resulting solution was washed with 2 N aqueous NaOH, brine,
dried, and concentrated to give a residue that was purified by
chromatography. On elution with 95:5 CH2Cl2-EtOAc, alcohol
10a (286 mg, 73%) was obtained as a yellowish solid: Rf 0.75
(4% MeOH in EtOAc); mp 168-170 °C; IR (KBr) 3408, 3340,
1677; 1H NMR (500 MHz, COSY) 0.55 (t, J ) 14 Hz, 1H, H-5),
1.10 (tm, J ) 16 Hz, 1H, H-5), 1.6-1.9 (m, 2H, H-6 and H-7),
2.14 (d, J ) 12 Hz, 1H, H-7), 2.31 (t, J ) 11 Hz, 1H, H-4),
2.6-2.9 (m, 2H, H-2 and H-1), 3.0-3.2 (m, 1H, H-1), 3.6-4.0
(m, 5H, H-4 and OCH2), 4.2-4.4 (m, 1H, H-2), 4.60 and 4.83
(2 d J ) 3 Hz, 1H, OCHO), 4.76 (2 dd, J ) 12, 3 Hz, 1H, H-8),
5.08 and 5.12 (2d, J ) 14 Hz, 1H each, CH2Ar), 5.17 (s, CH2-
Ar other rotamer), 7.10 (t, J ) 7.1 Hz, 1H, H-12), 7.18 (t, J )
7 Hz, 1H, H-11), 7.3-7.4 (m, 7H), 8.50 (br s, 1H, NH); 13C
NMR, Table 2. Anal. Calcd for C26H30N2O5: C, 69.31; H, 6.66;
N, 6.22. Found: C, 69.33; H, 6.67; N, 6.16.
Rin g Clea va ge of 7b. Operating as above, but carrying
out the workup with an acid-base treatment of the CHCl3
solution, from acetal 7b (95 mg, 0.3 mmol), alcohol 10b was
obtained (50 mg, 35%, 50% based on recovered 7b) as a yellow
solid after chromatography (5% EtOAc in CH2Cl2). From the
acid aqueous phase, after being basified and extracted with
CHCl3, 29 mg of 7b was recovered: Rf 0.75 (4% MeOH in
EtOAc); mp 150 °C; IR (KBr) 3400, 3287, 1682; 1H NMR 1.5-
1.9 (m, 2H), 2.04-2.2 (m, 3H), 2.5-3.3 (m, 3H), 3.45 (d, J )
17 Hz, 1H), 3.6-4.0 (m, 5H), 4.05-4.2 (m, 1H), 4.37and 4.68
(br s and d J ) 3 Hz,1H), 4.42 and 4.48 (2 brs, 1H), 4.8-5.2
(m, 2H), 7.08 (t, J ) 7 Hz, 1H), 7.12 (t, J ) 7 Hz, 1H), 7.2-7.4
(m, 6H), 7.50 (d, J ) 7 Hz, 1H), 8.70 (br s, 1H); 13C NMR, Table
2. Anal. Calcd for C26H30N2O5: C, 69.31; H, 6.66; N, 6.22.
Found: C, 69.47; H, 6.79; N, 6.13.
(6RS,8RS)-8-Acetoxy-3-ben zyloxyca r bon yl-6-[2-(1,3-d i-
oxola n yl)]-2,3,4,5,6,7,8,9-octa h yd r o-1H-a zecin o[5,4-b]in -
d ole (14a ). To a solution of 10a (1.3 g, 2.8 mmol) in CH2Cl2
(35 mL) were added DMAP (85.5 mg, 0.7 mmol), pyridine (3.8
mL), and Ac2O (1.5 mL). After 2 h at room temperature, the
excess of reagents was removed in vacuo. The residue was
dissolved in CH2Cl2 and washed with 1 N HCl and saturated
aqueous NaHCO3. The dried organic extract was concentrated
and chromatographed (CH2Cl2) to give 14a (1.25 g, 92%) as a
white solid: Rf 0.75 (5% EtOAc in CH2Cl2); mp 88-90 °C; IR
(KBr) 3324, 1736, 1678; 1H NMR (500 MHz, COSY) 0.69 (t, J
) 11.5 Hz, 1H, H-5), 1.36 and 1.20 (2 br d, J ) 10.5 Hz, 1H,
H-5), 1.80-1.90 (m, 2H, H-6 and H-7), 2.04 (s, 3H, CH3CO),
2.09-2.10 (td, J ) 9, 2.5 Hz, 1H, H-7), 2.55 (dd, J ) 8.5, 2.0
Hz, 1H, H-4), 2.86 (t, J ) 7 Hz, 1H, H-2), 2.90-3.00 (m, 1H,
H-1), 3.10-3.20 (m, 1H, H-1), 3.6-4.0 (m, 5H, H-4 and OCH2),
4.29-4.36 (m, 1H, H-2), 4.58 and 4.83 (2 br s,1H, OCHO),
5.11-5.24 (m, 2H, CH2Ar), 5.87 (t, J ) 10.5 Hz, 1H, H-8), 7.11
(td, J ) 7.0, 4.5 Hz, 1H, H-12), 7.21 (t, J ) 7 Hz, 1H, H-11),
7.3-7.4 (m, 7H), 7.46 i 7.51 (2d, J ) 8 Hz, 1H, H-13), 8.50 (br
s, 1H, NH); 13C NMR, Table 2. Anal. Calcd for C28H32N2O6‚
1/4H2O: C, 67.67; H, 6.54; N, 5.63. Found: C, 67.65; H, 6.53;
N, 5.56.
Acetyla tion of 10b. Operating as above, from alcohol 10b
(90 mg, 0.2 mmol) was obtained 14b (65 mg, 66%) as a white
solid: Rf 0.72 (5% EtOAc in CH2Cl2); mp 80-82 °C; IR (KBr)
3327, 1736, 1682; 1H NMR 1.47-2.0 (m, 4H), 2.03 (s, 3H),
2.06-2.15 (m, 1H), 2.47-3.45 (m, 4H), 3.6-4.0 (m, 5H), 4.26-
4.46 (m, 1H), 4.54 and 4.60 (2 d, J ) 12 Hz, 1H), 4.9-5.2 (m,
2H), 6.2-6.3 (m, 1H), 6.9 (t, J ) 7 Hz, 1H), 7.09-7.4 (m, 7H),
7.52 (d, J ) 7 Hz, 1H), 8.2 (brs, 1H); 13C NMR, Table 2. Anal.
Calcd for
Found: C, 66.11; H, 6.43; N, 5.45.
C28H32N2O6‚H2O: C, 65.88; H, 6.66; N, 5.49.
3-Ben zyloxycar bon yl-6-[2-(1,3-dioxolan yl)]-2,3,4,5,6,7,8,9-
oct a h yd r o-1H -a zecin o[5,4-b]in d ole-8-ca r b on it r ile (15).
F r om 14a . A mixture of acetate 14a (956 mg, 1.9 mmol),
NaCN (2.5 g, 50.6 mmol), and NaI (18.2 mg, 0.12 mmol) in
DMSO (20 mL) was kept at 90-100 °C for 7 h. After cooling,
brine was added and the solution was extracted with CH2Cl2.
The organic extract was washed with brine, dried, and
concentrated to give a residue, which was chromatographed.
On elution with CH2Cl2 800 mg (88%) of nitriles 15, in a nearly
equimolecular ratio, was obtained as a white solid. Rf(15a )
0.41; Rf(15b) 0.37 (5% EtOAc in CH2Cl2); mp 98-100 °C (of
the mixture); IR (KBr) 3307, 2241, 1679-1692. 15a : 1H NMR
0.6-0.8 (m, 1H), 1.2-1.8 (m, 1H), 1.7-2.0 (m, 2H), 2.2-2.5
(m, 2H), 2.6-2.8 (m, 2H), 3.1-3.3 (m, 1H), 3.6-4.0 (m, 6H),
4.2-4.4 (m, 1H), 4.55 and 4.80 (2d, J ) 3 Hz, 1H), 5.18 (s,
2H), 7.03-7.30 (m, 3H), 7.4-7.5 (m, 6H), 8.60 (brs, 1H); 13C
NMR, Table 2. 15b: 1H NMR 1.50-1.75 (m, 3H), 1.90-2.05
(m, 1H), 2.3 (t, J ) 12.4 Hz, 1H), 2.93-3.01 (m, 2H), 3.12-
3.30 (m, 2H), 3.8-4.0 (m, 6H), 4.21(dd, J ) 11.3, 4.4 Hz, 1H),
4.45 and 4.56 (t, J ) 12.5 Hz, and brs 1H), 4.93 and 4.98 (2s,
2H), 7.0 (t, J ) 7 Hz, 1H), 7.1-7.4 (m, 7H), 7.5 (d, J ) 7 Hz,
1H), 8.60 (br s, 1H); 13C NMR, Table 2. Anal. Calcd for
C
27H29N3O4‚1/2H2O: C, 69.23; H, 6.41; N, 8.97. Found: C,
69.29; H, 6.41; N, 8.68.
Operating as above from acetate 14b (56 mg, 0.1 mmol),
NaCN (145 mg, 3 mmol), and NaI (1 mg, 0.01 mmol) in DMSO
(3 mL), an equimolecular mixture of 15a and 15b (30 mg, 70%)
was obtained after chromatography.
(()-Deeth ylibop h yllid in e (1). Dry HCl was bubbled
through a solution of a mixture of nitriles 15 (67 mg, 0.15
mmol) in MeOH (5 mL) at 0-5 °C until saturation (1 h 30
min). The mixture was then allowed to stand at 4 °C for 16 h
and poured into ice/water (20 mL). After standing at room
temperature for 1 h 30 min, the mixture was extracted with

Total Syntheses of (()-Deethylibophyllidine
J . Org. Chem., Vol. 63, No. 21, 1998 7345
CH2Cl2 and the aqueous phase was basified at 0 °C with NaOH
(pellets) and extracted with CH2Cl2 (3 × 50 mL). The organic
extract was washed with brine (3 × 50 mL), dried, and
concentrated, and the residue was chromatographed. Elution
with 5:1 EtOAc-MeOH gave deethylibophyllidine (1, 13 mg,
30%) and imidate 19 (12 mg, 29%). IR and 1H and 13C NMR
data of (()-deethylibophyllidine were identical with those we
had previously reported.7 TLC: Rf 0.17 (1:1 EtOAc-MeOH).
Meth yl 1,2,2a ,3,5,10,11,12a -octa h yd r op yr r olizin o[1,7-
cd ]ca r ba zole-4-ca r boxim id a te (19): Rf 0.06 (50% MeOH in
EtOAc); mp 125 °C (dec); UV (EtOH) λmax (log ꢀ) 224 (3.9), 298
(3.1), 328 (2.7); IR (KBr) 3421, 1652, 1605; 1H NMR (500 MHz,
COSY) 1.76 (dd, J ) 12.5, 5.5 Hz, 1H, H-10â), 1.81 (dd, J )
12.5, 5.5 Hz, 1H, H-2R), 1.89 (dd, J ) 15, 12 Hz, 1H, H-3R),
2.10 (td, J ) 13, 5 Hz, 1H, H-10R), 2.14 (m, 1H, H-2a), 2.20
(td, J ) 14, 7 Hz, 1H, H-2â), 2.69 (dd, J ) 15, 5.5 Hz, 1H,
H-3â), 2.75 (m, 1H, H-1R), 2.93 (dd, J ) 12.5, 7 Hz, 1H, H-11R),
3.45 (t, J ) 6 Hz, 1H, H-1â), 3.47 (t, J ) 5.5 Hz, 1H, H-11â),
3.75 (s, 3H, OCH3), 3.90 (d, J ) 7 Hz, 1H, H-12a), 6.78 (d, J )
7.5 Hz, 1H, H-16), 6.83 (td, J ) 7.5, 1 Hz, 1H, H-8), 7.12 (td,
LDA (1.5 M in cyclohexane, 0.3 mL, 0.45 mmol). This solution
was allowed to warm slowly to room temperature, stirred for
30 min, and returned to -78 °C when methyl cyanoformate
(0.1 mL, 1.6 mmol) was added. After 2 h at -78 °C, the ice
bath was removed. The temperature was raised to room
temperature, and stirring was maintained overnight. The
reaction was quenched with aqueous NH4Cl and extracted with
EtOAc (3 × 50 mL). The organic phase was washed with brine
(10 × 50 mL), dried, and concentrated. Chromatography (CH2-
Cl2) afforded 22 as a pale yellow solid (105 mg. 95%): Rf 0.88
(CH2Cl2/EtOAc 4:1); IR (neat) 1736, 1690; 1H NMR 1.15-1.60
(m, 3H), 1.65-1.80 (m, 1H), 1.85-2.01 (m, 1H), 2.50-2.72 (m,
1H), 2.8-3.2 (m, 4H), 3.2-3.5 (m, 1H), 3.6-4.0 (m, 5H), 4.02
(s, 3H), 4.25-4.50 (m, 1H), 4.55 and 4.85 (2 d J ) 3 Hz, 1H),
5.0-5.1 (m, 2H), 7.02-7.6 (m, 9H), 8.1 (d, J ) 8.5 Hz, 1H);
13C NMR, Table 2. Anal. Calcd for C28H32N2O6: C, 68.27; H,
6.55; N, 5.68. Found: C, 68.01; H, 6.61; N, 5.59.
6-[2-(1,3-Dioxolan yl)]-9-m eth oxycar bon yl-2,3,4,5,6,7,8,9-
octa h yd r o-1H-a zecin o[5,4-b]in d ole (23). Benzyl carbamate
22 (86 mg, 0.2 mmol), MeOH (2.5 mL), and activated Pd(OH)2
(18 mg) were stirred under 1 atm of H2 until the disappearance
of the starting compound was observed by TLC (3 days).
Additional Pd(OH)2 (8 mg) was added after the second day.
The mixture was filtered through Celite, the retained solid was
rinsed with MeOH, and the combined solvent was evaporated
and the residue chromatographed (2% MeOH in EtOAc) to
provide amine 23 (22 mg, 35%) as a yellowish solid: Rf 0.55
J ) 7.5, 1 Hz, 1H, H-7), 7.35 (dd, J ) 7.5, 1 Hz, 1H, H-9); 13
C
NMR (HMQC) 26.7 (C-3), 31.8 (C-2), 38.5 (C-2a), 3.8 (C-10),
51.5 (OCH3), 51.8 (C-11), 54.7 (C-1), 56.5 (C-9b), 72.8 (C-12a),
93.2 (C-4), 108.8 (C-6), 120.3 (C-8), 122.5 (C-9), 128.1 (C-7),
135.8 (C-9a), 144.1 (C-5a), 156.5 (O-CdNH). 167.1 (C-4a);
HRMS calcd for C18H21N3O 295.1684, found 295.1687.
In one run, small amounts of 1,2,2a ,3,5,10,11,12a -octa h y-
d r op yr r olizin o[1,7-cd ]ca r ba zole-4-ca r bon itr ile (20) were
isolated: IR (KBr) 3390, 2187, 1646, 1614; 1H NMR 1.70 (dd,
J ) 12.5, 5 Hz, 1H, H-10â), 1.80 (dd, J ) 11.5, 6 Hz, 1H, H-2R),
1.9-2.2 (m, 4H), 2.38 (dd, J ) 13, 4 Hz, 1H), 2.76 (m, 1H, H-1R),
2.94 (dd, J ) 12, 7.5 Hz, 1H, H-11R), 3.28-3.40 (m, 2H), 3.80
(d, J ) 6.5 Hz, 1H, H-12a), 6.84 (d, J ) 7.5 Hz, 1H, H-6), 6.92
(td, J ) 7.5, 1 Hz, 1H, H-8), 7.19 (td, J ) 7.5, 1 Hz, 1H, H-7),
7.32 (d, J ) 7.5, 1H, H-9), 7.43 (br s, 1H, NH); 13C NMR 28.1
(C-3), 31.1 (C-2), 37.8 (C-2a), 38.5 (C-10), 51.6 (C-11), 54.4 (C-
1), 56.1 (C-9b), 72.8 (C-12a), 91.0 (C-4), 109.2 (C-6), 119.7 (CN),
121.1 (C-8), 122.3 (C-9), 128.6 (C-7), 135.0 (C-9a), 143.5 (C-
5a), 164.8 (C-4a).
3-Ben zyloxycar bon yl-6-[2-(1,3-dioxolan yl)]-2,3,4,5,6,7,8,9-
octa h yd r o-1H-a zecin o[5,4-b]in d ole (21). Meth od A. To
a cooled (-78 °C) solution of alcohol 10a (50 mg, 0.1 mmol) in
glacial AcOH (1 mL) were added NaCNBH3 (21 mg, 0.3 mmol)
and then TFA (0.01 mL, 0.16 mmol). The resulting mixture
was stirred at room temperature for 15 min and sequentially
basified with 6 N aqueous NaOH and extracted with CH2Cl2.
The organic extracts were washed with brine, dried, and
concentrated, and the residue was chromatographed (CH2Cl2)
to give 21 (26 mg, 53%) as a yellow solid. On elution with 4:1
CH2Cl2-EtOAc, unreacted alcohol 10a (6 mg, 11%) was
recovered. 21: Rf 0.85 CH2Cl2/EtOAc (4:1); mp 72-74 °C; IR
(KBr) 3405, 3340, 1676-1682; 1H NMR 1.0-1.3 (m, 1H), 1.3-
1.5 (m, 2H), 1.7-1.8 (m, 1H), 1.85-1.99 (m, 1H), 2.55-2.70
(m, 2H), 2.81-3.00 (m, 3H), 3.01-3.15 (m, 1H), 3.6-4.0 (m,
5H), 4.25-4.40 (m, 1H), 4.55 and 4.85 (2 d J ) 3 Hz, 1H), 4.70
(brd, J ) 15 Hz, 1H), 5.2 (m, 1H), 7.01 (t, J ) 7.5 Hz, 1H),
7.11 (t, J ) 7.5 Hz, 1H), 7.24-7.49 (m, 7H), 7.84 (br s, 1H);
13C NMR, Table 2. Anal. Calcd for C26H30N2O4‚1/2H2O: C,
70.42; H, 6.99; N, 6.32. Found: C, 70.34; H, 6.92; N, 6.20.
Meth od B. To a cooled (-78 °C) solution of amine 7a (100
mg, 0.34 mmol) in THF (10 mL) was slowly added benzyl
chloroformate (0.25 mL, 1.7 mmol). The mixture was stirred
at -78 °C for 1 h and then 64 mg (1 mmol) of NaCNBH3 in
THF (5 mL) was added. After 1 h, the reaction mixture was
allowed to warm to room temperature and the stirring was
maintained for 16 h. Evaporation of the solvent gave a residue
which was stirred with CH2Cl2 and filtered. The filtrate was
washed with 2 N aqueous NaOH and brine, dried, and
concentrated, and the residue was chromatographed (CH2Cl2)
to give 21 (38 mg, 27%). The starting material as its
aminoborane adduct (23 mg, 20%) was also isolated.
1
EtOAc/ MeOH/TEA (8:2:0.1); IR (Film) 3405, 1735; H NMR
1.36-1.63 (m, 5H), 2.30 (ddd, J ) 13, 7, 0.8 Hz, 1H), 2.74-
2.95 (m, 3H), 3.2-3.4 (m, 2H), 3.74-4.00 (m, 4H), 4.05 (s, 3H),
4.64 (d, J ) 3 Hz, 1H), 7.19-7.30 (m, 2H), 7.45 (dd, J ) 7.5,
1.5 Hz, 1H), 8.09 (dd, J ) 7.5, 1.5 Hz, 1H); 13C NMR, Table 2;
HRMS calcd for C20H26N2O4 358.1893, found 358.1885.
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 (24). To a solution of 23
(10 mg, 0.03 mmol) in toluene (1 mL) was added TFA (0.02
mL, 0.3 mmol). The mixture was heated at reflux for 9 h. A
saturated aqueous Na2CO3 solution was added, and the
solution was extracted with EtOAc. After concentration, crude
24 (8 mg, 90%) was obtained as a brown solid: Rf 0.5, (Al2O3,
3:2:drops CH2Cl2/EtOAc/DEA); IR (film) 1717, 1610; 1H NMR
(500 MHz, COSY) 1.70 (ddd, J ) 12.4, 5.7, 2, H-10â), 1.75-
1.83 (m, H-2â), 1.82 (dt, J ) 11.5, 3.2, H-3R), 2.04 (td, J ) 11.6,
5.1, H-3â), 2.10 (m, H-2a), 2.18 (dd, J ) 11.4, 7, H-10R), 2.34
(dddd, J ) 14.3, 8.2, 5.2, 1, H-2R), 2.81 (m, H-1R), 2.87 (ddd, J
) 12.2, 7.5, 2, H-11R), 3.30 (t, J ) 8.5, H-1â), 3.32 (td, J ) 12,
5.5, H-11â), 3.76 (d, J ) 6, H-12a), 3.95 (s, CO2Me), 6.23 (dd,
J ) 8, 3, H-4), 7.07 (td, J ) 7.5, 1, H-7), 7.24 (td, J ) 7.5, 1,
H-8), 7.34 (dd, J ) 7.5, 1, H-9), 7.81 (dd, J ) 7.5, 1, H-6); 13C
NMR (HMQC) 27.8 (C-2), 32.1 (C-3), 38.1 (C-2a), 40.1 (C-10),
52.1 (C-1), 52.7 (OCH3), 53.5 (C-9b), 54.6 (C-11), 74.0 (C-12a),
106.5 (C-4), 115.2 (C-6), 122.3 (C-9), 123.7 (C-8), 127.6 (C-7),
137.9 (C9a), 144.3 (C4a), 140.2 (C-5a), 153.1 (CO); HRMS calcd
for C18H20N2O2 296.1525, found 296.1517. Anal. Calcd for
C
18H20N2O2‚H2O: C, 68.77; H, 7.05; N, 8.91. Found: C, 68.65;
H, 6.98; N, 8.76.
2-[2-(1,3-Dioxolan yl)]-5-m eth yl-1,2,3,4,6,7,12,12b-octah y-
d r oin d olo[2,3-a ]qu in olizin iu m Iod id e (25). To a solution
of 7a (470 mg, 1.6 mmol) in a 1:1 mixture of CH2Cl2 and MeOH
(4 mL) was added methyl iodide (0.8 mL, 12.6 mmol). The
mixture was warmed at 65 °C for 30 min. The metho salt
25a -2 was collected by filtration as a white solid (225 mg, 32%).
Concentration of the resulting filtrate and crystallization
(EtOH-EtOAc) of the resulting solid gave metho salt 25a -1
(410 mg, 58%). 25a -1: 1H NMR (CDCl3 + drops of CD3OD)
1.80 (q, J ) 12.5 Hz, 1H), 1.95-2.13 (m, 2H), 2.4-2.6 (m, 2H),
3.19-3.22 (m, 2H), 3.36 (s, 3H), 3.63 (m, 2H), 3.84-4.05 (m,
7H), 4.76 (d, J ) 4.8 Hz, 1H), 5.25 (dd, J ) 12.5, 2.5 Hz, 1H),
7.05 (td, J ) 7.5, 0.5 Hz, 1H), 7.14 (td, J ) 7.5, 0.5 Hz, 1H),
7.37 (d, J ) 7.5 Hz, 1H), 7.49 (d, J ) 7.5 Hz, 1H); 13C NMR,
Table 1. Anal. Calcd for C19H25IN2O2: C, 51.81; H, 5.68; N,
6.36. Found: C, 51.73; H, 5.71; N, 6.29. 25a -2: mp 280-282
3-Ben zyloxyca r bon yl-6-[2-(1,3-d ioxola n yl)]-9-m eth oxy-
ca r b on yl-2,3,4,5,6,7,8,9-oct a h yd r o-1H -a zecin o[5,4-b]in -
d ole (22). To a solution of indole 21 (100 mg, 0.23 mmol) in
a 10:1 mixture of THF-HMPA (3.3 mL) at -78 °C was added
1
°C; IR (KBr) 3170; H NMR (DMSO-d6) 1.78 (q, J ) 12.5 Hz,
1H), 1.95-2.13 (m, 3H), 2.61 (brd, J ) 14.5 Hz, 1H), 2.91 (s,
3H), 3.01-3.15 (m, 2H), 3.60-3.79 (m, 3H), 3.84-3.99 (m, 5H),

7346 J . Org. Chem., Vol. 63, No. 21, 1998
Bonjoch et al.
4.81 (d, J ) 5.2 Hz, 1H), 5.14 (d, J ) 12.4 Hz, 1H), 7.05 (t, J
) 7 Hz, 1H), 7.14 (t, J ) 7 Hz, 1H), 7.37 (d, J ) 8 Hz, 1H),
7.49 (d, J ) 7.5 Hz, 1H), 11.29 (s, 1H); 13C NMR, Table 1. Anal.
Calcd for C19H25IN2O2: C, 51.81; H, 5.68; N, 6.36. Found: C,
51.70; H, 5.73; N, 6.31.
From the synthetic standpoint, a mixture of acetals 7a and
7b can be used for the preparation of 25 (see Supporting
Information).
solution. Chromatography (Al2O3, CH2Cl2) yielded 15 mg
(60%) of secondary amine 23 (see above for NMR data).
B. Via Ca r ba m a te 29b. 1-Chloroethyl chloroformate (0.6
mL, 5.4 mmol) was added dropwise to compound 28 (200 mg,
0.54 mmol) at room temperature. After being heated at 130
°C for 6 h, the reaction mixture was concentrated, diluted with
CH2Cl2, and washed with 1 N HCl. After drying and concen-
tration, the resulting solid was dissolved in MeOH (5 mL) and
the solution was heated at reflux for 8 h. Without purification,
the brownish solid was dissolved in MeOH (2 mL) and TFA
(0.2 mL) was added. The resulting mixture was heated at
reflux overnight. After being cooled to room temperature, the
mixture was basified with aqueous Na2CO3 solution and
extracted with CH2Cl2. Evaporation of the solvents gave a
residue that was chromatographed (Al2O3, CH2Cl2). Initially,
starting amine 28 (22 mg) was recovered. Further elution gave
methyl didehydrodeethylibophyllidine-1-carboxylate (24, 47
mg, 29%), identical in all respects to the previously synthesized
from 23. Finally, methyl 4a-hydroxy-1,2,2a,3,4,4a,5,10,11,12a-
decahydropyrrolizino[1,7-cd]carbazole-5-carboxylate (30, 48
mg, 30%) was obtained: IR (neat) 1698-1702; Rf 0.35; 1H NMR
(500 MHz, COSY) 1.36 (t, J ) 13 Hz, 1H, H-3R), 1.41 (t, J )
13.5 Hz, 1H, H-4â), 1.53 (q, J ) 6 Hz, 1H, H-3â), 1.83 (dd, J )
12.5, 5 Hz, 1H, H-2â), 1.89 (dt, J ) 12, 7 Hz, 1H, H-10â), 2.01
(sextet, J ) 6 Hz, 1H, H-2a), 2.23 (dt, J ) 12.5, 7 Hz, 1H,
H-2R), 2.28 (m, 1H, H-4R), 2.64 (dddd, J ) 12.5, 9, 6, 3.5 Hz,
1H, H-1â), 2.77 (m, 1H, H-11â), 2.83 (dd, J ) 12.2, 5.5, 1H,
H-10R), 3.13 (dd, J ) 13, 7.5 Hz, 1H, H-1R), 3.14 (dd, J ) 12,
8 Hz, 1H, H-11R), 3.89 (s, 3H, OCH3), 4.05 (d, J ) 6.5 Hz, 1H,
H-12a), 7.01 (td, J ) 7.5, 1 Hz, 1H, H-7), 7.14 (td, J ) 7.5, 1.5
Hz, 1H, H-8), 7.24 (dd, J ) 7, 0.5 Hz, 1H, H-9), 7.41 (br s, 1H,
H-6); 13C NMR (HMQC) 22.8 (C-3), 32.9 (C-4), 35.4 (C-2a), 35.9
(C-2), 42.8 (C-10), 52.3 (C-1), 52.7 (OCH3), 53.2 (C-9b), 56.0
(C-11), 71.2 (C-12a), 95.2 (C-4a), 114.5 (C-6), 122.8 (C-9), 123.7
(C-8), 127.8 (C-7), 135.1 (C-9a); HRMS calcd for C18H20N2O3
314.6304, found 314.1628.
6-[2-(1,3-Dioxolan yl)]-3-m eth yl-2,3,4,5,6,7,8,9-octah ydr o-
1H-a zecin o[5,4-b]in d ole (26). A cold (-78 °C) solution of
25 (181 mg, 0.4 mmol), as a mixture of diastereoisomers, in
THF (15 mL), EtOH (0.42 mL), and liquid NH3 (80 mL) was
treated with lithium metal (43 mg, 6.2 mmol) until a blue color
persisted. After 15 min, the reaction mixture was allowed to
warm to room temperature. After NH3 was evaporated, the
mixture was extracted with EtOAc. The combined organic
phases were washed with brine, dried, and concentrated. The
residue was chromatographed (Al2O3, CH2Cl2) to give 26 (79
mg, 60%) and a dihydro derivative (26 mg, 20%). The latter
was rearomatized by stirring a solution of it in the minimum
quantity of CH2Cl2 under an oxygen atmosphere (1 day,
quantitative). From the aqueous phase of the workup process,
the starting material 25 can be recovered by extraction with
CHCl3 in a 10-15% yield: Rf 0.83 (Al2O3, 3:2 CH2Cl2/EtOAc);
1
mp 62 °C; IR (KBr) 3400; H NMR 1.19-1.35 (m, 1H), 1.54-
1.82 (m, 2H), 1.90-2.10 (m, 3H), 2.06 (s, 3H), 2.50-2.60 (m,
1H), 2.70-3.10 (m, 6H), 3.70-3.90 (m, 4H), 4.59 (d, J ) 6 Hz,
1H), 7.01-7.15 (m, 2H), 7.25 (dd, J ) 8, 1.5 Hz, 1H), 7.44 (dd,
J ) 8, 1.5 Hz, 1H), 7.81 (br s, 1H). 13C NMR, Table 2. Anal.
Calcd for C19H26N2O2: C, 72.61; H, 8.28; N, 8.92. Found: C,
72.50; H, 8.28; N, 8.79.
6-[2-(1,3-Dioxola n yl)]-3-m e t h yl-8-m e t oxyca r b on yl-
2,3,4,5,6,7,8,9-octa h yd r o-1H-a zecin o[5,4-b]in d ole (28). Op-
erating as in the preparation of 22, from indole 26 (190 mg,
0.60 mmol), LDA (0.8 mL, 1.21 mmol), and methyl cyanofor-
mate (0.3 mL, 4 mmol) in a 1:10 mixture of HMPA-THF (3.3
mL), indole 28 (210 mg, 94%) was obtained after chromatog-
raphy (CH2Cl2): Rf 0.25 (3:2 CH2Cl2/EtOAc), Rf 0.85 (Al2O3,
3:2 CH2Cl2/EtOAc); IR (film) 1736; 1H NMR (500 MHz, COSY)
1.12-1.18 (m, 1H, H-5), 1.36-1.43 (m, 1H, H-7), 1.62-1.67
(m, 1H, H-5), 1.82 (t, J ) 10 Hz, 1H, H-6), 1.93-1.96 (m, 1H,
H-4), 2.06 (s, 3H, NCH3), 2.20 (ddd, J ) 13.5, 6, 1.5 Hz, 1H,
H-7), 2.46 (dt, J ) 11.5, 3.5 Hz, 1H, H-2), 2.67-2.77 (m, 2H,
H-1 and H-4), 2.78-2.87 (m, 2H, H-2 and H-1), 3.07 (dt, J )
14.5, 5 Hz, 1H, H-8), 3.19 (dq, J ) 14.5, 3 Hz, 1H, H-8), 3.65-
3.80 (m, 4H, OCH2), 4.01 (s, 3H, OCH3), 4.49 (d J ) 4 Hz, 1H,
OCHO), 7.11 (dt, J ) 7.5, 1.5 Hz, 1H, H-12), 7.15 (dt, J ) 7.5,
1.5 Hz, 1H, H-11), 7.45 (dd, J ) 7.5, 0.5 Hz, 1H, H-13), 7.98
(dd, J ) 8, 0.5 Hz, 1H, H-10); 13C NMR, Table 2; HRMS calcd
for C21H28N2O4 372.2049, found 372.2068.
Treatment of 30 (48 mg) with TsOH (1.1 equiv) in a benzene
solution at reflux for 1 day with a Dean-Strak apparatus gave
ene carbamate 24 (42 mg) in 92% yield.
C. Via Ca r ba m a te 29c. A mixture of 28 (60 mg, 0.16
mmol) and allyl chloroformate (0.2 mL, 1.6 mmol) was heated
at reflux for 20 h. After evaporation of excess reagent, the
residue was taken up on CH2Cl2 and the solution washed with
1 N HCl. The dried organic phase was chromatographed
(Al2O3, CH2Cl2) to give carbamate 29c (38 mg, 54%): Rf 0.87
(3:2 CH2Cl2/EtOAc); IR (film) 1736, 1697; 1H NMR 1.18-1.53
(m, 3H), 1.76 (t, J ) 9.5 Hz, 1H), 2.04 (q, J ) 9.5 Hz, 1H),
2.63-2.69 (m, 1H), 2.78-3.44 (m, 5H), 3.6-4.16 (m, 5H), 4.03
(s, 3H), 4.34-4.47(m, 1H), 4.59 (brs, 2H), 4.72 and 4.85 (2 d,
J ) 3 Hz, 1H), 5.11-5.34 (m, 2H), 5.72 and 5.92 (2m, 1H),
7.21-7.27 (m, 2H), 7.39 (dd, J ) 6.5, 2 Hz, 1H), 8.08 (d, J )
7.5 Hz, 1H); 13C NMR (two rotamers) 24.8, 25.3, 25.8, 26.1,
26.5, 26.9, 28.0, 28.7, 37.3, 38.7, 47.4, 48.0, 48.3, 49.8, 53.4,
65.0, 65.9, 66.1, 106.8, 115.8, 117.0, 117.2, 118.3, 118.4, 119.1,
122.7, 122.8, 123.8, 124.0, 129.7, 133.2, 136.0, 137.6, 152.4,
156.9, 156.5; HRMS calcd for C24H30N2O6 442.2103, found
442.2106.
To a solution of carbamate 29c (30 mg, 0.1 mmol), Pd(PPh3)4
(7.9 mg, 6.8 × 10-3 mmol), and AcOH (0.02 mL, 0.3 mmol) in
CH2Cl2 (2 mL) was added Bu3SnH (0.04 mL). After 16 h at
room temperature, the solvent was evaporated and the residue
partitioned between CH2Cl2 and 1 N HCl. The aqueous acid
phase, after being washed with ether and hexane, was kept
standing for 48 h and then basified with a saturated aqueous
Na2CO3 solution and extracted with CH2Cl2 to give crude 30
(7 mg, 33%). For conversion of 30 to 24, see above.
Con ver sion of Tr icyclic Der iva tive 28 to P en ta cyclic-
Der iva tive 24. A. Via Ca r ba m a te 29a . Vinyl chlorofor-
mate (0.1 mL, 1.1 mmol) was slowly added to amine 28 (40
mg, 0.1 mmol) at room temperature. The mixture was heated
at reflux for 24 h and then partitioned between CH2Cl2 and 1
N HCl. The organic layer was dried, concentrated, and
chromatograped (Al2O3, CH2Cl2) to give vinyl carbamate 29a
(38 mg, 82%): Rf 0.86 (3:2 CH2Cl2/EtOAc); IR (film) 1736, 1712;
1H NMR (500 MHz, COSY) 1.11-1.49 (m, 3H, H-5 and H-7),
1.68 (dt, J ) 9, 2 Hz, 1H, H-6), 1.94-2.02 (m, 1H, H-7), 2.59-
2.67 (m, 1H, H-4), [2.76 (t, J ) 13 Hz), 2.82-2.90 (m), 3.35
(m), 3.38 (m), 5H, H-8, H-1 and H-6], 3.74-3.92 (m, 4H, OCH2),
4.02 (s, 3H, OCH3), [4.04 (m) and 4.20 (d, J ) 5.5 Hz), 4.3-4.4
(m), 4H, H-4, CdCH2, H-2)], 4.68 and 4.78 (2 d, J ) 4 Hz, 1H,
OCHO), 6.95 and 7.13-7.25 (2m, 3H, OCHdC, H-10 and
H-11), 7.32 and 7.35 (2dd, J ) 7.5, 2 Hz, 1H, H-13), 8.02 (2dd,
J ) 7.5, 2 Hz, 1H, H-10); 13C NMR, Table 2; HRMS calcd for
2-[2-(1,3-Dioxolan yl)]-4-eth yl-5-m eth yl-1,2,3,4,6,7,12,12b-
octa h yd r oin d olo [2,3-a ]qu in olizin iu m Iod id e (32). To a
solution of 31a 39 (474 mg, 1.45 mmol) in the minimum quantity
of a 5:1 mixture of CH2Cl2 and MeOH was added MeI (0.72
mL, 1.45 mmol). The mixture was heated at 65 °C until the
disappearance of the starting compound was observed by TLC
(2-3 h). The solvent was evaporated to give, as a dark powder,
metho salt 32 (620 mg) as a mixture of diastereoisomers. For
the major isomer 32a -1: 1H NMR 1.08 (t, J ) 7 Hz, 3H), 3.23,
C
23H28N2O6 428.1947, found 428.1950.
Dry HCl was bubbled through a solution of 29a (30 mg, 0.1
mmol) in CH2Cl2 (5 mL) for 20 min. After the solution was
concentrated, MeOH (2 mL) was added to the residue and the
solution was heated at reflux for 30 min. The solvent was
removed, the residue was taken up with CH2Cl2, and the
resulting solution was washed with an aqueous Na2CO3

Total Syntheses of (()-Deethylibophyllidine
J . Org. Chem., Vol. 63, No. 21, 1998 7347
(s, 3H), 5.35 (d, J ) 12 Hz, 1H); 13C NMR, see Table 1. Anal.
organic phase was dried and concentrated. After the residue
was dissolved in MeOH (5 mL), the solution was heated at
reflux for 5 h. MeOH was removed, toluene (2 mL) and TFA
(0.2 mL) were added, and the mixture was heated at reflux
for 24 h. After being cooled to room temperature, the mixture
was diluted with EtOAc, washed with an aqueous Na2CO3
solution, and dried. After concentration, purification by chro-
matography (Al2O3, CH2Cl2) gave 20 mg of the starting amine
34 and 4 mg (8%) of 37 as a mixture of diastereomers in a 1:9
ratio, according to a GC-MS analysis: Rf 0.7 (Al2O3, 3:2 CH2-
Cl2/EtOAc); IR (film) 1718, 1602. For the major isomer 37a :
1H NMR (200 MHz) 0.88 (t, J ) 7.5 Hz, 3H), 3.95 (s, 3H), 6.23
(dd, J ) 8, 3 Hz, 1H), 7.07 (t, J ) 7.5 Hz, 1H), 7.24-7.34 (m,
2H), 7.81 (d, J ) 7.5 Hz, 1H); 13C NMR 11.6 (CH3), 27.1 (CH2),
29.5 (C-2), 36.9 (C-3), 36.2 (C-2a), 38.9 (C-10), 70.0 (C-1), 53.1
(OCH3), 51.5 (C-9b), 49.7 (C-11), 74.5 (C-12a), 106.5 (C-4), 115.4
(C-6), 123.6 (C-9), 125.0 (C-8), 129.1 (C-7), 133.7 (C-9a), 141.8
(C-4a), 143.8 (C-5a), 152.9 (CO); HRMS calcd for C20H24N2O2
324.1838, found 324.1823.
Calcd for
C21H29IN2O2‚H2O: C, 51.85; H, 6.37; N, 5.76.
Found: C, 51.85; H, 6.20; N, 5.77.
6-[2-(1,3-Dioxola n yl)]-4-eth yl-3-m eth yl-8-m eth oxyca r -
b on yl-2,3,4,5,6,7,8,9-oct a h yd r o-1H -a zecin o[5,4-b]in d ole
(34). The procedure described above for the preparation of
26 was carried out with crude metho salts 32 (440 mg, 0.9
mmol), this time addying MeOH (1 mL for each mmol of 32),
to afford, after chromatography (Al2O3, CH2Cl2), 33 (188 mg,
66% overall yield from 31) as a mixture of epimers. From the
aqueous phase of the workup, the starting material 32 can be
recovered in a 10-20% yield, by extraction with CHCl3: Rf
0.85 (Al2O3, 3:2 CH2Cl2/EtOAc); 1H NMR (200 MHz) 0.81 and
0.91 (2t, J ) 8 Hz, CH3), 1.91 and 2.26 (2s, NCH3), 3.7-3.9
(m, 4H, OCH2), 4.59 and 4.65 (2 d, J ) 6 Hz, OCHO), 7.05-
7.15 (m, 2H, H-10 and H-11), 7.26 (d, J ) 8 Hz, 1H, H-12),
7.45 (d, J ) 8 Hz, 1H, H-9), 7.78 (br s, 1H, NH). The procedure
described above for methoxycarbonylation of indole 21 was
carried out with indole 33 (320 mg, 0.93 mmol). Chromatog-
raphy (CH2Cl2) afforded 289 mg (79%) of indole 34 as a mixture
of epimers in a 4:1 ratio (GC-MS analysis): Rf 0.25 (3:2 CH2-
Cl2/EtOAc); IR (film) 1734. Anal. Calcd for C23H32N2O4: C,
68.97; H, 8.05; N, 6.99. Found: C, 68.74; H, 8.30; N, 6.78.
Ack n ow led gm en t. Financial support from the DGI-
CYT, Spain (Project PB94-0858), is gratefully acknowl-
edged. Thanks are also due to the DGEU, Catalonia,
for Grant 1997SGR-00166 and a fellowship to J .-C.F.
1
34a : H NMR 0.90 (t, J ) 7.3 Hz, 3H), 1.05-1.14 (m, 1H),
1.20-1.60 (m, 4H), 1.78-1.83 (m, 1H), 2.02-2.14 (m, 1H),
2.20-2.32 (m, 1H), 2.27 (s, 3H), 2.60-3.38 (m, 6H), 3.72-3.88
(m, 4H), 4.02 (s, 3H), 4.63 (d, J ) 3.8 Hz, 1H) 7.18-7.24 (m,
2H), 7.42 (m, 1H), 8.06 (m, 1H); 13C NMR, Table 2. 34b: 1H
NMR 0.84 (t, J ) 7.2 Hz, 3H), 1.92 (s, 3H), 4.02 (s, 3H), 4.55
(d, J ) 3.7 Hz, 1H); 13C NMR, Table 2.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation and characterization data for 8a , 8b,
9, 11a , 12a , 13, 17a , 17b, 18a , 18b, 25b-1, 25b-2 and 28 and
NMR data for 16. MS data of compounds described in the
Experimental Section (10 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
Meth yl 1-Eth yl-1,2,2a ,3,5,10,11,12a -octa h yd r op yr r oliz-
in o[1,7-cd]car bazole-5-car boxylate (37). 1-Chloroethyl chlo-
roformate (0.24 mL, 2 mmol) was added dropwise to compound
34 (60 mg, 0.15 mmol) at room temperature. After being
stirred at 130 °C for 6 h, the reaction mixture was concen-
trated, taken up with CH2Cl2, and washed with 1 N HCl. The
J O980909O