Synthetic applications of 2-(1,3-dithian-2-yl)indoles. 7. Synthesis of aspidospermidine

Article abstract of DOI:10.1021/jo9609900

A new method of synthesizing the alkaloid aspidospermidine (1), based on building ring E on the pyridocarbazole [ABCD] ring structure, is reported. The preparation of the pyridocarbazole framework of Aspidosperma alkaloids is a new three-step synthetic application of 2-(1,3-dithian-2-yl)indoles. A tandem conjugate addition-alkylation reaction starting from indolyldithiane (4), 3-methylenelactam 6, and EtI yields the adduct 17. Treatment of lactam 17 with DIBALH leads to formation of the naphthyridoindole 18. Compound 18 isomerizes in aqueous AcOH to yield pyridocarbazole 3. Finally, closure of ring E and subsequent reduction of the dithiane ring produces aspidospermidine. Pyridocarbazoles 2 and 10 were prepared as models.

Full text of DOI:10.1021/jo9609900

7882
J . Org. Chem. 1996, 61, 7882-7888
Syn th etic Ap p lica tion s of 2-(1,3-Dith ia n -2-yl)in d oles. 7. Syn th esis
of Asp id osp er m id in e
Pilar Forns, Anna Diez, and Mario Rubiralta*
Laboratori de Quı´mica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona,
08028 Barcelona, Spain
Received May 29, 1996X
A new method of synthesizing the alkaloid aspidospermidine (1), based on building ring E on the
pyridocarbazole [ABCD] ring structure, is reported. The preparation of the pyridocarbazole
framework of Aspidosperma alkaloids is a new three-step synthetic application of 2-(1,3-dithian-
2-yl)indoles. A tandem conjugate addition-alkylation reaction starting from indolyldithiane (4),
3-methylenelactam 6, and EtI yields the adduct 17. Treatment of lactam 17 with DIBALH leads
to formation of the naphthyridoindole 18. Compound 18 isomerizes in aqueous AcOH to yield
pyridocarbazole 3. Finally, closure of ring E and subsequent reduction of the dithiane ring produces
aspidospermidine. Pyridocarbazoles 2 and 10 were prepared as models.
In tr od u ction
In the context of our studies on the application of
2-(1,3-dithian-2-yl)indoles to the synthesis of indole
alkaloids, we reported the synthesis of 20-epidasycarpi-
done1 and several derivatives.2 The key reactions were
the conjugate addition of the indolyldithiane dianion on
appropriate ∆3-piperidein-2-ones and the partial reduc-
tion of the lactam adduct with spontaneous cyclization.
An appropriate substitution on the piperidine nitrogen
atom of these uleine-type structures allows the formation
of the pyrrolidine E-ring of the Strychnos alkaloids.3 We
have now developed a similar strategy for the synthesis
of the pyridocarbazole nucleus of the Aspidosperma
alkaloids ([ABCD] ring structure). Only a few of the
many reported syntheses of Aspidosperma alkaloids4
involve the formation of the pyridocarbazole framework
and final closure of the pyrrolidine ring.5-9
F igu r e 1.
On the basis of our previous work, we envisaged the
formation of pyridocarbazoles by conjugate addition of
indolyldithiane (4) (Figure 1) on a 3-methylenelactam and
treatment of the resulting adduct with DIBALH.
A
2-hydroxyethyl chain on the piperidine nitrogen atom
would allow us to build the fifth ring of Aspidosperma
alkaloids by using a nucleophilic attack of the indole to
displace the hydroxy group.10
* To whom correspondence should be addressed. Phone: 34-3-402
45 39. FAX: 34-3-402 18 96. E-mail: adiez@farmacia.far.ub.es.
X Abstract published in Advance ACS Abstracts, October 1, 1996.
(1) Part 6: Forns, P.; Diez, A.; Rubiralta, M.; Solans, X.; Font-
Bard´ıa, M. Tetrahedron 1996, 52, 3563-3574.
(2) (a) Using (R)-1-(1-phenyl-2-hydroxyethyl)-∆3-piperidein-2-one as
the piperidine synthon: Micouin, L.; Diez, A.; Castells, J .; Lo´pez, D.;
Rubiralta, M.; Quirion, J .-C.; Husson, H.-P. Tetrahedron Lett. 1995,
36, 1693-1696. (b) Using 1-benzyl- or 1-(2-hydroxyethyl)-∆3-piperidein-
2-one and 2-cyano-3-ethyl-1-methyl-∆3-piperidein-2-one as the electro-
phile: Diez, A.; Castells, J .; Forns, P.; Rubiralta, M.; Grierson, D. S.;
Husson H.-P.; Solans, X.; Font-Bard´ıa, M. Tetrahedron 1994, 50, 6585-
6602. (c) Using 1-methyl- or 1-benzyl-3-ethyl-3,4-epoxypiperidine as
the electrophile: Rubiralta, M.; Torrens, A.; Reig, I. Heterocycles 1989,
29, 2121-2133.
(3) For the closure of ring E in the Strychnos series via Pummerer
reaction, see: Amat, M.; Bosch, J . J . Org. Chem. 1992, 57, 5792-5796.
(4) (a) Saxton, J . E. The Aspidospermine Group. In The Monoter-
penoid Indole Alkaloids; Saxton, J . E., Ed. In The Chemistry of
Heterocyclic Compounds; J ohn Wiley and Sons, Inc.: New York, 1983;
Vol. 25, Part 4, pp 331-437; (b) 1994; Vol. 25, Supplement to Part 4,
pp 357-436.
(5) For the synthesis of aspidospermidine by closure of ring E
through a Pummerer reaction on the [ABCD] framework, in turn
constructed by an intramolecular Diels-Alder reaction, see: Exon, C.;
Gallagher, T.; Magnus, P. J . Am. Chem. Soc. 1983, 105, 4739-4749.
(6) For the synthesis of 18-noraspidospermidine by construction of
ring E via Pummerer reaction on the pyridocarbazole nucleus, prepared
by closure of ring D via an azide, see: Desmaele, D.; D’Angelo, J .
Tetrahedron Lett. 1990, 31, 883-886.
(7) For the synthesis of aspidospermidine by construction of ring E
with ethylene bromide from the pyridocarbazole nucleus, built from a
2-(3-indolyl)piperidine-3-acetate, see: Wenkert, E.; Hudlicky, T. J . Org.
Chem. 1988, 53, 1953-1957.
Resu lts a n d Discu ssion
We first tested the method using 1-methyl-3-meth-
ylene-2-piperidone (5)11 as the piperidine synthon (Figure
2). Treatment of 2-(1,3-dithian-2-yl)indole (4) with 2
equiv of n-BuLi in dry THF afforded dianion 7, which
was condensed with 5 in the presence of HMPA to give
the lactam adduct 9, in 64% yield. In the absence of
HMPA the condensation was slower and gave diconden-
sation products.
(8) For the synthesis of deethylaspidospermidine from the [ABCD]
ring system, built by closure of ring C from a 2-(3-indolyl)piperidine-
3-acetate, see: Natsume, M.; Utsunomiya, I. Heterocycles 1982, 17,
111-115.
(9) For the synthesis of pyridocarbazole derivatives by intramolecu-
lar cyclization of an iminium salt, see: (a) J oule, J . A.; Salas, M.-L. J .
Chem. Res., Miniprint 1990, 664-673. (b) Troin, Y.; Diez, A.; Bettiol,
J .-L.; Rubiralta, M.; Grierson, D. S.; Husson, H.-P. Heterocycles 1991,
32, 663-668.
(10) (a)See ref 8. (b) Rubiralta, M.; Diez, A.; Bosch, J .; Solans, X. J .
Org. Chem. 1989, 54, 5591-5597. (c) Lo´pez, I.; Diez, A.; Rubiralta, M.
Tetrahedron 1996, 52, 000.
(11) . Lee, D. L.; Morrow, C. J .; Rapoport, H. J . Org. Chem. 1974,
39, 893-902.
S0022-3263(96)00990-5 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Aspidospermidine
J . Org. Chem., Vol. 61, No. 22, 1996 7883
F igu r e 2.
Ta ble 1. Sp ectr a l Da ta of Na p h th yr id oin d oles 11, 14, a n d 18
H-atom
11a,b
14a,b
18a,b
C-atom
11a
14a
18a
2-Heq
2-Hax
3-Heq
3-Hax
4-Heq
4-Hax
4a-H
5-Heq
5-Hax
7-H
2.98 dd (12,3)
2.40 m
1.53 m
1.85 m
1.85 m
3.01 dm (12)
2.32 td (12, 2)
1.57 dm (12)
1.96 tt (12, 4)
1.77 dm (12)
1.43 td (12, 5)
3.21-3.30 m
2.39 td (14, 3)
1.55 dm (14)
1.92 qt (14, 5)
1.73 dm (14)
1.41 td (14, 5)
C-2
C-3
C-4
C-4a
C-5
C-6
C-6a
C-7
C-7a
C-8
C-9
C-10
56.0
20.8
29.6
33.6
35.8
55.9
20.3
33.2
39.4
38.6
53.7
21.1
33.2
39.7
38.6
1.85 m
2.40 m
47.7
44.9
44.8
137.8
104.0
127.8
120.9
119.9
121.6
110.4
137.1
72.5
137.4
103.0
127.8
120.9
120.0
121.6
109.8
137.2
77.5
28.9
29.2
24.9
28.5
137.8
102.9
127.8
120.9
120.1
121.9
109.6
137.0
76.3
28.6
29.2
24.8
28.5
2.55 dd (12,3)
3.38 t (12)
6.93 s
7.57 dm (7)
7.08 ddd (8,7,1)
7.17 ddd (8,7,1)
7.41 br d (8)
4.42 d (3)
2.85 dt (13,4)
2.75 dt (13,4)
3.30 ddd (13,11,3)
3.20 ddd (13,11,3)
2.00-2.20 m
2.50 d (14)
3.31 d (14)
6.98 s
2.42 d (14)
3.31 d (14)
6.96 s
8-H
9-H
10-H
11-H
7.60 br d (8)
7.09 ddd (8, 7, 1)
7.18 ddd (8, 7, 1)
7.40 br d (8)
4.08 s
2.87 dt (14, 4)
2.94 dt (14, 4)
3.26 ddd (14, 11, 3)
3.30 ddd (14, 11, 3)
2.03-2.25 m
1.02 m<Tc>
1.16 m
7.59 d (8)
7.07-7.28 m
7.07-7.28 m
7.35 d (8)
C-11
C-11a
C-12a
SCH2
SCH′2
SCCH2
CH2CH3
CH2CH3
NCH3
NCH2
CH2OBn
OCH2Ph
C-i Ph
C-o Ph
C-m Ph
C-p Ph
12a-H
SCHeq
SCHeq′
SCHax
SCHax′
SCCH2
CHACH3
CHBCH3
CH2CH3
NCH3
NCHA
NCHB
CHAOBn
CHBOBn
OCHAPh
OCHBPh
4.26 s
2.85 dt (14, 4)
2.97 dt (14, 4)
3.18 ddd (14, 11, 3)
3.21-3.30 m
2.05-2.20
0.96 m
28.0
29.3
24.9
7.4
42.8
7.3
43.2
1.11 m
0.70 t (7)
51.9
69.8
0.72 t (7)
2.01 s
2.03 s
72.4
2.27 ddd (13, 7)
2.65 ddd (13, 7)
2.99 ddd (13, 7)
3.33 ddd (13, 7)
4.13 d (12)
138.4
127.5
128.1
127.2
4.19 d (12)
a
b
All data are confirmed by COSY (H,H) and (H,C) experiments. Coupling constants are given in parentheses (Hz).
When piperidone 9 was reduced with DIBALH at 0 °C,
the expected mixture of trans-10a (3%), cis-10b (31%),
cis-11 (35%), and piperidine 12 (5%) was obtained, and
the compounds were isolated by flash chromatography.
The cyclization was demonstrated by the loss from the
1H NMR spectra of the In-3H proton in compounds 10
and of the In-NH proton in compound 11, as well as by
the lack of the carbonyl absorption signal in their IR
spectra. The main differences between pyridocarbazoles
10 were the chemical shift and the coupling constant
value of the angular proton 11c-H (10a : δ11c-H 4.02,
J 11c-4a ) 10 Hz; 10b: δ11c-H 3.18, J 11c-4a ) 3.2 Hz),
spectrum of naphthyridoindole 11 (Table 1) showed the
aromatic 7-H proton at δ 6.93 and the methine aminal-
type 12a-H proton as a doublet at δ 4.42. The latter was
correlated with the signal at δ 72.5 assigned to C-12a
carbon in the COSY (C,H) spectrum. It is also worth
mentioning that only the C/D cis isomer was obtained,
as shown by the coupling constant value of the 12a-H
proton (J ) 3 Hz).
As in the case of methanodiazocinoindoles obtained in
the Strychnos series,1 the isomerization of naphthyrido-
indole 11 was performed in 50% aqueous AcOH and
yielded a 1:3 mixture of pyridocarbazoles trans-10a and
cis-10b. The fact that the isomerization occurs in the
C/D condensed (naphthyridine) as well as in the C/D
1
observed in the H NMR spectra (Table 2), which corre-
sponds to the assignments described.9a The 1H NMR

7884 J . Org. Chem., Vol. 61, No. 22, 1996
Ta ble 2. 1H NMR Da ta of P yr id oca r ba zoles 10, 2, 3, a n d 23a
Forns et al.
H-atom
trans-10a b
cis-10bb
2
3b
23b
2-Heq
2-Hax
3-Heq
3-Hax
4-Heq
4-Hax
4a-H
5-HR
5-Hâ
7-H
3.04-3.30 m
3.04-3.30 m
1.39 br d (13)
1.85-2.06 m
1.84 dm (13)
1.44 dddd (13, 3)
2.35 masked
2.08 d (11)
2.95 dt (13, 3)
2.15-2.30 m
1.55 dt (12, 3)
1.80-1.90 m
1.74-1.80 m
1.74-1.80 m
2.15-2.30 m
2.53 dd (13, 3)
3.25 t (12)
2.97 dm (11)
2.10-2.25 m
1.58 dm (13)
1.97 qt (13, 4)
1.75 dm (14)
1.33 td (14, 5)
3.11-3.25 m
2.25-2.36 m
1.54 dm (13)
1.88 qt (13, 4)
1.73 br d (13)
1.31 td (13, 5)
3.12 dm (13)
2.19-2.27 m
1.62 dm (13)
1.90 qt (13, 4)
1.74 dm (13)
1.41 td (13, 5)
2.61 d (14)
3.29 d (14)
8.55 s
2.53 d (14)
3.33 d (14)
8.58 s
2.60 d (13)
3.35 d (13)
8.60 br s
2.76 dd (11, 2)
8.42 br s
8.50 br s
8-H
9-H
10-H
11-H
7.31 dt (8,1)
7.17 td (7, 1)
7.07 td (7, 1)
7.94 br d (8)
4.02 d (10)
3.04-3.30 m
3.04-3.30 m
2.72 dt (12, 3)
2.81 dt (12, 3)
1.85-2.06 m
2.19 dm (14)
7.30 d (7)
7.36 d (8)
7.33 br d (8)
7.18 td (8, 1)
7.07-7.27 m
7.57 br d (8)
3.19 s
3.27-3.40 m
3.11-3.25 m
2.80 dt (14, 3)
2.86 dt (14, 6)
1.98 qt (14, 3)
2.18 dm (14)
0.98 m
7.35 br s (8)
7.19 td (8, 1)
7.12 td (8, 1)
7.50 br d (8)
3.33 s
3.27-3.40 m
3.27-3.40 m
2.83 dt (14, 3)
2.90 dt (14, 3)
2.00 qt (14, 3)
2.19-2.27 m
1.04 m
7.15 td (7, 1)
7.10 td (7, 1)
7.55 d (7)
3.18 d (3, 2)
3.21 ddd (13, 12, 3)
3.30 ddd (13, 12, 3)
2.72 dt (13, 3)
2.81 dt (13, 3)
1.99 qt (13, 3)
2.15-2.30 m
7.19 td (8, 1)
7.11 td (8, 1)
7.58 d (8)
11c-H
2.92 s
SCHax
SCHax′
SCHeq
SCHeq′
SCCHax
SCCHeq
CHACH3
CHBCH3
CH2CH3
NCH3
NCHA
NCHB
CHAOR
CHBOR
OCHAPh
OCHBPh
3.38 ddd (15, 13, 3)
3.32 ddd (15, 13, 3)
2.83 dt (15, 3)
2.89 dt (15, 3)
2.01 qt (13, 3)
2.10-2.25 m
0.99 ddd (21, 7)
1.48 ddd (21, 7)
0.73 t (7)
1.45 m
0.72 t (7)
1.38 m
0.72 t (7)
2.29 s
2.29 s
2.19 s
2.25-2.36 m
3.02 ddd (13, 7)
3.11-3.25 m
3.27-3.40 m
4.17 d (14)
2.16 ddd (13, 11, 3)
2.96 ddd (13, 11, 4)
3.07 br t (11)
3.48 td (11, 3)
4.20 d (14)
a
b
Coupling constants are given in parentheses (Hz). All data are confirmed by COSY (H,H) and (H,C) experiments.
bridged (methanodiazocino) compounds confirms the
mechanism that we proposed for these acid-induced
rearrangements.1
We then studied the possibility of inserting the ethyl
group by direct alkylation of the intermediate enolate (8).
Therefore, the conjugate addition of dianion 7 on lactam
5 in the presence of HMPA was quenched by addition of
EtI. Lactam 13 was obtained in 51% yield, accompanied
with compound 9 (10%). The latter was alkylated in the
presence of HMPA using s-BuLi as the base and EtI to
obtain 13. The reduction-cyclization reaction of com-
pound 13 with DIBALH yielded a 1:2.7 mixture of
piperidine 15 and naphthyridoindole 14. No pyridocar-
bazole was obtained in this case. Compound 14 was then
transformed to the desired pyridocarbazole 2 by aqueous
AcOH treatment. In this case, only the thermodynami-
cally more stable cis derivative was obtained (84%).
Concerning the modifications of the dithiane ring
(Figure 3), treatment of compound 10b with (CF3CO2)2-
IPh in CH3CN-H2O (9:1)12 yielded the acylindole deriva-
tive 20 (Tables 4 and 5). The clearest evidence for the
presence of the keto group in compound 20 was the
carbonyl absorption in its IR spectrum and the 13C NMR
signal at δ 192.6. As an alternative, dithianes 10b and
2 were reduced with Raney Ni in wet EtOH to obtain
compounds 21 and 22. In these cases, a new methylene
carbon corresponding to C-6 appeared in the 13C NMR
spectra, at ca. 20 ppm.
F igu r e 3.
nipecotic acid to give 3-methylene-2-piperidone 6 (see
Experimental Section). The tandem conjugate addition-
alkylation reaction of the dithianylindole dianion 7
on lactam 6 furnished the adduct 17, in 52% yield (Fig-
ure 2). As in the previous series, the deethyl analogue
16, isolated in 10% yield, was quantitatively converted
to 17 by alkylation with EtI in the presence of HMPA.
The reaction of lactam 17 with DIBALH yielded naph-
thyridoindole 18 (73%), as well as a small amount of
piperidine 19. Isomerization of naphthyridoindole 18 in
aqueous AcOH resulted in the target pyridocarbazole 3
(Tables 2 and 3), in 90% yield: this was identified by
comparison of its spectral data with those of the N-methyl
analogues.
Having shown the validity of the general method, we
applied the reaction sequence starting from methylene
lactam 6, which presented the appropriate substituent
on the nitrogen atom for assaying the formation of
pentacyclic Aspidosperma derivatives. Methylene lactam
6 was prepared by N-alkylation of ethyl nipecotate with
benzyl bromoethyl ether,13 acid hydrolysis, and subse-
quent Rapoport rearrangement11 of the corresponding
With pyridocarbazole 3 in hand, we proceeded to its
conversion to aspidospermidine (1).14 We performed the
(12) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.
(13) Grobelny, D.; Ma´slak, P.; Witck, S. Tetrahedron Lett. 1979,
2639.

Synthesis of Aspidospermidine
J . Org. Chem., Vol. 61, No. 22, 1996 7885
Ta ble 3. 13C NMR Da ta of P yr id oca r ba zoles 10, 2, 3, a n d
23
Ta ble 5. 13C NMR Da ta of P yr id oca r ba zoles 20-22
C-atom
20
21a
22a
C-atom
C-2
trans-10a a
cis-10ba
2
3a,b
23a
C-2
C-3
57.1
21.2
57.5
21.6
57.4
21.8
54.1
19.3
57.3
57.2
21.8
54.2
21.8
52.4
21.9
C-3
21.9
C-4
29.6
30.5
34.4
C-4
C-4a
31.6
28.3
30.2
33.8
34.3
39.1
34.3
39.6
34.0
40.0
C-4a
C-5
38.6
39.7
35.5
23.2
36.3
24.3
C-5
C-6
C-6a
C-7a
C-8
C-9
C-10
C-11
C-11a
C-11b
C-11c
NCH3
CH2CH3
CH2CH3
SCH2
SCH′2
SCH2CH2
NCH2
CH2OR
43.6
47.6
38.3
48.5
39.4
46.2
39.3
46.4
40.5
45.8
C-6
192.6
131.6
137.2
112.7
126.6
121.6
120.9
128.8
127.3
59.4
23.2
20.3
C-6a
C-7a
C-8
135.9
136.6
110.4
120.7
119.3
118.3
128.9
135.4
135.9
110.3
120.5
119.1
118.2
129.8
134.2
136.1
110.9
122.6
119.8
121.6
125.9
113.8
63.7
135.1
135.8
111.2
122.3
119.8
119.5
127.8
masked
59.1
133.5
135.8
111.2
122.3
119.7
119.1
128.6
113.5
65.4
45.0
30.0
7.7
27.9
133.7
135.9
111.2
122.3
119.9
119.0
128.5
113.6
63.8
133.8
136.0
111.5
122.5
120.0
118.4
128.5
112.7
63.1
C-9
C-10
C-11
C-11a
C-11b
C-11c
NCH3
CH2CH3
CH2CH3
59.8
45.3
64.9
45.6
29.5
7.8
45.1
34.1
44.9
29.9
7.7
30.1
7.6
a
All data are confirmed by COSY (H,H) and (H,C) experiments.
27.0
28.7
24.9
26.9
28.6
24.9
27.9
28.2
25.0
53.6
69.4
27.9
28.1
25.0
54.4
58.2
28.3
25.0
a
All data are confirmed by COSY (H,H) and (H,C) experiments.
b Signals of the benzyl group in compound 3: 72.2 (OCH2Ph), 127.1
(C-para), 127.6 (C-ortho), 128.1 (C-meta), 138.5 (C-ipso).
Ta ble 4. 1H NMR Da ta of P yr id oca r ba zoles 20-22a
H-atom
20
21b
22b
2-Heq
2-Hax
3-Heq
3-Hax
4-Heq
4-Hax
4a-H
5-HR
5-Hâ
6-H
7-H
3.00 dt (12, 2)
2.20-2.40 m
1.65 dm (13)
1.83-2.00 m
1.83-2.00 m
1.72-1.79 m
2.20-2.40 m
2.54 dt (12, 3)
3.42 t (13)
2.91 br d (13)
2.19 ddd (13, 8, 3) 2.21 td (11, 3)
2.95 dm (11)
1.76-1.92 m
1.44-1.52 m
1.62-1.70 m
1.62-1.70 m
1.76-1.92 m
1.44-1.52 m
2.50-2.60 m
2.50-2.70 m
8.20 br s
1.58 dm (13)
1.95 qt (13, 4)
1.73 dm (13)
1.38 td (13, 5)
1.32-1.38 m
2.56-2.75 m
2.56-2.75 m
8.16 br s
9.20 br s
8-H
9-H
10-H
11-H
11c-H
CHACH3
CHBCH3
CH2CH3
NCH3
7.44 dt (7, 1)
7.12-7.18 m
7.20 m
7.07 m
7.07 m
7.51 m
7.33 ddd (8, 7, 1) 6.96-7.04 m
7.19 ddd (8, 7, 1) 6.96-7.04 m
7.75 br d (8)
3.43 d (1)
7.44-7.50 m
3.13 d (3)
F igu r e 4.
2.83 s
0.94 ddd (14, 7)
1.21 ddd (14, 7)
0.74 t (7)
2.28 s
signals corresponding to the ethyl substituent, and
confirmed by MS. The formation of 26 suggested that
the EtOH used as the solvent participates in the reac-
tion.16
The Raney Ni reduction of 24 was then performed in
dioxane, and a 1.2:1 mixture of dehydroaspidospermidine
(25) and aspidospermidine (1) was obtained, in 65% yield.
Finally, dehydroaspidospermidine was reduced with Li-
AlH4 under the described conditions,7 and yielded aspi-
dospermidine.
2.27 s
2.29 s
a
b
Coupling constants are given in parentheses (Hz). All data
are confirmed by COSY (H,H) and (H,C) experiments.
debenzylation of compound 3 with Me2S and BF3‚Et2O
and obtained aminoalcohol 23 (Figure 4), which was
characterized by the hydroxy absorption in its IR spec-
trum. Compound 23 was then tosylated with TsCl in the
presence of an excess of KtBuO, which yielded the
expected indolenine system 24. The structure of com-
pound 24 was shown by the lack of the indole NH proton,
the shift of the 5-H and the 6-H protons, and the narrow
doublet at δ 2.42 corresponding to the angular methine
21-H proton (∆δ ) -0.91), observed in the 1H NMR
spectrum (Table 6). The most definitive 13C NMR data
of indolenine 24 were the olefine carbon signal of C-2 (δ
187.6) and the quaternary C-7 (δ 62.6) (Table 7).
Exp er im en ta l Section 1
3-[2-(2-In d olyl)-2,2-(p r op yle n e d isu lfa n yl)e t h yl]-1-
m eth ylp ip er id in -2-on e (9). To a solution of 2-(2-indolyl)-
1,3-dithiane (4) (235 mg, 1 mmol) in dry THF (20 mL), cooled
at -78 °C and under nitrogen atmosphere, was added n-BuLi
(14) For the biogenetic numbering, see: (a) Southon, I. W.; Buck-
ingham, J . Dictionary of Alkaloids; Chapman and Hall: London, 1989;
p xxxviii. The biogenetic numbering is used in this paper when
referring to Aspidosperma-type compounds 1, 24, and 25.
(15) Le Me´nez, P.; Kunesch, N.; Liu, S.; Wenkert, E. J . Org. Chem.
1991, 56, 2915-2918.
(16) The N-alkylation of pyridine during its Raney Ni reduction in
EtOH is well known: Morlacchi, F.; Losacco, V.; Tortorella, V. J .
Heterocycl. Chem. 1979, 16, 297-299 and references cited therein.
Interestingly, the reduction of 24 with W-2 Raney Ni
in EtOH yielded a 1:1 mixture of aspidospermidine and
its 1-ethyl analogue 26. Compound 1 was identified by
comparison of its spectral data with those described
previously,15 and 26 was distinguished by the analytical

7886 J . Org. Chem., Vol. 61, No. 22, 1996
Forns et al.
Ta ble 6. 1H NMR Da ta of Com p ou n d s 24, 26, a n d 1a
3400 (NH), 1621 (CdO) cm-1; MS m/ z 360 (M+, 67), 254 (100).
Anal. Calcd for C19H24N2OS2: C, 63.30; H, 6.71; N, 7.77.
Found: C, 63.20; H, 6.75; N, 7.61.
H-atom
24b
26b,c
1b
H-2
3.51 dd (11, 6)
3.06 br d (12)
1.95 td (12, 3)
2.22 dt (10, 8)
3.50 dd (11, 6)
3.06 br d (14)
1.93 td (14, 3)
2.19-2.35 m
1-Met h yl-6,6-(p r op ylen ed isu lfa n yl)-1,2,3,4,4a ,5,6,11c-
octa h yd r op yr id o[3,2-c]ca r ba zoles (10a ,b), 1-Meth yl-6,6-
(p r op ylen ed isu lfa n yl)-1,2,3,4,4a ,5,6,12a -oct a h yd r o-1,8-
n a p h t h yr id o[1,2-a ]in d ole (11), a n d 3-[2-(2-In d olyl)-2,2-
(p r op ylen ed isu lfa n yl)eth yl]-1-m eth ylp ip er id in e (12). To
a solution of piperidone 9 (228 mg, 0.63 mmol) in dry THF (40
mL) cooled at -20 °C was slowly added a solution of DIBALH
(1 M in THF, 633 µL, 0.63 mmol). The reaction mixture was
allowed to reach 0 °C, and its evolution was monitored by TLC
after 1 h. The procedure was repeated until completion (6 h).
The reaction was quenched with H2O, the phases were
separated, and the aqueous layer was extracted with EtOAc.
The organic extracts, dried and evaporated, yielded an oil that
was flash chromatographed (hexane/EtOAc, 7/3) to isolate
compounds 10-12. Compound 11 (higher Rf, 76 mg, 35%):
mp 200-201 °C (EtOAc/hexane); MS m/ z 344 (M+, 5), 110
(100). Anal. Calcd for C19H24N2S2: C, 66.24; H, 7.02; N, 8.13.
Found: C, 66.37; H, 6.98; N, 8.20. Compound 10a (second Rf,
H-3eq
H-3ax
H-5R
H-5â
H-6R
H-6â
H-9
H-10
H-11
H-12
3.12-3.20 m
2.20 dt (12, 3)
2.61-2.71 m
3.12-3.20 m
1.63-1.73 m
3.12-3.20 m
7.68 d (7)
7.23 t (7)
7.28-7.35 m
7.28-7.35 m
3.11 ddd (10, 8, 1) 3.05-3.15 m
1.41-1.55 m
2.31 dt (13, 8)
7.00-7.04 m
6.60 t (7)
7.00-7.04 m
6.37 d (7)
1.32-1.54 m
2.19-2.35 m
7.08 d (7)
6.73 t (7)
7.01 t (7)
6.64 d (7)
H-14eq 1.47-1.57 m
H-14ax 1.73-1.84 m
H-15eq 1.47-1.57 m
H-15ax 1.03 td (13, 5)
H-16R
1.41-1.55 m
1.67-1.80 m
1.63 br d (15)
1.05-1.20 m
1.05-1.20 m
1.89 td (13, 3)
1.15-1.30 m
1.67-1.80 m
0.63 t (7)
1.32-1.54 m
1.73 qt (13, 4)
1.58-1.67 m
1.10 td (13, 5)
1.05 br d (13)
1.91-2.01 m
1.32-1.54 m
1.58-1.67 m
0.63 t (7)
H-16â
H-17R
H-17â
H-18
1.86 dd (15, 2)
3.06 d (15)
0.61 t (7)
7 mg, 3%): IR (NaCl) 3375 (NH) cm-1
. Anal. Calcd for
H-19
0.66-0.72 m
0.85-0.91 m
2.42 d (2)
1.41-1.55 m
0.79-0.94 m
2.20 s
1.32-1.54 m
0.76-0.96 m
2.22 s
C19H24N2S2: C, 66.13; H, 7.02; N, 8.13. Found: C, 66.13; H,
7.10; N, 8.00. Compound 10b (third Rf, 68 mg, 31%): MS m/ z
344 (M+, 13), 269 (100). Anal. Calcd for C19H24N2S2: C, 66.24;
H, 7.02; N, 8.13. Found: C, 66.11; H, 7.04; N, 7.92. Piperidine
1217 (lower Rf, 11 mg, 5%): MS m/ z 346 (M+, 10), 97 (100).
Anal. Calcd for C19H26N2S2: C, 65.85; H, 7.56; N, 8.08.
Found: C, 65.62; H, 7.58; N, 7.98.
Isom er iza tion of 1,8-Na p h th yr id o[1,2-a ]in d ole 11 To
Give 10. A solution of naphthyridoindole 11 (126 mg, 0,366
mmol) in 50% aqueous AcOH (10 mL) was refluxed for 2 h.
The mixture was basified with Na2CO3 and extracted with
CH2Cl2. The organic extracts, dried and evaporated, were
flash chromatographed (hexane/EtOAc, 3/7) to give compounds
10a (20 mg, 16%) and 10b (56 mg, 44%).
H-21
SCHax 3.07 ddd (12, 10, 2)
SCH'ax 4.25 td (14, 3)
SCHeq
2.61-2.71 m
SCH′eq 2.77 dt (14, 3)
SCCHax 2.00 qt (12, 3)
SCCHeq 2.18 dm (12)
a
b
Coupling constants are given in parentheses (Hz). All data
are confirmed by COSY (H,H) and (H,C) experiments. c Signals
of the ethyl group in compound 26: 1.23 (t, J ) 7 Hz, 3H,
NCH2CH3), 2.89-3.00 (m, 1H, NCHACH3), 3.20-3.30 (m, 1H,
NCHBCH3).
3-Eth yl-3-[2-(2-in dolyl)-2,2-(pr opylen edisu lfan yl)eth yl]-
1-m eth ylp ip er id in -2-on e (13). Meth od A. To a solution
of 2-(2-indolyl)-1,3-dithiane (4) (470 mg, 2 mmol) in dry THF
(25 mL), cooled at -78 °C and under nitrogen atmosphere, was
added n-BuLi (1.6 M in hexane, 2.8 mL, 4.4 mmol) dropwise.
After 20 min, HMPA (1.08 mL, 6.2 mmol) and a solution of
lactam 5 (250 mg, 2 mmol) in dry THF (5 mL) were slowly
added, and the mixture was maintained at -78 °C for 30 min.
EtI (780 µL, 12 mmol) was added, and the mixture was
maintained at -78 °C for an additional hour. The reaction
was quenched by addition of HCl until pH ) 1. Then the
mixture was basified with K2CO3, the layers were separated,
and the aqueous phase was extracted with EtOAc. The
organic extracts, dried and evaporated, furnished a brown oil
that was flash chromatographed (EtOAc/hexane, 7/3) to isolate
compounds 9 (lower Rf, 71 mg, 10%) and 13 (higher Rf, 400
mg, 51%). Lactam 13:17 mp 119-120 °C (EtOAc/hexane); IR
(NaCl) 3325 (NH), 1616 (CdO) cm-1; MS m/ z 388 (M+, 23),
141 (100). Anal. Calcd for C21H28N2OS2: C, 64.91; H, 7.26;
N, 7.21. Found: C, 64.89; H, 7.32; N, 7.10. Meth od B. To a
solution of piperidone 9 (360 mg, 1 mmol) in dry THF (25 mL),
cooled at -78 °C under nitrogen atmosphere, was added s-BuLi
(1.3 M in cyclohexane, 1.92 mL, 2.5 mmol) dropwise. After
20 min, HMPA (540 µL, 4 mmol) was added, and the mixture
was maintained at -78 °C for 1 h. The reaction was treated
as in method A, and lactam 13 was obtained (276 mg, 71%).
cis-4a-Eth yl-1-m eth yl-6,6-(pr opylen edisu lfan yl)-1,2,3,4,-
4a ,5,6,12a -octa h yd r o-1,8-n a p h th yr id o[1,2-a ]in d ole (14)
a n d 3-E t h yl-3-[2-(2-in d olyl)-2,2-(p r op ylen ed isu lfa n yl)-
eth yl]-1-m eth ylp ip er id in e (15). To a solution of piperidone
13 (344 mg, 0.886 mmol) in dry THF (50 mL), cooled at 0 °C,
was slowly added a solution of DIBALH (1 M in THF, 3.54
mL) until the reaction was complete. The reaction was
quenched with H2O (30 mL), the phases were separated, and
the aqueous layer was extracted with EtOAc. The organic
extracts, dried and evaporated, yielded an oil that was flash
chromatographed (EtOAc/hexane, 3/7) to isolate compounds
Ta ble 7. 13C NMR Da ta of Com p ou n d s 24-26 a n d 116
24a
26a
25
1a,b
C-2
C-3
C-5
C-6
C-7
C-8
C-9
C-10
C-11
C-12
C-13
C-14
C-15
C-16
C-17
C-18
C-19
C-20
C-21
SCH2
SCH′2
SCCH2
NCH2CH3
NCH2CH3
187.6
51.5
54.0
39.8
62.6
147.9
121.3
126.1
127.2
120.6
152.6
21.9
33.0
47.9
44.3
7.4
68.1
53.8
53.0
38.7
52.3
136.7
122.3
116.8
127.1
106.2
149.8
21.8
34.4
23.0
22.0
6.8
192.4
52.0
54.5
35.1
66.2
147.0
120.9
125.0
127.4
120.1
154.0
22.0
65.7 (65.7)
53.9 (53.9)
53.0 (53.0)
38.8 (38.8)
53.3 (53.7)
135.7 (135.7)
122.8 (122.8)
119.9 (119.0)
127.0 (127.1)
110.3 (110.2)
149.4 (149.4)
21.8 (23.0)
34.5 (34.5)
23.0 (21.8)
28.1 (28.1)
6.8 (6.8)
33.1
27.1c
23.7c
7.3
28.8
38.0
77.1
28.5
30.7
24.7
30.1
35.5
71.1
29.7
36.2
79.0
30.0 (30.0)
35.6 (35.6)
71.3 (71.3)
37.8
13.3
a
All assignments have been confirmed by COSY (H,H) and
(H,C) experiments. The described assignments15 are given in
b
parentheses. c These assignments are exchangeable.
(1.6 M in hexane, 1.35 mL, 2.2 mmol) dropwise. After 20 min,
HMPA (540 µL, 3.1 mmol) and a solution of lactam 5 (125 mg,
1 mmol) in dry THF (5mL) were slowly added, and the mixture
was maintained at -78 °C for 1.5 h. The reaction was
quenched by addition of HCl until pH ) 1. The mixture was
basified with K2CO3, the layers were separated, and the
aqueous phase was extracted with EtOAc. The organic
extracts, dried and evaporated, furnished a brown oil that,
after chromatography (EtOAc/hexane, 7/3), gave piperidone 917
(230 mg, 64%): mp 211-212 °C (EtOAc-hexane); IR (NaCl)
(17) For the NMR data of this compound, see the supporting
information.

Synthesis of Aspidospermidine
J . Org. Chem., Vol. 61, No. 22, 1996 7887
14 and 15.17 Com p ou n d 14 (higher Rf, 185 mg, 56%): mp
185-187 °C (EtOAc/hexane); MS m/ z 372 (M+, 14), 125 (100).
Anal. Calcd for C21H28N2S2: C, 67.70; H, 7.57; N, 7.52.
Found: C, 67.76; H, 7.78; N, 7.38. Piperidine 15 (lower Rf, 70
mg, 21%): IR (NaCl) 3350 (NH) cm-1; MS m/ z 374 (M+, 3),
125 (100). Anal. Calcd for C21H30N2S2: C, 67.33; H, 8.07; N,
7.48. Found: C, 67.25; H, 8.05; N, 7.37.
was dissolved in Ac2O. The solution was refluxed for 4 h under
N2 atmosphere, cooled, poured into aqueous K2CO3 (300 g in
600 mL of H2O), and stirred for 4 h at 0 °C. The pH was
adjusted to pH ) 8 with additional K2CO3. The aqueous
solution was then extracted with CH2Cl2, and the combined
organic extracts were dried, filtered, and evaporated to yield
lactam 6 (6.2 g, 86%): IR (NaCl) 1634 (CO) cm-1 1H NMR
;
1.75 (qt, J ) 4 Hz, 2H, H-5), 2.55 (br t, J ) 4 Hz, 2H, H-4),
3.50 (t, J ) 4 Hz, 2H, H-6), 3.63 (A2B2, 4H, NCH2CH2O), 4.50
(s, 2H, OCH2Ph), 5.26 (dd, J ) 1.5, 1 Hz, 1H, dCHA), 6.19 (d,
J ) 1 Hz, 1H, dCHB), 7.30 (m, 5H, H-Ph); 13C NMR 22.9 (C-
5), 29.7 (C-4), 47.6 (NCH2), 49.9 (C-6), 68.2 (OCH2), 72.6 (OCH2-
Ph), 120.9 ()CH2), 127.1 (o-Ph), 127.9 (m-Ph and p-Ph), 137.5
(i-Ph), 137.8 (C-3), 163.7 (CdO); MS m/ z 246 (M+ + 1, 2), 124
(100). Anal. Calcd for C15H19NO2: C, 73.47; H, 7.75; N, 5.71.
Found: C, 73.67; H, 7.51; N, 5.23.
cis-4a-Eth yl-1-m eth yl-6,6-(pr opylen edisu lfan yl)-1,2,3,4,-
4a ,5,6,11c-octa h yd r op yr id o[3,2-c]ca r ba zole (2). Operat-
ing as for the isomerization of 11, from the naphthyridoindole
14 (125 mg, 0.336 mmol) and AcOH (50%, 12 mL) was obtained
pyridocarbazole 2 (105 mg, 84%), after flash chromatography
(Al2O3, CH2Cl2), as a white solid: mp 203-204 °C (EtOAc/
hexane); IR (KBr) 3430 (NH) cm-1; MS m/ z 372 (M+, 23), 71
(100). Anal. Calcd for C21H28N2S2‚2H2O: C, 61.73; H, 7.89;
N, 6.86. Found: C, 62.07; H, 7.56; N, 6.85.
1-[2-(Ben zyloxy)eth yl]-3-[2-(2-in d olyl)-2,2-(p r op ylen e-
d isu lfa n yl)eth yl]p ip er id in -2-on e (16) a n d 1-[2-(Ben zyl-
oxy)eth yl]-3-eth yl-3-[2-(2-in d olyl)-2,2-(p r op ylen ed isu lfa -
n yl)eth yl]p ip er id in -2-on e (17). Operating as for the prepa-
ration of lactam 13, from dithiane 4 (941 mg, 4 mmol), THF
(55 mL), n-BuLi (1.6M, 5.3 mL, 8.8 mmol), HMPA (3.5 mL, 20
mmol), lactam 6 (980 mg, 4 mmol), and EtI (1.56 mL, 24 mmol)
was obtained a mixture of 2-piperidones 16 and 17, which was
separated by chromatography (EtOAc/hexane, 7/3). Lactam
1617 (lower Rf, 192 mg, 10%): IR (NaCl) 3300 (NH), 1624
(CdO) cm-1; MS m/ z 480 (M+, 32), 374 (100). Anal. Calcd
for C27H32N2O2S2: C, 67.47; H, 6.71; N, 5.83. Found: C, 67.16;
H, 7.14; N, 5.36. Lactam 1717 (higher Rf, 1.068 g, 52%): mp
123-124 °C (EtOAc/hexane); IR (NaCl) 3300 (NH), 1619 (CdO)
cm-1; MS m/ z 508 (M+, 5), 262 (100). Anal. Calcd for
C29H36N2O2S2: C, 68.47; H, 7.13; N, 5.51. Found: C, 68.39;
H, 7.34; N, 5.36.
cis-1-[2-(Ben zyloxy)eth yl]-4a -eth yl-6,6-(p r op ylen ed is-
u lfa n yl)-1,2,3,4,4a ,5,6,12a -octa h yd r o-1,8-n a p h th yr id o[1,2-
a ]in d ole (18) a n d 1-[2-(Ben zyloxy)eth yl]-3-eth yl-3-[2-(2-
in d olyl)-2,2-(p r op ylen ed isu lfa n yl)eth yl]p ip er id in e (19).
Operating as for the reduction of lactam 13, from piperidone
17 (448 mg, 0.882 mmol), THF (50 mL), and DIBALH (1 M in
THF, 3.53 mL) was obtained a mixture of compounds 18 and
19, which was chromatographed (Al2O3, EtOAc/hexane, 2/8).
Naphthyridoindole 18 (higher Rf, 318 mg, 73%): mp 140-141
°C (EtOAc/hexane); MS m/ z 492 (M+, 10), 245 (100). Anal.
Calcd for C29H36N2OS2‚1/4H2O: C, 70.05; H, 7.40; N, 5.63.
Found: C, 69.88; H, 7.31; N, 5.58. Piperidine 19 (lower Rf,
45 mg, 10%): mp 109-110 °C (EtOAc/hexane); IR 3400
(NH) cm-1; MS m/ z 494 (M+, 2), 245 (100). Anal. Calcd for
C29H38N2OS2: C, 70.40; H, 7.74; N, 5.66. Found: C, 70.42; H,
7.90; N, 5.63.
cis-1-[2-(Ben zyloxy)et h yl]-4a -et h yl-6,6-(p r op ylen ed i-
su lfa n yl)-1,2,3,4,4a ,5,6,11c-octa h yd r op yr id o[3,2-c]ca r ba -
zole (3). Operating as for the isomerization of 11, from
naphthyridoindole 18 (200 mg, 0.406 mmol) and AcOH (50%,
20 mL) was obtained pyridocarbazole 3 (180 mg, 90%), after
chromatography (Al2O3, EtOAc/hexane, 1/9), as a white solid:
mp 131-133 °C; IR (NaCl) 3250-3350 (NH) cm-1; MS m/ z
492 (M+, 4), 371 (100). Anal. Calcd for C29H36N2OS2: C, 70.69;
H, 7.36; N, 5.69. Found: C, 70.46; H, 7.35; N, 5.48.
cis-4a -Eth yl-1-(2-h yd r oxyeth yl)-6,6-(p r op ylen ed isu lfa -
n yl)-1,2,3,4,4a ,5,6,11c-oct a h yd r op yr id o[3,2-c]ca r b a zole
(23). To a solution of 3 (150 mg, 0.305 mmol) in dry CH2Cl2
(8 mL) were added Me2S (671 µL, 9.15 mmol) and BF3‚Et2O
(4.21 µL, 3.35 mmol). The reaction mixture was heated at 35
°C for 2 h. The reaction was quenched by addition of NaHCO3
and extracted with CH2Cl2. The combined organic extracts,
dried and evaporated, gave a yellow solid that was chromato-
graphed (Al2O3, CH2Cl2) to yield 23 (105 mg, 86%) as a white
solid: mp 242-243 °C (CH2Cl2); IR (KBr) 3375, 3225 (NH,
OH) cm-1; MS m/ z 402 (M+, 3), 371 (100). Anal. Calcd for
C22H30N2OS2: C, 65.63; H, 7.51; N, 6.96. Found: C, 65.61; H,
7.57; N, 6.80.
cis-1-Meth yl-1,2,3,4,4a ,5,6,11c-octa h yd r op yr id o[3,2-c]-
ca r ba zol-6-on e (20). To a solution of compound 10b (50 mg,
0.145 mmol) in CH3CN-H2O (9:1, 5 mL) was added (CF3-
COO)2IPh (144 mg, 0.334 mmol). The mixture was stirred at
room temperature for 45 min, poured on aqueous NaHCO3,
and extracted with CH2Cl2. The organic extracts, dried and
evaporated, yielded an oil that was flash chromatographed
(CH2Cl2/MeOH, 95/5) to give ketone 20 (13 mg, 35%): IR
(NaCl) 3350 (NH), 1650 (CdO) cm-1; MS m/ z 254 (M+, 100).
Anal. Calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01.
Found: C, 75.40; H, 7.19; N, 10.93.
cis-1-Meth yl-1,2,3,4,4a ,5,6,11c-octa h yd r op yr id o[3,2-c]-
ca r ba zole (21).6 A mixture of 10b (50 mg, 0.145 mmol) and
an excess of W-2 Raney-Ni in EtOH (10 mL) was refluxed for
15 min. The mixture was filtered, and the filtrate was
evaporated to give an oil, which, after flash chromatography
(CH2Cl2/MeOH, 93/7), furnished the tetracyclic system 21 (22
mg, 63%).
cis-4a-Eth yl-1-m eth yl-1,2,3,4,4a,5,6,11c-octah ydr opyr ido-
[3,2-c]ca r ba zole (22). Operating as for the preparation of
21, from pyridocarbazole 2 (75 mg, 0.202 mmol), EtOH (10
mL), and W-2 Raney Ni, was obtained pyridocarbazole 22 (40
mg, 75%) after chromatography (Al2O3, EtOAc/hexane, 2/8):
IR (NaCl) 3450 (NH) cm-1; MS m/ z 268 (M+, 32), 239 (100).
Anal. Calcd for C18H24N2: C, 80.55; H, 9.01; N, 10.44.
Found: C, 80.50; H, 9.06; N, 10.35.
N-[2-(Ben zyloxy)eth yl]-3-m eth ylen e-2-p ip er id on e (6).
To a mixture of commercial ethyl nipecotate (3.97 g, 25.3
mmol) and K2CO3 (3.34 g, 24.2 mmol) in C6H6 (60 mL) was
slowly added bromoethyl benzyl ether (6.53 g, 30.4 mmol). The
mixture was refluxed for 24 h, cooled, and poured into H2O
(25 mL). The layers were separated, and the solvent was
evaporated to give a residue that was flash chromatographed
(CH2Cl2/MeOH, 98/2) to obtain eth yl N-[2-(ben zyloxy)eth yl]-
n ip ecota te (6.6 g, 89%): 1H NMR 1.23 (t, J ) 7 Hz, 3H, CH3),
1.41 (qt, J ) 12, 4 Hz, 1H, H-4ax), 1.60 (m, 1H, H-5ax), 1.65-
1.75 (m, 1H, H-5eq), 1.92 (dd, J ) 12, 4 Hz, 1H, H-4eq), 2.02
(td, J ) 11, 3 Hz,1H, H-6ax), 2.18 (t, J ) 11 Hz, 1H, H-2ax),
2.58 (td, J ) 12, 4 Hz, 1H, H-3ax), 2.62 (t, J ) 6 Hz, 2H, NCH2),
2.81 (br d, J ) 11 Hz, 1H, H-6eq), 3.05 (dd, J ) 12, 3 Hz, 1H,
H-2eq), 3.57 (t, J ) 6 Hz, 2H, OCH2), 4.10 (q, J ) 7 Hz, 2H,
CH2OBn), 4.52 (s, 2H, OCH2Ph), 7.2-7.4 (m, 5H, H-Ph); 13C
NMR 14.0 (CH3), 24.3 (C-5), 26.6 (C-6), 41.6 (C-3), 53.8 (C-6),
55.6 (C-2), 57.9 (NCH2), 60.0 (CH2OBn), 67.4 (OCH2), 72.8
(OCH2Ph), 127.3 (p-Ph), 127.4 (o-Ph), 128.0 (m-Ph), 138.1 (i-
Ph), 173.9 (CdO). The previous ethyl ester was stirred
overnight in 6 N HCl at room temperature. Evaporation of
the solvent yielded quantitatively the N-[2-(ben zyloxy)eth yl]-
n ip ecotic a cid h yd r och lor id e: IR (CHCl3) 3350-3450 (OH),
1727 (CdO) cm-1 1H NMR 1.55 (ddd, J ) 12, 8, 3 Hz, 1H,
;
H-4ax), 1.80-2.00 (m, 2H, H-5), 2.17 (br d, J ) 12 Hz, 1H,
H-4eq), 2.90-3.10 (m, 3H, H-3, H-2ax, and H-6ax), 3.39 (t, J )
5 Hz, 2H, NCH2), 3.55 (br d, J ) 12 Hz, 1H, H-6eq), 3.77 (br d,
J ) 11 Hz, 1H, H-2eq), 3.84 (t, J ) 5 Hz, 2H, OCH2), 4.57 (s,
2H, OCH2Ph), 7.25-7.42 (m, 5H, H-Ph); 13C NMR 23.4 (C-5),
26.1 (C-4), 40.4 (C-3), 53.9 (C-6), 54.4 (C-2), 58.1 (NCH2), 64.5
(CH2O) 74.1 (OCH2Ph), 129.0 (p-Ph), 129.2 (o-Ph), 129.5 (m-
Ph), 138.7 (i-Ph), 174.0 (CO). Anal. Calcd for C15H22ClNO3‚
1/4H2O: C, 59.21; H, 7.45; N, 4.60. Found: C, 58.97; H, 7.51;
N, 4.69. The previous cyclic â-amino acid (8,84 g, 29,6 mmol)
16,16-(P r op ylen ed isu lfa n yl)-1,2-d id eh yd r oa sp id osp er -
m id in e (24). To a solution of 23 (110 mg, 0.274 mmol) in dry
THF (20 mL) were added K-t-BuO (92.2 mg, 0.822 mmol) and
TsCl (104.5 mg, 0.548 mmol). After 1 h at room temperature,
the reaction was quenched by addition of H2O and extracted

7888 J . Org. Chem., Vol. 61, No. 22, 1996
Forns et al.
with EtOAc. The organic extracts, dried and evaporated,
furnished a yellow oil, which after chromatography (Al2O3,
EtOAc/hexane, 5/95) gave indolenine 24 (81 mg, 77%) as a
white foam: mp 132-134 °C; IR (NaCl) 1550 (CdN) cm-1; MS
m/ z 384 (M+, 23), 124 (100). Anal. Calcd for C22H28N2S2: C,
68.71; H, 7.34; N, 7.28. Found: C, 68.63; H, 7.34; N, 7.24.
(()-Asp id osp er m id in e (1).16 Meth od A. Operating as
for the preparation of 21, from 24 (84 mg, 0.219 mmol) and
W-2 Raney-Ni in EtOH (10 mL) was obtained a 1:1 mixture
of N-ethylaspidospermidine (26) and aspidospermidine (1)
after 30 min of reaction, which was flash chromatographed
(Al2O3, EtOAc/hexane, 1/9) to isolate the products. Compound
26 (higher Rf, 17 mg, 25%): MS m/ z 310 (M+, 19), 282 (10),
124 (100). Anal. Calcd for C21H30N2: C, 81.29; H, 9.67; N,
9.03. Found: C, 81.43; H, 9.54; N, 9.25. 116 (lower Rf, 14 mg,
23%): IR (NaCl) 3375 (NH) cm-1; MS m/ z 282 (M+, 20), 254
(20), 124 (100). Meth od B. A mixture of compound 24 (32
mg, 83 µmol) and excess W-2 Raney-Ni in dioxane (8 mL) was
refluxed for 30 min. The mixture was filtered, and the filtrate
was evaporated to give an oil, which was flash chromato-
graphed (Al2O3, EtOAc/hexane, 1/9) to isolate the products:
dehydroaspidospermidine (25, higher Rf, 8.13 mg, 35%) and
aspidospermidine (1, lower Rf, 7.02 mg, 30%).
Ack n ow led gm en t. Support for this research has
been provided by the CIRIT (Generalitat de Catalunya)
through Grants No. QFN95-4703 and 1995SGR 00429.
We also thank the CIRIT for a fellowship given to one
of us (P.F.).
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR of compounds 1, 25, and 26 are available, as well as
copies of the 2D COSY (H,H) and (H,C) of compounds 1 and
26. The detailed NMR data of lactams 9, 13, 16, and 17 and
of piperidines 12, 15, and 19 are listed in Tables 8-10 (17
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.
J O9609900