Total syntheses of vincadifformine, 3-oxovincadifformine, pseudo- and 20-epi-pseudovincadifformine, tabersonine, and Δ18-tabersonine through radical reactions and heck reactions

Article abstract of DOI:10.1021/jo960607r

The pentacyclic alkaloids vincadifformine (9), ψ-vincadifformine (15), and epi-ψ-vincadifformine (16) could be synthesized by intramolecular free-radical-induced cyclizations of the tetracyclic intermediates 7, 8, and 18, which were respectively obtained by condensation of the indoloazepine 1 with 2-(phenylselenyl)butyraldehyde and subsequent N^b-alkylation of the resulting tetracyclic amines 2 and 3, or from condensation of (phenylselenyl)acetaldehyde with the alkylated indoloazepine 17. The intermediates 2 and 3 also gave 3-oxovincadifformine (21) by an intermolecular radical alkylation with methyl acrylate. Their alkylation with (Z)-1,3-diiodopropene, phenyl selenoxide elimination, and intramolecular Heck reactions provided tabersonine (24) and 18,19-didehydrotabersonine (27).

Full text of DOI:10.1021/jo960607r

J . Org. Chem. 1996, 61, 6001-6008
6001
Tota l Syn th eses of Vin ca d iffor m in e, 3-Oxovin ca d iffor m in e,
P seu d o- a n d 20-epi-P seu d ovin ca d iffor m in e, Ta ber son in e, a n d
∆18
-Ta ber son in e th r ou gh Ra d ica l Rea ction s a n d Heck Rea ction s
Martin E. Kuehne,* Tiansheng Wang, and Pamela J . Seaton
Department of Chemistry, University of Vermont, Burlington, Vermont 05405
Received March 28, 1996X
The pentacyclic alkaloids vincadifformine (9), ψ-vincadifformine (15), and epi-ψ-vincadifformine
(16) could be synthesized by intramolecular free-radical-induced cyclizations of the tetracyclic
intermediates 7, 8, and 18, which were respectively obtained by condensation of the indoloazepine
b
1
with 2-(phenylselenyl)butyraldehyde and subsequent N -alkylation of the resulting tetracyclic
amines 2 and 3, or from condensation of (phenylselenyl)acetaldehyde with the alkylated in-
doloazepine 17. The intermediates 2 and 3 also gave 3-oxovincadifformine (21) by an intermolecular
radical alkylation with methyl acrylate. Their alkylation with (Z)-1,3-diiodopropene, phenyl
selenoxide elimination, and intramolecular Heck reactions provided tabersonine (24) and 18,19-
didehydrotabersonine (27).
In our previous studies, we have obtained high-yielding
syntheses of a variety of vincadifformine and ψ-vincadif-
formine class alkaloids by exploitation of secodine-type
cyclization reactions (intramolecular Diels-Alder reac-
tions, Figure 1).1
,2
While the elaboration of diverse
functionality in rings D and E of these products has been
successful (e.g., resulting in the enantioselective synthe-
3
4-6
ses of vindoline and vinblastine ), we still faced a need
for improvement in some late-stage functional group
introductions as well as the consideration that a specific
synthetic precursor for the intramolecular enamine/
indoloacrylate reaction had to be generated for each
alkaloid product.5 It was therefore of interest to explore
the syntheses of a few A,B,C,E-tetracyclic intermediates
which might be converted into a variety of pentacyclic
alkaloids by transformations that we had not yet utilized.
Thus, we initiated a program of ring D annelations
through radical and Heck-type cyclization reactions.
F igu r e 1.
b
favoring the N /Se cis isomer. That the relative amounts
of the products are not the result of product equilibration
during the reaction (see below) was shown by heating
either pure tetracycle 2 or 3 in toluene, without formation
of the corresponding epimer. However, when either pure
epimer was heated in toluene with p-toluenesulfonic acid,
a 1:2.5 equilibration ratio of the tetracyclic amines 2 and
3
resulted.
Alkylation of the tetracyclic amines 2 and 3 with 2,3-
7
Condensation of R-(phenylselenyl)butyraldehyde with
dibromopropene9 furnished the corresponding tertiary
the indoloazepine 1 (Scheme 1)8 in refluxing toluene
provided two tetracyclic amines, 2 (49%) and 3 (20%),
with orientation of the amine function and the phenylse-
lenyl substituent cis and trans, respectively. The relative
configurations of these products were established by NOE
NMR studies of the corresponding propargyl derivatives
b
amines 7 and 8. The N /Se trans isomer 3 was alkylated
much more rapidly than the cis isomer 2. A reaction of
either of the products 7 or 8 with 2.5 equiv of tri-n-
butyltin hydride and a radical initiator (AIBN) then
resulted in the formation of vincadifformine (9). The
reducible (Br) substituent in the allylic amines 7 and 8
was required for this reaction to avoid the otherwise
anticipated preferred cyclization to five-membered ring
D products 10 and 11. Indeed, these products were found
in the cyclizations of the allylic amines 12 and 13.
Formation of a five-membered ring was also observed
with the tetracyclic propargylic amines 4 and 5, leading
to the olefin 14.
4
and 5, which showed an interaction between the
propargyl and ethyl methylene hydrogens (8%) and the
o-phenyl and C-17 and C-21 hydrogens (5%) for the N /
Se trans isomer 5.
The formation of two stereoisomers was expected as a
consequence of the reaction of (E)- and (Z)-enamine
isomers 6 in the intramolecular Diels-Alder reaction,
b
Stereochemical assignments to the methyl compounds
X
Abstract published in Advance ACS Abstracts, August 1, 1996.
1
0 and 11 could be made from NOE NMR spectra, which
showed interaction of the R-N-methine hydrogen at C-21
with the methyl group (17% by irradiation of CH
, 3%
(
1) Kuehne, M. E.; Roland, D. M.; Hafter, R. J . Org. Chem. 1978,
3, 3705.
2) Kuehne, M. E.; Kirkemo, C. L.; Matsko, T. H.; Bohnert, J . C. J .
Org. Chem. 1980, 45, 3259.
3) Kuehne, M. E.; Podhorez, D. E.; Mulamba, T.; Bornmann, W.
G. J . Org. Chem. 1987, 52, 347.
4) Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J . Org. Chem.
991, 56, 513.
4
(
3
by irradiation of methine H) or, respectively, with its
R-methine hydrogen (13% and 17%). Hydrogenation of
the olefin 14 gave only the minor cyclization product 11.
In all of these radical cyclization reactions, the relative
stereochemistry of the phenylselenyl substituent in the
tetracyclic substrate had little, if any, influence on the
product yield.
(
(
1
(5) Kuehne, M. E.; Bornmann, W. G. J . Org. Chem. 1992, 57, 1752.
(6) Kuehne, M. E.; Bandarage, U. K. J . Org. Chem. 1996, 61, 1175.
(7) (a) Ryu, I.; Murai, S.; Niwa, I.; Sonoda, N. Synthesis 1977, 874.
(
b) House, H. O.; Czuba, L. J .; Gall, M.; Olmstead, J . H. D. J . Org.
Chem. 1969, 34, 2324.
8) Kuehne, M. E.; Bohnert, J . C.; Bornmann, W. G.; Kirkemo, C.
L.; Kuehne, S. E.; Seaton, P. J .; Zebowitz, T. C. J . Org. Chem. 1989,
4, 3407.
(
5
(9) Aldrich Chemical Co.
S0022-3263(96)00607-X CCC: $12.00 © 1996 American Chemical Society

6
002 J . Org. Chem., Vol. 61, No. 17, 1996
Kuehne et al.
Sch em e 1a
Sch em e 2a
a
Conditions: (a) 2-ethyl-3-bromopropene, K2CO3, acetone; (b)
PhSeCH2CHO, toluene, reflux, 8 h; (c) Bu3SnH/AIBN, syringe
pump, 0.015 M in benzene, 85 °C.
Sch em e 3a
a
Conditions: (a) Bu3SnH, AIBN, CH2dCHCOOCH3; (b) 1 equiv
a
Conditions: (a) CH3CH2CH(SePH)CHO, toluene, reflux, 18 h;
of p-TsOH, toluene, reflux, 18 h.
(
b) 2,3-dibromopropene, THF, 5 days; (c) 2.5 equiv of Bu3SnH,
AIBN, benzene, 85 °C, 2 h; (d) propargyl bromide, THF, 50 °C, 48
h; (e) Bu3SnH, AIBN, benzene, 85 °C, 4 h; (f) allyl bromide, THF,
a stereoselective hydrogen radical transfer to a penta-
cyclic C-20 radical intermediate.
5
days; (g) 3 equiv of Bu3SnH, AIBN, benzene, 85 °C, 12 h; (h)
H2/Pd.
In a variation of these ring D annelations, which is also
based on a radical alkylation reaction, the tetracyclic
phenylselenyl ethers 2 and 3 were treated with tri-n-
butyltin hydride and AIBN and an excess of methyl
acrylate (Scheme 3). The resulting mixture of epimeric
An analogous strategy could also be used for annelation
of ring D in syntheses of ψ-vincadifformine (15) and 20-
epi-ψ-vincadifformine (16, Scheme 2). Here, the in-
doloazepine 1 was first alkylated with 3-bromo-2-
ethylpropene.10 Condensation of the resulting tertiary
esters 19 and 20, on heating in the presence of acid, then
13
provided 3-oxovincadifformine (21).
Once again, the
1
1
amine 17 with (phenylselenyl)acetaldehyde gave the
tetracyclic phenylselenyl ether 18. An (E)-enamine
intermediate in the intramolecular Diels-Alder reaction
b
N -H tetracycles 19 and 20 undergo epimerization.
To elaborate the phenylselenyl tetracyclic intermedi-
ates into more unsaturated congeners of vincadifformine,
an alternative to the above radical cyclization strategy
b
step leads only to the N /Φ-Se trans product 18, in
analogy to formation and reaction of alkyl-substituted
b
seemed more promising. Alkylation of the cis-N -phen-
enamines.12
14
ylselenyl ether 2 with (Z)-1,3-diiodopropene provided
On slow addition of tri-n-butyltin hydride and AIBN
to the phenylselenyl ether 18 in refluxing benzene,
ψ-vincadifformine (15) and 20-epi-ψ-vincadifformine (16)
were formed in a 2:1 ratio. The separate products did
not epimerize under the reaction conditions, indicating
the (3-iodoallyl)amine 22 (Scheme 4). On oxidation of
this selenyl ether 22 with m-chloroperoxybenzoic acid,
followed by treatment with triphenylphosphine for N-
oxide reduction, the tetracyclic conjugated diene 23 was
formed. A reductive Heck reaction with palladium
(
10) Prepared according to the published method: Corey, E. J .; Kirst,
(13) Kuehne, M. E.; Matsko, T. H.; Bohnert, J . C.; Motyka, L.; Oliver-
Smith, D. J . Org. Chem. 1981, 46, 2002.
H. A.; Katzenellenbogen, J . A. J . Am. Chem. Soc. 1970, 92, 6314.
(
(
11) Baudat, R.; Petrzilka, M. Helv. Chim. Acta 1979, 62, 1406.
12) Kuehne, M. E.; Zebovitz, T. C. J . Org. Chem. 1987, 52, 4331.
(14) Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahedron
1994, 50, 371.

Ring D Annelations To Form Pentacyclic Alkaloids
J . Org. Chem., Vol. 61, No. 17, 1996 6003
Sch em e 4a
nine (27). Unfortunately, a tandem double cyclization
to vindolinine (28) could not be obtained using either
catalytic or excess amounts of palladium acetate.
1
5
The foregoing ring D annelation reactions expand the
versatility of our biomimetic, secodine-type, intramolecu-
lar Diels-Alder approach to the aspidosperma and other
vinca alkaloids. They also provide instructive novel
examples demonstrating the compatibility of radical
cyclizations and Heck reactions with basic amine and
aminoacrylate functionalities.
Exp er im en ta l Section
Meth yl (()-(3a R*,4S*,11bR*)-an d (()-(3a R*,4R*,11bR*)-
,3,3a ,4,5,7-Hexa h yd r o-4-eth yl-4-(p h en ylselen yl)-1H-p yr -
2
r olo[2,3-d ]ca r ba zole-6-ca r boxyla te (2 a n d 3). To a solu-
8
tion of 1.024 g (4.19 mmol) of the indoloazepine 1, dissolved
in 70 mL of dry toluene at 60 °C, was added a solution of
7
2
-(phenylselenyl)butyraldehyde (0.955 g, 4.20 mmol) in 30 mL
of dry toluene in one portion. The mixture was heated at
reflux under argon for 18 h, until TLC showed that the reaction
was complete. The reaction mixture was cooled, and the
solvent was removed under reduced pressure to give a residue,
which was purified by silica gel flash chromatography, eluting
with 1:1 ethyl ether/pentane, to give 0.938 g (49.4%) of cis
isomer 2 and 0.384 g (20.2%) of trans isomer 3, both as white
foams.
F or th e less p ola r cis isom er 2: mp 122-123 °C (ether/
pentane 1:1); R
) 0.58 (1:1 ethyl acetate/hexane), 0.43 (1:1
f
ethyl ether/pentane); CAS spray, blue; UV (EtOH) λmax 204,
2
1
22, 300, 332 nm; IR (thin film) νmax 3374, 2962, 2928, 2882,
-
1 1
676, 1609, 1437, 1284, 1247, 1201, 1103, 741 cm ; H NMR
, TMS) δ 9.00 (br s, 1 H), 7.75 (dd, J ) 8.1, 1.4 Hz, 2
(CDCl
3
H), 7.35-7.27 (m, 3 H), 7.19 (d, J ) 7.5 Hz, 1 H), 7.14 (td, J
)
)
3
7.7, 1.2 Hz, 1 H), 6.86 (td, J ) 7.5, 1.0 Hz, 1 H), 6.81 (d, J
7.7 Hz, 1 H), 3.76 (s, 3 H), 3.39 (d, J ) 1.8 Hz, 1 H), 3.26-
.13 (m, 2 H), 2.81 (dd, J ) 15.1, 1.9 Hz, 1 H), 2.51 (d, J )
a
15.1 Hz, 1 H), 2.02 (td, J ) 12, 6.8 Hz, 1 H), 1.88 (ddd, J ) 12,
Conditions: (a) (Z)-1,3-diiodopropene, K2CO3, THF, reflux, 6
2
.5, 2.5 Hz, 1 H), 1.04-0.87 (m, 2 H), 0.79 (t, J ) 7.1 Hz, 3 H);
h; (b) 2.2 equiv of m-CPBA, -75 °C, CH2Cl2; 2.2 equiv of Ph3P,
1
3
C NMR (CDCl ) δ 168.37, 166.70, 143.03, 137.39, 137.05,
3
-
30 °C; (c) Pd(OAc)2, Ph3P, HCOONa, Et3N/CH3CN, reflux, 12 h;
d) 0.4 equiv of Pd(OAc)2, Ph3P, Et3N/CH3CN, reflux, 3 h; (e) 1.5
(
128.85, 128.43, 127.96, 127.28, 121.85, 120.88, 109.36, 90.04,
68.27, 61.92, 57.30, 51.00, 45.49, 45.23, 27.89, 27.57, 8.58; MS
m/ z (relative intensity) 454 (2), 298 (3), 297 (16), 242 (7), 240
equiv of Pd(OAc)2, 3 equiv of Ph3P, CH3CN, reflux, 3 h.
(
1
(
6
9), 238 (8), 237 (11), 236 (4), 222 (4), 215 (8), 208 (8), 194 (8),
60 (10), 155 (7), 154 (15), 144 (7), 91 (12), 78 (8), 77 (10), 44
100). Anal. Calcd for C24 Se: C, 63.42; H, 5.77; N,
.17. Found: C, 63.84; H, 5.89; N, 6.01.
F or th e m or e p ola r tr a n s isom er 3: mp 140-145 °C
acetate, triphenylphosphine, and sodium formate then
resulted in cyclization to tabersonine 24. No tabersonine
was formed on treatment of the iodide 23 with tri-n-
butyltin hydride and AIBN in refluxing benzene.
When the epimeric phenylselenyl ether 3 was subjected
to the same reaction sequence, it was found that the
selenoxide elimination derived from the trans-N -phen-
ylselenyl intermediate 25 gave only the regiochemical
alternative formation of the exocyclic olefin 26 (Scheme
26 2 2
H N O
(ether/pentane 1:1); R ) 0.26 (1:1 hexane/ethyl acetate), 0.20
f
(1:1 ethyl ether/pentane); CAS spray, yellow; UV (EtOH) λmax
b
204, 222, 298, 330 nm; IR (thin film) νmax 3373, 2965, 2934,
848, 1675, 1609, 1465, 1437, 1284, 1247, 1203, 742 cm- ; H
1
1
2
NMR (CDCl
7
)
1
3
, TMS) δ 9.15 (br s, 1 H), 7.27-7.29 (m, 3 H),
.20 (d, J ) 7.5 Hz, 2 H), 7.15 (d, J ) 7.4 Hz, 1 H), 7.14 (t, J
4
). The differing direction of selenoxide eliminations
7.7 Hz, 1 H), 6.94 (t, J ) 7.4 Hz, 1 H), 6.91 (d, J ) 7.7 Hz,
H), 3.85 (d, J ) 1.7 Hz, 1 H), 3.69 (s, 3 H), 3.15-3.07 (m, 2
derived from the epimeric series 22 and 25 is a conse-
quence of better â-allylic/π orbital overlap in 22 vs
R-allylic/π orbital overlap in 25. There is also hindrance
to achieving coplanarity of the R-selenoxide and adjacent
allylic hydrogen by the required torsion of an initial
quasi-boat-like ring E selenoxide derived from 25, be-
cause of increasing 1,3-quasi-diaxial repulsion of the
ethyl and C-6 methylene groups in that process, thus
favoring formation of the exocyclic double-bond product
H), 2.64 (dd, J ) 16, 1.7 Hz, 1 H), 2.35 (d, J ) 16 Hz, 1 H),
1.95-1.89 (m, 1 H), 1.84-1.76 (m, 2 H), 1.57-1.53 (m, 1 H),
1
1
1
2
.21 (t, J ) 7.2 Hz, 3 H); 13C NMR (CDCl
) δ 168.64, 168.47,
3
43.26, 138.06, 137.80, 128.45, 128.28, 127.86, 127.26, 121.32,
20.61, 109.60, 91.40, 66.92, 62.80, 57.13, 50.79, 44.91, 44.89,
8.05, 27.62, 10.30; MS m/ z (relative intensity) 454 (2), 298
(
(
3), 297 (13), 265 (4), 242 (3), 240 (5), 238 (6), 237 (10), 236
3), 215 (5), 214 (5), 209 (5), 207 (4), 194 (5), 180 (8), 168 (5),
167 (7), 157 (7), 155 (6), 154 (10), 144 (6), 98 (5), 69 (11), 57
(14), 55 (10), 44 (100). Anal. Calcd for C24 Se: C,
63.42; H, 5.77; N, 6.17; Se, 17.60. Found: C, 63.66; H, 5.69;
N, 6.20; Se, 17.57.
Ep im er iza tion Stu d y of Cis (2) a n d Tr a n s (3) Isom er s.
Heating each isomer at reflux in toluene for 18 h did not result
in any epimerization, and only the starting isomer was
recovered. However, heating each isomer (10 mg) in toluene
2
6.
Cyclization of the exocyclic olefin 26 by a nonreductive
Heck reaction with palladium acetate, triphenylphos-
26 2 2
H N O
1
8
phine, and triethylamine provided ∆ -dehydrotaberso-
(15) While the second reaction step would require a 5-endo-trig
cyclization, it should be noted that an analogous formation of the
vindolinine skeleton has been accomplished by a reductive cyclization
of 19-iodotabersonine with sodium: Hugel, G.; Cartier, D.; L e´ vy, J .
Tetrahedron Lett. 1989, 30, 4513.
2
with 5 mg of p-TsOH‚H O at reflux for 15 min afforded a ratio
of 1:2.5 cis/ trans isomers (determined by integration of the
side-chain methyl proton in the H NMR spectra) in both cases.
1

6
004 J . Org. Chem., Vol. 61, No. 17, 1996
Kuehne et al.
Meth yl (()-(3a R*,4S*,11bR*)-3-P r op a r gyl-2,3,3a ,4,5,7-
hexane/ethyl acetate), 0.22 (ethyl acetate); CAS spray, blue;
UV (EtOH) λmax 204, 226, 298, 328 nm; IR (thin film) νmax 3377,
3368, 2966, 2948, 2847, 1676, 1610, 1467, 1436, 1244, 1201,
h exa h yd r o-4-eth yl-4-(p h en ylselen yl)-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (4). To a solution of 0.050 g (0.11
mmol) of cis-amino selenide 2 in 3 mL of dry THF were added
-
1
1
1121, 1100, 749 cm ; H NMR (CDCl , TMS) δ 9.08 (br s, 1
3
0
.164 g (1.1 mmol) of an 80% solution of propargyl bromide in
toluene (available from Aldrich) and 0.152 g (1.1 mmol) of
potassium carbonate. The mixture was heated at reflux for
0 h, until TLC (SiO , 9:1 hexane/ethyl acetate) showed that
2
no starting material was left. After cooling and removal of
THF with a rotary evaporator, the residue was suspended in
H), 7.45 (d, J ) 7.4 Hz, 1 H), 7.17 (t, J ) 7.7 Hz, 1 H), 6.93 (t,
J ) 7.4 Hz, 1 H), 6.84 (d, J ) 7.7 Hz, 1 H), 5.13 (s, 1 H), 4.98
(s, 1 H), 3.79 (s, 3 H), 3.78 (d, J ) 15 Hz, 1 H), 3.56 (d, J ) 15
Hz, 1 H), 3.40-3.49 (m, 1 H), 3.42 (s, 1 H), 2.87 (d, J ) 16 Hz,
1 H), 2.80 (t, d, J ) 9.7, 6 Hz, 1 H), 2.23-2.34 (m, 1 H), 2.08
(d, J ) 16 Hz, 1 H), 1.97-2.07 (m, 1 H), 1.23-1.37 (m, 2 H),
4
5
3
0 mL of water and extracted with methylene chloride (3 ×
0.75 (t, J ) 7 Hz, 3 H); 13C NMR (CDCl
) δ 168.85, 163.79,
3
0 mL). The CH Cl layer was dried (Na SO ) and concen-
2
2
2
4
155.72, 143.44, 138.21, 127.96, 122.88, 121.34, 109.04, 106.20,
91.25, 78.68, 61.33, 57.54, 54.71, 50.88, 48.78, 40.55, 34.49,
30.87, 8.85; MS m/ z (relative intensity) 337 (M + 1, 4), 336
(17), 277 (2), 269 (2), 214 (3), 204 (2), 167 (3), 154 (6), 123 (9),
122 (100), 107 (4), 86 (52), 84 (50); high-resolution MS, EI,
trated. The crude product was purified by silica gel column
chromatography, eluting with 9:1 hexane/ethyl acetate, yield-
b
ing 0.038 g (70.2%) of N -alkylated product as a white foam:
R
(
2
1
(
f
) 0.28 (hexane/ethyl acetate 9:1); CAS spray, blue; UV
EtOH) λmax 204, 222, 298, 330 nm; IR (thin film) νmax 3294,
24 2 2
calcd for C21H N O 336.1838, found 336.1829.
968, 2947, 2843, 1677, 1608, 1466, 1438, 1285, 1249, 1231,
P r oced u r e b: F r om th e Tr a n s Isom er 5. The same
-
1
1
b
103, 741 cm ; H NMR (CDCl
3
, TMS) δ 8.97 (br s, 1 H), 7.75
procedure was repeated starting with 57 mg of N -propargyl
dd, J ) 7.6, 1.4 Hz, 2 H), 7.62 (d, J ) 7.5 Hz, 1 H), 7.33-7.26
selenide 5 to give 24.6 mg (63.1%) of cyclized product, which
showed TLC and spectra identical to those of the product
obtained above.
(
m, 3 H), 7.17 (td, J ) 7.7, 0.9 Hz, 1 H), 6.89 (t, J ) 7.5 Hz, 1
H), 6.88 (d, J ) 7.7 Hz, 1 H), 4.57 (dd, J ) 17.6, 2.4 Hz, 1 H),
4
.00 (dd, J ) 17.6, 2.4 Hz, 1 H), 3.71 (s, 3 H), 3.41 (d, J ) 1.5
Hz, 1 H), 3.30-3.20 (m, 2 H), 2.85 (dd, J ) 15.3, 1.5 Hz, 1 H),
.74 (d, J ) 15.3 Hz, 1 H), 2.41 (t, J ) 2.4 Hz, 1 H), 2.23 (td,
J ) 12, 7 Hz, 1 H), 1.74 (dd, J ) 12, 4.7 Hz, 1 H), 1.29-1.21
m, 1 H), 1.17-0.97 (m, 1 H), 0.76 (t, J ) 7.2 Hz, 3 H); 13
NMR (CDCl ) δ 168.39, 163.94, 143.00, 137.26, 136.84, 128.90,
Meth yl (()-(3a R*,4S*,11bR*)- a n d (3a R*,4R*,11bR*)-3-
Allyl-2,3,3a ,4,5,7-h exa h yd r o-4-et h yl-4-(p h en ylselen yl)-
1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te (12 a n d 13). A
mixture of 0.200 g (0.44 mmol) of the cis tetracyclic amine 2,
0.076 mL (0.88 mmol) of allyl bromide, 0.2 g of potassium
carbonate, and 5 mL of THF was stirred in an oil bath at 65
°C for 2 d. Filtration and washing with dichloromethane gave
a filtrate that was concentrated on a rotary evaporator. The
crude product was purified by flash chromatography (SiO2,
hexane/ether 3:1) to give 0.157 g of the product 12 (72%) as a
2
(
C
3
1
7
2
(
(
(
28.58, 128.11, 128.00, 123.59, 120.62, 109.20, 90.60, 81.36,
3.64, 71.10, 61.07, 58.21, 50.95, 50.90, 44.54, 40.67, 31.76,
8.79, 9.03; MS m/ z (relative intensity) 492 (1), 411 (1), 336
8), 335 (34), 237 (31), 208 (15), 195 (6), 194 (10), 193 (7), 181
6), 180 (11), 168 (9), 167 (13), 154 (12), 122 (10), 91 (6), 83
6), 82 (100), 78 (7).
white foam: R ) 0.41 (1:1 ether/hexane); CAS spray, blue;
f
UV (EtOH) λ 206, 224, 300, 332 nm; IR (thin film) ν 3383,
max
max
Meth yl (()-(3a R*,4R*,11bR*)-3-P r op a r gyl-2,3,3a ,4,5,7-
3071, 3056, 2971, 2947, 2911, 2850, 2815, 1679, 1611, 1477,
1466, 1436, 1295, 1279, 1249, 1239, 1209, 1118, 1105, 1046,
h exa h yd r o-4-eth yl-4-(p h en ylselen yl)-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (5). A solution of 0.164 g (0.36
mmol) of tetracyclic phenyl selenide 3 (trans) and 0.258 g (1.73
mmol) of propargyl bromide (80% solution) in 15 mL of dry
THF was stirred at 50 °C for 48 h. To the reaction mixture
were then added 0.3 g of sodium carbonate and 5 drops of
water, and stirring was continued at 40 °C for 24 h. A workup
-
1 1
912, 740, 695 cm ; H NMR (CDCl , TMS) δ 8.98 (br s, 1 H),
3
7.76 (d, J ) 7.5 Hz, 2 H), 7.35-7.27 (m, 3 H), 7.18 (t, J ) 7.5
Hz, 1 H), 7.16 (d, J ) 7.7 Hz, 1 H), 6.92 (t, J ) 7.5 Hz, 1 H),
6.82 (d, J ) 7.7 Hz, 1 H), 6.19-6.14 (m, 1 H), 5.38 (br d, J )
17.1 Hz, 1 H), 5.19 (d, J ) 10.1 Hz, 1 H), 4.21-4.17 (m, 1 H),
3.69 (s, 3 H), 3.47 (dd, J ) 13, 8 Hz, 1 H), 3.31 (dd, J ) 10, 7
Hz, 1 H), 3.22 (s, 1 H), 3.08 (d, J ) 15.3 Hz, 1 H), 2.95 (d, J )
15.3 Hz, 1 H), 2.79-2.73 (m, 1 H), 2.43-2.36 (m, 1 H), 1.75
(dd, J ) 12.4, 5.6 Hz, 1 H), 1.30-1.23 (m, 1 H), 0.99-0.96 (m,
procedure similar to the one for isomer 4 gave 110 mg (61.9%)
b
of N -alkylated product as a white foam: R
f
) 0.24 (9:1 hexane/
ethyl acetate); CAS spray, blue; UV (EtOH) λmax 204, 220, 300,
1 H), 0.81 (t, J ) 7.2 Hz, 3 H); 13C NMR (CDCl
) δ 168.37,
3
1
32 nm; IR (thin film) νmax 3297, 2969, 2946, 2831, 1675, 1602,
3
476, 1466, 1437, 1304, 1138, 1123, 740 cm-1; 1H NMR (CDCl
,
3
162.77, 143.15, 138.01, 136.65, 135.83, 129.61, 128.46, 128.12,
128.08, 122.97, 120.73, 116.89, 109.26, 91.42, 72.17, 62.01,
61.42, 57.92, 51.43, 50.94, 39.38, 35.04, 29.16, 9.87; MS m/ z
(relative intensity) 495 (3), 494 (3), 493 (2), 492 (1), 339 (1),
338 (13), 337 (61), 323 (2), 305 (2), 282 (10), 280 (16), 278 (8),
268 (6), 238 (9), 237 (42), 222 (5), 221 (4), 214 (5), 209 (5), 208
(14), 200 (5), 193 (5), 180 (9), 168 (9), 167 (6), 154 (8), 86 (23),
TMS) δ 9.12 (br s, 1 H), 7.60 (d, J ) 7.5 Hz, 1 H), 7.28 (dd, J
)
8.0, 1.3 Hz, 2 H), 7.27-7.13 (m, 4 H), 6.94 (td, J ) 7.5, 0.9
Hz, 1 H), 6.90 (d, J ) 7.7 Hz, 1 H), 3.96 (d, J ) 2.0 Hz, 1 H),
3
1
.78 (s, 3 H), 3.52 (dd, J ) 17.6, 2.4 Hz, 1 H), 3.47 (dd, J )
7.6, 2.4 Hz, 1 H), 3.22-3.17 (m, 1 H), 3.05 (dd, J ) 8.9, 6.4
Hz, 1 H), 2.99 (dd, J ) 15.9, 2.0 Hz, 1 H), 2.41 (d, J ) 15.9 Hz,
1
1
(
1
1
5
H), 2.30 (t, J ) 2.4 Hz, 1 H), 2.05 (t, d, J ) 12, 6.4 Hz, 1 H),
.90-1.83 (m, 1 H), 1.72 (dd, J ) 12, 5 Hz, 1 H), 1.40-1.35
30 2 2
85 (6), 84 (100), 57 (6). Anal. Calcd for C27H N O Se: C,
65.57; H, 6.12; N, 5.67; Se, 16.17. Found: C, 65.86; H, 6.17;
N, 5.58; Se, 16.44.
F or m a tion of 13 fr om th e Tr a n s Isom er 3. A mixture
of 0.100 g (0.22 mmol) of the trans amine 3, 0.1 mL of allyl
bromide, and 0.3 g of potassium carbonate in 4 mL of THF
was heated at reflux for 12 h. The workup procedure shown
above then gave 0.077 g (71%) of the product as a white foam
after chromatographic purification (flash SiO2, 2:1
1
3
m, 1 H), 1.17 (t, J ) 7.2 Hz, 3 H); C NMR (CDCl ) δ 168.38,
3
67.94, 143.06, 138.20, 137.86, 128.52, 128.31, 127.88, 127.84,
22.89, 120.63, 109.53, 90.39, 80.49, 73.64, 71.94, 64.63, 58.36,
1.57, 50.99, 43.42, 41.60, 27.12, 26.50, 10.15; MS m/ z (relative
intensity) 492 (0.5), 411 (0.2), 336 (3), 335 (14), 280 (2), 268
2), 252 (2), 237 (13), 236 (3), 221 (3), 194 (6), 180 (7), 168 (6),
67 (7), 155 (4), 154 (7), 83 (6), 82 (100).
()-3-n or -14-Meth ylen evin ca d iffor m in e (14). P r oce-
(
1
(
f
hexane/ether): R ) 0.38 (hexane/ether 1:1); CAS spray, blue;
b
d u r e a : fr om th e Cis Isom er 4. A solution of N -propargyl
selenide 4 (66 mg, 0.13 mmol) in 15 mL of dry benzene was
degassed with argon for 10 min. To the solution were added
UV (EtOH) λmax 206, 222, 302, 334 nm; IR (thin film) νmax 3383,
3071, 3067, 2968, 2944, 2876, 2802, 1676, 1610, 1478, 1466,
-
1
1436, 1283, 1248, 1199, 1161, 1122, 1105, 1047, 914, 741 cm
;
1
0
1
.056 mL (0.208 mmol, 1.5 equiv) of tri-n-butyltin hydride and
mg of AIBN. The mixture was stirred under argon at 85 °C
3
H NMR (CDCl , TMS) δ 9.11 (br s, 1 H), 7.26-7.13 (m, 7 H),
6.96 (t, J ) 7.2 Hz, 1 H), 6.91 (d, J ) 7.6 Hz, 1 H), 5.91-5.83
(m, 1 H), 5.13 (d, J ) 16.9 Hz, 1 H), 5.09 (d, J ) 10.1 Hz, 1 H),
3.78 (s, 3 H), 3.59 (s, 1 H), 3.29 (dd, J ) 13.7, 3.7 Hz, 1 H),
3.14 (t, J ) 7.7 Hz, 1 H), 3.06-3.02 (m, 1 H), 3.01 (d, J ) 16
Hz, 1 H), 2.69-2.63 (m, 1 H), 2.41 (d, J ) 16 Hz, 1 H), 2.09-
1.97 (m, 2 H), 1.71 (dd, J ) 12.1, 4.8 Hz, 1 H), 1.43-1.35 (m,
for 2 h, at which point TLC showed that there was some
starting material left. To this reaction mixture were added a
further 0.056 mL of tri-n-butyltin hydride and 1 mg of AIBN,
and heating was continued for 2 h at 85 °C. TLC then showed
the reaction to be complete. The mixture was cooled and
concentrated. The residue was purified by flash chromatog-
raphy on silica gel, eluting with 1:1 hexane/ethyl acetate, to
1 H), 1.18 (t, J ) 7.1 Hz, 3 H); 13C NMR (CDCl
) δ 168.36,
3
167.80, 143.14, 138.25, 137.65, 135.39, 128.50, 128.33, 127.95,
127.89, 122.09, 120.68, 116.99, 109.61, 90.45, 74.79, 64.65,
give 29 mg (64.2%) of pure cyclized product: R
) 0.18 (1:1
f

Ring D Annelations To Form Pentacyclic Alkaloids
J . Org. Chem., Vol. 61, No. 17, 1996 6005
5
9.83, 57.97, 51.99, 50.96, 41.51, 27.30, 26.05, 10.02; MS m/ z
62.78, 57.84, 52.04, 50.95, 47.84, 40.56, 38.83, 29.22, 25.72,
10.97, 9.32; MS m/ z (relative intensity) 338 (M , 3), 209 (0.3),
+
(relative intensity) 495 (2), 494 (1), 493 (1), 492 (1), 339 (1),
3
2
38 (11), 337 (37), 323 (2), 305 (3), 282 (6), 280 (13), 278 (6),
77 (4), 268 (6), 238 (7), 237 (28), 222 (6), 221 (4), 214 (5), 209
167 (2), 155 (1), 154 (7), 153 (2), 149 (2), 128 (1), 127 (1), 125
(3), 124 (100), 109 (1), 95 (1), 94 (2), 80 (1), 78 (1), 71 (1), 70
(2), 69 (1), 67 (3), 58 (1), 56 (6), 55 (1), 54 (7), 53 (2).
(5), 208 (11), 206 (4), 194 (7), 193 (5), 168 (6), 167 (5), 85 (6),
8
6
4 (100), 56 (5). Anal. Calcd for C27
.12; N, 5.67; Se, 16.17. Found: C, 65.80; H, 6.27; N, 5.52;
H
30
N
2
O
2
Se: C, 65.57; H,
Meth yl (()-(3a R*,4S*,11bR*)- a n d (3a R*,4R*,11bR*)-3-
(2-br om oallyl)-2,3,3a,4,5,7-h exah ydr o-4-eth yl-4-(ph en ylse-
len yl)-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te (7 a n d
8). cis-Am in o Selen id e 7. A mixture of 0.100 g (0.22 mmol)
of the cis tetracyclic selenide 2, 0.52 g of 85% 2,3-dibromopro-
pene (2.2 mmol), and 0.3 g of the potassium carbonate in 3
mL of THF was heated at reflux for 2 d. Filtration and
concentration of the filtrate gave a residue, which was purified
Se, 16.27.
(
()-3-n or -14-(r a n d â)-Meth ylvin ca d iffor m in e (10 a n d
1
0
1). P r oced u r e a : F r om th e Cis Isom er 12. A solution of
.082 g (0.166 mmol) of the cis-N-allyl selenide 12, 0.067 mL
(0.249 mmol) of tri-n-butyltin hydride, and 5 mg of AIBN in
1
1 mL of dry benzene was degassed with argon for 10 min
and then heated in an oil bath at 85 °C for 3 h. After addition
of another 0.067 mL of tri-n-butyltin hydride and 5 mg of
AIBN, the reaction was continued at 85 °C overnight. Cooling
to rt and evaporation gave a residue, which was purified by
by flash chromatography (SiO
0.097 g of the alkylated product (77%) as a white foam: R
0.46 (ether/hexane 1:1); CAS spray, blue; UV (EtOH) λmax 212,
226, 300, 332 nm; IR (thin film) νmax 3381, 3068, 2947, 2872,
1678, 1611, 1478, 1466, 1436, 1386, 1377, 1283, 1248, 1200,
2
, hexane/ether 3:1) to afford
f
)
flash chromatography (SiO
2
, 0.5:30:70 triethylamine/methanol/
-
1
1
ethyl acetate) to give 28 mg of the pure less polar (R-methyl)
1149, 1126, 1105, 1084, 1046, 1021, 896, 741, 695 cm ; H
NMR (CDCl , TMS) δ 8.98 (br s, 1 H), 7.72 (d, J ) 7.5 Hz, 2
isomer 10 and 26 mg of a mixture (1:1.3 R/â, as determined
3
1
by integration of H NMR methyl protons at 0.77 and 0.72
H), 7.35-7.25 (m, 3 H), 7.18 (t, J ) 7.7 Hz, 1 H), 7.11 (d, J )
7.5 Hz, 1 H), 6.92 (t, J ) 7.5 Hz, 1 H), 6.82 (d, J ) 7.8 Hz, 1
H), 6.22 (s, 1 H), 5.72 (s, 1 H), 4.35 (d, J ) 15.4 Hz, 1 H), 3.77
(d, J ) 15.4 Hz, 1 H), 3.69 (s, 3 H), 3.44 (dd, J ) 9.1, 7.4 Hz,
1 H), 3.14 (d, J ) 15.4 Hz, 1 H), 3.00 (d, J ) 15.4 Hz, 1 H),
2.79-2.74 (m, 1 H), 2.47-2.41 (m, 1 H), 1.80 (dd, J ) 12.4,
ppm) of isomers 10 and 11. Total yield: 54 mg (96%, R/â 2.6:
1
).
F or th e less p ola r (r) isom er 10: R ) 0.34 (1:1 methanol/
f
ethyl acetate); CAS spray, blue; UV (EtOH) λmax 206, 228, 300,
3
1
7
)
7
30 nm; IR (thin film) νmax 3378, 2959, 1676, 1610, 1479, 1466,
436, 1378, 1309, 1291, 1272, 1244, 1201, 1151, 1108, 1042,
5.5 Hz, 1 H), 1.29-1.23 (m, 1 H), 0.96-0.90 (m, 1 H), 0.75 (t,
-
1
1
13
43 cm ; H NMR (CDCl
7.4 Hz, 1 H), 7.16 (td, J ) 7.7, 1.1 Hz, 1 H), 6.88 (td, J )
.4, 0.8 Hz, 1 H), 6.83 (d, J ) 7.7 Hz, 1 H), 3.78 (s, 3 H), 3.37
td, J ) 12.3, 5.2 Hz, 1 H), 3.30 (s, 1 H), 3.10 (dd, J ) 9.0, 5.5
Hz, 1 H), 3.03 (d, J ) 9.0 Hz, 1 H), 2.90 (dd, J ) 12.3, 7.3 Hz,
H), 2.80 (dd, J ) 15.2, 1.4 Hz, 1 H), 2.17 (td, J ) 12.3, 7.3
Hz, 1 H), 2.09-2.04 (m, 1 H), 1.98 (d, J ) 15.2 Hz, 1 H), 1.66
dd, J ) 12.3, 5.2 Hz, 1 H), 1.18-1.11 (m, 1 H), 1.16 (d, J )
3
, TMS) δ 9.04 (br s, 1 H), 7.31 (d, J
J ) 7.2 Hz, 3 H); C NMR (CDCl ) δ 168.31, 162.47, 143.10,
3
138.04, 136.23, 129.41, 129.26, 128.50, 128.26, 128.17, 122.79,
120.83, 118.50, 109.36, 91.58, 72.27, 66.26, 61.61, 57.73, 51.83,
50.99, 39.63, 35.29, 28.91, 9.82; MS m/ z (relative intensity)
574 (1), 572 (2), 433 (3), 431 (4), 429 (2), 418 (10), 417 (52),
416 (14), 415 (51), 378 (5), 376 (6), 362 (6), 360 (17), 358 (15),
357 (5), 356 (7), 355 (4), 336 (4), 335 (5), 296 (6), 291 (24), 289
(27), 268 (21), 254 (10), 253 (8), 252 (21), 239 (7), 238 (27), 237
(95), 236 (13), 235 (9), 224 (12), 222 (21), 221 (15), 220 (10),
214 (24), 209 (17), 208 (43), 207 (17), 196 (13), 195 (17), 194
(27), 193 (17), 182 (18), 181 (18), 180 (30), 170 (11), 169 (20),
168 (24), 167 (27), 164 (100), 162 (96), 157 (24), 155 (22), 154
(41), 144 (11), 143 (17), 130 (13), 122 (10). Anal. Calcd for
(
1
(
7
1
9
2
.1 Hz, 1 H), 0.77 (t, J ) 7.4 Hz, 1 H); 13C NMR (CDCl
) δ
3
68.82, 164.09, 143.49, 137.16, 127.96, 122.44, 120.87, 109.16,
0.25, 77.98, 63.22, 57.72, 52.11, 50.90, 50.26, 40.77, 39.15,
8.14, 24.58, 16.25, 9.10; MS m/ z (relative intensity) 340 (M
+
2, 1), 339 (M + 1, 8), 338 (M, 14), 307 (1), 216 (1), 214 (1),
2
08 (1), 206 (1), 194 (1), 193 (1), 192 (1), 191 (1), 180 (1), 168
C
27 29 2 2
H N O SeBr: C, 56.65; H, 5.11; N, 4.90; Se, 13.97; Br,
(
(
1), 167 (1), 154 (2), 125 (10), 124 (100), 122 (1), 110 (1), 109
2), 108 (1), 95 (1), 94 (1), 80 (1), 56 (1), 55 (1), 54 (1).
For the more polar (â) isomer 11, see below in the hydro-
13.96. Found: C, 56.98; H, 5.32; N, 4.68; Se, 13.84; Br, 13.76.
tr a n s-Am in o Selen id e 8. A mixture of 0.285 g of the trans
tetracycle 3 (0.63 mmol), 0.74 g (3.15 mmol) of 85% 2,3-
dibromopropene, and 0.5 g of potassium carbonate in 5 mL of
THF was heated at reflux for 2 d. Filtration and subsequent
concentration of the filtrate gave the crude product, which was
genation procedure.
b
P r oced u r e b: fr om tr a n s-N -Allyl Selen yl Isom er 13.
A degassed solution, containing 0.039 g (0.90 mmol) of the
trans-N-allyl compound 13, 0.031 mL of tri-n-butyltin hydride,
and 5 mg of AIBN in 5 mL of dry benzene was heated in an
oil bath at 85 °C for 3 h. After 0.031 mL of tri-n-butyltin
hydride and 5 mg of AIBN were added, heating at 85 °C was
continued overnight. Cooling to rt and evaporation then gave
purified by flash chromatography (SiO
2
, hexane/ether 2:1) to
afford 0.286 g of the product (80%): R
f
) 0.50 (hexane/ether
1:1); CAS spray, blue; UV (EtOH) λmax 214, 224, 300, 332 nm;
IR (thin film) νmax 3383, 3059, 2969, 2945, 2821, 1678, 1610,
1478, 1466, 1436, 1386, 1283, 1248, 1200, 1149, 1126, 1082,
-
1 1
a residue, which was purified by flash chromatography (SiO
0
2
,
3
1047, 906, 741, 695 cm ; H NMR (CDCl , TMS) δ 9.12 (br s,
.5:50:50 triethylamine/ethyl acetate/methanol) to afford 0.022
1 H), 7.26-7.12 (m, 7 H), 6.96 (t, J ) 7.4 Hz, 1 H), 6.91 (d, J
) 7.7 Hz, 1 H), 5.90 (s, 1 H), 5.52 (s, 1 H), 3.77 (s, 3 H), 3.61
(s, 1 H), 3.41 (d, J ) 15.2 Hz, 1 H), 3.29 (d, J ) 15.2 Hz, 1 H),
3.21 (dd, J ) 8.9, 6.8 Hz, 1 H), 3.04 (d, J ) 15.9 Hz, 1 H),
2.61-2.56 (m, 1 H), 2.41 (d, J ) 15.9 Hz, 1 H), 2.14-2.04 (m,
2 H), 1.73 (dd, J ) 12.2, 5 Hz, 1 H), 1.36-1.26 (m, 1 H), 1.18
g (82%) of the cyclized product as a 2.6:1 R/â methyl mixture.
P r oced u r e c. To a solution of 0.014 g (0.042 mmol) of the
methylene compound 14 in 1 mL of ethyl acetate, under argon,
was added 5 mg of 10% palladium on carbon. The mixture
was stirred under 1 atm of hydrogen at rt overnight. Filtration
through Celite and washing the residue with dichloromethane
gave a combined filtrate, which was concentrated and purified
by flash chromatography (SiO
methanol/ethyl acetate) to give 0.012 g (85%) of the â-methyl
compound 11: R
spray, blue; UV (EtOH) λmax 206, 228, 300, 330 nm; IR (thin
film) νmax 3376, 2959, 2919, 2878, 2856, 1678, 1609, 1480, 1466,
1
7
)
1
(t, 7.1 Hz, 3 H); 13C NMR (CDCl
) δ 168.20, 167.45, 143.07,
3
138.09, 137.21, 130.96, 128.53, 128.38, 127.97, 127.68, 121.80,
120.67, 117.68, 109.66, 90.47, 74.97, 65.04, 64.60, 57.76, 52.04,
50.92, 41.50, 27.29, 25.59, 9.97; MS m/z (relative intensity)
575 (7), 574 (19), 417 (7), 415 (7), 298 (5), 289 (3), 283 (14),
282 (100), 268 (3), 252 (5), 238 (7), 237 (30), 236 (5), 226 (5),
224 (16), 222 (6), 214 (8), 208 (12), 207 (5), 195 (6), 194 (9),
193 (5), 182 (8), 181 (11), 180 (15), 170 (7), 169 (12), 168 (7),
167 (9), 164 (40), 162 (49), 157 (7), 155 (10), 154 (30), 137 (19),
2
, 0.5:30:70 triethylamine/
f
) 0.24 (1:1 methanol/ethyl acetate); CAS
436, 1383, 1288, 1273, 1244, 1196, 1144, 1122, 1092, 1046,
-
1 1
45 cm ; H NMR (CDCl
3
, TMS) δ 9.01 (br s, 1 H), 7.29 (d, J
7.4 Hz, 1 H), 7.16 (t, J ) 7.7 Hz, 1 H), 6.87 (t, J ) 7.4 Hz,
H), 6.82 (d, J ) 7.7 Hz, 1 H), 3.77 (s, 3 H), 3.49 (s, 1 H),
29 2 2
130 (5), 121 (11), 105 (8). Anal. Calcd for C27H N O SeBr:
C, 56.65; H, 5.11; N, 4.90; Se, 13.97; Br, 13.96. Found: C,
56.32; H, 5.00; N, 4.72; Se, 13.53; Br, 13.75.
(()-Vin ca d iffor m in e (9). P r oced u r e a : fr om t h e Cis
Isom er 7. The starting vinyl bromide 7 (60 mg, 0.105 mmol),
0.0705 mL of tri-n-butyltin hydride (0.262 mmol, 2.5 equiv),
and 10 mg of AIBN were mixed in 7.5 mL of benzene. After
degassing with argon for 10 min, the resulting solution was
3
2
2
1
0
1
.35-3.27 (m, 2 H), 2.90 (dd, J ) 12.4, 7.1 Hz, 1 H), 2.58-
.54 (m, 1 H), 2.55 (d, J ) 15.2 Hz, 1 H), 2.45-2.40 (m, 1 H),
.16-2.10 (m, 1 H), 2.00 (d, J ) 15.2 Hz, 1 H), 1.62 (dd, J )
2.2, 5 Hz, 1 H), 1.32-1.21 (m, 2 H), 1.00 (d, J ) 6.8 Hz, 3 H),
.72 (t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl
) δ 168.95, 163.49,
43.56, 136.98, 128.01, 122.45, 120.85, 109.16, 90.19, 76.95,
3

6
006 J . Org. Chem., Vol. 61, No. 17, 1996
Kuehne et al.
immersed and stirred in an 85 °C oil bath for 2 h. After
addition of 0.1 mL of triethylamine, the reaction was continued
at 85 °C for 1 h. Cooling to rt and concentration on a rotary
evaporator gave a residue, which was purified by flash
chromatography (ether/hexane 1:1) to afford 30 mg (85%) of
vincadifformine, which matched a known sample in TLC,
(()-P seu d o- a n d 20-epi-P seu d ovin ca d iffor m in e (15
a n d 16). To a solution of 0.045 g (0.091 mmol) of the selenide
18 in 6 mL of benzene at 85 °C was added a solution of 0.086
mL (0.32 mmol) of tri-n-butyltin hydride in 2 mL of benzene
through a syringe pump over 8 h. After removal of the solvent
under vacuum with a rotary evaporator, the residue was flash
1
NMR, IR, and mass spectra.
chromatographed (SiO
2
, 3:1 hexane/ether) to provide 0.021 g
(
68%) of the product as a 2:1 mixture of ψ- and epi-ψ-
P r oced u r e b: fr om th e Tr a n s Isom er 8. The same
procedure was repeated, starting with 60 mg of the amino
selenide trans isomer 8, to produce 25 mg of vincadifformine
1
vincadifformine (the ratio was determined by H NMR inte-
gration of the indole proton signals at δ 8.88 and 8.92).
2
(
()-3-Oxovin ca d iffor m in e (21). P r oced u r e a : fr om th e
Tetr a cyclic Selen id e 2 (Cis Isom er ). A solution of 50 mg
0.11 mmol) of the selenide 2, 0.14 mL (1.55 mmol, 14 equiv)
(71%).
(
()-Meth yl 3-(2-Eth ylp r op -2-en yl)-1,2,3,4,5,6-h exa h y-
(
d r oa zep in o[4,5-b]in d ole-5-ca r boxyla te (17). To a solution
of 1.00 g (11.6 mmol) of 2-ethylallyl alcohol in 15 mL of dry
ether at 5 °C was added dropwise 0.44 mL (4.63 mmol) of
phosphorous tribromide. The reaction mixture was stirred at
of methyl acrylate, and a crystal of AIBN in 10 mL of dry
benzene was degassed with argon for 10 min. At 85 °C, a
solution of 0.090 mL (0.33 mmol, 3 equiv) of tri-n-butyltin
hydride and 8 mg of AIBN in 2.5 mL of dry benzene was added
over 7 h with a syringe pump. The reaction mixture was
concentrated, the residue was dissolved in 10 mL of toluene,
and 21 mg (0.11 mmol, 1 equiv) of p-toluenesulfonic acid
monohydrate was added. The mixture was heated at reflux
under nitrogen for 18 h and then cooled and concentrated
under vacuum. The crude product was purified by flash
1
5-20 °C for 18 h, diluted with 25 mL of ether, and washed
successively with saturated aqueous sodium bicarbonate solu-
tion and brine. Drying (Na SO ) and concentration then gave
2
4
the bromide, which was used directly for the next step.
A mixture of 1.00 g (4.09 mmol) of the indoloazepine 1, all
of the above-formed bromide, 1.7 g of potassium carbonate,
and 1.7 mL of triethylamine in 20 mL of acetone was stirred
vigorously at rt for 2 h. Filtration, washing with acetone, and
concentration of the combined filtrate gave the crude product,
chromatography (SiO
acetate/hexane. Concentration of appropriate fractions gave
3 mg (34%) of pure 3-oxovincadifformine (21), which showed
2
, 2 cm × 23 cm), eluting with 4:1 ethyl
1
which was purified by flash chromatography (SiO
hexane) to afford 0.955 g of the alkylated azepine (74.7%): mp
0-91 °C (MeOH); R ) 0.48 (ether/hexane 2:1); CAS spray,
2
, 1:1 ether/
13
TLC behavior identical to that of a known sample in several
different solvent systems. A sample recrystallized from ben-
zene had mp 203-204 °C: R ) 0.33 (ethyl acetate), 0.48 (4%
methanol in methylene chloride), 0.55 (5% methanol in meth-
ylene chloride); CAS spray, blue; UV (EtOH) λmax 204, 224,
2
1
9
f
f
blue; UV (EtOH) λmax 208, 228, 284, 292 nm; IR (thin film)
ν
max 3399, 3356, 2962, 2915, 2822, 1730, 1648, 1460, 1434,
-
1
1
1
340, 1278, 1206, 1162, 1030, 899, 742, 721 cm ; H NMR
, TMS) δ 8.22 (br s, 1 H), 7.46 (d, J ) 7.5 Hz, 1 H), 7.19
96, 328 nm; IR (thin film) νmax 3340, 2966, 2948, 2879, 1675,
(CDCl
3
656, 1609, 1466, 1435, 1309, 1275, 1242, 1195, 1112, 732
(
1
d, J ) 8.0 Hz, 1 H), 7.14-7.05 (m, 2 H), 4.93 (s, 1 H), 4.89 (s,
-1 1
cm ; H NMR (CDCl
H), 6.86-6.95 (m, 2 H), 4.16 (dd, J ) 12, 7.6 Hz, 1 H), 3.79
s, 3 H), 3.48 (s, 1 H), 3.42 (td, J ) 12, 5.5 Hz, 1 H), 2.66 (d, J
15.4 Hz, 1 H), 2.25-2.46 (m, 2 H), 1.81-2.10 (m, 4 H), 1.37
td, J ) 12, 4 Hz, 1 H), 0.99 (q, J ) 7 Hz, 2 H), 0.72 (t, J ) 7
3
, TMS) δ 9.01 (br s, 1 H), 7.18-7.30 (m,
H), 3.90 (dd, J ) 6.5, 2.1 Hz, 1 H), 3.69 (s, 3 H), 3.32 (dd, J
12.9, 6.6 Hz, 1 H), 3.16 (s, 2 H), 2.97-2.81 (m, 4 H), 2.63-
2
(
)
(
)
2
.58 (m, 1 H), 2.11 (q, J ) 7.4 Hz, 2 H), 1.06 (t, J ) 7.4 Hz, 3
13
H); C NMR (CDCl
1
5
3
) δ 172.54, 148.98, 134.79, 132.26, 128.53,
21.35, 119.11, 117.95, 114.11, 110.93, 110.64, 63.71, 57.99,
5.27, 52.06, 45.81, 26.63, 24.34, 12.14; MS m/ z (relative
13
Hz, 3 H); C NMR (CDCl
1
5
3
) δ 171.16, 168.35, 164.16, 143.30,
36.14, 128.69, 121.66, 121.24, 109.74, 91.57, 68.29, 57.06,
0.89, 43.21, 40.48, 39.63, 31.11, 30.44, 28.98, 28.33, 7.40; MS
intensity) 313 (M + 1, 8), 312 (M, 33), 239 (3), 216 (3), 215
(13), 214 (12), 203 (3), 202 (21), 184 (5), 183 (14), 182 (18), 170
(6), 169 (7), 157 (5), 156 (35), 155 (5), 154 (13), 144 (5), 143
(7), 129 (7), 128 (7), 112 (8), 111 (19), 110 (100), 99 (9), 98 (16),
m/ z (relative intensity) 353 (M + 1, 8), 352 (35), 321 (2), 277
(1), 229 (4), 228 (16), 227 (100), 222 (2), 215 (5), 214 (32), 206
(3), 196 (10), 195 (57), 194 (5), 182 (7), 168 (13), 167 (13), 154
(19), 138 (6), 73(18), 55 (9).
9
24 2 4
7 (6), 96 (74), 82 (20), 69 (5). Anal. Calcd for C19H N O :
C, 73.05; H, 7.74; N, 8.97. Found: C, 73.11; H, 7.75; N, 8.97.
P r oced u r e b: fr om th e Tetr a cyclic Selen id e 3 (Tr a n s
Met h yl (()-(3a R*,4R*,11bR*)-3-(2-E t h ylp r op -2-en yl)-
,3,3a ,4,5,7-h exa h yd r o-4-(p h en ylselen yl)-1H-p yr r olo[2,3-
Isom er ). The same procedure was repeated, starting with 50
mg of the trans selenide 3, and 13.9 mg (35.8%) of 3-ox-
ovincadifformine (21) was obtained after flash chromato-
graphic purification.
Meth yl (()-(3a R*,4S*,11bR*)-3-(3-Iodoallyl)-2,3,3a,4,5,7-
h exa h yd r o-4-eth yl-4-(p h en ylselen yl)-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (22). A mixture of 0.325 g (0.717
2
d ]ca r ba zole-6-ca r boxyla te (18). A mixture of 0.107 g (0.34
mmol) of the azepine 17 and 0.072 g (0.36 mmol) of (phenylse-
lenyl)acetaldehyde in 3 mL of dry toluene was heated at reflux
for 3 h. After addition of another 0.072 g of (phenylselenyl)-
acetaldehyde, the reaction was continued at reflux for 5 h.
Cooling and concentration then gave a crude syrup, which was
1
4
mmol) of the cis tetracyclic selenide 2, (Z)-1,3-diiodopropene
purified by flash column chromatography (SiO
ether) to afford 0.127 g (75.1%) of the pure product as a viscous
oil:
2
, 4:1 hexane/
(0.5 g, 1.7 mmol), and 0.3 g of potassium carbonate in 6 mL of
THF was stirred at rt overnight and then heated at reflux for
6 h. After filtration to remove the solid, the filtrate was
concentrated and the crude product purified by flash chroma-
R
f
) 0.55 (ether/hexane 1:1); CAS spray, yellow; UV
(
EtOH) λmax 206, 220, 300, 332 nm; IR (thin film) νmax 3379,
3
1
1
9
7
072, 3057, 2964, 2946, 2848, 2803, 1677, 1610, 1477, 1466,
437, 1385, 1341, 1294, 1279, 1249, 1199, 1151, 1125, 1080,
tography (SiO , hexane/ether 2:1), to afford 0.360 g (81%) of
2
the alkylated product as a white foam: R ) 0.60 (ether/hexane
f
054, 1021, 905, 772, 742, 691 cm-1; 1H NMR (CDCl
, TMS) δ
3
1:1); CAS spray, blue; UV (EtOH) λ
max
212, 222, 300, 332 nm;
IR (thin film) νmax 3379, 3054, 2967, 2946, 2849, 2822, 1678,
.07 (br s, 1 H), 7.40 (d, J ) 7 Hz, 2 H), 7.24-7.17 (m, 4 H),
.14 (d, J ) 7.5 Hz, 1 H), 6.91 (t, J ) 7.5 Hz, 1 H), 6.87 (d, J
1611, 1477, 1465, 1435, 1389, 1380, 1281, 1248, 1209, 1191,
-
1 1
)
7.7 Hz, 1 H), 4.89 (s, 1 H), 4.77 (s, 1 H), 3.76 (s, 3 H), 3.49
1121, 1104, 1045, 1022, 798, 741, 695 cm ; H NMR (CDCl ,
3
TMS) δ 9.01 (br s, 1 H), 7.74 (d, J ) 8.1 Hz, 2 H), 7.33-7.25
(m, 4 H), 7.17 (t, J ) 7.7 Hz, 1 H), 6.94 (t, J ) 7.5 Hz, 1 H),
6.80 (d, J ) 7.6 Hz, 1 H), 6.64-6.60 (m, 1 H), 6.40 (br d, J )
7.7 Hz, 1 H), 4.11 (ddd, J ) 14, 4.3, 1.9 Hz, 1 H), 3.80 (dd, J
) 14, 7.8 Hz, 1 H), 3.68 (s, 3 H), 3.30-3.26 (m, 1 H), 3.26 (s,
1 H), 3.05 (d, J ) 15.3 Hz, 1 H), 2.95 (d, J ) 15.3 Hz, 1 H),
2.93-2.86 (m, 1 H), 2.40-2.34 (m, 1 H), 1.75 (dd, J ) 12.4,
5.5 Hz, 1 H), 1.29-1.22 (m, 1 H), 1.01-0.88 (m, 1 H), 0.75 (t,
(
br s, 1 H), 3.30 (s, 1 H), 3.19 (d, J ) 13.1 Hz, 1 H), 3.04 (br d,
J ) 15.5 Hz, 1 H), 2.99 (d, J ) 13.1 Hz, 1 H), 2.99-2.85 (m, 1
H), 2.86 (dd, J ) 15.5, 2.5 Hz, 1 H), 2.56-2.50 (m, 1 H), 2.12-
2
.00 (m, 3 H), 1.72 (dd, J ) 11.9, 4.6 Hz, 1 H), 1.03 (t, J ) 7.4
13
Hz, 3 H); C NMR (CDCl
3
) δ 168.55, 166.17, 149.01, 142.91,
1
1
4
4
37.67, 135.14, 129.50, 128.78, 127.85, 127.45, 121.92, 120.71,
10.41, 109.49, 91.46, 73.34, 59.85, 55.43, 51.04, 50.93, 46.75,
2.40, 26.80, 24.59, 12.22; MS m/ z (relative intensity) 495 (2),
93 (1), 338 (10), 337 (8), 335 (1), 314 (1), 312 (1), 310 (2), 280
J ) 7.2 Hz, 3 H); 13C NMR (CDCl
) δ 168.14, 162.40, 143.01,
3
(
1
(
2), 278 (2), 277 (1), 240 (2), 228 (2)l 227 (2), 226 (2), 209 (3),
84 (3), 180 (4), 167 (4), 157 (6), 155 (4), 154 (6), 113 (5), 112
62), 88 (8), 87 (4), 86 (68), 84 (100), 77 (6), 69 (7) 57 (7).
138.32, 137.74, 136.25, 129.33, 128.41, 128.12, 128.03, 122.84,
120.82, 109.22, 91.23, 83.06, 72.33, 61.94, 61.63, 57.82, 51.40,
50.87, 39.25, 34.83, 29.13, 9.77; MS m/ z (relative intensity)

Ring D Annelations To Form Pentacyclic Alkaloids
J . Org. Chem., Vol. 61, No. 17, 1996 6007
6
4
21 (M + 2, 0.54), 620 (M + 1, 0.53), 619 (M, 0.11), 493 (0.66),
122.02, 120.82, 109.66, 90.48, 83.22, 75.29, 64.26, 60.46, 57.95,
52.36, 50.99, 41.54, 27.36, 26.36, 10.00; MS m/ z (relative
intensity) 621 (0.44), 620 (0.52), 619 (0.10), 618 (0.12), 495
(0.14), 493 (0.52), 480 (0.63), 465 (0.70), 464 (7.0), 463 (26),
408 (3), 406 (4), 404 (2), 403 (1), 338 (2), 337 (2), 335 (2), 323
(8), 314 (6), 312 (6), 277 (15), 254 (17), 252 (11), 237 (32), 222
(15), 221 (14), 211 (6), 210 (100), 208 (21), 195 (10), 194 (16),
193 (12), 182 (14), 181 (17), 180 (41), 179 (10), 168 (12), 167
(56), 165 (34), 157 (38), 155 (22), 154 (36), 153 (16), 137 (12),
65 (0.91), 464 (8.81), 463 (32), 408 (4), 406 (4), 404 (2), 337
(2), 324 (3), 323 (9), 316 (3), 314 (11), 312 (12), 311 (4), 310
(7), 296 (4), 277 (19), 268 (6), 255 (12), 250 (26), 238 (17), 237
(70), 232 (11), 222 (15), 221 (14), 210 (64), 209 (12), 208 (30),
1
(
1
(
96 (15), 195 (23), 194 (31), 193 (14), 192 (8), 182 (19), 181
16), 180 (35), 172 (54), 170 (28), 169 (16), 168 (32), 167 (52),
59 (17), 158 (16), 157 (86), 156 (12), 155 (49), 154 (56), 153
19), 142 (100), 141 (10), 130 (14), 128 (28), 127 (41), 117 (19),
1
16 (21), 115 (17), 108 (10), 107 (12), 106 (10).
127 (19), 111 (9). Anal. Calcd for C27
29 2 2
H N O SeI: C, 52.36;
Met h yl (()-(3a S*,11b R*)-3-(3-Iod oa llyl)-2,3,3a ,7-t et -
H, 4.72; N, 4.52. Found: C, 52.76; H, 5.16; N, 4.40.
r a h yd r o-4-et h yl-1H -p yr r olo[2,3-d ]ca r b a zole-6-ca r b oxy-
la te (23). To a solution of 0.189 g (0.305 mmol) of the selenide
2
Met h yl (()-(3a S*,11b R*)-3-(3-Iod oa llyl)-2,3,3a ,4,5,7-
h exa h yd r o-4-(et h ylen yl)-1H -p yr r olo[2,3-d ]ca r b a zole-6-
ca r boxyla te (26). To a solution of 0.500 g (0.807 mmol) of
the trans-amino phenyl selenide 25 in 50 mL of dichlo-
romethane at -75 °C was added dropwise a solution of 0.306
g (1.77 mmol) of m-CPBA in 5 mL of dichloromethane. The
reaction mixture was stirred at -75 °C for 10 min and then
the temperature was raised to -40 °C, and 0.465 g (1.77 mmol)
of solid triphenylphosphine was then added. The mixture was
warmed to rt and washed with saturated aqueous sodium
2 in 6 mL of dichloromethane at -78 °C was added dropwise
.116 g of m-CPBA (0.67 mmol) in 2 mL of dichloromethane.
0
After 10 min, the temperature was raised to -40 °C, and 0.176
g of triphenylphosphine (0.67 mmol) was added. The mixture
was brought to rt, stirred for 30 min, and diluted with 20 mL
of dichloromethane. After washing with saturated aqueous
sodium bicarbonate solution, the dichloromethane layer was
dried (Na
which was purified by flash chromatography (SiO
ether 2:1) to afford 0.126 g of the pure diene 23 as a yellow
foam (89%): R ) 0.41 (ether/hexane 1:1); CAS spray, green;
2
SO
4
) and concentrated to give the crude product,
, hexane/
2
bicarbonate solution. After drying (Na
the residue was purified by flash chromatography (SiO
hexane/ether 3:1) to afford 0.233 g (62%) of the pure product
as a white foam: R ) 0.38 (ether/hexane 1:1); CAS spray,
2 4
SO ) and concentration,
2
,
f
UV (EtOH) λmax 210, 220, 250, 298, 372 nm; IR (thin film) νmax
374, 2960, 2839, 1678, 1636, 1603, 1464, 1436, 1387, 1322,
279, 1252, 1229, 1206, 1145, 1119, 1081, 1041, 881, 744 cm ;
f
3
greenish blue; UV (EtOH) λmax 206, 220, 298, 330 nm; IR (thin
film) νmax 3376, 3059, 2969, 2948, 2917, 2849, 2805, 1684, 1653,
1636, 1609, 1559, 1540, 1477, 1465, 1457, 1437, 1280, 1247,
-1
1
1
H NMR (CDCl , TMS) δ 9.19 (s, 1 H), 7.28 (d, J ) 7.5 Hz, 1
3
-1 1
H), 7.20 (t, J ) 7.7 Hz, 1 H), 6.95 (t, J ) 7.5 Hz, 1 H), 6.89 (d,
J ) 7.7 Hz, 1 H), 6.55-6.51 (m, 1 H), 6.38 (br d, J ) 7.4 Hz,
3
1191, 1118, 1041, 910, 733 cm ; H NMR (CDCl , TMS) δ 8.86
(br s, 1 H), 7.20 (d, J ) 7.4 Hz, 1 H), 7.13 (t, J ) 7.7 Hz, 1 H),
6.87 (t, J ) 7.4 Hz, 1 H), 6.77 (d, J ) 7.7 Hz, 1 H), 6.48-6.41
(m, 2 H), 5.20 (q, J ) 6.6 Hz, 1 H), 3.77 (s, 3 H), 3.59-3.54 (m,
1 H), 3.50 (d, J ) 15.3 Hz, 1 H), 3.41 (dd, J ) 14.6, 6.6 Hz, 1
H), 3.33 (s, 1 H), 3.05 (br t, J ) 7.1 Hz, 1 H), 2.87-2.82 (m, 1
H), 2.73 (d, J ) 15.3 Hz, 1 H), 2.25-2.19 (m, 1 H), 1.80 (dd, J
1
H), 6.02 (s, 1 H), 3.93-3.76 (m, 2 H), 3.89 (s, 1 H), 3.79 (s, 3
H), 3.05-3.02 (m, 1 H), 2.80-2.76 (m, 1 H), 2.42-2.33 (m, 2
H), 2.19-2.14 (m, 1 H), 1.69 (dd, J ) 12.7, 5.7 Hz, 1 H), 1.10
1
3
(
t, J ) 7.4 Hz, 3 H); C NMR (CDCl ) δ 167.37, 164.12, 143.31,
3
1
9
1
3
2
2
(
1
7
39.24, 135.28, 132.50, 128.04, 123.25, 120.78, 113.29, 109.50,
) 11.9, 4.6 Hz, 1 H), 1.66 (d, J ) 6.6 Hz, 3 H); 13C NMR (CDCl
)
1.54, 82.42, 70.17, 60.70, 56.51, 50.90, 48.47, 41.94, 25.44,
2.44; MS m/ z (relative intensity) 463 (M + 1, 3), 462 (M, 18),
35 (11), 277 (8), 266 (6), 263 (4), 254 (19), 253 (52), 252 (100),
39 (3), 152 (8), 238 (19), 236 (10), 235 (10), 222 (23), 221 (53),
10 (24), 208 (10), 207 (9), 206 (18), 196 (79), 194 (11), 193
15), 192 (19), 180 (11), 178 (14), 167 (44), 165 (14), 155 (15),
51 (13), 139 (34), 127 (12), 88 (12), 86 (29), 84 (70), 82 (11),
7 (11), 69 (21), 68 (15), 56 (19), 55 (12), 54 (13); high-resolution
3
δ 168.14, 165.21, 143.46, 138.00, 137.15, 127.93, 122.02,
120.57, 119.89, 109.21, 109.10, 94.75, 83.55, 72.94, 57.33,
55.90, 50.99, 50.78, 42.26, 20.79, 13.55; MS m/ z (relative
intensity) 462 (M, 2), 337 (1), 295 (3), 294 (3), 254 (13), 253
(22), 252 (95), 236 (5), 235 (7), 222 (5), 220 (12), 210 (12), 208
(5), 206 (7), 194 (16), 193 (9), 192 (8), 191 (5), 180 (10), 168
(8), 167 (58), 165 (9), 154 (10), 142 (100), 141 (12), 139 (12),
128 (16), 127 (44), 84 (9), 56 (18); high-resolution MS, EI, calcd
MS, EI, calcd for C21
23 2 2
H N O I 462.0804, found 462.0804.
(
()-Ta ber son in e (24). A mixture of 0.070 g (0.15 mmol)
23 2 2
for C21H N O I 462.0804, found 462.0799.
of the cyclohexadiene 23, 0.010 g of palladium diacetate, 0.023
g of triphenylphosphine, 0.020 g of sodium formate, and 0.100
mL of triethylamine in 1 mL of dry acetonitrile was heated at
reflux overnight. After cooling and evaporation, the residue
(()-18,19-Dideh ydr otaber son in e (27). A mixture of 0.037
g (0.08 mmol) of the ethylene compound 26, 0.007 g (0.03
mmol) of palladium acetate, 0.016 g (0.06 mmol) of triphen-
ylphosphine, and 0.056 mL (0.4 mmol) of triethylamine in 1
mL of acetonitrile was stirred under reflux for 3 h. The
mixture was cooled and concentrated. The residue was
2
was purified by flash chromatography (SiO , 2:1 hexane/ether)
to afford 22 mg (43%) of tabersonine, which showed TLC and
spectroscopic behaviors identical with those of a known
sample.
purified by flash chromatography (SiO , 2:1 hexane/ether) to
2
generate 0.0095 g (36%) of 18,19-didehydrotabersonine: R )
f
Meth yl (()-(3aR*,4R*,11bR*)-3-(3-Iodoallyl)-2,3,3a,4,5,7-
h exa h yd r o-4-eth yl-4-(p h en ylselen yl)-1H-p yr r olo[2,3-d ]-
ca r ba zole-6-ca r boxyla te (25). A mixture of trans-amino
phenyl selenide 3 (0.085 g, 0.19 mmol), 0.083 g (0.28 mmol) of
0.51 (ether/hexane 1:1); CAS spray, blue; UV (EtOH) λmax 206,
224, 302, 330 nm; IR (thin film) νmax 3368, 3028, 2954, 2922,
2856, 1683, 1653, 1636, 1609, 1559, 1540, 1507, 1473, 1465,
1457, 1437, 1280, 1204, 1183, 1161, 1112, 1103, 1038, 926
-
1
1
(Z)-1,3-diiodopropene, and 0.10 g of potassium carbonate in 2
3
cm ; H NMR (CDCl , TMS) δ 8.95 (br s, 1 H), 7.25 (d, J )
mL of THF was stirred at rt overnight and heated at reflux
for 2 h. After cooling, filtration, and washing with dichlo-
romethane, the combined filtrate was concentrated to give a
7.5 Hz, 1 H), 7.14 (td, J ) 7.6, 1.2 Hz, 1 H), 6.87 (td, J ) 7.5,
0.8 Hz, 1 H), 6.80 (d, J ) 7.6 Hz, 1 H), 5.80 (ddd, J ) 9.7, 5.0,
1.5 Hz, 1 H), 5.59 (dt, J ) 9.7, 1.7 Hz, 1 H), 5.44 (dd, J ) 17.7,
11 Hz, 1 H), 4.76 (dd, J ) 11, 0.8 Hz, 1 H), 4.52 (dd, J ) 17.7,
0.8 Hz, 1 H), 3.76 (s, 3 H), 3.49 (ddd, J ) 15.8, 5.0, 1.5 Hz, 1
H), 3.22 (dt, J ) 15.8, 1.7 Hz, 1 H), 3.09-3.06 (m, 1 H), 2.98
(d, J ) 1 Hz, 1 H), 2.79-2.75 (m, 1 H), 2.66 (dd, J ) 14.9, 1
Hz, 1 H), 2.61 (d, J ) 14.9 Hz, 1 H), 2.11-2.05 (m, 1 H), 1.82
residue, which after flash chromatographic purification (SiO
:1 hexane/ether) afforded 0.090 g of the alkylated product
76%): R ) 0.50 (hexane/ether 1:3); CAS spray, blue; UV
2
,
1
(
(
f
EtOH) λmax 212, 222, 300, 334 nm; IR (thin film) νmax 3379,
055, 2966, 2944, 2875, 2831, 2816, 1677, 1610, 1478, 1465,
3
1
8
9
6
3
5
1
1
436, 1385, 1283, 1248, 1200, 1144, 1123, 1082, 1046, 1021,
(dd, J ) 11.4, 4.5 Hz, 1 H); 13C NMR (CDCl
) δ 168.91, 166.68,
3
97, 796, 773, 741, 695, 669 cm-1; H NMR (CDCl
1
, TMS) δ
143.23, 142.23, 137.73, 132.98, 127.71, 124.81, 121.25, 120.63,
115.02, 109.34, 92.79, 69.64, 55.39, 50.99, 50.90, 50.39, 45.68,
44.65, 30.28; MS m/ z (relative intensity) 335 (M + 1, 2), 334
(M, 14), 229 (9), 228 (4), 217 (1), 214 (5), 204 (2), 195 (2), 191
(2), 170 (7), 169 (4), 168 (10), 167 (17), 166 (4), 155 (1), 154
(19), 153 (2), 149 (7), 143 (2), 142 (2), 141 (5), 140 (5), 139 (3),
134 (3), 133 (100), 132 (4), 129 (3), 128 (8), 127 (8), 120 (35),
119 (22), 118 (3), 115 (11), 111 (2), 109 (2), 106 (4), 105 (58),
103 (3), 97 (3), 95 (5), 93 (7), 92 (4), 91 (35), 83 (8), 79 (6), 78
3
.11 (br s, 1 H), 7.28-7.15 (m, 7 H), 6.99 (t, J ) 7.5 Hz, 1 H),
.91 (d, J ) 7.7 Hz, 1 H), 6.34-6.29 (m, 2 H), 3.78 (s, 3 H),
.64 (s, 1 H), 3.32 (dd, J ) 14.4, 5 Hz, 1 H), 3.25 (dd, J ) 14.4,
Hz, 1 H), 3.13 (br t, J ) 7.7 Hz, 1 H), 3.01 (d, J ) 15.9 Hz,
H), 2.80-2.75 (m, 1 H), 2.38 (d, J ) 15.9 Hz, 1 H), 2.09-
.94 (m, 2 H), 1.73 (dd, J ) 12.1, 5 Hz, 1 H), 1.44-1.39 (m, 1
1
3
H), 1.18 (t, J ) 7.1 Hz, 3 H); C NMR (CDCl
1
3
) δ 168.31, 167.49,
43.11, 138.14, 138.06, 137.40, 128.61, 128.43, 127.98, 127.83,

6
008 J . Org. Chem., Vol. 61, No. 17, 1996
Kuehne et al.
(
9), 77 (20), 71 (9), 70 (5), 69 (8), 67 (4), 65 (5), 56 (18), 54 (15);
high-resolution MS, EI, calcd for C21 334.1681, found
34.1680.
At t em p t ed Ta n d em H eck R ea ct ion t o Vin d olin in e
28). F or m a tion of Meth yl (()-(3a S*,11bR*)-3-Acetyl-
,3,3a ,4,5,7-h exa h yd r o-4-(et h ylen yl)-1H -p yr r olo[2,3-d ]-
1.88 (m, 1 H), 1.75, 1.70 (2 d, J ) 6.6 Hz, 2:1, 3 H); MS m/ z
(relative intensity) 340 (28), 339 (60), 338 (38), 323 (2), 311
(14), 310 (70), 307 (7), 295 (25), 279 (22), 278 (22), 268 (19),
267 (41), 266 (11), 265 (7), 264 (9), 263 (10), 254 (41), 253 (36),
252 (100), 251 (10), 238 (12), 237 (19), 236 (41), 235 (45), 234
(15), 222 (18), 221 (50), 220 (66), 219 (26), 218 (10), 206 (47),
194 (62), 193 (44), 192 (40), 180 (30), 168 (31), 167 (40), 70
(48), 56 (28).
22 2 2
H N O
3
(
2
ca r ba zole-6-ca r boxyla te (29). A mixture of 0.013 g (0.028
mmol) of the ethylene compound 26, 0.0095 g (0.042 mmol) of
palladium diacetate, and 0.022 g (0.084 mmol) of triphen-
ylphosphine in 0.5 mL of acetonitrile was heated at reflux for
Ack n ow led gm en t. This work was supported by the
Cancer Institute of the National Institutes of Health,
Grant RO1CA12010. We are indebted to Robert Ben-
nett of our group for obtaining low-resolution mass
spectra and to the Emory University Mass Spectrometry
Facility for providing high-resolution mass spectra.
3
h. After addition of 0.020 mL (0.143 mmol) of triethyl-
amine, the reaction was continued at reflux for 2 h. After
cooling and concentration, the residue was flash chromato-
graphed, first eluting with 2:1 hexane/ether to give a trace
amount of 18,19-didehydrotabersonine, and then with ether
to give 6 mg of the N-acetyl derivative 29 (63.1%): R
ether); CAS spray, yellow; UV (EtOH) λmax 206, 226, 298, 328
nm; IR (thin film) νmax 3364, 3054, 2953, 2925, 2858, 1734,
f
) 0.23
(
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and 13C
NMR spectra for compounds 2-5, 7, 8, 10-14, 17, 18, 21-
1
1
(
6
5
685, 1636, 1610, 1466, 1436, 1419, 1273, 1242, 1217, 1191,
-
1 1
095, 1038, 772, 749 cm ; H NMR (CDCl , TMS) δ 9.12, 9.04
3
2
3, and 25-27 (37 pages). This material is contained in
2 br s, 2:1, 1 H), 7.20-7.15 (m 1 H), 6.94 (d, J ) 7.2 Hz, 1 H),
.88-6.81 (m, 2 H), 5.80, 5.60 (2 qd, J ) 6.6, 2.2 Hz, 1:2, 1 H),
.03 and 4.42 (2 s, 1:2, 1 H), 3.90-3.68 (m, 1 H), 3.80, 3.79 (2
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.
s, 2:1, 3 H), 3.53-3.35 (m, 2 H), 3.20, 3.09 (2 d, J ) 19 Hz,
2
:1, 1 H), 2.24-1.96 (m, 1 H), 2.24, 2.16 (2 s, 1:2, 3 H), 1.92-
J O960607R