Syntheses of Strychnan- and Aspidospermatan-Type Alkaloids. 9.1 The Enantioselective Generation of Tetracyclic ABCE Intermediates by a Tandem Condensation, [3,3]-Sigmatropic Rearrangement, and Cyclization Sequence

Article abstract of DOI:10.1021/jo970207j

Reactions of substituted acroleins with the tryptophan-derived benzyl 2-(benzylamino)-3-[3-[2-[(methoxycarbonyl)methyl]indolyl]]propionate gave tetracyclic hexahydro-1H-pyrrolo[2,3-d] intermediates with stereoselective placement of substituents for cycliz

Full text of DOI:10.1021/jo970207j

7950
J . Org. Chem. 1997, 62, 7950-7960
Syn th eses of Str ych n a n - a n d Asp id osp er m a ta n -Typ e Alk a loid s. 9.1
Th e En a n tioselective Gen er a tion of Tetr a cyclic ABCE
In ter m ed ia tes by a Ta n d em Con d en sa tion , [3,3]-Sigm a tr op ic
Rea r r a n gem en t, a n d Cycliza tion Sequ en ce
Martin E. Kuehne* and Feng Xu
Department of Chemistry, University of Vermont, Burlington, Vermont 05405
Received February 5, 1997 (Revised Manuscript Received September 24, 1997X)
Reactions of substituted acroleins with the tryptophan-derived benzyl 2-(benzylamino)-3-[3-[2-
[(methoxycarbonyl)methyl]indolyl]]propionate gave tetracyclic hexahydro-1H-pyrrolo[2,3-d] inter-
mediates with stereoselective placement of substituents for cyclization to pentacyclic Strychnos
alkaloids. The benzyl ester moiety was readily removed by formation of a corresponding nitrile
and reduction, thus providing enantioselective syntheses of the tetracyclic compounds.
Sch em e 1
In 1992, Rodney Parsons found in our laboratories a
remarkable new condensation, [3,3]-sigmatropic rear-
rangement, and cyclization reaction sequence (Scheme
1).2 It provides, in one operation and with complete
diastereoselectivity, tetracyclic intermediates 1 for syn-
theses of Strychnos alkaloids3 by the acid-catalyzed
reaction of an Nb-alkyl-2-[(methoxycarbonyl)methyl-
]tryptamine derivative 2 with R,â-unsaturated alde-
hydes.4,5 In this paper, we report a more detailed study
of the scope of this reaction and its extension to the
enantioselective generation of tetracyclic ABCE Strych-
nos alkaloid precursors.
Alder reaction of that enamine with a third equivalent
of crotonaldehyde would lead to the formation of product
6.
Structure assignment to the aminocyclohexene 4 was
derived from an H-H COSY spectrum, which clearly
showed respective C-C connections. The stereochemis-
try of substitution of the cyclohexene ring is based on
coupling constants J H-H ) 10.8 Hz for the three adjacent
methine hydrogens.
The stereochemistry of the indoloazonine 5 was eluci-
dated by its NOESY spectrum. NOE links between the
acrylate hydrogen and the methyl and adjacent methine
hydrogens indicate an E geometry for the acrylate double
bond. NOE signals for interaction of the methyl group
with the two methine hydrogens adjacent to Nb and the
acrylate substituent and the NOE of the acrylate hydro-
gen with the methyl group and with its adjacent methine
hydrogen establish the relative stereochemistry of sub-
stitution and the conformation of the cyclohexene ring.
In the triene 6 the Z,E diene ester moiety was revealed
by J ) 11.3 and 13.6 Hz coupling constants. Interest-
ingly, the cyclohexenyl olefinic hydrogens appeared as a
two-hydrogen singlet at δ 5.77. An H-C COSY spectrum
showed coupling of the δH 5.77 peak to the δC 129.04 and
125.54 ppm olefinic carbon peaks.
For optimization of this transformation crotonaldehyde
was chosen as a model aldehyde, with variations of the
acid catalyst. In addition to the desired product 1a , four
other products were generated in these reactions (Scheme
2). Best yields of the tetracyclic product 1a were obtained
at 70 °C in benzene, with benzoic acid and magnesium
sulfate. At elevated temperatures, some cyclization of
the amino ester 2 to the lactam 3 was always found
(Table 1). In addition, the Diels-Alder reaction product
of a crotonaldehyde and amine 2 derived enamine, with
crotonaldehyde, furnished the aldehyde 4. While the
other two products 5 and 6 are formally derived, respec-
tively, from cyclization of the aldehyde 4 and from its
condensation with a third equivalent of crotonaldehyde,
the actual formation of these products is more likely to
arise by alternative condensations. Thus, N,N-dibenzyl-
2-[(methoxycarbonyl)methyl]tryptamine2 failed to react
with crotonaldehyde under the same reaction conditions,
and prolonged heating of the aldehyde 4 in toluene led
only to a retro-Diels-Alder reaction and cyclization to
the lactam 3. For the formation of products 5 and 6,
condensation R to the ester function may be obtained by
an intramolecular alkyl transfer from an initial N-
benzyliminium salt. A subsequent second enamine for-
mation and intramolecular Diels-Alder reaction would
provide the tetracycle 5, while an intermolecular Diels-
Variations of substituents on the acrolein reactant
(Table 2) revealed that formation of the tetracyclic
products 1 was only incompatible with simultaneous R-
and â-substitution of the unsaturated aldehyde (last
entry).6,7 In these examples diastereoselectivity for
formation of cis Nb- and R-substituents in the tetracyclic
X Abstract published in Advance ACS Abstracts, November 1, 1997.
(1) Part 8: Kuehne, M. E.; Wang, T.; Seraphin, D. J . Org. Chem.
1996, 61, 7873.
(2) Parsons, R. L.; Berk, J . D.; Kuehne, M. E. J . Org. Chem. 1993,
58, 7482.
(3) For a review of Strychnos alkaloid syntheses see: Bosch, J .;
Bonjoch, J .; Amat, M. Cordell, G. A., Ed. Alkaloids (Academic Press)
1996, 48, 75.
(4) Kuehne, M. E.; Xu, F. J . Org. Chem. 1993, 58, 7490.
(5) Kuehne, M. E.; Xu, F.; Brook, C. S. J . Org. Chem. 1994, 59, 7803.
(6) Compound 1j was previously synthesized by two alternative
methods. Spectroscopic comparisons with the product of the present
method showed their identity. (a) Kuehne, M. E.; Matsko, T. H.;
Bohnert, J . C.; Motyka, L.; Oliver-Smith, D. J . Org. Chem. 1981, 46,
2002. (b) Kuehne, M. E.; Kuehne, S. E. J . Org. Chem. 1993, 58, 4147.
(7) Only an insignificant amount of the disubstituted tetracyle 1k
was formed. Such compounds would be of interest for the synthesis of
tubotaiwine-type alkaloids. Kuehne, M. E.; Frasier, D. A.; Spitzer, T.
D. J . Org. Chem. 1991, 56, 2696.
S0022-3263(97)00207-7 CCC: $14.00 © 1997 American Chemical Society

Syntheses of Strychnan- and Aspidospermatan-Type Alkaloids
J . Org. Chem., Vol. 62, No. 23, 1997 7951
Sch em e 2
Ta ble 1
Sch em e 3
yields (%)
acids
T (°C) solvents
1a
6
4a
5
3
1
2
3
4
5
6
7
8
9
BF3‚Et2O
CF3CO2H
B(OH)3
70
35
70
C6H6
4 Å M.S.g 30
8
23 10
CH2Cl2
C6H6
7
32
6
4 Å M.S. 35
15
8
B(OH)3
RTb C6H6
4 Å M.S. 20c
PhCO2H
PhCO2H
Et3N‚HCl
(CHCO2H)2
PPTS
70
35
70
70
70
70
60
70
C6H6
CH2Cl2 MgSO4
MgSO4
54d Te
T
12
18
14
30
9
7
8
6
40
48
35
19
34
36
40
8
4
6
C6H6
C6H6
C6H6
C6H6
THF
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
8
T
10
14
17
f
10 NaH2PO4
11 PhCO2H
12 PhCO2H
16 19 14
10
9
5
5
12
10
dioxane MgSO4
6
a
b
4 could be converted into 3 under conditions of reaction 1.
2
days. c Recover 50% of 2. Add 2 slowly or fast. e T ) trace.
d
fFumaric acid. M.S. ) molecular sieves.
g
Ta ble 2
bration with aqueous HCl reversed the equilibrium to
>9:1 of 1i/1h (Scheme 3). The epimerization in these
examples may be due to repulsion of a positive protonated
Nb-amonium group and the positive ester or bulky aryl
substituent, in accord with a ring E boatlike conforma-
tion, which had been established by molecular modeling
calculations and by an X-ray structure determination for
product 1g.2 Solvation of the amonium group would
magnify this effect, as seen in the dramatic increase of
1i/1h in aqueous acid.
Having demonstrated the generality of diastereoselec-
tive formation of the tetracyclic products 1, it became of
interest to explore their enantioselective formation.
Initially, we examined the effect of some chiral Nb-
substituents in the tryptamine esters 7-9 on the reac-
tion. However, the diastereomeric ratio (Nb-substituent
vs chiral centers of the tetracyclic products 10-13) was
quite low (Scheme 4, Table 3), prompting us to examine
reactions of a tryptophan derived diester 14 with R,â-
unsaturated aldehydes.
The key Nb-benzyl diester 14 was readily prepared
from L-tryptophan benzyl ester (Scheme 5). Reductive
benzylation of the tryptophan benzyl ester with benzal-
dehyde and Nb-acylation of the secondary amine 15 with
BOC-anhydride (16) allowed installation of an indolic
2-malonyl substituent (17) by chlorination and reaction
of the resulting chloroindoline imine with lithium di-
methyl malonate and zinc chloride.8 A final decar-
products was >97-98%. It was somewhat diminished
with ester and alkoxyaryl substituents (Table 2, entries
3 and 7) due to partial epimerization of the products.
Thus, the major 2-methoxyphenyl-substituted product
1h , or the minor epimer 1i, could be equilibrated to a
7:1 mixture of N and methoxyaryl cis (1h ) and trans (1i)
compounds with benzoic acid in benzene, but an equili-
(8) This methodology was developed by J . Champoux and S. Cowen
in our laboratories. It avoids the use of the potentially toxic thallium
malonate. A full report of its scope will be published later.
(9) Modified methodology of Krapcho et al.: Krapcho, A. P.; Wei-
master, J . F.; Eldridge, J . M.; J ahngen, E. G. E. J r.; Lovey, A. J .;
Stephens, W. P. J . Org. Chem. 1978, 43, 138.

7952 J . Org. Chem., Vol. 62, No. 23, 1997
Kuehne and Xu
Sch em e 4
Sch em e 6
Ta ble 3
Ta ble 4. NMR Cor r ela tion s
Sch em e 5
1H no.
δ
H-H COSY
NOESY
1R
1.98
2.42
3.74
3.57
1.29
1.75
3.05
1.47
7.37-7.25
7.11
6.77
6.67
1â, 2
1R, 2
1R, 1â
4R
1â
5-Me
3a, 11, NCH2Ph
2, 11, 4R, 4â, NCH2Ph
5
5-Me, NCH2Ph, 3a, 5
4R, 4â
4â, 1â
2
3a
4R
4â, 3a
4R
4â
5
5-Me
5
9
10, 8
11, 9
10
5-Me
8
9
10
11
3a, 2
CO2Me
NH
PhCH2O
PhCH2N
3.75
8.98
4.90, 4.87
3.98
bomethoxylation (18)9 and urethane cleavage provided
the diester 14 in 75% overall yield. No racemization
could be detected by NMR using a chiral Eu shift reagent
and comparison with the independently prepared racemic
compound (()-14.
PhCH2O
4â, 3a, 2
borohydride. Thus, the tetracyclic compound (-)-1a ,
[R]22 ) -387, was obtained with complete enantiose-
D
On condensation of the tryptophan-derived diester 14
with crotonaldehyde, a single diastereomer of the tetra-
cyclic product (-)-19a was generated (Scheme 6). Analo-
gously, a condensation with 4,4-dimethoxycrotonaldehyde
led selectively to the synthetically valuable tetracyclic
acetal (-)-19b. The stereochemistry of these products
was established by 2D-NOESY spectra (Tables 4, 5),
which showed pertinent NOE’s for H-3a/H-11, H-3a/H-
2, H-2/H-11, and H-1b/C-5 CH3 but no NOE for H-3a/
C-5 CH3 in product (-)-19a and H-3a/H-11, H-3a/H-2,
H-2/H-11, but no NOE for the acetal hydrogen/H-2 or
H-3a in product (-)-19b. The o-methoxyphenyl congener
(-)-19c was obtained in relatively highest yield (74%) as
the only isolated product.
lection, as demonstrated, again by comparison with the
racemic compound, in an NMR-chiral europium shift
reagent study. Exclusive formation of the tetracyclic
ABCE enantiomer (-)-1a from L-tryptophan may be
contrasted with the formation of an analogous tetracyclic
ABCE Strychnos alkaloid precursor from L-tryptophan,
using the seco-secamine type intramolecular Diels-Alder
cyclization methodology, where primarily the enantio-
merically opposite (unnatural) stereochemistry was ob-
tained (70% ee).10,11 On the other hand, enantioselective
syntheses of tetracyclic ABCE intermediates, using chiral
Nb-substituents and seco-secodine cyclizations, have pro-
vided the desired enantiomeric series of products with
The utility of this process depends, of course, on a facile
removal of the tryptophan-derived benzyl ester substitu-
ent. This was readily achieved by conversion to an
amide, (-)-20, its dehydration to a nitrile, (-)-21, and
final reduction of the R-aminonitrile with potassium
(10) Henin, J .; Massiot, G.; Vercauteren, J . Tetrahedron Lett. 1987,
28, 1271.
(11) An inventive photochemical cyclization, also starting from L-
tryptophan as precursor, provided another noteworthy approach to
such tetracyclic ABCE alkaloid intermediates. Winkler, J . D.; Scott,
R. D.; Williard, P. G. J . Am. Chem. Soc. 1990, 112, 8971.

Syntheses of Strychnan- and Aspidospermatan-Type Alkaloids
J . Org. Chem., Vol. 62, No. 23, 1997 7953
Ta ble 5. NMR Cor r ela tion s
For the final cyclization step, which requires protona-
tion of the nine-membered ring enamine 32, a conforma-
tion of the indolic iminium intermediate 35, analogous
to that for the preceding sigmatropic rearrangement step,
is clearly advantageous over the enantiofacial alternative
36, where one encounters not only the congestion of ester,
benzyl, and aryl substituents but also now the new
enantiomerically fixed vicinal methyl ester and R [CH-
(OCH3)2] substituents would have to be axial on the
incipient six-membered ring.
δ
1H no.
CDCl3
1.99
C6D6
1.83
2.37
3.79
3.38
1.03
2.26
H-H COSY
NOESY
12, OMea
3a, 11, NCH2Ph
4â, 11, NCH2Ph
Under typical reaction conditions for the preparation
of the tetracyclic products 1 (benzene, benzoic acid,
MgSO4, 70 °C), the initially generated three spiroindo-
lenines that do not undergo a [3,3]-sigmatropic rear-
rangement (28-30) were not separated, but they could
be identified by NMR. With prolonged heating (48 h)
they reverted to starting materials and thus led to
eventual generation of the tetracyclic product (-)-19
through formation of the one uniquely reactive spiroin-
dolenine diastereomer 31.
1R
1â
2
3a
4R
4â
1â, 2
1R, 2
1R, 1â
4R
4â, 3a, 5
4R
2.22
3.77
3.52
1.20
2.22
3a, 5, 12, OMeb,
NCH2Ph
5
8
9
10
11
12
3.28
6.75
7.09
6.70
6.38
5.23
3.70
6.18
6.87
6.45
6.62
5.57
4R, 12
9
8, 10
9, 11
10
4â, OMea
2, 3a
5
4â, 1â, OMea,
OMeb
The application of this new synthetic methodology to
the enantioselective generation of (-)-ent-lochneridine,
(-)-20-epi-lochneridine, and the Wieland-Gumlich al-
dehyde (and thus strychnine) will be presented in sub-
sequent papers.
CO2Me
NH
3.76
9.13
3.29
3.53
3.61
9.41
3.37
3.59
OMea
OMeb
1â, 12, OMeb
4â. 12, OMea,
NCH2Ph
PhCH2O 4.99
PhCH2N 3.96, 4.03 3.93, 3.83
4.80, 4.77
PhCH2O
PhCH2N
4â, 3a, 2, OMeb
Exp er im en ta l Section
excellent to good selectivity (in contrast to the results
shown in Table 3).12-15
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Tetr a -
cyclic Com p ou n d s 1a -k . A mixture of Nb-benzyl-2-[(meth-
oxycarbonyl)methyl]tryptamine (2, 1 mmol),2 a catalytic amount
of acid from Table 1, but preferably benzoic acid (0.1 mmol),
an unsaturated aldehyde from Table 2 (1.2-1.4 mmol), and
600 mg of freshly activated MgSO4 in 8 mL of anhydrous
solvent, under an atmosphere of Ar, was heated at 70-75 °C
for 6-10 h. Filtration and concentration gave the crude
product, which was dissolved in dichloromethane and washed
with 2% Na2CO3. Chromatography on a silica gel column
afforded the desired product. Products 1b,e,g,j matched
authentic samples in TLC, NMR, and IR spectra that are given
in refs 2, 5, and 6. Respective yields are listed in Table 2.
An explanation of the remarkable diastereoselectivity
found on formation of the racemic tetracycles 1 and the
additional stereoselectivity introduced with the tryp-
tophan-derived ester functionality leading to (-)-19 can
be derived from the proposed tandem condensation and
[3,3]-sigmatropic rearrangement sequence, followed by
a final indole-iminium cyclization step (Scheme 7). In
support of this three-step pathway, one finds that the
sequence is stopped after the first step if the diester 14
is condensed with an aryl aldehyde (rather than an
olefinic aldehyde) and that four diastereomeric spiroin-
dolenines 22-25 are then formed (Scheme 8). These
diastereomers were readily recognized in an NMR spec-
trum of the total reaction product by comparison with
the two diastereomeric products 26 and 27, formed in a
2:1 ratio, from condensation of the tryptamine derived
monoester 2 with benzaldehyde (Scheme 8).
On the other hand, with 4,4-dimethoxycrotonaldehyde
only three analogous spiroindolenines 28-30 could be
isolated, in a ratio of 11:17:10 (69% yield), accompanied
by the tetracyclic product (-)-19b (22%). A fourth
stereoisomer 31 (Scheme 7), with optimum geometry for
a [3,3]-sigmatropic rearrangement, eludes capture and
proceeds to formation of an indolic nine-membered ring
enamine 32 (Scheme 7). In two of the alternative
spiroindolenines (29, 30) the olefinic functions are trans
substituents on a five-memberd ring and thus unsuitable
for the sigmatropic rearrangement. In the third spiroin-
dolenine 28 (enantiomeric with 31 at all but the prede-
termined R-amino ester carbon), steric congestion of the
benzyl, saturated ester and indolic moieties (33) hinders
formation of the conformation required for the sigma-
tropic rearrangement. Formation of epimeric substitu-
tion (Nb, R trans) of the tetracyclic product (-)-19 would
require a boat rather than the chair conformation 34 for
this rearrangement.
(()-Meth yl (3aS*,5S*,11bR*)-3-Ben zyl-2,3,3a ,4,5,7-h exa -
h yd r o-5-m et h yl-1H -p yr r olo[2,3-d ]ca r b a zole-6-ca r b oxy-
la te (1a ). Using the general procedure with crotonaldehyde,
and with benzoic acid as catalyst, this product was obtained
in 54% yield after eluting the crude reaction mixture from a
silica gel column with CH2Cl2/hexane/Et2O (3:6:1): TLC Rf )
0.22 (hexane/EtOAc 92:8; CAS blue); mp 209 °C (HCl salt);
UV (EtOH) λmax 324, 300, 228, 204 nm; IR (KBr) νmax 3369,
3057, 3029, 2949, 2920, 2868, 2788, 1674, 1610, 1465, 1435,
1292, 1277, 1236, 1215, 1190, 1149, 1230, 1103, 1049, 791, 742,
1
769 cm-1; H NMR (500 MHz, CDCl3) δ 9.48 (s, 1 H), 7.41 (d,
J ) 7.4 Hz, 2 H), 7.34 (t, J ) 7.4 Hz, 2 H), 7.26 (t, J ) 7.4 Hz,
1 H), 7.16 (d, J ) 7.3 Hz, 1 H), 7.15 (t, J ) 7.7 Hz, 1 H), 6.86
(t, J ) 7.4 Hz, 1 H), 6.82 (d, J ) 7.6 Hz, 1 H), 4.20 (d, J ) 13.3
Hz, 1 H), 3.78 (s, 3 H), 3.54 (d, J ) 13.3 Hz, 1 H), 3.33 (d, J )
5.2 Hz, 1 H), 3.11 (m, 1 H), 2.92 (dd, J ) 6.4, 9.2 Hz, 1 H),
2.56 (ddd, J ) 5.0, 9.2, 12.2 Hz, 1 H), 2.20 (ddd, J ) 6.4, 12.2,
12.2 Hz, 1 H), 1.89 (d, J ) 14.0 Hz, 1 H), 1.72 (dd, J ) 5.0,
12.2 Hz, 1 H), 1.47 (d, J ) 7.3 Hz, 3 H), 1.41 (ddd, J ) 5.2,
5.2, 14.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 168.99,
166.28, 143.03, 139.79, 138.32, 127.69, 126.88, 121.57, 120.15,
109.18, 99.97, 66.89, 58.66, 55.41, 50.93, 50.89, 45.95, 33.34,
29.13, 21.77; MS m/z (relative intensity) 375 (4), 374 (M+, 11),
283 (2), 241 (31), 226 (7), 209 (3), 180 (7), 167 (11), 154 (5),
146 (60), 134 (7), 117 (5), 107 (4), 91 (100). Anal. Calcd for
C
24H26N2O2‚HCl‚0.83H2O: C, 67.66; H, 6.86; N, 6.58; Cl, 8.32.
Found: C, 67.73; H, 6.70; N, 6.35, Cl, 8.13.
(()-2-[(Me t h oxyca r b on yl)m e t h yl]-3-[2-[N -b e n zyl-N -
(3S*,4S*,5R*)-3-(4-for m yl-5-m eth ylcycloh exen yl)a m in o]-

7954 J . Org. Chem., Vol. 62, No. 23, 1997
Kuehne and Xu
Sch em e 7
) 13.8 Hz, 1 H), 3.80 (d, J ) 10.8 Hz, 1 H), 3.71 (s, 3 H), 3.67
(s, 2 H), 3.60 (d, J ) 13.8 Hz, 1 H), 2.81 (m, 1 H), 2.72 (m, 1
H), 2.66 (m, 2 H), 2.24 (ddd, J ) 5.2, 10.8, 10.8 Hz, 1 H), 2.14
(app d, J ) 17.3 Hz, 1 H), 1.96 (m, 1 H), 1.71 (m, 1 H), 0.90 (d,
J ) 6.5 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 205.39, 171.05,
140.02, 135.68, 129.26, 128.91, 128.28, 128.00, 127.04, 126.69,
125.39, 121.75, 119.29, 118.46, 111.63, 110.73, 58.08, 57.93,
55.77, 52.26, 51.27, 33.94, 31.51, 29.47, 24.59, 19.62; MS m/z
(relative intensity) 445 (2), 444 (M+, 3), 242 (71), 202 (5), 172
(6), 156 (4), 142 (14), 123 (12), 120 (69), 91 (100); HRMS calcd
for C28H32N2O3 444.2413, found 444.2412.
Sch em e 8
In d oloa zon in e 5. This product was obtained in 23% yield
using the general procedure and BF3 etherate as catalyst,
followed by chromatography on a silica gel column, eluting
with CH2Cl2/hexane/Et2O (3:6:1): TLC Rf ) 0.27 (hexane/
EtOAc, 4:1; CAS violet); UV (EtOH) λmax 290, 226, 204 nm; IR
(KBr) νmax 3387, 3060, 3025, 2948, 2922, 2840, 1714, 1604,
1493, 1460, 1436, 1435, 1239, 1153, 1141, 1047, 1028, 909, 738
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.93 (s, 1 H), 7.54 (d, J )
9.1 Hz, 1 H), 7.52 (d, J ) 8.1 Hz, 1 H), 7.35 (t, J ) 8.1 Hz, 1
H), 7.31 (m, 4 H), 7.21 (m, 1 H), 7.19 (dt, J ) 1.0, 8.1 Hz, 1 H),
7.11 (dt, J ) 0.8, 7.9 Hz, 1 H), 5.76 (m, 1 H), 5.71 (m, 1 H),
3.95 (d, J ) 15.2 Hz, 1H), 3.88 (d, J ) 15.2 Hz, 1 H), 3.79 (s,
3 H), 3.64 (m, 1 H), 3.17 (m, 1 H), 2.80 (m, 2 H), 2.72 (m, 1 H),
2.40 (ddd, J ) 6.9, 6.9, 9.1 Hz, 1 H), 2.34 (app d, J ) 18.7 Hz,
1 H), 1.80 (m, 1 H), 1.62 (app d, J ) 18.7 Hz, 1 H), 0.92 (d, J
) 6.8 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 166.85, 154.32,
141.21, 135.92, 128.92, 128.28, 128.16, 128.06, 127.46, 126.88,
126.48, 122.00, 119.18, 118.52, 115.78, 110.78, 59.78, 54.20,
52.17, 51.69, 47.90, 30.00, 23.33, 20.14; MS m/z (relative
intensity) 426 (M+, 2), 335 (2), 332 (3), 274 (7), 267 (3), 241
(4), 225 (4), 217 (2), 204 (2), 194 (7), 180 (6), 172 (56), 167 (6),
154 (6), 146 (10), 135 (3), 129 (3), 117 (4), 105 (6), 91 (100);
HRMS calcd for C28H30N2O2 426.2307, found 426.2300.
(()-Meth yl 2-[3-[2-[N-Ben zyl-N-(3S*,4S*,5R*)-3-(4-for m yl-
5-m eth ylcycloh exen yl)a m in o]eth yl]in d ol-2-yl]-2,4-h exa -
d ien oa te (6). This product was obtained in 8% yield using
the general procedure and benzoic acid as catalyst: TLC Rf )
0.13 (hexane/EtOAc, 4:1; CAS green); UV (EtOH) λmax 320, 268,
224, 204 nm; IR (KBr) νmax 3387, 3058, 3027, 2955, 2924, 2850,
2709, 1717, 1639, 1454, 1437, 1336, 1282, 1239, 1174, 1130,
1048, 1025, 980, 741 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.41
(d, J ) 5.0 Hz, 1 H), 8.00 (s, 1 H), 7.50 (d, J ) 11.3 Hz, 1 H),
eth yl]in d ole (4). Obtained in 32% yield with trifluoroacetic
acid as catalyst: TLC Rf ) 0.11 (hexane/EtOAc, 4:1; CAS
green); UV (EtOH) λmax 288, 224, 204 nm; IR (KBr) νmax 3403,
3059, 3027, 2952, 2923, 2873, 2852, 2830, 2707, 1725, 1459,
1436, 1440, 1435, 1342, 1310, 1265, 1233, 1165, 1123, 1027,
1014, 741 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.41 (d, J ) 5.2
Hz, 1 H), 8.44 (s, 1 H), 7.32 (m, 5 H), 7.26 (m, 2 H), 7.12 (t, J
) 7.3 Hz, 1 H), 7.04 (t, J ) 7.3, 1 H), 5.83 (m, 2 H), 3.87 (d, J

Syntheses of Strychnan- and Aspidospermatan-Type Alkaloids
J . Org. Chem., Vol. 62, No. 23, 1997 7955
7.37 (d, J ) 8.0 Hz, 1 H), 7.28 (m, 6 H), 7.25 (t, J ) 7.5 Hz, 1
H), 7.16 (t, J ) 7.3 Hz, 1 H), 6.26 (qd, J ) 6.8, 13.6 Hz, 1 H),
6.05 (dd, J ) 11.3, 13.6 Hz, 1 H), 5.77 (s, 2 H), 3.79 (d, J )
13.9, 1 H), 3.74 (m, 1 H), 3.73 (s, 3 H), 3.52 (d, J ) 13.9 Hz, 1
H), 2.75 (m, 2 H), 2.60 (m, 2 H), 2.20 (ddd, J ) 5.0, 10.9, 10.9
Hz, 1 H), 2.12 (m, 1 H), 1.94 (m, 1 H), 1.78 (d, J ) 6.8 Hz, 3
H), 1.69 (m, 1 H), 0.99 (d, J ) 6.5 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 205.26, 167.58, 144.44, 141.53, 140.09, 136.05,
129.04, 128.80, 128.61, 128.20, 128.13, 127.92, 126.90, 125.54,
122.18, 120.89, 119.26, 119.10, 114.08, 110.83, 57.93, 57.69,
55.33, 52.11, 50.76, 33.92, 29.42, 25.15, 19.61, 18.92; MS m/z
(relative intensity) 497 (1), 496 (M+, 2), 374 (1), 274 (2), 268
(2), 255 (7), 242 (94), 222 (2), 208 (3), 194 (11), 181 (2), 179
(8), 167 (5), 154 (2), 146 (3), 142 (2), 123 (12), 120 (58), 105
(6), 91 (100); HRMS calcd for C32H36N2O3 496.2726, found
496.2701.
6.00 (dd, J ) 4.8, 14.8 Hz, 1 H), 5.45 (qd, J ) 6.3, 14.8 Hz, 1
H), 4.19 (d, J ) 13.4 Hz, 1 H), 3.76 (s, 3 H), 3.67 (s, br, 1 H),
3.53 (d, J ) 13.4 Hz, 1 H), 3.32 (d, J ) 5.5 Hz, 1 H), 2.89 (dd,
J ) 6.4, 8.8 Hz, 1 H), 2.55 (ddd, J ) 4.8, 8.8, 11.9 Hz, 1 H),
2.26 (ddd, J ) 6.4, 11.9, 11.9 Hz, 1 H), 2.03 (d, J ) 13.8 Hz, 1
H), 1.73 (d, J ) 6.3 Hz, 3 H), 1.62 (dd, J ) 4.8, 11.9 Hz, 1 H),
1.42 (ddd, J ) 5.5, 5.5, 12.8 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 168.88, 166.23, 142.88, 139.88, 138.19, 136.34, 128.38,
128.14, 127.63, 126.73, 122.57, 121.55, 120.22, 109.14, 97.48,
66.22, 58.16, 55.56, 50.91, 50.77, 44.38, 36.80, 33.80, 17.73;
MS m/z (relative intensity) 401 (5), 400 (M+, 14), 332 (2), 309
(2), 267 (15), 254 (3), 222 (4), 208 (7), 199 (4), 194 (10), 180
(5), 175 (7), 167 (6), 154 (3), 146 (71), 134 (3), 117 (5), 91 (100).
Anal. Calcd for C26H28N2O2‚0.5CH2Cl2: C, 71.85; H, 6.60; N,
6.32. Found: C, 72.06; H, 6.54; N, 6.37.
(()-Met h yl (3a S*,5-(S* a n d R*),11b R*)-3-Ben zyl-
2,3,3a ,4,5,7-h exa h yd r o-5-(2-m eth oxyp h en yl)-1H-p yr r olo-
[2,3-d ]ca r ba zole-6-ca r boxyla te (1h a n d 1i). The Nb/aryl
cis product 1h was obtained in 58% yield, using the general
procedure with o-methoxycinamaldehyde and benzoic acid as
catalyst, together with 7.5% of its C-5 (R*)-epimer 1i.
(()-Met h yl (3a S*,5R* a n d 5S*,11b R*)-3-Ben zyl-
2,3,3a ,4,5,7-h exa h yd r o-5-(et h oxyca r b on yl)-1H -p yr r olo-
[2,3-d ]ca r ba zole-6-ca r boxyla te (1c a n d 1d ). Using the
general procedure, 3-formyl ethyl acrylate, and benzoic acid
as catalyst, a 74% yield of the Nb-ethoxycarbonyl cis product
1c was obtained, together with 9% of its C-5 epimer 1d . For
1c: TLC Rf ) 0.28 (hexane/EtOAc/CH2Cl2, 6:1:3, CAS blue
fades to gray); UV (EtOH) λmax 322, 296, 226, 204 nm; IR (KBr)
νmax 3374, 3060, 3028, 2980, 2950, 2927, 2788, 1724, 1682,
1609, 1477, 1463, 1438, 1379, 1341, 1279, 1256, 1231, 1210,
For 1h : TLC Rf ) 0.28 (hexane/CH2Cl2/Et2O, 7:2:1, CAS
blue); mp 212-3 °C (HCl salt); UV (EtOH) λmax 326, 298, 230,
206 nm; IR (KBr) νmax 3364, 3058, 3026, 2950, 2916, 2837,
2789, 1672, 1608, 1487, 1476, 1464, 1435, 1276, 1293, 1215,
1
1188, 1125, 1028, 750, 733 cm-1; H NMR (500 MHz, CDCl3)
1185, 1151, 1123, 1041, 747, 735 cm-1
;
1H NMR (500 MHz,
δ 9.42 (s, 1 H), 7.30 (d, J ) 7.3 Hz, 1 H), 7.23 (m, 2 H), 7.15
(m, 4 H), 6.89 (m, 4 H), 6.82 (m, 2 H), 4.47 (dd, J ) 3.7, 6.2
Hz, 1 H), 3.97 (d, J ) 13.5 Hz, 1 H), 3.82 (s, 3 H), 3.62 (s, 3 H),
3.37 (d, J ) 13.5 Hz, 1 H), 3.30 (dd, J ) 3.7, 4.7 Hz, 1 H), 2.66
(ddd, J ) 3.7, 3.7, 14.3 Hz, 1 H), 2.49 (m, 1 H), 2.39 (m, 2 H),
1.76 (ddd. J ) 4.7, 6.2, 14.3 Hz, 1 H), 1.61 (m, 1 H); 13C NMR
(125 MHz, CDCl3) δ 169.09, 167.25, 157.63, 143.24, 139.90,
138.34, 134.27, 128.73, 128.01, 127.91, 127.64, 126.43, 126.32,
121.88, 120.48, 120.04, 110.42, 109.18, 96.46, 65.90, 57.20,
55.20, 55.12, 50.99, 50.19, 42.36, 34.99, 29.94; MS m/z (relative
intensity): 467 (2), 466 (M+, 6), 345 (2), 333 (15), 320 (3), 300
(8), 288 (5), 274 (8), 265 (6), 260 (6), 241 (3), 230 (3), 225 (6),
217 (3), 180 (3), 167 (3), 154 (3), 146 (44), 135 (9), 130 (2), 212
(3), 117 (4), 107 (4), 91 (100). Anal. Calcd for C30H30N2O3‚
HCl‚0.5H2O: C, 70.37; H, 6.30; N, 5.47; Cl, 6.93. Found: C,
70.29; H, 6.24; N, 5.41, Cl, 7.22.
CDCl3) δ 9.11 (s, 1 H), 7.34 (m, 4 H), 7.26 (m, 1 H), 7.14 (t, J
) 7.7 Hz, 1 H), 7.04 (d, J ) 7.3 Hz, 1 H), 6.86 (t, J ) 7.5 Hz,
1 H), 6.83 (d, J ) 8.0 Hz, 1 H), 4.23 (m, 1 H), 4.14 (d, J ) 13.1
Hz, 1 H), 4.08 (m, 1 H), 3.84 (dd, J ) 2.4, 6.9, 1 H), 3.76 (s, 3
H), 3.51 (d, J ) 13.1 Hz, 1 H), 3.27 (d, J ) 4.2 Hz, 1 H), 2.77
(dd, J ) 5.6, 8.0 Hz, 1 H), 2.63 (d, J ) 13.9 Hz, 1 H), 2.46 (m,
2 H), 1.58 (dd, J ) 4.1, 10.1 Hz, 1 H), 1.51 (ddd, J ) 5.6, 5.6,
13.9 Hz, 1 H), 1.21 (t, J ) 7.1 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 174.59, 168.28, 167.25, 142.83, 138.48, 137.68, 129.17,
128.10, 127.80, 127.02, 121.42, 120.63, 109.39, 93.17, 65.02,
60.49, 58.04, 55.92, 51.08, 50.60, 43.81, 38.86, 30.79, 14.13;
MS m/z (relative intensity) 433 (7), 432 (M+, 7), 373 (2), 359
(2), 341 (2), 327 (2), 300 (15), 267 (2), 226 (4), 207 (3), 194 (6),
180 (8), 167 (10), 146 (52), 91 (100). Anal. Calcd for
C26H28N2O4: C, 72.20; H, 6.52; N, 6.48. Found: C, 71.92; H,
6.28; N, 6.48.
For 1i: TLC Rf ) 0.17 (hexane/CH2Cl2/Et2O, 7:2:1; CAS
blue); mp 215-216 °C (HCl salt); UV (EtOH) λmax 326, 296,
226, 204 nm; IR (KBr) νmax 3374, 3057, 3024, 2939, 2839, 1676,
1607, 1493, 1476, 1464, 1437, 1288, 1278, 1232, 1200, 1119,
For the C-5 (S*)-epimer 1d : TLC Rf ) 0.17 (hexane/EtOAc/
CH2Cl2, 6:1:3, CAS blue fades to gray); UV (EtOH) λmax 324,
294, 224, 206 nm; IR (KBr) νmax 3375, 3058, 3030, 2979, 2949,
2924, 2850, 2793, 1734, 1683, 1609, 1468, 1437, 1279, 1251,
1
1027, 751, 700 cm-1; H NMR (500 MHz, CDCl3) δ 9.07 (s, 1
1
1235, 1195, 1154, 1120, 1042, 746 cm-1; H NMR (500 MHz,
H), 7.40 (d, J ) 7.4 Hz, 2 H), 7.31 (t, J ) 7.4 Hz, 2 H), 7.27 (d,
J ) 7.3 Hz, 1 H), 7.23 (m, 1 H), 7.16 (dt, J ) 1.1, 7.6 Hz, 1 H),
7.12 (dt, J ) 1.6, 7.6 Hz, 1 H), 6.96 (d, J ) 7.2 Hz, 1 H), 6.85
(m, 4 H), 4.46 (s, br, 1 H), 3.95 (d, J ) 13.4 Hz, 1 H), 3.85 (s,
3 H), 3.71 (d, J ) 13.4 Hz, 1 H), 3.37 (s, 3 H), 3.30 (dd, J )
4.4, 4.4 Hz, 1 H), 2.83 (dd, J ) 8.1, 8.1 Hz, 1 H), 2.72 (ddd, J
) 5.4, 8.1, 11.7 Hz, 1 H), 2.26 (ddd, J ) 8.1, 11.7, 11.7 Hz, 1
H), 2.02 (ddd, J ) 4.4, 4.4, 13.5 Hz, 1 H), 1.80 (dd, J ) 5.4,
11.7 Hz, 1 H), 1.71 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ
169.00, 166.12, 156.73, 143.68, 139.76, 137.62, 135.07, 128.59,
128.17, 127.94, 127.68, 126.82, 126.42, 122.18, 120.40, 120.35,
110.51, 109.18, 98.02, 62.55, 56.95, 55.56, 55.47, 50.28, 49.41,
44.12, 35.11; MS m/z (relative intensity) 467 (3), 466 (M+, 9),
345 (2), 333 (13), 320 (2), 300 (12), 288 (5), 274 (7), 265 (5),
260 (6), 240 (3), 230 (3), 225 (5), 217 (3), 209 (2), 180 (3), 167
(2), 154 (3), 146 (38), 135 (10), 130 (2), 121 (3), 117 (4), 107
(7), 91 (100). Anal. Calcd for C30H30N2O3‚HCl‚0.5H2O: C,
70.37; H, 6.30; N, 5.47; Cl, 6.93. Found: C, 70.48; H, 6.03; N,
5.40; Cl, 7.19.
CDCl3) δ 8.99 (s, 1 H), 7.39 (d, J ) 7.2 Hz, 2 H), 7.34 (t, J )
7.3 Hz, 2 H), 7.27 (t, J ) 7.2 Hz, 1 H), 7.16 (t, J ) 7.5 Hz, 1
H), 7.05 (d, J ) 7.3 Hz, 1 H), 6.87 (t, J ) 7.5 Hz, 1 H), 6.83 (d,
J ) 7.7 Hz, 1 H), 4.19 (m, 1 H), 4.15 (m, 1 H), 4.08 (d, J ) 13.4
Hz, 1 H), 3.73 (d, J ) 13.4 Hz, 1 H), 3.72 (s, 3 H), 3.59 (dd, J
) 3.1, 10.7, 1 H), 3.33 (d, J ) 3.1, 1 H), 2.86 (dd, J ) 6.8, 7.8
Hz, 1 H), 2.64 (ddd, J ) 4.9, 7.8, 11.8 Hz, 1 H), 2.04 (ddd, J )
2.2, 2.2, 13.4, 1 H), 1.99 (ddd, J ) 6.8, 11.8, 11.8 Hz, 1 H),
1.72 (dd, J ) 4.9, 11.8 Hz, 1 H), 1.57 (ddd, J ) 4.1, 10.8, 13.4
Hz, 1 H), 1.27 (t, J ) 7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 174.98, 167.55, 166.48, 142.90, 138.72, 136.92, 128.75,
128.24, 127.88, 127.02, 121.80, 120.71, 109.35, 94.02, 67.71,
60.40, 57.59, 55.86, 50.78, 49.84, 44.17, 37.92, 33.93, 14.17;
MS m/z (relative intensity) 433 (4), 432 (M+, 9), 299 (13), 226
(9), 194 (10), 180 (11), 166 (13), 154 (6), 146 (57), 134 (10), 117
(4), 107 (4), 91 (100).
(()-Met h yl (3a S*,5R*,11b R*)-3-Ben zyl-2,3,3a ,4,5,7-
h exa h yd r o-5-a llyl-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxy-
la te (1f). Using the general condensation procedure with 2,4-
hexadienal and with benzoic acid as catalyst, a 54% yield of
the tetracyclic product 1f was obtained: TLC Rf ) 0.38
(hexane/EtOAc, 9:1; CAS blue fade to violet); mp 140 °C (dec,
HCl salt); UV (EtOH) λmax 324, 298, 226, 208 nm; IR (KBr)
Equ ilibr a tion of C-5 Ar yl P r od u cts 1h a n d 1i w ith
Ben zoic Acid or HCl. a . A solution of 20 mg of the minor
epimer 1i and 2 mg of PhCOOH in 2 mL of dry benzene was
heated at reflux for 6 h. The solution was diluted with ethyl
acetate and washed with 5% Na2CO3 solution. The residue,
1
obtained upon drying and concentration, was subjected to H
ν
max 370, 3062, 3025, 2945, 2918, 2855, 2787, 1675, 1609, 1479,
NMR analysis, showing a 7:1 ratio of 1h /1i. Purification on a
silica gel column gave 15 mg of the epimer 1h (75% yield).
b. A solution of 20 mg of the 5S* epimer 1h and three drops
of 2 N HCl in 2 mL of THF-H2O (4:1) was kept at rt for 5 h.
1466, 1436, 1474, 1277, 1234, 1213, 1188, 1147, 1118, 1053,
744 cm-1; H NMR (500 MHz, CDCl3) δ 9.16 (s, 1 H), 7.42 (d,
1
J ) 7.5 Hz, 2 H), 7.33 (t, J ) 7.4 Hz, 2 H), 7.25 (m, 1 H), 7.16
(m, 2 H), 6.87 (t, J ) 7.5 Hz, 1 H), 6.82 (d, J ) 8.1 Hz, 1 H),

7956 J . Org. Chem., Vol. 62, No. 23, 1997
Kuehne and Xu
The solution was then basified with 10% Na2CO3 solution and
extracted with ethyl acetate. Using the above workup proce-
dure and NMR analysis of the product (1h /1i ) 1:9), 17 mg of
the C-5 (R*)-epimer 1i was obtained (85% yield).
122.38, 119.34, 118.67, 112.23, 110.92, 67.66, 65.16, 53.60,
52.95, 52.92, 43.42, 24.41, 16.59; MS m/z (relative intensity)
529 (M+ + 1, 4), 393 (8), 274 (7), 261 (44), 258 (5), 228 (15),
200 (7), 172 (4), 169 (22), 154 (3), 140 (3), 120 (22), 105 (49),
91 (100). Anal. Calcd for C31H32N2O6‚0.5H2O: C, 69.25; H,
6.18; N, 5.21. Found: C, 68.92; H, 5.84; N, 4.98.
N b -(Be n zyloxyca r b on yl)-N b -((R )-1-p h e n e t h yl)t r yp -
ta m in e. To a solution of Nb-((R)-R-phenethyl)tryptamine,
prepared by alkylation12,17 of the corresponding amine with
tryptophyl bromide, (4.0 g, 15 mmol) and Na2CO3 (2.4 g, 22.5
mmol) in 60 mL of THF and 20 mL of H2O at 0 °C, was added
CbzCl (2.9 mL, 19.5 mmol) dropwise. The solution was stirred
at 0 °C for an additional 30 min and then at room temperature
for 30 min. Water was added to the reaction mixture, and
the aqueous phase was extracted with EtOAc. The residue,
obtained upon drying and concentration, was purified on a
silica gel column, eluting with Et2O/hexane (1:1) to afford 5.8
g of the desired product (97% yield): TLC Rf ) 0.22 (hexane/
For the mono ester: TLC Rf ) 0.37 (hexane/EtOAc 7:3; CAS
green); [R]27 ) 45 (c ) 0.5, MeOH); IR (KBr) νmax 3392, 3335,
D
3060, 3033, 2981, 2953, 1737, 1692, 1496, 1462, 1451, 1416,
1368, 1332, 1298, 1278, 1245, 1202, 1168, 1121, 1025, 743, 700
cm-1 1H NMR (500 MHz, CDCl3) δ 8.36 (s, br, 1 H), 7.49-
;
7.14 (m, 11 H), 7.08 (s, br, 1 H), 6.95 (s, br, 1 H), 6.87 (s, br, 1
H), 5.68 (s, br, 0.7 H), 5.34 (s, br, 0.3 H), 5.29 (s, 2 H), 3.69 (s,
3 H), 3.34 (s, br, 1 H), 3.17 (s, br, 1 H), 3.05 (s, br, 1 H), 2.80
(s, br, 1 H), 2.39 (s, br, 1 H), 1.58 and 1.56 (s, 3 H); 13C NMR
(125 MHz, CDCl3) δ 141.12, 135.53, 128.61, 128.48, 127.52,
121.78, 119.33, 118.39, 110.59, 53.78, 52.21, 31.13; MS m/z
(relative intensity) 471 (M+ + 1, 6), 366 (2), 335 (2), 279 (1),
216 (12), 202 (33), 195 (2), 183 (1), 170 (4), 156 (4), 142 (30),
134 (3), 120 (24), 115 (6), 105 (51), 91 (100).
Et2O 3:2; CAS brown); [R]30 ) 60 (c ) 0.3, MeOH); IR (KBr)
D
νmax 3423, 3331, 3062, 3036, 2977, 2931, 2855, 1686, 1457,
1418, 1341, 1295, 1202, 1173, 1093, 1028, 987, 911, 769, 742,
699 cm-1;1H NMR (500 MHz, CDCl3) δ 7.82 (s, 1 H), 7.45-
7.16 (m, 12 H), 7.07 (m, 2 H), 6.90 (s, br, 1 H), 6.65 (s, br, 1
H), 5.56 (s, br, 1 H), 5.23 (d, J ) 12.4 Hz, 1 H), 5.19 (d, J )
12.4 Hz, 1 H), 3.20 (s, br, 2 H), 2.82 (s, br, 1 H), 2.55 (s, br, 1
H), 1.51 (d, J ) 6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
141.23, 136.79, 136.13, 128.51, 128.40, 128.01, 127.36, 121.83,
121.66, 119.17, 118.81, 113.44, 110.97, 67.39, 53.96, 29.65; MS
m/z (relative intensity) 399 (M+ + 1, 25), 264 (2), 203 (2), 196
(2), 159 (2), 143 (22), 130 (39), 120 (33), 105 (46), 91 (100).
Anal. Calcd for C26H26N2O2: C, 78.36; H, 6.58; N, 7.03.
Found: C, 78.19; H, 6.56; N, 6.77.
2-[(Meth oxycar bon yl)m eth yl]-3-[2-[(R)-1-ph en eth ylam i-
n o]eth yl]in d ole (8). A mixture of 1.0 g (2.125 mmol) of
2-[(methoxycarbonyl)methyl]-3-[2-(benzyloxycarbonyl)-(R)-1-
(phenethylamino)ethyl]indole and 226 mg (0.213 mmol) of 10%
Pd-C in 20 mL of MeOH was vigorously stirred for 1 h at
room temperature under 1 atm of H2. Filtration and concen-
tration gave the crude product, which was purified on a silica
gel column, eluting with CH2Cl2/MeOH (96:4), to give 660 mg
of the title product (92% yield): TLC Rf ) 0.24 (CH2Cl2/MeOH,
96:4; CAS green); [R]29 ) 49 (c ) 0.23, CHCl3); IR (KBr) νmax
D
3400, 3062, 3028, 2953, 2926, 2852, 1736, 1494, 1461, 1437,
1340, 1305, 1267, 1239, 1213, 1167, 1123, 1011, 764, 741, 703
2-[(Meth oxycar bon yl)m eth yl]-3-[2-(ben zyloxycar bon yl)-
(R)-1-(p h en eth yla m in o)eth yl]in d ole. To a solution of 6.5
g (16.3 mmol) of Nb-(benzyloxycarbonyl)-Nb-((R)-1-phenethyl)-
tryptamine and 2.5 mL (17.93 mmol) of Et3N in 150 mL of
THF, at -78 °C, was added 2.1 mL (17.93 mmol) of t-BuOCl
dropwise. The solution was stirred for another 40 min, 3.26
mL of a 1.0 M solution of ZnCl2 in Et2O (3.26 mmol) was
introduced, and the reaction mixture was stirred for 5 min. A
solution of 2.7 g (19.56 mmol) of lithium dimethyl malonate
in 10 mL of THF was added dropwise, and the resulting
solution was stirred for another 40 min at -78 °C and for 1 h
at room temperature. The reaction was quenched by adding
water, and the aqueous layer was extracted with EtOAc. The
combined organic phase was twice washed with brine. The
residue, obtained upon concentration, was pure enough for the
next reaction.
The above diester product was taken into 100 mL of DMF,
and 760 mg (17.93 mmol) of LiCl and 561 mg (4.08 mmol) of
Et3N‚HCl were added. The solution was heated in a 130 °C
oil bath for 4 h and cooled to room temperature. Water was
added. The aqueous layer was extracted with ether several
times. The combined organic phase was washed with water
and brine several times. The residue, obtained upon concen-
tration, was purified on a silica gel column (EtOAc/Hex, 1:4)
to give 7.2 g of the monoester (85% yield).
1
cm-1; H NMR (500 MHz, CDCl3) δ 8.80 (s, 1 H), 7.48 (d, J )
7.9 Hz, 1 H), 7.34-7.22 (m, 5 H), 7.20 (m, 1 H), 7.17 (t, J )
8.0 Hz, 1 H), 7.05 (t, J ) 7.6 Hz, 1 H), 3.74 (s, 2 H), 3.72 (m,
1 H), 3.68 (s, 3 H), 2.90 (m, 2 H), 2.76 (m, 1 H), 2.67 (m, 1 H),
1.78 (s, br, 1 H, NH), 1.28 (d, J ) 6.5 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 171.14, 145.61, 135.79, 128.37, 128.07, 127.16,
126.80, 126.56, 121.87, 119.34, 118.58, 111.47, 110.74, 58.20,
52.27, 47.84, 31.67, 24.88, 24.31; MS m/z (relative intensity)
337 (M+ + 1, 13), 217 (2), 204 (69), 170 (2), 156 (4), 142 (17),
134 (30), 105 (100), 91 (3).
Meth yl (3a S*,5S*,11bR*) a n d (3a R*,5R*,11bS*)-3-((R)-
1-P h en eth yl)-2,3,3a,4,5,7-h exah ydr o-5-(dim eth oxym eth yl)-
1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te (11). Using the
general procedure for preparation of the N-benzyl compound
1b, the title compound was obtained as a 3:2 ratio of diaster-
eomers and purified on a silica gel column, which was eluted
with hexane/EtOAc (9:1) (40% yield): TLC Rf ) 0.25 (hexane/
EtOAc/CH2Cl2, 7:2:1; CAS blue); UV (EtOH) λmax: 328, 294,
224, 208 nm; IR (KBr) νmax 3371, 3058, 3028, 2972, 2948, 2831,
1677, 1608, 1466, 1436, 1373, 1277, 1237, 1212, 1189, 1152,
1123, 1090, 910, 745, 731, 702 cm-1; MS m/z (rel intens) 449
(2), 448 (M+, 0.4), 434 (7), 418 (7), 374 (19), 342 (4), 282 (2),
270 (9), 238 (3), 228 (10), 215 (3), 210 (6), 194 (8), 182 (5), 180
(6), 167 (7), 160 (10), 154 (3), 148 (6), 130 (2), 119 (35), 105
(100), 91 (3).
Selected distinguishing data for obtaining the product
ratio: 1H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 7.14 (t, J )
7.6 Hz, 1 H), 6.90 (t, J ) 7.3 Hz, 1 H), 6.80 (d, J ) 7.9 Hz, 1
H), 4.79 (d, J ) 5.7 Hz, 1 H), 3.79 (s, 3 H), 3.42 (s, 3 H), 3.41
(s, 3 H), 1.49 (d, J ) 6.6 Hz, 3 H). Compared with: δ 9.80 (s,
1H), 7.08 (t, J ) 7.6 Hz, 1 H), 6.75 (d, J ) 7.8 Hz, 1 H), 4.90
(d, J ) 7.1 Hz, 1 H), 3.78 (s, 3 H), 3.51 (s, 3 H), 3.40 (s, 3 H),
1.54 (d, J ) 6.7 Hz, 3 H).
For the diester: TLC Rf ) 0.5 (hexane/EtOAc 3:2; CAS
greenish); [R]31 ) 50 (c ) 0.4, MeOH); IR (KBr) νmax 3404,
D
3060, 3031, 2953, 1750, 1737, 1697, 1686, 1457, 1418, 1375,
1299, 1243, 1201, 1172, 1152, 1026, 908, 744, 700 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 8.75 (s, br, 1 H), 7.52-7.25 (m, 5
H), 7.14 (s, br, 2 H), 6.97 (s, br, 1 H), 6.88 (s, br, 1 H), 5.72 (s,
br, 1 H), 5.33 (s, 2 H), 4.54 (s, br, 1 H), 3.77 (s, 3 H), 3.70 (s,
3 H), 3.22 (s, br, 1 H), 3.09 (s, br, 1 H), 2.86 (s, br, 1 H), 2.42
(s, br, 1 H), 1.58 (s, br, 3 H); 13C NMR (125 MHz, CDCl3, 25
peaks due to rotomers) δ 167.49, 140.97, 136.51, 135.73,
128.49, 128.35, 128.10, 127.66, 127.42, 127.13, 126.81, 124.78,
N b -(t er t -Bu t oxyca r b on yl)-N b -[1(R )-(1-n a p h t h yle t h -
yl)]t r yp t a m in e. To a solution of Nb-[1(R)-(1-naphthyleth-
yl)]tryptamine, prepared by alkylation12,17,18 of the correspond-
ing amine with tryptophyl bromide (4.30 g, 13.68 mmol) and
K2CO3 (3.80 g, 27.35 mmol) in 30 mL of THF and 30 mL of
H2O, was added (t-BuOCO)2O (3.3 g, 15.04 mmol) in several
portions at room temperature. After the addition, the solution
was stirred for another 1 h. The aqueous phase was extracted
(12) Legseir, B.; Henin, J .; Massiot, G.; Vercauteren, J . Tetrahedron
Lett. 1987, 28, 3573.
(13) Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J . Org. Chem.
1991, 56, 514.
(14) Kuehne, M. E.; Bandarage, U. K. J . Org. Chem. 1996, 61, 1175.
(15) Kuehne, M. E.; Bandarage, U. K.; Hammach, A.; Li, Y.-L.;
Wang, T. J . Org. Chem. Submitted.
(16) Arai, I; Muramatsu, I. J . Org. Chem. 1983, 48, 121.
(17) Soe, T.; Kawate, T.; Fukui, N.; Nakagawa, M. Tetrahedron Lett.
1995, 36, 1857.
(18) Waldman, H.; Schmidt, G.; J ansen, M.; Geb, J . Tetrahedron
Lett. 1993, 34, 5867 (ref 6); Tetrahedron 1994, 50, 11865.

Syntheses of Strychnan- and Aspidospermatan-Type Alkaloids
J . Org. Chem., Vol. 62, No. 23, 1997 7957
with EtOAc. The residue, obtained upon drying and concen-
tration, was purified on a silica gel column, eluting with
EtOAc/Hex (1:4) to afford 5.3 g of the title product (96%
yield): TLC Rf ) 0.35 (hexane/EtOAc 4:1; CAS yellow); mp
7.5 Hz, 1 H), 4.80 (d, J ) 6.3 Hz, 1 H), 3.81 (s, 3 H), 3.48 (s, 3
H), 3.38 (s, 3 H). Minor product: 1H NMR (500 MHz, CDCl3):
δ 9.30 (s, 1H), 7.12 (t, J ) 7.4 Hz, 1 H), 6.78 (d, J ) 7.7 Hz, 1
H), 4.92 (d, J ) 6.0 Hz, 1 H), 3.76 (s, 3 H), 3.54 (s, 3 H), 3.40
(s, 3 H).
79-81 °C; [R]29 ) 98 (c ) 0.3, MeOH); UV (EtOH) λmax 222,
D
274, 282, 292 nm; IR (KBr) νmax 3423, 3329, 3051, 2977, 2931,
2874, 1664, 1511, 1458, 1408, 1367, 1337, 1303, 1253, 1170,
1160, 1106, 1034, 911, 868, 803, 780, 738 cm-1; 1H NMR (500
MHz, CDCl3) δ 8.23 (s, br, 1 H), 7.84 (m, 2 H), 7.80 (s, 1 H),
7.54 (m, 2 H), 7.50 (m, 2 H), 7.20 (m, 1 H), 7.08 (m, 1 H), 6.97
(m, 2 H), 6.50 (s, br, 1 H), 6.22 (s, br, 1 H), 3.21 (s, br, 1 H),
2.98 (s, br, 1 H), 2.03 (s, br, 2 H), 1.60 (m, 12 H); MS m/z
(relative intensity) 415 (8), 414 (M+, 30), 358 (6), 228 (11), 184
(9), 155 (100), 143 (18), 130 (55), 128 (4), 103 (4). Anal. Calcd
for C27H30N2O2‚0.5H2O: C, 76.57; H, 7.38; N, 6.62. Found: C,
76.48; H, 7.35; N, 6.47.
2-[(Meth oxyca r bon yl)m eth yl]-3-[2-[N-(ter t-bu toxyca r -
bon yl)-N-[1(R)-(1-n a p h th yleth yl]a m in o]eth yl]in d ole. Us-
ing the preceding procedures for preparation of the corre-
sponding R-phenethyl analogue, the title product was obtained
in 85% yield (two steps) after purification by silica gel column
chromatography, eluting with Et2O/hexane (1:1): TLC Rf )
0.28 (hexane/EtOAc, 4:1, CAS, gray); mp 76-8 °C; IR (KBr)
νmax 3397, 3055, 2974, 1740, 1735, 1685, 1680, 1664, 1459,
1407, 1366, 1337, 1306, 1244, 1159, 1119, 1027, 910, 870, 806,
782, 741 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.35 (s, br, 1 H),
8.24 (s, br, 1 H), 7.89 (d, J ) 8.1 Hz, 2 H), 7.52 (m, 4 H), 7.20
(m, 1 H), 7.07 (t, J ) 6.7 Hz, 1 H), 6.97 (m, 2 H), 6.27 (s, br, 1
H), 3.77 (s, 0.6 H), 3.71 (s, 3 H), 3.70 (s, 0.4 H), 3.26 (s, br, 2
H), 2.83 (s, br, 1 H), 2.64 (s, br, 1 H), 1.68 (s, 9 H), 1.62 (m, 3
H); 13C NMR (125 MHz, CDCl3) (29 peaks due to the rotomers)
δ 136.76, 135.72, 135.43, 133.74, 132.58, 128.68, 127.68,
126.61, 125.88, 125.02, 124.60, 124.30, 122.43, 121.64, 119.13,
118.99, 118.44, 110.53, 79.95, 52.98, 55.15, 49.76, 48.42, 43.14,
30.92, 28.77, 23.93, 16.98; MS m/z (relative intensity) 487 (5),
486 (M+, 16), 275 (9), 260 (5), 231 (4), 226 (6), 215 (8), 202
(42), 184 (9), 169 (4), 155 (100), 142 (22), 130 (4), 115 (6). Anal.
Calcd for C30H34N2O4‚H2O: C, 71.41; H, 7.19; N, 5.55.
Found: C, 71.08; H, 6.88; N, 5.39.
Meth yl (3a S*,5S*,11bR*)- a n d (3a R*,5R*,11bS*)-3-[(R)-
1-(1-Na p h th yleth yl)]-2,3,3a ,4,5,7-h exa h yd r o-5-[1-(2-eth yl-
en ed ioxy)p r op yl]-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r box-
yla te (13). Using the general procedure for preparation of
the N-benzyl compound 1b, the title compounds were obtained
as a 3:2 ratio of diastereomers and purified on a silica gel
column, which was eluted with hexane/EtOAc (4:1) (26%
yield): TLC Rf ) 0.33 (hexane/EtOAc, 7:3; CAS violet); UV
(EtOH) λmax: 326, 294, 226, 206 nm; IR (KBr) νmax: 3375, 3049,
2979, 2948, 2927, 2878, 1677, 1609, 1466, 1435, 1380, 1275,
1236, 1215, 1190, 1149, 1097, 1048, 801, 781, 746 cm-1; MS
m/z (rel intens) 525 (M+ + 1, 5), 510 (2), 397 (3), 384 (6), 370
(5), 328 (3), 268 (1), 243 (2), 226 (2), 211 (8), 194 (3), 180 (3),
167 (4), 155 (100), 141 (2), 129 (4), 115 (3), 87 (78).
Selected distinguishing data for the major diastereomer: 1H
NMR (500 MHz, CDCl3) δ 9.26 (s, 1H), 7.16 (s, 1 H), 3.78 (s, 3
H), 1.48 (s, 3 H). Selected data for the minor diastereomer:
1H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 7.11 (s, 1 H), 3.80
(s, 3 H), 1.55 (s, 3 H).
2-[(Meth oxyca r bon yl)m eth yl]-3-[2-[(S)-[[(m eth oxyca r -
bon yl)p h en ylm eth yl]a m in o]eth yl]in d ole (7). The title
compound was prepared starting from tryptophyl bromide and
(S)-phenylglycine, using the preceding procedures for prepara-
tion of the tryptamine ester compounds 8-10 and obtained in
61% overall yield (four steps) after final purification on a silica
gel column, eluting with CH2Cl2/EtOAc (7:3): TLC Rf ) 0.18
1
(CH2Cl2/EtOAc, 7:3; CAS green); H NMR (500 MHz, CDCl3)
δ 8.62 (s, 1 H), 7.49 (d, J ) 7.8 Hz, 1 H), 7.33 (m, 6 H), 7.15 (t,
J ) 7.8 Hz, 1 H), 7.07 (t, J ) 7.7 Hz, 1 H), 4.41 (s, 1 H), 3.80
(s, 2 H), 3.68 (s, 3 H), 3.61 (s, 3 H), 2.95 (m, 2 H), 2.85 (m, 1
H), 2.78 (m, 1 H), 2.10 (s, 1 H, NH); 13C NMR (125 MHz, CDCl3)
δ 173.37, 138.18, 135.82, 128.65, 128.03, 128.01, 127.46,
127.27, 121.87, 119.35, 118.50, 111.08, 110.83, 65.61, 52.26,
52.10, 49.97, 31.68, 24.99.
2-[(Met h oxyca r b on yl)m et h yl]-3-[2-[1(R)-(1-n a p h t h yl-
eth yl)a m in o]eth yl)in d ole (9). The title compound was
prepared using the preceding procedures for preparation of
the corresponding R-phenethyl compound 8. After purification
by silica gel column chromatography, eluting with EtOAc, an
88% yield was obtained: TLC Rf ) 0.21 (EtOAc, CAS green);
Meth yl (3a S*,5R* a n d S*,11bR*)- a n d (3a R*,5S* a n d
R *,11b S *)-3-[(S )-(Me t h o x y c a r b o n y l)p h e n y lm e t h y l]-
2,3,3a ,4,5,7-h exa h yd r o-5-m eth yl-1H-p yr r olo[2,3-d ]ca r ba -
zole-6-ca r boxyla te (10). Using the general procedure for
preparation of the N-benzyl compound 1a , the title compounds
were obtained as a 5:1:1:0.9 ratio of diastereomers and purified
on a silica gel column, which was eluted with hexane/EtOAc
[R]30 ) 67 (c ) 0.5, MeOH); IR (KBr) νmax 3406, 3057, 2953,
D
2928, 2846, 1734, 1457, 1436, 1306, 1259, 1208, 1168, 1122,
) 0.24 (hexane/EtOAc, 9:1; CAS
(9:1) (35% yield): TLC Rf
1
1010, 847, 802, 780, 742 cm-1; H NMR (500 MHz, CDCl3) δ
blue); UV (EtOH) λmax 326, 294, 226, 208 nm; IR (KBr) νmax
3372, 3060, 3032, 2951, 2927, 2854, 1739, 1680, 1609, 1479,
1467, 1453, 1434, 1352, 1291, 1279, 1252, 1236, 1215, 1191,
1167, 1132, 1104, 1048, 1024, 788, 749, 702 cm-1; MS m/z (rel
intens) 433 (8), 432 (M+, 22), 401 (3), 389 (8), 373 (57), 341
(10), 283 (34), 267 (13), 241 (81), 226 (23), 208 (20), 204 (83),
193 (23), 182 (27), 170 (40), 149 (100), 121 (60).
8.49 (s, 1 H), 8.10 (d, J ) 7.6 Hz, 1 H), 7.85 (d, J ) 7.2 Hz, 1
H), 7.71 (d, J ) 8.0 Hz, 1 H), 7.53-7.38 (m, 5 H), 7.32 (d, J )
8.0 Hz, 1 H), 7.17 (t, J ) 7.8 Hz, 1 H), 7.07 (m, 1 H), 4.60 (q,
J ) 6.4 Hz, 1 H), 3.79 (s, 2 H), 3.66 (s, 3 H), 2.97-2.82 (m, 4
H), 1.69 (s, br, 1 H), 1.45 (d, J ) 6.4 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 171.07, 141.23, 135.01, 133.94, 131.31, 128.85,
128.05, 127.22, 127.00, 125.62, 125.19, 122.90, 122.65, 121.88,
119.34, 118.59, 111.47, 110.73, 53.64, 52.20, 47.97, 31.65,
24.97, 23.50; MS m/z (relative intensity) 387 (M+ + 1, 7), 276
(7), 262 (3), 204 (50), 185 (9), 170 (3), 156 (100), 142 (21), 129
(6), 115 (9).
Selected data for the major diastereomer: 1H NMR (500
MHz, CDCl3) δ 9.08 (s, 1H), 7.67 (d, J ) 7.5 Hz, 1 H), 7.44-
7.24 (m, 5 H), 7.15 (t, J ) 7.5 Hz, 1 H), 6.93 (t, J ) 7.5 Hz, 1
H), 6.81 (d, J ) 7.7 Hz, 1 H), 4.69 (s, 1 H), 3.80 (s, 3 H), 3.77
(s, 3 H), 3.59 (m, 1 H), 3.11 (m, 1 H), 2.70 (dd, J ) 7.1, 7.1 Hz,
1 H), 2.06 (m, 1 H), 1.91 (d, J ) 14.1 Hz, 1 H), 1.70 (dd, J )
5.1, 11.7 Hz, 1 H), 1.39 (d, J ) 7.3 Hz, 3 H).
Meth yl (3a S*,5S*,11bR*)- a n d (3a R*,5R*,11bS*)-3-[(R)-
1-(1-Na p h t h ylet h yl)]-2,3,3a ,4,5,7-h exa h yd r o-5-(d im et h -
oxym eth yl)-1H-pyr r olo[2,3-d]car bazole-6-car boxylate (12).
Using the general procedure for preparation of the N-benzyl
compound 1b, the title compounds were obtained as a 5:4 ratio
of diastereomers and purified on a silica gel column, which
was eluted with hexane/EtOAc (4:1) (30% yield): TLC Rf )
0.39 (hexane/EtOAc, 4:1; CAS blue); UV (EtOH) λmax 328, 296,
224, 206 nm; IR (KBr) νmax 3369, 3049, 2968, 2949, 2932, 2830,
1675, 1608, 1466, 1437, 1376, 1278, 1236, 1212, 1191, 1128,
1081, 970, 802, 793, 781, 744 cm-1; MS m/z (rel intens) 499
(2), 498 (M+, 0.5), 484 (7), 467 (7), 424 (13), 312 (2), 270 (6),
243 (2), 227 (5), 210 (2), 194 (5), 180 (4), 167 (6), 155 (97), 145
(11), 127 (6), 119 (4), 115 (5), 101 (6), 97 (5).
L-[Nb-Ben zyl-Nb-(ter t-bu toxycar bon yl)]tr yptoph an Ben -
zyl Ester (16). A mixture of 2.20 g (7.48 mmol) of tryptophan
benzyl ester,16 794 mg (7.48 mmol) of benzaldehyde, and 2.0 g
of magnesium sulfate in 25 mL of dichloromethane was stirred
for 8 h. Filtration and concentration gave an imine, which
was dissolved in 25 mL of methanol. At 0 °C, 314 mg (8.23
mmol) of sodium borohydride was added. After 1 h at 0 °C,
the solvent was evaporated and the residue partitioned
between ethyl acetate and a saturated sodium bicarbonate
solution. Concentration and chromatography on silica gel,
eluted with ethyl acetate/hexane, gave 2.73 g (95% yield) of
the Nb-benzylated product 15: TLC Rf 0.10 (EtOAc/hexane,
3:7, CAS brown).
Selected distinguishing data for determination of diastere-
omeric ratio follows. Major product: 1H NMR (500 MHz,
CDCl3) δ 9.47 (s, 1H), 6.97 (t, J ) 7.3 Hz, 1 H), 6.83 (d, J )
To a solution of 12.0 g (31.3 mmol) of L-benzyl-Nb-benzyl-
tryptophan benzyl ester (15) in 200 mL of THF and H2O (1:1)

7958 J . Org. Chem., Vol. 62, No. 23, 1997
Kuehne and Xu
was added 8.64 g (62.5 mmol) of potassium carbonate, followed
by 7.5 g (34 mmol) of (t-BOC)2O, added in several portions at
room temperature. The solution was stirred for another 1 h.
The residue, obtained upon concentration, was dissolved in
ethyl acetate and washed with water and brine. The crude
product was pure enough for the next reaction, but it could be
further purified on a silica gel column (EtOAc/hexane, 3:7) to
afford 14.6 g of the desired product (96% yield): TLC Rf ) 0.24
(hexane/EtOAc 7:3; CAS brown); [R]27D ) -74 (c ) 0.5, MeOH);
IR (KBr) νmax 3351, 3060, 3035, 2979, 2933, 1740, 1735, 1701,
1696, 1685, 1676, 1496, 1456, 1366, 1340, 1274, 1252, 1215,
2-[(Met h oxyca r b on yl)m et h yl]-3-[2(S)-(b en zyloxyca r -
bon yl)-2-(Nb-ben zyla m in o)eth yl]in d ole (14). To a solution
of 4.0 g (7.2 mmol) of the urethane 18 and 2.0 mL (14 mmol)
of triethylamine in 60 mL of dichloromethane, at 0 °C, was
added 2.8 mL (14 mmol) of TMSOTf, dropwise. The solution
was stirred at room temperature for 2 h, and then saturated
sodium bicarbonate was added and the aqueous layer was
extracted with dichloromethane. The residue, obtained upon
concentration, was chromatographed on a silica gel column,
eluting with CH2Cl2/EtOAc (9:1), to provide 3.0 g of the amine
14 (91% yield): TLC Rf ) 0.22 (CH2Cl2/EtOAc 9:1; CAS green);
[R]24 ) 0.9 (c ) 1.1, CHCl3); UV (EtOH) λmax 282, 222, 210
1
1161, 743, 697 cm-1; H NMR (500 MHz, CDCl3) δ 8.01 (s, 1
D
nm; IR (KBr) νmax 3402, 3090, 3063, 3034, 2953, 2928, 2850,
H), 7.46-6.89 (m, 15 H), 5.05 (s, br, 1.6 H), 4.95 (app s, br, 0.4
H), 4.57 (d, br, J ) 12.9 Hz, 0.6 H), 4.37 (app s, 0.8 H), 4.18 (s,
br, 0.6 H), 3.79 (d, br, J ) 12.9 Hz, 0.4 H), 3.64 (d, br, J )
13.9 Hz, 0.6 H), 3.52 (m, 1 H), 3.40 (s, br, 0.4 H), 3.26 (s, br,
0.6 H), 1.55 (s, 5.4 H), 1.52 (s, 3.6 H); MS m/z (relative
intensity) 485 (2), 484 (M+, 6), 385 (5), 277 (13), 220 (5), 186
(2), 157 (3), 143 (8), 130 (100), 117 (4), 103 (5), 91 (69). Anal.
1733, 1497, 1460, 1437, 1340, 1309, 1172, 1127, 1008, 740, 298
1
cm-1; H NMR (500 MHz, CDCl3) δ 8.55 (s, 1 H), 7.49 (d, J )
7.8 Hz, 1 H), 7.32-7.13 (m, 12 H), 7.07 (m, 3 H), 4.97 (s, 2 H),
3.78 (d, J ) 16.8 Hz, 1 H), 3.76 (d, J ) 13.1 Hz, 1 H), 3.70 (d,
J ) 16.8 Hz, 1H), 3.66 (t, J ) 6.8 Hz, 1 H), 3.64 (s, 3 H), 3.61
(d, J ) 13.1 Hz, 1 H), 3.11 (d, J ) 6.8 Hz, 2 H), 1.75 (s, br, 1
H); 13C NMR (125 MHz, CDCl3) δ 175.00, 171.08, 139.73,
135.67, 128.43, 128.27, 128.12, 128.08, 126.93, 121.94, 119.54,
118.57, 110.75, 108.80, 66.47, 61.43, 52.23, 52.20, 31.49, 28.69;
MS m/z (relative intensity) 458 (10), 457 (M+, 46), 321 (2), 292
(2), 254 (3), 230 (3), 202 (92), 188 (2), 169 (5), 142 (26), 130
(3), 115 (7), 91 (100).
Calcd for
Found: C, 72.11; H, 6.91; N, 5.02.
C30H32N2O4‚H2O: C, 71.69; H, 6.82; N, 5.57.
2-[Bis(m et h oxyca r b on yl)m et h yl]-3-[2(S)-(b en zyloxy-
ca r bon yl)-2-[Nb-ter t-(bu toxyca r bon yl)-Nb-ben zyla m in o-
]eth yl]in d ole (17) a n d 2-[(Meth oxyca r bon yl)m eth yl]-3-
[2-(S)-(ben zyloxyca r bon yl)-2-[Nb-(ter t-bu toxyca r bon yl)-
Nb-ben zyla m in o]eth yl]in d ole (18). To a solution of 11.0 g
(22.7 mmol) of the urethane ester 16 and 3.47 mL (25.0 mmol)
of Et3N in 250 mL of THF, at -78 °C, was added 3.0 mL (25
mmol) of tert-butyl hypochlorite dropwise. The solution was
stirred for a further 20 min, and 4.54 mL of a 1.0 M solution
of ZnCl2 in Et2O (4.54 mmol) was introduced. The reaction
mixture was stirred for 5 min. A solution of 3.79 g (27.2 mmol)
of lithium dimethyl malonate in 20 mL of THF was added
dropwise, and the resulting solution was stirred for 1 h at -78
°C and for 1 h at room temperature. The reaction was
quenched by adding water, and the aqueous layer was
extracted with dichloromethane. The product 17, obtained
upon concentration, was pure enough for the next reaction,
but it could be purified by chromatography on silica gel
(EtOAc/hexane, 1:4).
(-)-Meth yl (2S,3a S,5R,11bR)-2-(Ben zyloxyca r bon yl)-3-
b en zyl-2,3,3a ,4,5,7-h exa h yd r o-5-m et h yl-1H -p yr r olo[2,3-
d ]ca r ba zole-6-ca r boxyla te ((-)-19a ). A mixture of the
amine 14 (290 mg, 0.636 mmol), benzoic acid (78 mg, 0.64
mmol), crotonaldehyde (63 uL, 0.76 mmol), and 600 mg of
freshly activated MgSO4, in 8 mL of anhydrous benzene under
an atmosphere of Ar, was heated at 65-70 °C for 2 days. The
residue, obtained upon filtration and concentration, was
dissolved in CH2Cl2 and washed with 5% Na2CO3. Purification
of the crude product on a silica gel column (hexane/EtOAc,
9:1) afforded 165 mg of the product 19a (51% yield): TLC Rf
) 0.22 (hexane/EtOAc 9:1; CAS blue); mp 86-7 °C (HCl salt);
[R]23D ) -236 (c ) 1.0, CHCl3); UV (EtOH) λmax 326, 300, 232,
204 nm; IR (KBr) νmax 3379, 3059, 3033, 2982, 2954, 2933,
2794, 1723, 1684, 1614, 1478, 1466, 1437, 1377, 1343, 1278,
1257, 1229, 1213, 1183, 1153, 1119, 1085, 1056, 1043, 749, 732,
The above product was taken into 120 mL of DMF, and 1.9
g (45.4 mmol) of LiCl was added. The solution was heated in
at 130 °C in an oil bath for 3 h and cooled to room temperature.
Water was added. The aqueous layer was extracted with ether
several times. The combined organic phase was washed with
water and brine several times. The residue, obtained upon
concentration, was purified on a silica gel column (EtOAc/
hexane, 25:75) to give 11.0 g of product 18 (87% yield for two
steps).
1
701 cm-1; H NMR (500 MHz, CDCl3) δ 8.98 (s, 1 H), 7.37-
7.25 (m, 11 H), 7.11 (dd, J ) 7.6 Hz, 1 H), 6.77 (dd, J ) 7.6 H,
1 H), 6.67 (d, J ) 7.5 Hz, 1 H), 4.90 (d, J ) 12.4 Hz, 1 H), 4.87
(d, J ) 12.4 Hz, 1 H), 3.98 (s, 2 H), 3.75 (s, 3 H), 3.74 (dd, J )
5.3, 11.8 Hz, 1 H), 3.57 (d, J ) 5.4 Hz, 1 H), 3.05 (m, 1 H),
2.42 (dd, J ) 11.8, 11.8 Hz, 1 H), 1.98 (dd, J ) 5.3, 11.8 Hz, 1
H), 1.75 (d, J ) 14.1 Hz, 1 H), 1.47 (d, J ) 7.1 H, 3 H), 1.29
(m, 1 H); 13C NMR (125 MHz, CDCl3) δ 172.30, 168.86, 164.75,
142.87, 137.20, 137.05, 135.63, 129.97, 128.47, 128.18, 128.02,
127.34, 121.47, 120.32, 109.29, 100.40, 66.71, 66.53, 64.34,
57.34, 54.05, 50.94, 49.59, 33.95, 28.95, 20.92; MS m/z (relative
intensity) 509 (1), 508 (M+, 2), 280 (2), 242 (5), 228 (27), 208
(4), 196 (5), 180 (6), 167 (10), 154 (2), 134 (1), 107 (4), 91 (100).
(-)-Meth yl (2S,3a S,5S,11bR)-2-(Ben zyloxyca r bon yl)-3-
ben zyl-2,3,3a ,4,5,7-h exa h yd r o-5-(d im eth oxym eth yl)-1H-
p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te ((-)-19b). A solu-
tion of the amine 14 (400 mg, 0.877 mmol), benzoic acid (107
mg, 0.877 mmol), and 4,4-dimethoxycrotonaldehyde (137 mg,
1.05 mmol) in 10 mL of benzene, under an atmosphere of Ar,
was heated at reflux with a Dean-Stark water trap for 3 days.
A workup as for 19a , above, and chromatography on a silica
gel column (EtOAc/Hex, 25:75) gave 205 mg of the product 19b
(41% yield): TLC Rf ) 0.26 (hexane/EtOAc 75:25; CAS blue);
mp 65-67 °C; [R]23D ) -182 (c ) 1.2, CHCl3); UV (EtOH) λmax
324, 296, 230, 206 nm; IR (KBr) νmax 3371, 3059, 3031, 2948,
2845, 1743, 1675, 1610, 1468, 1493, 1284, 1238, 1192, 1160,
1126, 1095, 1078, 1002, 72, 749, 699 cm-1; 1H NMR (500 MHz,
CDCl3) δ 9.13 (s, 1 H), 7.38-7.26 (m, 10 H), 7.09 (dd, J ) 7.7,
7.7 Hz, 1 H), 6.75 (d, J ) 7.7 Hz, 1 H), 6.70 (dd, J ) 7.5, 7.5
1H), 6.38 (d, J ) 7.3 Hz, 1 H), 5.23 (d, J ) 9.0 Hz, 1 H), 4.99
(s, 2 H), 4.03 (d, J ) 13.8 Hz, 1 H), 3.96 (d, J ) 13.8 Hz, 1 H),
3.77 (dd, J ) 5.2, 12.0 Hz, 1 H), 3.76 (s, 3 H), 3.53 (s, 3 H),
3.52 (d, J ) 5.5 Hz, 1 H), 3.29 (s, 3 H), 3.28 (m, 1 H), 2.22 (m,
2 H), 1.99 (dd, J ) 5.2, 12.0 Hz, 1 H), 1.20 (ddd, J ) 5.5, 5.5,
For triester 17: TLC Rf ) 0.2 (hexane/EtOAc 4:1; CAS light
green); IR (KBr) νmax 3397, 3059, 3031, 2974, 2955, 2930, 1740,
1735, 1718, 1700, 1686, 1457, 1436, 1368, 1317, 1277, 1247,
1211, 1160, 743, 699 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.89
(s, 1 H), 7.36-6.94 (m, 14 H), 5.12-5.05 (m, 2 H), 4.94 (m, 1
H), 4.45 (d, br, J ) 13.2 Hz, 0.6 H), 4.28 (d, br, J ) 13.2 H, 0.4
H), 4.11 (m, 1 H), 3.76 (s, 6 H), 3.74-3.52 (m, 2.6 H), 3.25 (m,
br, 0.4 H), 1.49-1.40 (3 s, 9 H).
For diester 18: TLC Rf ) 0.16 (hexane/EtOAc 4:1; CAS
o
green/gray); mp 92-4 C; [R]24D ) -100 (c ) 0.23, CHCl3); UV
(EtOH) λmax 286, 224, 210 nm; IR (KBr) νmax 3382, 3063, 3030,
3007, 2980, 2957, 2930, 1739, 1693, 1497, 1457, 1435, 1367,
1313, 1275, 1245, 1217, 1165, 998, 744, 898 cm-1 1H NMR
;
(500 MHz, CDCl3) δ 8.62 (s, 1 H), 7.38-6.92 (m, 14 H), 5.08-
4.92 (m, 2 H), 4.51 (d, br, J ) 14.7 Hz, 0.53 H), 4.29 (d, br, J
) 14.9 Hz, 0.47 H), 4.09 (t, J ) 7.6 Hz, 1 H), 3.76 (s, 2 H), 3.72
(s, 3 H), 3.58 (m, 1 H), 3.47 (app s, br, 1.47 H), 3.22 (m, 0.53
H), 1.49 (s, 5 H), 1.40 (s, 4 H); 13C NMR (125 MHz, CDCl3) δ
170.89, 155.00, 137.02, 135.69, 128.69, 128.36, 128.22, 128.02,
127.13, 121.95, 119.54, 118.31, 118.06, 110.94, 66.87, 60.66,
59.65, 52.80, 52.24, 51.99, 31.24, 28.36, 25.22, 24.25; MS m/z
(relative intensity) 557 (0.5), 556 (M+, 2), 500 (2), 457 (2), 349
(3), 292 (3), 260 (5), 254 (2), 218 (4), 202 (100), 188 (2), 169
(5), 154 (2), 142 (22), 130 (2), 115 (4). Anal. Calcd for
C33H36N2O6: C, 71.20; H, 6.52; N, 5.03. Found: C, 71.06; H,
6.46; N, 5.02.
1
14.2 Hz, 1 H); H NMR (500 MHz, C6D6) δ 9.41 (s, 1 H), 7.29

Syntheses of Strychnan- and Aspidospermatan-Type Alkaloids
J . Org. Chem., Vol. 62, No. 23, 1997 7959
(d, J ) 7.0 Hz, 2 H), 7.18-7.10 (m, 6 H), 7.04 (m, 2 H), 6.87
(ddd, J ) 1.0, 7.7, 7.7 Hz, 1 H), 6.62 (dd, J ) 7.3, 7.3 Hz, 1 H),
6.45 (d, J ) 7.4 Hz, 1 H), 6.18 (d, J ) 7.7 Hz, 1 H), 5.57 (d, J
) 8.9 Hz, 1 H), 4.80 (d, J ) 12.2 Hz, 1H), 4.77 (d, J ) 12.2 Hz,
1 H), 3.93 (d, J ) 13.8 Hz, 1 H), 3.83 (d, J ) 13.8 Hz, 1 H),
3.79 (dd, J ) 5.3, 11.9, 1 H), 3.70 (dd, J ) 6.1, 8.9 Hz, 1 H),
3.61 (s, 3 H), 3.59 (s, 3 H), 3.38 (d, J ) 5.6 Hz, 1 H), 3.37 (s, 3
H), 2.37 (dd, J ) 11.9, 11.9 Hz, 1 H), 2.26 (d, J ) 14.3 Hz, 1
H), 1.83 (dd, J ) 5.3, 11.9 Hz, 1 H), 1.03 (ddd, J ) 5.6, 5.6,
14.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 172.24, 169.22,
164.77, 142.72, 136.96, 135.50, 135.05, 130.56, 128.59, 128.53,
128.47, 128.07, 127.61, 121.34, 120.44, 109.30, 106.83, 96.61,
66.71, 63.51, 62.61, 55.68, 55.57, 55.06, 53.53, 51.15, 48.77,
38.49, 28.88; MS m/z (relative intensity) 568 (M+, 1), 494 (1),
433 (1), 387 (1), 359 (7), 276 (3), 268 (3), 229 (5), 226 (5), 218
(3), 202 (4), 194 (3), 182 (2), 177 (4), 155 (8), 150 (2), 139 (1),
107 (5), 91 (100).
For 29: 1H NMR (500 MHz, CDCl3) δ 9.72 (s, 1 H), 7.87 (d,
J ) 7.4 Hz, 1 H), 7.46-7.23 (m, 10 H), 7.10 (t, J ) 6.8 Hz, 1
H), 6.89 (t, J ) 6.4 Hz, 1 H), 6.73 (d, J ) 7.7 Hz, 1 H), 5.50
(dd, J ) 4.6, 15.9 Hz, 1 H), 5.21 (m, 1 H), 4.92 (d, J ) 12.1 Hz,
1 H), 4.88 (d, J ) 12.1 Hz, 1 H), 4.84 (s, 1 H), 4.41 (d, J ) 4.6
Hz, 1 H), 3.99 (m, 1 H), 3.71 (s, 3 H), 3.63 (d, J ) 12.4 Hz, 1
H), 3.58 (m, 1 H), 3.25 (d, J ) 8.5 Hz, 1 H), 3.06 (s, 3 H), 2.94
(s, 3 H), 2.42 (m, 2 H).
For 30: 1H NMR (500 MHz, CDCl3) δ 9.70 (s, 1 H), 7.50 (d,
J ) 6.8 Hz, 1 H), 7.46-7.23 (m, 10 H), 7.17 (t, J ) 7.9 Hz, 1
H), 6.98 (t, J ) 7.4 Hz, 1 H), 6.76 (d, J ) 7.8 Hz, 1 H), 5.56
(dd, J ) 4.6, 15.8 Hz, 1 H), 5.17 (s, 1 H), 5.16 (m, 1 H), 5.10
(m, 2 H), 4.47 (d, J ) 4.6 Hz, 1 H), 4.08 (d, J ) 8.8 Hz, 1 H),
3.99 (m, 2 H), 3.74 (s, 3 H), 3.67 (m, 1 H), 3.07 (s, 3 H), 2.97 (s,
3 H), 2.55 (m, 1 H), 2.25 (dd, J ) 4.4, 13.9 Hz, 1 H).
(-)-Meth yl (2S,3a S,5R,11bR)-2-(Am in oca r bon yl)-3-ben -
zyl-2,3,3a,4,5,7-h exah ydr o-5-m eth yl-1H-pyr r olo[2,3-d]car -
ba zole-6-ca r boxyla te ((-)-20). Meth od a . A solution of the
tetracyclic diester (-)-19a (220 mg, 0.509 mmol) in 8 mL of
absolute MeOH was cooled to 0 °C and saturated with dry NH3
(g). The solution was stirred at room temperature for 5 days.
Concentration and chromatography on a silica gel column,
eluting with EtOAc/Hex (7:3), gave 150 mg of amide 20 (71%
yield).
(-)-Meth yl (2S,3a S,5S,11bR)-2-(Ben zyloxyca r bon yl)-3-
ben zyl-2,3,3a ,4,5,7-h exa h yd r o-5-(2-m eth oxyp h en yl)-1H-
p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te ((-)-19c). A solu-
tion of the amine 14 (300 mg, 0.658 mmol), benzoic acid (80
mg, 0.658 mmol), and 3-(2-methoxyphenyl)propenal (133 mg,
0.79 mmol) in 8 mL of benzene, under an atmosphere of Ar,
was heated in a 100 °C oil bath with a Dean-Stark water trap
for 36 h. Workup as above for (-)-19a and chromatography
on a silica gel column (EtOAc/Hex, 1:9) afforded 290 mg of the
product (-)-19c, (74% yield): TLC Rf ) 0.25 (hexane/Et2O, 4:1;
Meth od b. The above reaction solution, in a sealed tube,
was heated at 100-110 °C for 18 h. Workup as above gave
95 mg of amide (45% yield): TLC Rf ) 0.5 (hexane/EtOAc 3:7;
CAS blue); [R]23 ) -306 (c ) 1.0, CHCl3); mp 125 °C (from
CAS blue); mp 99-100 °C (HCl salt); [R]23 ) -234 (c ) 0.5,
D
D
CH2Cl2/hexane); UV (EtOH) λmax 328, 298, 228, 208 nm; IR
(KBr) νmax 3448, 3379, 3064, 3034, 2985, 2953, 2925, 2868,
1682, 1609, 1478, 1466, 1455, 1436, 1386, 1355, 1285, 1237,
1216, 1197, 1164, 1131, 1103, 1080, 1027, 988, 910, 790, 735,
702 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.98 (s, 1 H), 7.39 (m,
3 H), 7.32 (m, 2 H), 7.31 (t, J ) 7.6 Hz, 1 H), 6.86 (s, br, 1 H),
6.77 (d, J ) 7.7 Hz, 1 H), 6.71 (t, J ) 7.6 Hz, 1 H), 6.42 (d, J
) 7.4 Hz, 1 H), 5.52 (s, br, 1 H), 4.08 (d, J ) 13.4 Hz, 1 H),
3.90 (d, J ) 13.4 Hz, 1 H), 3.75 (s, 3 H), 3.68 (m, 2 H), 3.06 (m,
1 H), 2.25 (dd, J ) 12.1, 12.1 Hz, 1 H), 2.10 (dd, J ) 5.6, 12.1
Hz, 1 H), 1.62 (d, J ) 13.8 Hz, 1 H), 1.39 (d, J ) 7.5 Hz, 3 H),
1.35 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 175.11, 168.57,
164.55, 142.58, 136.79, 135.53, 130.35, 128.65, 128.08, 127.86,
121.46, 120.45, 109.90, 99.48, 65.88, 65.78, 57.09, 54.29, 50.91,
50.11, 34.65, 28.69, 21.77; MS m/z (relative intensity) 418 (8),
417 (M+, 7), 405 (2), 389 (11), 373 (49), 341 (6), 326 (13), 267
(2), 259 (2), 241 (7), 228 (57), 208 (11), 196 (9), 189 (6), 180
(11), 178 (4), 168 (16), 154 (4), 134 (5), 91 (100). Anal. Calcd
for C25H27N3O3‚CH2Cl2: C, 62.15; H, 5.82; N, 8.36. Found: C,
62.36; H, 5.54; N, 8.26.
CHCl3); UV (EtOH) λmax 326, 298, 230, 208 nm; IR (KBr) νmax
3369, 3061, 3031, 2948, 2834, 1742, 1674, 1607, 1487, 1466,
1436, 1285, 1234, 1210, 1157, 1128, 1089, 1031, 908, 752, 734,
700 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.38 (s, 1 H), 7.25 (m,
3 H), 7.21 (m, 3 H), 7.15 (d, J ) 7.8 Hz, 2 H), 7.10 (m, 3 H),
7.04 (m, 2 H), 6.86 (d, J ) 7.7 Hz, 1 H), 6.79 (m, 3 H), 6.72 (t,
J ) 7.3 Hz, 1 H), 4.69 (d, J ) 12.3 Hz, 1 H), 4.53 (d, J ) 12.3
Hz, 1 H), 4.42 (dd, J ) 3.7, 6.1 Hz, 1 H), 3.92 (d, J ) 14.0 Hz,
1 H), 3.82 (d, J ) 14.0 Hz, 1 H), 3.80 (s, 3 H), 3.60 (dd, J )
5.5, 11.5 Hz, 1 H), 3.57 (s, 3 H), 3.47 (dd, J ) 2.9, 5.4 Hz, 1 H),
2.73 (ddd, J ) 3.2, 3.2, 14.5 Hz, 1 H), 2.62 (dd, J ) 11.5, 11.5
Hz, 1 H), 1.84 (dd, J ) 5.5, 11.5 Hz, 1 H), 1.70 (ddd, J ) 6.1,
6.1, 14.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 171.46,
168.79, 165.20, 157.58, 143.11, 137.52, 137.08, 135.88, 133.11,
129.24, 128.85, 128.28, 128.24, 127.99, 127.91, 127.87, 126.83,
126.44, 121.66, 120.44, 119.96, 110.01, 109.24, 97.21, 65.85,
65.56, 63.67, 56.10, 55.03, 53.68, 50.90, 45.56, 35.02, 32.03;
MS m/z (relative intensity) 601 (M+ + 1, 5), 510 (10), 466 (70),
334 (5), 321 (36), 301 (7), 289 (25), 274 (5), 265 (7), 260 (26),
241 (5), 230 (5), 212 (5), 180 (7), 167 (5), 154 (2), 121 (2), 107
(3), 91 (100). Anal. Calcd for C30H30N2O3: C, 74.98; H, 6.04;
N, 4.66; Found: C, 75.01; H, 5.93; N, 4.60.
(-)-Meth yl (3a S,5S,11bR)-3-Ben zyl-2,3,3a ,4,5,7-h exa h y-
d r o-5-m eth yl-1H-p yr r olo[2,3-d ]ca r ba zole-6-ca r boxyla te
((-)-1a ). To a solution of the amide (-)-20 (80 mg, 0.192
mmol) and Et3N (187 uL, 1.344 mmol) in 3 mL of dichlo-
romethane, at 0 °C, was added (CF3CO)2O (81 µL, 0.576 mmol),
dropwise. The solution was allowed to warm to room temper-
ature and stirred for an additional 2 h, and the reaction was
quenched by adding 10% Na2CO3 solution. The aqueous phase
was extracted with dichloromethane. The residual nitrile (-)-
21, obtained upon drying (MgSO4) and concentration, was
dissolved in 3 mL of dry EtOH. KBH4 (52 mg, 0.96 mmol)
was added in several portions at room temperature. Then,
the reaction mixture was heated in a 75-80 °C oil bath for 4
h. The solvent was removed in vacuum. Water was added,
and the aqueous solution was basified with concentrated NH4-
OH to pH 10. The aqueous phase was extracted with dichlo-
romethane. The residue, obtained upon drying and concen-
tration, was chromatographed on a silica gel column, eluting
with EtOAc/Hex (1:9) to afford 52 mg of the product (72%
Sp ir o[p yr r olid in oin d olen in es] 28-30. A solution of the
amine 14 (200 mg, 0.438 mmol), benzoic acid (54 mg, 0.438
mmol), and 4,4-dimethoxycrotonaldehyde (51 mg, 0.395 mmol)
in 6 mL of benzene, under an atmosphere of Ar, was heated
at reflux with a Dean-Stark water trap for 3 h. Workup as
for (-)-19a , above, and chromatography on a silica gel column
(Et2O/Hex, 1:1) gave 125 mg of the spiro compounds 28-30
(69% yield) and 50 mg of tetracyclic product (-)-19a (22%
yield). For the spiro compounds: TLC Rf ) 0.12 (Et2O/Hex,
1:1; CAS blue); UV (EtOH) λmax 328, 296, 232, 206 nm; IR (KBr)
νmax 3355, 3087, 3063, 3033, 2993, 2948, 2833, 1731, 1672,
1609, 1482, 1472, 1455, 1443, 1285, 1229, 1164, 1106, 1073,
1051, 980, 792, 748, 697 cm-1; MS m/z (relative intensity) 569
(3), 568 (M+, 9), 553 (2), 536 (3), 493 (2), 433 (7), 352 (3), 292
(2), 276 (17), 268 (9), 248 (2), 232 (3), 220 (3), 214 (2), 202 (5),
194 (2), 188 (3), 169 (4), 154 (34), 140 (2), 122 (2), 114 (3), 101
(4), 91 (100).
yield): [R]22 ) -387.5 (c ) 0.24, CHCl3).
D
Determination of the ratio of the spiro compounds (ratio 28:
29:30 ) 11:17:10) by NMR follows. For 28: 1H NMR (500
MHz, CDCl3) δ 9.72 (s, 1 H), 7.87 (d, J ) 7.4 Hz, 1 H), 7.46 --
7.23 (m, 10 H), 7.10 (t, J ) 6.8 Hz, 1 H), 6.89 (t, J ) 6.4 Hz,
1 H), 6.73 (d, J ) 7.7 Hz, 1 H), 5.62 (dd, J ) 9.1, 15.6 Hz, 1
H), 5.30 (s, 1 H), 5.25 (m, 1 H), 5.10 (m, 2 H), 4.57 (d, J ) 9.1
Hz, 1 H), 3.95 (m, 2 H), 3.76 (s, 3 H), 3.61 (m, 1 H), 3.09 (s, 3
H), 3.03 (s, 3 H), 2.55 (m, 1 H), 2.42 (m, 1 H).
Sp ir o[p yr r olid in oin d olen in es] 26 a n d 27. A mixture of
Nb-benzyl-2-[(methoxycarbonyl)methyl]tryptamine (2, 322 mg,
1 mmol), benzaldehyde (122 uL, 1.2 mmol), BF3‚Et2O (4 µL,
0.03 mmol), and 4 Å molecular sieve powder in 8 mL of dry
toluene was heated at reflux for 5.5 h. Using the workup of
the general procedure and purification on a silica gel column
(EtOAc/hexane, 1:9) afforded 240 mg of a 2:1 mixture (by
NMR) of the products 26 and 27 as a white foam (58% yield):

7960 J . Org. Chem., Vol. 62, No. 23, 1997
Kuehne and Xu
TLC Rf ) 0.17 (hexane/EtOAc, 9:1; CAS blue); UV (EtOH) λmax
328, 298, 232, 216 nm; IR (KBr) νmax 3356, 3086, 3060, 3028,
2948, 2796, 1668, 1609, 1482, 1471, 1451, 1440, 1284, 1227,
1150, 1104, 790, 745, 700 cm-1; MS m/z (relative intensity)
411 (6), 410 (M+, 21), 319 (3), 230 (1), 216 (6), 208 (26), 196
(3), 183 (4), 169 (6), 156 (14), 140 (2), 128 (4), 118 (95), 105
(5), 91 (100).
Ack n ow led gm en t. This work was supported by the
Cancer Institute of the National Institutes of Health
with Grant No. RO1 CA 12010. We are indebted to
Robert Bennett and Patrick J okiel of our group for low-
resolution mass spectra and to Dr. Fred Strobel of the
Emory University Mass Spectrometry Facility for high-
resolution mass spectra.
For the major product 26: 1H NMR (500 MHz, CDCl3) d
9.53 (s, 1 H), 7.51 (d, J ) 7.4 Hz, 1 H), 7.43-7.01 (m, 11 H),
6.86 (dt, J ) 0.7, 7.4 Hz, 1 H), 6.50 (d, J ) 7.7 Hz, 1 H), 5.13
(s, 1 H), 4.04 (d, J ) 13.4 Hz, 1 H), 3.79 (s, 1 H), 3.77 (s, 3 H),
3.43 (ddd, J ) 4.7, 9.4, 9.4 Hz, 1 H), 3.11 (d, J ) 13.4 Hz, 1
H), 2.63 (ddd, J ) 7.6, 9.8, 9.8 Hz, 1 H), 2.29 (m, 2 H).
For the minor product 27: 1H NMR (500 MHz, CDCl3) δ
9.22 (s, 1 H), 7.43-7.01 (m, 13 H), 6.60 (d, J ) 7.7 Hz, 1 H),
5.33 (s, 1 H), 4.06 (d, J ) 13.3 Hz, 1 H), 3.86 (s, 1 H), 3.70 (s,
1 H), 3.39 (ddd, J ) 5.7, 9.3, 9.3 Hz, 1 H), 3.06 (d, J ) 13.3
Hz, 1 H), 2.59 (m, 1 H), 2.44 (ddd, J ) 3.5, 10.0, 13.5 Hz, 1 H),
2.29 (m, 1 H).
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds 1a ,c,d ,f,h ,i, 4-6, 8, 9, 14, 15,
18-20, 22-25, and 28-30, and 1H NMR spectra for com-
pounds 1e, 7, 16, 17, 26, and 27. Spectra for compound 1g
are found in ref 2 (75 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 O970207J