Synthesis of vinca alkaloids and related compounds. Part 106. An efficient convergent synthetic pathway to build up the ibophyllidine skeleton II. Total synthesis of (±)-deethylibophyllidine and (±)-14-EPI-deethylibophyllidine

Article abstract of DOI:10.3987/com-06-10845

Starting from 2,3-dihydrofuran (7) we prepared aldehyde (5) which, in a [4+2] cycloaddition reaction with the tryptamine derivative (4) gave, as a final step, compound (10) having a D-seco-aspidospermane skeleton. We synthesized (±)-14-epi-deethylibophyll

Full text of DOI:10.3987/com-06-10845

HETEROCYCLES, Vol. 68, No. 11, 2006
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HETEROCYCLES, Vol. 68, No. 11, 2006, pp. 2301 - 2317. © The Japan Institute of Heterocyclic Chemistry
Received, 25th July, 2006, Accepted, 1st September, 2006, Published online, 1st September, 2006. COM-06-10845
SYNTHESIS OF VINCA ALKALOIDS AND RELATED COMPOUNDS.
PART 106. AN EFFICIENT CONVERGENT SYNTHETIC PATHWAY TO
BUILD UP THE IBOPHYLLIDINE SKELETON II.
TOTAL SYNTHESIS OF (±)-DEETHYLIBOPHYLLIDINE AND
(±)-14-EPI-DEETHYLIBOPHYLLIDINE
Flórián Tóth,a György Kalaus,a,* István Greiner,b Mária Kajtár-Peredy,c
Ágnes Gömöry,c László Hazai,a and Csaba Szántay a,c,
*
aDepartment for Organic Chemistry, Research Group for Alkaloid Chemistry of
the Hungarian Academy of Sciences, Budapest University of Technology and
b
Economics, Gellért tér 4, H-1521 Budapest, Hungary. Chemical Works of
Gedeon Richter Ltd, Gyömrői út 19-21, H-1103 Budapest, Hungary. cInstitute of
Chemistry, Chemical Research Center, Hungarian Academy of Sciences,
Pusztaszeri út 59-67, H-1025 Budapest, Hungary
Corresponding author. Tel.: +36-1-463-1285; e-mail: kalaus@mail.bme.hu
Abstract – Starting from 2,3-dihydrofuran (7) we prepared aldehyde (5) which,
in a [4+2] cycloaddition reaction with the tryptamine derivative (4) gave, as a
final step, compound (10) having a D-seco-aspidospermane skeleton. We
synthesized (±)-14-epi-deethylibophyllidine (3) via the mesylate (12) of alcohol
(11) which had been obtained from 10, whereas the cyclization of the benzoate
ester (15) resulted in (±)-deethylibophyllidine (2). We have managed to build up
(±)-2 via the tetracyclic intermediates (16) and (20).
INTRODUCTION
The skeleton of indole alkaloids is characterized by a great deal of diversity. Ibophyllidine alkaloids, such
as deethylibophyllidine (2) have a five-membered D-ring and biogenetically deduced from one group of the
pseudoaspidospermane alkaloids (e.g. 1a and 1b) 1-4 (Figure 1). Deethylibophyllidine (2) was isolated in
1980 by French researchers from the bark of Tabernaemontana albiflora.5 As compared to the
Aspidosperma and Strychnos alkaloids,6, 7 much less attention has been given to the investigation of

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HETEROCYCLES, Vol. 68, No. 11, 2006
Ibophyllidine alkaloids. Therefore we aimed to achieve a simple synthetic route for the preparation of
9-14
alkaloid (2) from Ibophyllidine family and its analogue compound (3).8 Our previous experiences
gave us a reason to regard this as a plausible objective.
21
C2H5
OH
5
5
4
N
4
N
20
15
20
C
D
6
6
H
H
D
C
9
9
15
3
3
8
8
14
10
11
10
11
7
14
7
H
H
A
B
E
A
B
E
2
2
17
17
13
13
N
H
1
N
H
1
16
16
12
12
COOCH3
COOCH3
2
3
C14-αH Deethylibophyllidine
C14-βH 14-Epi-deethylibophyllidine
1a C20-βOH Pandoline
1b C20-αOH 20-Epi-pandoline
Figure 1
RESULTS AND DISCUSSION
As a substrate for the planned synthesis we utilized the tryptamine derivative (4) which we had used
successfully in our earlier works.9 We anticipated that the appropriately functionalized aldehydes (5, 6)
and (4) would give, in several steps, molecules with D-seco-aspidospermane skeleton, from which the
pentacyclic alkaloid (2) can be made to form easily (Figure 2).
N
H
Ph
O
R
+
2
N
OH
R= -CH2-OTBDMS (5)
R= -COOEt (6)
H
COOCH3
4
Figure 2
One of the reaction partners (5) was formed from 2,3-dihydrofuran (7), as a molecule containing a
masked aldehyde function. In the first step, using a method known from the literature,15 we opened up the
ring of compound (7) by the application of boron trifluoride-diethyl etherate and ethanethiol (8), then we
protected the alcohol (8) with tert-butyldimethylsilyl chloride in the presence of imidazole (9). Finally,

HETEROCYCLES, Vol. 68, No. 11, 2006
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after removing the dithioacetal protective group with mercury (II) chloride in the presence of calcium
carbonate in aqueous acetonitrile at room temperature, we arrived at aldehyde (5) (Scheme 1).
SEt
SEt
b
a
HO
TBDMSO
O
SEt
SEt
7
8
9
c
5
.
Scheme 1. Reagents and conditions: (a) EtSH, BF3 Et2O, CHCl3, 0oC, (86%); (b) TBDMSCl,
imidazole, CH2Cl2, rt, (92%); (c) HgCl2, CaCO3, CH3CN, H2O, rt, (78%).
As a continuation, we allowed 5 to react with the tryptamine derivative (4) in boiling toluene in the
presence of a catalytic amount of p-toluenesulfonic acid monohydrate. From the reaction mixture the
tertiary amine (10) was obtained in a good yield. We intended to construct the five-membered D-ring of
the Ibophyllidine alkaloids by intramolecular alkylation, therefore, by hydrolysis of the derivative (10)
containing the silyl moiety, we produced the alcohol (11) (Scheme 2).
N
Ph
R
H
a
H
4
+
5
N
H
COOCH3
R= -(CH2)2-OTBDMS 10
R= -(CH2)2-OH 11
b
Scheme 2. Reagents and conditions: (a) p-TsOH.H2O, toluene, reflux, (67%);
(b) 5M HCl, THF, rt, (88%).
Subsequently 11 was acylated with methanesulfonic acid chloride in the presence of triethylamine, then
the mesylate (12) was converted to the quaternary salt (13) in boiling tetrahydrofuran from which, after
catalytic debenzylation, the (±)-14-epi-deethylibophyllidine (3) was obtained in a good yield. The
formation of the product with the trans D/E ring connection can be explained by the fact that under the
conditions applied, prior to cyclization, the complete epimerization that had previously been observed by
us,16 and which would result in alkaloid (2), does not take place (Scheme 3).

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Ph
-
CH3SO3
N +
N
Ph
H
H
(CH2)2OMs
H
a
b
11
H
N
N
H
H
COOCH3
COOCH3
12
13
c
3
Scheme 3. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0oC, (82%); (b) THF, reflux, (69%);
(c) H2, Pd/C, CH3COOH, rt, (83%).
In the course of further studying the intramolecular alkylation reaction, we prepared the benzoate ester
(14) of the alcohol (11) as well. The catalytic debenzylation of 14 in glacial acetic acid resulted in the
expected molecule (15). Boiling the secondary amine (15) in toluene, after full epimerization, according
to our previous results and described mechanism,16 we obtained racemic deethylibophyllidine (2)
(Scheme 4).
R
N
H
(CH2)2OCOPh
a
c
11
2
H
N
H
COOCH3
R= Bn
R= H
14
15
b
Scheme 4. Reagents and conditions: (a) PhCOOH, DCC, DMAP, CH2Cl2, 0oC, (85%);
(b) H2, Pd/C, CH3COOH, rt, (92%); (c) toluene, reflux, (71%).
Utilizing our experiences from earlier syntheses,9-14 we also synthesized the ibophyllidine skeleton via the
lactam (18) known in the literature.8c We allowed the secondary amine (4) to react with
ethyl-4-oxobutanoate (6)17 in boiling toluene in the presence of p-toluenesulfonic acid monohydrate,
yielding the tetracyclic ester (16). Following catalytic debenzylation, by boiling the secondary amine (17)

HETEROCYCLES, Vol. 68, No. 11, 2006
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in toluene we obtained the lactam (18) in a good yield. Further on, we converted 18 with phosphorus
pentasulfide in tetrahydrofuran into thiolactam (19) and finally, the reductive desulfuration of the latter
compound furnished (±)-deethylibophyllidine (2) (Scheme 5).
R
R
N
N
H
H
CH2COOC2H5
a
c
4 + 6
H
H
N
H
N
H
COOCH3
COOCH3
R= Bn
R= H
16
17
R= O
R= S
18
19
2
d
e
b
R= H2
Scheme 5. Reagents and conditions: (a) p-TsOH.H2O, toluene, reflux, (61%); (b) H2, Pd/C, CH3COOH, rt
(95%); (c) toluene, reflux, (78%); (d) P4S10, THF, rt, (83%); (e) Raney Ni, THF, rt, (81%).
When ester (16) was reduced to aldehyde (20) with diisobutylaluminium hydride, the tertiary amine was
catalytically debenzylated and under the reaction conditions applied (±)-2 was obtained via epimerization,
cyclization and reduction steps. (Scheme 6).
N
Ph
H
CH2CHO
H
a
b
16
2
N
H
COOCH3
20
Scheme 6. Reagents and conditions: (a) DIBAL, CH2Cl2, -70oC, (66%);
(b) H2, Pd/C, CH3COOH, rt, (82%).
CONCLUSION
Starting from 2,3-dihydrofuran (7) we produced aldehyde (5), the reaction of which with the tryptamine
derivative (4) yielded compound (10) with D-seco-aspidospermane skeleton. The intramolecular

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HETEROCYCLES, Vol. 68, No. 11, 2006
alkylation reaction of the mesyl ester (12), which had been prepared from alcohol (11) led to
(±)-14-epi-deethylibophyllidine (3) as a final result, whereas the cyclization achieved via the benzoate
ester (15) furnished (±)-deethylibophyllidine (2). The synthesis of (±)-2 from ester (16) was performed via
two other reaction paths as well (see: 16→17→18→19→2, and 16→20→2, respectively).
EXPERIMENTAL
Melting points were determined on a hot-stage microscope Boetius and are uncorrected. IR spectra were
recorded on a Specord JR-75 spectrophotometer. NMR spectra were recorded on a Varian Unity
1
13
INOVA-400 instrument at 400 MHz for H and 100 MHz for C. All NMR spectra were recorded at rt.
1
J1r, long range coupling constant. Chemical shifts are relative to Me4Si (δ=0 ppm). Mutual H-1H
couplings are given only once, at the first occurrences. MS spectra were recorded on a PE Sciex API 2000
triple-quadrupole mass spectrometer equipped with a Turbo Ion Spray source and VG ZAB2-SEQ tandem
mass spectrometer (high resolution mass spectra). Preparative TLC analyses were performed on silica gel
F254 plates, and column chomatography was carried out on Merck Kieselgel 60 (0.063-0.200 mm).
4,4-Bis(ethylthio)butan-1-ol (8)
2,3-Dihydrofuran (7) (3.52 g, 3.8 mL, 50 mmol) was dissolved in dry CHCl3 (50 mL) and EtSH (6.21 g,
.
7.4 mL, 100 mmol) was added to the solution. It was cooled to 0oC and BF3 OEt2 (6.38 g, 5.7 mL, 50
mmol) was added dropwise to the solution over 10 min period. After the addition, the reaction mixture
was allowed to warm up to rt, and then stirred for 30 min. It was then poured into water (20 mL). The
aqueous phase extracted with CHCl3 (2×30 mL) and the combined organic phases were washed with 1 M
aqueous solution of NaOH (20 mL) and brine (20 mL). It was dried (MgSO4) and concentrated in vacuo,
to yield 8 (8.36 g, 86%) as a colorless oil (TLC: acetone/hexane=1:2, Rf=0.72). IR (neat) νmax 3352, 2928,
1452, 1264, 1060. MS m/z (%) (rel intensity) 194 (16.0, M+), 133 (30.0), 115 (23.0), 87 (10.0), 71 (100.0).
1
HRMS (EI) calcd for C8H18OS2 194.0799, found for 194.0805. H NMR δH (CDCl3): 1.26 (6H, t, J=7.4
Hz; 2×SCH2CH3), 1.74 (1H, t, J=4.5 Hz; OH), 1.76-1.94 (4H, m; 2-H2+3-H2), 2.60+2.69 (2×2H, 2×dq,
J
gem=12.5 Hz, Jvic=7.4 Hz; 2×SCH2CH3), 3.67 (2H, td, Jvic=5.8 and 4.5 Hz; 4-H2), 3.82 (1H, t, J=6.8 Hz;
1-H). 13C NMR δC (CDCl3): 14.50+24.18 (2×SCH2CH3), 30.57 (C3), 32.54 (C2), 51.19 (C1), 62.25 (C4).
(4,4-Bis(ethylthio)butoxy)(tert-butyl)dimetylsilane (9)
Imidazole (2.10 g, 31 mmol) was added to a solution of 8 (5.00 g, 26 mmol) in dry CH2Cl2 (50 mL). Then
tert-butyldimethylsilyl chloride (4.65 g, 31 mmol) in dry CH2Cl2 (20 mL) was added dropwise to the
stirred solution. After the addition, the mixture was stirred for 2 h at rt. The salts were separated by

HETEROCYCLES, Vol. 68, No. 11, 2006
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filtration and the organic phase was washed with water (2×15 mL) and brine (20 mL), dried (MgSO4) and
concentrated in vacuo to give 9 (7.38 g, 92%) a colorless liquid (TLC: AcOEt/hexane=1:4, Rf=0.9). IR
(neat) νmax 2960, 2928, 1256, 1176, 840. MS m/z (%) (rel intensity) 308 (2.0, M+), 247 (24.0), 189 (48.0),
1
115 (100.0), 73 (22.0). HRMS (EI) calcd for C14H32OS2Si 308.1664, found for 308.1665. H NMR δH
(CDCl3): 0.07 (6H, s; Si(CH3)2, 0.91 (9H, s; SiC(CH3)3), 1.28 (6H, t, J=7.5 Hz; 2×SCH2CH3), 1.73-1.93
(4H, m; 2-H2+3-H2), 2.61+2.70 (2×2H, 2×dq, Jgem=12.5 Hz, Jvic=7.5 Hz; 2×SCH2CH3), 3.65 (2H, t, J=6.1
Hz; 4-H2) 3.83 (1H, t, J=6.9 Hz; 1-H). 13C NMR δC (CDCl3): -5.28 (Si(CH3)2, 14.57+24.13 (2×SCH2CH3),
18.33 (SiC(CH3)3), 25.97 (SiC(CH3)3), 30.61 (C3), 32.52. (C2), 51.27 (C1), 62.53 (C4).
4-(tert-Butyldimethylsilanyloxy)butanal (5)
9 (2.00 g, 6.5 mmol) was dissolved in acetonitrile (50 mL) and water (5 mL) was added to the solution.
CaCO3 (2.60 g, 26 mmol) and mercury(II) chloride (7.10 g, 26 mmol) were added to a stirred solution.
After the addition the mixture was stirred for 1 h. The salts were filtrated and the acetonitrile was
removed at 40oC under reduced pressure to leave a yellow oil. This was then taken up into CH2Cl2 (50
mL) and washed with 20 mL portion of aqueous solution of NaI, 20 mL portion of aqueous solution of
Na2S2O8 and brine (20 mL). The combined organic phases were dried (MgSO4) and concentrated under
vacuum, yielded 1.03 g (78 %) of 5 as a colorless oil (TLC: AcOEt/hexane=1:4, Rf=0.69). IR (neat) νmax
2928, 1728, 1468, 1256, 1100. MS m/z (%) (rel intensity) 202 (2.0, M+), 161 (12.0), 145 (17.0), 75
(100.0). HRMS (EI) calcd for C10H22O2Si 202.1389, found for 202.1392. 1H NMR δH (CDCl3): 0.06 (6H,
s; Si(CH3)2), 0.91 (9H, s; SiC(CH3)3), 1.88 (2H, m; 3-H2), 2.52 (2H, td, Jvic=7.0 and 1.8 Hz; 2-H2), 3.67
(2H, t, J=6.0 Hz; 4-H2), 9.81 (1H, t, J=1.8 Hz; CHO). 13C NMR δC (CDCl3): -5.41 (Si(CH3)2), 18.29
(SiC(CH3)3), 25.52 (C3), 25.90 (SiC(CH3)3), 40.78 (C2), 62.09 (C4), 202.58 (C1).
3-Benzyl-4-[2-(tert-butyldimethylsilanyloxy)-ethyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carb-a
zole-6-carboxylic acid methyl ester (10)
A solution of 4 (1.00 g, 2.85 mmol), 5 (0.69 g, 3.42 mmol), and p-toluenesulfonic acid monohydrate (10
mg, 0.06 mmol) in dry toluene (50 mL) was refluxed under argon over 24 h, then the reaction mixture
was cooled and extracted with brine (2×40 mL) and the combined organic phases were dried (MgSO4)
and evaporated in vacuo. The residue was purified by column chromatography (eluting with
AcOEt/hexane=1:4, Rf=0.65) to yield 0.99 g (67 %) of 10 as a yellow oil. IR (neat) νmax 3384, 2928, 1676,
1612, 1464, 1440, 1248, 1104, 744. MS m/z (%) (rel intensity) 518 (33.0, M+), 385 (65.0), 304 (100.0),
1
168 (11.0), 91 (74.0). HRMS (EI) calcd for C31H42N2O3Si 518.2965, found for 518.2973. H NMR δH
(CDCl3): -0.02+ -0.01 (2×3H, 2×s; Si(CH3)2), 0.85 (9H, s; SiC(CH3)3), 1.12 (2H, m; 15-H2), 1.67+2.03
(2×1H, 2×ddd, Jgem=11.6 Hz, Jvic=4.9+<1 and 12.0+6.0 Hz; 6-H2), 2.09 (1H, m; 14-H), 2.53+2.62 (2×1H,

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2×dd, Jgem=15.0 Hz, Jvic=3.3 and 3.0 Hz; 17-H2), 2.65+2.90 (2×1H, 2×ddd, Jgem=9.0 Hz, Jvic=12.0+4.9 and
6.0+<1 Hz; 5-H2), 2.98 (1H, br s; 3-H), 3.49 (2H, m; 20-H2), 3.72+4.13 (2×1H, 2×d, Jgem=13.0 Hz;
NCH2Ph), 3.77 (3H, s; OCH3), 6.80 (1H, d, J=7.7 Hz; 12-H), 6.82 (1H, ddd, J=7.5+7.4+1.4 Hz; 10-H),
6.94 (1H, br d, J=7.5 Hz; 9-H), 7.13 (1H, ddd, J=7.7+7.4+1.6 Hz; 11-H), 7.24-7.40 (5H, m; Ph), 8.94 (1H,
13
br s; N1-H). C NMR δC (CDCl3): -5.39 and -5.32 (Si(CH3)2), 18.34 (SiC(CH3)3), 22.46 (C17), 25.99
(SiC(CH3)3), 33.96 (C15), 35.28 (C14), 42.33 (C6), 50.40 (C5), 50.92 (OCH3), 55.16 (C7), 58.02
(NCH2Ph), 61.11 (C20), 71.56 (C3), 90.87 (C16), 109.18 (C12), 120.51 (C9), 122.26 (C10), 127.77 (C11),
127.05+128.31+129.05+138.98 (Ph), 137.97 (C8), 143.08 (C13), 165.33 (C2), 169.08 (16-COOCH3).
3-Benzyl-4-(2-hydroxyethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylic acid
methyl ester (11)
5 M aqueous solution of HCl (0.75 mL) was added to a solution of 10 (1.00 g, 1.92 mmol) in 10 mL THF
and the mixture was stirred for 45 min at rt. After stirring the mixture was concentrated in vacuo, then the
residue was dissolved in CH2Cl2 (25 mL) and washed with water (10 mL) and brine (10 mL). The organic
phase was dried (MgSO4) and the solvent was evaporated in vacuo. The residue was purified by column
chromatography (eluting with acetone/hexane=1:2, Rf=0.4) to yield a yellow oil, which was crystallized
from CH3OH to afford 11 ( 0.69 g, 88 %) as white crystals. IR (neat) νmax 3376, 2952, 1676, 1608, 1464,
1440, 744. MS m/z (%) (rel intensity) 404 (10.0, M+), 373 (4.0), 271 (4.0), 190 (36.0), 91 (100.0). HRMS
(EI) calcd for C25H28N2O3 404.2099, found for 404.2099. 1H NMR δH (CDCl3): 1.11+1.18 (2×1H, 2×dm,
Jgem=13.8 Hz; 15-H2), 1.68+2.05 (2×1H, 2×ddd, Jgem=11.7 Hz, Jvic=4.9+<1 and 12.0+6.0 Hz; 6-H2), 2.04
(1H, m; 14-H), 2.55+2.63 (2×1H, 2×dd, Jgem=15.2 Hz, Jvic=3.3 and 3.0 Hz; 17-H2), 2.68+2.96 (2×1H,
2×ddd, Jgem=9.0 Hz, Jvic=12.0+4.9 and 6.0+<1 Hz; 5-H2), 2.98 (1H, br s; 3-H), 3.10 (1H, br s; OH), 3.50
(2H, t, J=6.7 Hz; 20-H2), 3.79+4.11 (2×1H, 2×d, Jgem=13.0 Hz; NCH2Ph), 3.77 (3H, s; OCH3), 6.81 (1H,
br d, J=7.7 Hz; 12-H), 6.83 (1H, ddd, J=7.5+7.4+1.4 Hz; 10-H), 6.94 (1H, br d, J=7.5 Hz; 9-H), 7.13 (1H,
ddd, J=7.7+7.4+1.6 Hz; 11-H), 7.25-7.40 (5H, m; Ph), 8.94 (1H, br s; N1-H). 13C NMR δC (CDCl3):
22.50 (C17), 33.94 (C15), 35.30 (C14), 42.17 (C6), 50.56 (C5), 51.02 (OCH3), 55.20 (C7), 58.15
(NCH2Ph), 60.77 (C20), 71.72 (C3), 90.67 (C16), 109.25 (C12), 120.58 (C9), 122.22 (C10), 127.88 (C11),
127.21+128.36+129.16+138.64 (Ph), 137.74 (C8), 143.02 (C13), 165.02 (C2), 169.01 (16-COOCH3).
Anal. Calcd for C25H28N2O3: C, 74.23; H, 6.98; N, 6.93. Found C, 73.94; H, 6.87; N 7.00.
2-(9-(Methoxycarbonyl)-1-benzyl-2,3,8,10,11,11a-hexahydro-1H-pyrrolo[2,3-d]carbazol-11-yl)ethyl
methanesulfonate (12)
11 (1.00 g, 2.47 mmol) was dissolved in dry CH2Cl2 (20 mL), triethylamine (0.41 mL, 0.30 g, 2.97 mmol)
and 4-dimethylaminopyridine (35 mg, 0.3 mmol) were added to the solution. After the addition it was

HETEROCYCLES, Vol. 68, No. 11, 2006
2309
cooled to 0oC and methanesulfonyl chloride (0.23 mL, 0.34 g, 2.97 mmol) was added dropwise at 0oC.
The mixture was stirred 1 h and poured into water (5 mL). The phases were separated and the organic
phase was washed with brine (10 mL). It was dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography (eluent: Et2O/hexane=1:5, Rf=0.45) to afford 1.08 g (82 %) of the
product (12) as a yellow oil. IR (neat) νmax 3376, 2936, 1676, 1608, 1464, 1352, 1208, 746. MS m/z
(FAB) (%) (rel intensity) 483 (10.0, M+H+), 387 (45.0), 268 (12.0), 194 (13.0), 168 (15.0), 91 (100.0).
1
HRMS (FAB) calcd for C26H31N2O5S (M+H+) 483.1958, found for (M+H+) 483.1951. H NMR δH
(CDCl3): 1.33 (2H, m; 15-H2), 1.70+2.06 (2×1H, 2×ddd, Jgem=12.1 Hz, Jvic=4.8+<1 and 12.0+6.7 Hz;
6-H2), 2.07 (1H, m; 14-H), 2.59+2.65 (2×1H, 2×dd, Jgem=15.5 Hz, Jvic=3.5 and 3.0 Hz; 17-H2), 2.70+2.98
(2×1H, 2×m; 5-H2), 2.93 (3H, s; OSO2CH3), 2.97 (1H, br s; 3-H), 3.78 (3H, s; OCH3), 3.80+4.13 (2×1H,
2×d, Jgem=14.0 Hz; NCH2Ph), 4.00-4.14 (2H, m; 20-H2), 6.82 (1H, d, J=7.7 Hz; 12-H), 6.85 (1H, ddd,
J=7.5+7.2+1.0; 10-H), 6.96 (1H, br d; J=7.2 Hz; 9-H), 7.15 (1H, ddd, J=7.7+7.5+1.3 Hz; 11-H), 7.27-7.42
(5H, m; Ph), 8.94 (1H, br s; N1-H). 13C NMR δC (CDCl3): 21.94 (C17), 30.15 (C15), 35.11 (C14), 37.31
(OSO2CH3), 42.09 (C6), 50.58 (C5), 51.11 (OCH3), 55.15 (C7), 58.16 (NCH2Ph), 68.13 (C20), 71.44
(C3), 90.14 (C16), 109.36 (C12), 120.75 (C9), 122.21 (C10), 128.04 (C11),
127.31+128.43+129.08+138.4 (Ph), 137.50 (C8), 142.88 (C13), 164.90 (C2), 168.73 (16-COOCH3).
12-Benzyl-4-(methoxycarbonyl)1,2,2a,3,5,10,11,12a-octahydropyrrolizino[1,7-cd]carbazol-12-ium
mesylate (13)
12 (0.50 g, 1 mmol) was dissolved in dry THF (10 mL) and it was refluxed over 12 h. Then it was cooled
and the salt was separated by filtration. The crystals were washed with cold THF and dried in vacuo to
give 345 mg (69 %) of 13 as white crystals. IR (KBr) νmax 3320, 2944, 1680, 1608, 1464, 1204, 748. MS
m/z (%) (rel intensity) 483 (100.0, M+), 387 (10.0), 297 (35.0), 216 (4.0), 149 (5.0). HRMS (EI) calcd for
1
C26H30N2O5S 482.9272, found for 482.9269. H NMR δH (CDCl3): 1.95-2.06 (2H, m; 15-H2), 2.15+2.80
(2×1H, 2×dd, Jgem=16.0 Hz, Jvic=12.0 and 4.5 Hz; 17-H2), 2.22+3.12 (2×1H, 2×ddd, Jgem=13.8 Hz,
-
Jvic=6.8+~1 and 12.6+8.0 Hz; 6-H2), 2.55 (1H, m; 14-H), 2.82 (3H, s; CH3SO3 ), 3.74 (3H, s; OCH3), 4.00
(1H, d, J=11.9 Hz; 3-H), 4.08+4.88 (2×1H, 2×ddd, Jgem=13.2 Hz, Jvic=12.4+5.6 and 7.0+<1 Hz; 20-H2),
4.22+4.79 (2×1H, 2×ddd, Jgem=14.0 Hz, Jvic=12.6+6.8 and 8.0+<1 Hz; 5-H2), 4.80+5.70 (2×1H, 2×d,
Jgem=13.0 Hz; N+CH2Ph), 6.92 (1H, d, J=8.0 Hz; 12-H), 6.97 (1H, ddd, J=7.9+7.2+1.5 Hz; 10-H), 7.29
13
(1H, ddd, J=8.0+7.2+1.0 Hz; 11-H), 7.44 (1H, d, J=7.9 Hz; 9-H), 9.48 (1H, br s; N1-H). C NMR δC
-
(CDCl3): 26.54 (C17), 29.25 (C15), 39.65 (CH3SO3 ), 40.26 (C6), 42.12 (C14), 51.62 (OCH3), 57.06 (C7),
67.93+68.75+6916 (C5+C20+N+CH2Ph), 77.85 (C3), 98.57 (C16), 111.15 (C12), 121.34 (C10), 122.28
(C9), 129.98 (C11), 129.05+129.65+130.93+132.94 (Ph), 131.46 (C8), 145.23 (C13), 159.67 (C2),
167.96 (16-COOCH3).

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HETEROCYCLES, Vol. 68, No. 11, 2006
(±)-14-Epi-deethylibophyllidine (3)
A mixture of 13 (0.50 g, 1 mmol) and 10 % palladium/charcoal (0.25 g) in glacial AcOH (10 mL) was
hydrogenated for 2 h at rt and then filtered. The filtrate was poured into ice-water (50 mL) and neutralized
with saturated Na2CO3 solution. The mixture was extracted with CH2Cl2 (3×50 mL) and the combined
organic phases were dried (MgSO4) and evaporated in vacuo. The residue was purufied by column
chromatography (eluting with AcOEt/methanol=1:1, Rf=0.15) yielded 0.26 g (83 %) of 3 as a colorless oil.
IR (neat) νmax 3384, 2952, 1676, 1608, 1468, 1440, 1208, 744. MS m/z (%) (rel intensity) 296 (21.0, M+),
202 (4.0), 167 (3.0), 91 (12.0), 82 (100.0), 44 (58.0). HRMS (EI) calcd for C18H20N2O2 296.1525, found
1
for 296.1528. H NMR δH (CDCl3): 1.59+2.13 (2×1H, 2×dddd, Jgem=11.7 Hz, Jvic=12.6+9.8+9.0 and
5.6+7.5+1.0 Hz; 15-H2), 1.82+2.63 (2×1H, 2×ddd, Jgem=12.5 Hz, Jvic=7.6+1.5 and 10.5+9.6 Hz; 6-H2),
1.91 (1H, m; 14-H), 2.18+2.84 (2×1H, 2×dd, Jgem=15.7 Hz, Jvic=12.0 and 4.7 Hz; 17-H2), 2.83+3.82
(2×1H, 2×ddd, Jgem=11.8 Hz, Jvic=9.6+1.5 and 10.5+7.6 Hz; 5-H2), 2.93+3.77 (2×1H, 2×ddd, Jgem=11.7
Hz, Jvic=9.8+7.5 and 9.0+1.0 Hz; 20-H2), 2.95 (1H, d, J=10.8 Hz; 3-H), 3.76 (3H, s; OCH3), 6.78 (1H, d;
13
12-H), 6.86 (1H, dd; 10-H), 7.14 (1H, dd; 11-H), 7.42 (1H, d; 9-H), 9.18 (1H, br s; N1-H). C NMR δC
(CDCl3): 27.30 (C17), 30.50 (C15), 39.67 (C6), 40.74 (C14), 51.20 (OCH3), 56.41 (C7), 56.71 (C5),
58.57 (C20), 71.86 (C3), 96.73 (C16), 109.57 (C12), 120.99 (C10), 122.15 (C9), 128.13 (C11), 135.71
(C8), 144.34 (C13), 164.11 (C2), 168.88 (16-COOCH3).
11-(2-(Benzoyloxy)ethyl)-1-benzyl-2,3,8,10,11,11a-hexahydro-1H-pyrrolo[2,3-d]carbazole-9-car-
boxylic acid methyl ester (14)
1,3-Dicyclohexylcarbodiimide (0.55 g, 2.6 mmol) and 4-dimethylaminopyridine (32 mg, 0.26 mmol)
were added to a solution of benzoic acid (0.32 g, 2.6 mmol) in dry CH2Cl2 (10 mL). The mixture cooled
to 0oC and at this temperature 11 (1.00 g, 2.5 mmol) in dry CH2Cl2 (10 mL) was added dropwise. The
mixture was allowed to warm up to rt and then stirred for 3 h. The suspension was extracted with brine
(2×10 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography (eluting with Et2O/hexane=1:1, Rf=0.45) to afford 1.08 g (85 %) of the
product (14) as white crystals after recrystallization from CH3OH. IR (KBr) νmax 3376, 2952, 1720, 1680,
1608, 1472, 1440, 1384, 1328, 748. MS m/z (%) (rel intensity) 508 (4.0, M+), 386 (29.0), 367 (13.0), 149
(15.0), 91 (5.0), 82 (100.0). HRMS (EI) calcd for C32H32N2O4 508.2362, found for 508.2357. 1H NMR δH
(CDCl3): 1.34+1.40 (2×1H, 2×dm, Jgem=14.0 Hz; 15-H2), 1.70+2.07 (2×1H, 2×ddd, Jgem=11.9 Hz,
Jvic=5.0+<1 and 12.0+6.2 Hz; 6-H2), 2.10 (1H, m; 14-H), 2.60+2.71 (2×1H, 2×dd, Jgem=15.5 Hz, Jvic=3.0
and 2.8 Hz; 17-H2), 2.68+2.94 (2×1H, 2×ddd, Jgem=9.0 Hz, Jvic=12.0+5.0 and 6.2+<1 Hz; 5-H2), 3.03 (1H,
br s; 3-H), 3.76+4.11 (2×1H, 2×d, Jgem=13.4 Hz; NCH2Ph), 3.77 (3H, s; OCH3), 4.14-4.26 (2H, m; 20-H2),
6.82 (1H, br d, J=7.7 Hz; 12-H), 6.85 (1H, ddd, J=7.5+7.4+1.4 Hz; 10-H), 6.99 (1H, br d, J=7.5 Hz; 9-H),

HETEROCYCLES, Vol. 68, No. 11, 2006
2311
7.15 (1H, ddd, J=7.7+7.4+1.6 Hz; 11-H), 7.20-7.42 (7H, m; Ph+3’-H+5’-H), 7.52 (1H, m; 4’-H), 7.96
(2H, m; 2’-H+6’-H), 8.99 )1H, br s; N1-H). 13C NMR δC (CDCl3): 22.56 (C17), 29.95 (C15), 36.00 (C14),
42.27 (C6), 50.66 (C5), 51.04 (OCH3), 55.23 (C7), 58.28 (NCH2Ph), 63.21 (C20), 71.58 (C3), 90.56
(C16), 109.30 (C12), 120.65 (C9), 122.29 (C10), 127.92 (C11), 127.14+128.33+128.95+138.88 (Ph),
128.36+129.56 (C2’+C3’+C5’+C6’), 130.37 (C1’), 132.84 (C4’), 137.76 (C8), 143.03 (C13), 165.08 (C2),
.
166.52 (OCOPh), 169.02 (16-COOCH3). Anal. Calcd for C32H32N2O4 CH3OH: C, 73.13; H, 6.71; N, 6.39.
Found C, 73.08; H, 6.55; N 5.38.
11-(2-(Benzoyloxy)ethyl)-2,3,8,10,11,11a-hexahydro-1H-pyrrolo[2,3-d]carbazole-9-carboxylic acid
methyl ester (15)
A mixture of 14 (0.50 g, 0.98 mmol) and 10 % palladium/charcoal (0.25 g) in glacial AcOH (10 mL) was
hydrogenated for 1 h at rt and then filtered. The filtrate was poured into ice-water (40 mL) and neutralized
with saturated Na2CO3 solution. The mixture was extracted with CH2Cl2 (3×50 mL) and the combined
organic phases were dried (MgSO4) and evaporated in vacuo. The main component was separated by
preparative TLC (eluting with CH2Cl2/CH3OH=20:1, Rf=0.32) yielded 0.38 g (92 %) of 15 as a yellow oil.
IR (neat) νmax 3368, 2952, 1720, 1676, 1608, 1464, 1440, 1276, 748. MS m/z (%) (rel intensity) 418 (3.0,
M+), 296 (27.0), 154 (5.0), 122 (16.0), 82 (100.0), 77 (12.0). HRMS (EI) calcd for C25H26N2O4 418.1893,
found for 418.1897. 1H NMR δH (CDCl3): 1.36-1.52 (2H, m; 15-H2), 1.80-2.10 (3H, m; 6-H2+14-H), 2.37
(1H, m; N4-H), 2.41+2.74 (2×1H, 2×dd, Jgem=15.5 Hz, Jvic=3.8 and 3.0 Hz; 17-H2), 3.10-3.20 (2H, m;
5-H2), 3.59 (1H, br s; 3-H), 3.77 (3H, s; OCH3), 4.21+4.28 (2×1H, 2×dt, Jgem=11.1 Hz, Jvic=7.0 and 6.2
Hz; 20-H2), 6.85 (1H, br d; 12-H), 6.90 (1H, ddd; 10-H), 7.17 (1H, ddd; 11-H), 7.24 (1H, br d; 9-H),
7.38-7.56 (3H, m; 3’-H+4’-H+5’-H), 7.98 (2H, m; 2-H+6’-H), 9.07 (1H, br s; N1-H). 13C NMR δC
(CDCl3): 22.17 (C17), 30.47 (C15), 38.04 (C14), 44.20 (C6), 45.18 (C5), 51.08 (OCH3), 55.71 (C7),
62.87 (C20), 66.32 (C3), 90.10 (C16), 109.37 (C12), 120.89 (C9), 121.95 (C10), 128.04 (C11),
128.33+129.57 (C2’+C3’+C5’+C6’), 130.32 (C1’), 132.87 (C4’), 137.48 (C8), 143.14 (C13), 165.22 (C2),
166.54 (OCOPh), 168.87 (16-COOCH3).
(±)-Deethylibophyllidine (2)
Method I.: A mixture of 15 (0.3 g, 0.72 mmol) and potassium iodide (0.12 g, 0.72 mmol) in dry DMF (7
mL) was refluxed 4 h, then was evaporated in vacuo. The main component was purified by preparative
TLC (eluting with AcOEt/CH3OH=1:1, Rf=0.15) to yield 2 (0.15 g, 71 %) as a yellow oil. IR (neat) νmax
3376, 2944, 1676, 1608, 1248, 1112, 744. MS m/z (%) (rel intensity) 296 (24.0, M+), 265 (4.0), 239 (5.0),
154 (30.0), 127 (13.0), 115 (6.0), 82 (100.). HRMS (EI) calcd for C18H20N2O2 296.1525, found for
1
296.1537. H NMR δH (CDCl3): 1.70+2.09 (2×1H, 2×ddd, Jgem=12.5 Hz, Jvic=5.5+1.2 and 12.0+7.5 Hz;

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HETEROCYCLES, Vol. 68, No. 11, 2006
6-H2), 1.80+2.16 (2×1H, 2×dddd, Jgem=12.8 Hz, Jvic=5.7+1.2+1.0 and 11.8+7.2+6.8 Hz; 15-H2),
1.89+2.81 (2×1H, 2×ddd, Jgem=15.4 Hz, Jvic=12.0 and 5.9 Hz; 17-H2), 2.07 (1H, m; 14-H), 2.77+3.33
(2×1H, 2×ddd, Jgem=9.5 Hz, Jvic=11.8+5.7 and 7.2+1.2 Hz; 20-H2), 2.93+3.40 (2×1H, 2×ddd, Jgem=12.2
Hz, Jvic=7.5+1.2 and 12.0+5.5 Hz; 5-H2), 3.77 (3H, s; OCH3), 3.79 (1H, d, J=7.0 Hz; 3-H), 6.82 (1H, d;
13
12-H), 6.90 (1H, dd; 10-H), 7.18 (1H, dd; 11-H), 7.36 (1H, d; 9-H), 9.06 (1H, br s; N1-H). C NMR δC
(CDCl3): 26.32 (C17), 31.82 (C15), 38.77 (C14), 38.94 (C6), 50.97 (OCH3), 52.48 (C5), 55.13 (C20),
57.55 (C7), 73.10 (C3), 91.74 (C16), 109.19 (C12), 120.99 (C10), 122.58 (C9), 128. 13 (C11), 136.62
(C8), 143.55 (C13), 164.29 (C2), 168.54 (16-COOCH3).
11-((Ethoxycarbonyl)methyl)-1-benzyl-2,3,8,10,11,11a-hexahydro-1H-pyrrolo[2,3-d]carbazole-9-car
boxylic acid methyl ester (16)
A solution of 4 (1.00 g, 2.85 mmol), 6 (0.45 g, 3.42 mmol) and p-toluenesulfonic acid monohydrate (10
mg, 0.06 mmol) in dry toluene (50 mL) was refluxed under argon over 24 h. The reaction mixture was
extracted with brine (2×40 mL) and the combined organic phases were dried (MgSO4) and evaporated in
vacuo. The residue was purified by column chromatography (eluting with AcOEt/hexane=1:2, Rf=0.42)
to yield a yellow oil, which was crystallized from methanol to afford 16 (0.78 g, 61 %) as white crystals.
IR (KBr) νmax 3376, 2976, 1736, 1680, 1612, 1464, 748. MS m/z (%) (rel intensity) 446 (25.0, M+), 401
(9.0), 313 (59.0), 232 (98.0), 91 (100.0). HRMS (EI) calcd for C27H30N2O4 446.2206, found for 446.2225.
1H NMR δH (CDCl3): 1.18 (3H, t, J=7.0 Hz; COOCH2CH3), 1.67+2.04 (2×1H, 2×ddd, Jgem=11.8 Hz,
Jvic=5.0+<1 and 12.0+6.1 Hz; 6-H2), 1.90+2.03 (2×1H, 2×dd, Jgem=16.0 Hz, Jvic=8.4 and 6.0 Hz; 15-H2),
2.51 (1H, m; 14-H), 2.63 (2H, m; 17-H2), 2.63+2.89 (2×1H, 2×ddd, Jgem=9.0 Hz, Jvic=12.0+5.0 and
6.1+<1 Hz; 5-H2), 3.04 (1H, br s; 3-H), 3.74+4.30 (2×1H, 2×d, Jgem=13.2 Hz; NCH2Ph), 3.76 (3H, s;
OCH3), 4.05 (2H, q, J=7.0 Hz; COOCH2CH3), 6.81 (1H, d, J=7.6 Hz;12-H), 6.82 (1H, ddd; 10-H), 6.92
(1H, br d, J=7.2 Hz; 9-H), 7.14 (1H, ddd, J=7.6+7.4+1.7 Hz; 11-H), 7.24-7.42 (5H, m; Ph), 8.96 (1H, br
13
s; N1-H). C NMR δC (CDCl3): 14.23 (COOCH2CH3), 23.49 (C17), 35.76 (C14), 36.16 (C15), 42.23
(C6), 50.10 (C5), 50.96 (OCH3), 55.02 (C7), 57.55 (NCH2Ph), 60.26 (COOCH2CH3), 70.55 (C3), 90.72
(C16), 109.26 (C12), 120.62 (C9), 122.30 (C10), 127.88 (C12), 127.00+128.28+128.99+139.02 (Ph),
137.67 (C8), 142.99 (C13), 164.77 (C2), 168.91 (16-COOCH3), 172.84 (COOCH2CH3). Anal. Calcd for
.
C27H30N2O4 CH3OH: C, 70.72; H, 6.04; N, 5.85. Found C, 70.79; H, 5.93; N 5.80.
11-((Ethoxycarbonyl)methyl)-2,3,8,10,11,11a-hexahydro-1H-pyrrolo[2,3-d]carbazole-9-carboxylic
acid methyl ester (17)
16 (1.00 g, 2.24 mmol) was dissolved in 10 mL of glacial AcOH and 10 % palladium/charcoal (0.50 g)
was added to the solution. It was hydrogenated for 2 h at rt and then filtered. The filtrtate was poured into

HETEROCYCLES, Vol. 68, No. 11, 2006
2313
ice-water (50 mL) and neutralized with saturated Na2CO3 solution. The mixture was extracted with
CH2Cl2 (3×70 mL) and the combined organic phases were dried (MgSO4) and evaporated in vacuo. The
residue was purified by column chromatography (eluent: CH2Cl2/CH3OH=9:1, Rf=0.65) to yield 0.77 g
(95 %) of the product (17) as a yellow oil. IR (neat) νmax 3368, 2944, 1732, 1676, 1608, 1464, 1248, 747.
MS m/z (%) (rel intensity) 356 (80.0, M+), 313 (24.0), 311 (25.0), 287 (15.0), 280 (14.0), 238 (15.0), 215
(96.0), 168 (16.0), 154 (31.0), 142 (100.0), 96 (24.0). ). HRMS (EI) calcd for C20H24N2O4 356.1736,
1
found for 446.2225. H NMR δH (CDCl3): 1.17 (3H, t, J=7.0 Hz; COOCH2CH3), 1.84+1.99 (2×1H,
2×ddd, Jgem=12.2 Hz, Jvic=5.0+2.0 and 10.3+7.6 Hz; 6-H2), 1.99+2.04 (2×1H, 2×dd, Jgem=16.0 Hz,
Jvic=7.6 and 7.1 Hz; 15-H2), 2.40 (1H, m; 14-H), 2.47+2.65 (2×1H, 2×dd, Jgem=15.5 Hz, Jvic=4.0 and 3.0
Hz; 17-H2), 2.85 (1H, br s; N4-H), 3.16-3.24 (2H, m; 5-H2), 3.57 (1H, br s; 3-H), 3.76 (3H, s; OCH3),
4.04 (2H, q, J=7.0 Hz; COOCH2CH3), 6.85 (1H, d, J=7.6 Hz; 12-H), 6.90 (1H, ddd, J=7.6+7.3+1.4 Hz;
10-H), 7.18 (1H, ddd, J=7.6+7.6+1.6 Hz; 11-H), 7.25 (1H, br d, J=7.3 Hz; 9-H), 9.05 (1H, br s; N1-H).
13C NMR δC (CDCl3): 14.12 (COOCH2CH3), 23.15 (C17), 36.76 (C15), 37.65 (C14), 43.44 (C6), 44.84
(C5), 51.00 (OCH3), 55.34 (C7), 60.34 (COOCH2CH3), 65.59 (C3), 90.37 (C16), 109.34 (C12), 120.88
(C9), 122.02 (C10), 128.08 (C11), 137.12 (C8), 143.09 (C13), 164.39 (C2), 168.77 (16-COOCH3),
172.47 (COOCH2CH3).
20-Oxodeethylibophyllidine (18)
A solution of 17 (0.50 g, 1.4 mmol) and p-toluenesulfonic acid monohydrate (10 mg, 0.06 mmol) in 15
mL of dry toluene was refluxed under argon for 16 h. Then it was cooled and concentrated in vacuo, the
residue was dissolved in CH2Cl2 (20 mL) and washed with water (10 mL) and brine (10 mL). The organic
phase was dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by preparative
TLC (eluting with CH2Cl2/CH3OH=9:1, Rf=0.85) to yield a colorless oil, which was crystallized from
CH3OH to afford 0.34 g (78 %) of 18 as white crystals. IR (KBr) νmax 3384, 2944, 1696, 1608, 1440,
1252, 748. MS m/z (%) (rel intensity) 310 (27.0, M+), 279 (3.0), 251 (6.0), 227 (44.0), 214 (100), 195
(46.0), 182 (21.0), 167 (20.0), 154 (40.0). HRMS (EI) calcd for C18H18N2O3 310.3471, found for
1
310.3475. H NMR δH (CDCl3): 1.79+2.78 (2×1H, 2×dd Jgem=15.3 Hz, Jvic=12.0 and 5.0 Hz; 17-H2),
1.84-1.94 (2H, m; 6-H2), 2.15+2.86 (2×1H, 2×dd, Jgem=16.2 Hz, Jvic=<1 and 6.5 Hz; 15-H2), 2.21 (1H, m;
14-H), 3.26+4.17 (2×1H, 2×dm, Jgem=12.0 Hz; 5-H2), 3.77 (3H, s; OCH3), 4.31 (1H, d, J=6.0 Hz; 3-H),
6.88 (1H, br d; J=7.9 Hz; 12-H), 6.94 (1H, ddd, J=7.6+7.4+1.0 Hz; 10-H), 7.22 (1H, ddd, J=7.9+7.6+1.2
13
Hz; 11-H), 7.27 (1H, br d, J=7.4 Hz; 9-H), 9.05 (1H, br s; N1-H). C NMR δC (CDCl3): 24.84 (C17),
36.10 (C14), 38.65 (C15), 42.60+43.19 (C5+C6), 51.14 (OCH3), 54.95 (C7), 67.74 (C3), 92.86 (C16),
109.66 (C12), 121.25+121.72 (C9+C10), 128.70 (C11), 135.59 (C8), 143.39 (C13), 163.10 (C2), 168.04

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HETEROCYCLES, Vol. 68, No. 11, 2006
(16-COOCH3), 176.70 (C20). Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found C, 69.57; H,
5.86; N 8.58.
20-Thioxodeethylibophyllidine (19)
To a solution of 20-oxodeethylibophyllidine (18) (0.50 g, 1.61 mmol) in dry THF (30 mL) was added
0.55 g (2.42 mmol) of phosphorus pentasulfide. The reaction mixture was stirred for 2 h at rt and then
diluted with 30 mL of CH2Cl2. The solution was extracted with 20 mL of brine and the aqueous phase
was extracted with 10 mL of CH2Cl2. The combined organic phases were dried (MgSO4) and the solvent
was evaporated in vacuo. The residue was purified by preparative TLC (eluting with acetone/hexane=1:2,
Rf=0.35) to yield a yellow oil, which was crystallized from CH3OH to afford 19 (0.44 g, 83 %) as white
crystals. IR (KBr) νmax 3384, 2944, 1672, 1624, 1608, 1456, 1176, 748. MS m/z (%) (rel intensity) 326
(100.0, M+), 293 (10.0), 267 (4.0), 227 (70.0), 195 (67.0), 167 (48.0). HRMS (EI) calcd for C18H18N2O2S
327.1167, found for 327.1206. 1H NMR δH (CDCl3): 1.78+2.78 (2×1H, 2×dd, Jgem=15.5 Hz, Jvic=12.0 and
5.0 Hz; 17-H2), 1.94-2.05 (2H, m; 6-H2), 2.28 (1H, m; 14-H), 2.88+3.27 (2×1H, 2×dd, Jgem=16.8 Hz,
Jvic=<1 and 5.8 Hz; 15-H2), 3.58+4.64 (2×1H, 2×dm, Jgem=12 Hz; 5-H2), 3.77 (3H, s; OCH3), 4.61 (1H, d,
J=6.0 Hz; 3-H), 6.89 (1H, br d, J=7.9 Hz; 12-H), 6.97 (1H, ddd, J=7.6+7.4+1.0 Hz; 10-H), 7.24 (1H, ddd,
13
J=7.9+7.6+1.2 Hz; 11-H), 7.31 (1H, br d, J=7.4 Hz; 9-H), 9.05 (1H, br s; N1-H). C NMR δC (CDCl3):
23.92 (C17), 38.43 (C14), 42.45 (C6), 47.25 (C15), 51.22 (OCH3), 51.47 (C5), 53.99 (C7), 73.80 (C3),
93.26 (C16), 109.84 (C12), 121.38+121.46 (C9+C10), 128.96 (C11), 134.96 (C8), 143.39 (C13), 162.77
(C2), 168.00 (16-COOCH3), 202.06 (C20). Anal. Calcd for C18H18N2O2S: C, 66.23; H, 5.56; N, 8.58; S,
9.82. Found C, 66.32; H, 5.66; N 8.56; S, 9.76.
(±)-Deethylibophyllidine (2)
Method II.: To a solution of 19 (0.25 g, 0.77 mmol) in dry THF (20 mL) was added ca. 1 g of water,
CH3OH and dry THF-washed Raney Ni. The suspension was stirred for 10 h at rt and then filtered. The
Raney Ni was washed with dry THF (10 mL) and the combined filtrates were concentrated in vacuo. The
residue was purified by preparative TLC (eluent: AcOEt/CH3OH=1:1, Rf=0.15) to afford 0.18 g (81 %) of
the deethylibophyllidine (2) as a yellow oil. The analytical data were identified in the previous method.
1-Benzyl-11-(formylmethyl)-2,3,8,10,11,11a-hexahydro-1H-pyrrolo[2,3-d]carbazole-9-carboxylic
acid methyl ester (20)
The ester (16) (1.00 g, 2.24 mmol) was dissolved in dry CH2Cl2 (50 mL) and cooled to -78oC. A solution
of 1.0 M diisobutylaluminium hydride in hexane ( 2.91 mL, 2.91 mmol) was added dropwise, and the
resulting solution was stirred at -78oC for 1 h. Then saturated aqueous NH4Cl (10 mL) was added, and the

HETEROCYCLES, Vol. 68, No. 11, 2006
2315
solution was allowed to warm to rt. After stirring for 30 min the white precipitate was filtered, the solvent
was extracted with water (2×20 mL) and brine (15 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (eluting with
Et2O/hexane=1:1, Rf=0.41) to yield a colorless oil, which was crystallized from CH3OH to afford 20
(0.77 g, 66 %) as white crystals. IR (KBr) νmax 3384, 2944, 1720, 1676, 1608, 1448, 1248, 744. MS m/z
(%) (rel intensity) 402 (20.0, M+), 269 (46.0), 214 (10.0), 188 (69.0), 91 (100.0). HRMS (EI) calcd for
1
C25H26N2O3 402.1943, found for 402.1922. H NMR δH (CDCl3): 1.68 (1H, dd, Jgem=11.9 Hz, Jvic=5.0
Hz; 6-HA), 2.05 (1H, m; 6-HB), 2.05+2.16 (2×1H, 2×ddd, Jgem=18.0 Hz, Jvic=8.4+1.6 and 5.8+1.5 Hz;
15-H2), 2.57 (1H, m; 14-H), 2.6-2.7 (3H, m; 17-H2+5-HA), 2.92 (1H, dd, Jgem=9.0 Hz, Jvic=6.7 Hz; 5-HB),
2.98 (1H, br s; 3-H), 3.80+4.28 (2×1H, 2×d, Jgem=13.4 Hz; NCH2Ph), 3.77 (3H, s; OCH3), 6.82 (1H, d;
12-H), 6.83 (1H, m; 10-H), 6.90 (1H, br d, J=7.1 Hz; 9-H), 7.14 (1H, ddd, J=7.6+7.4+1.7 Hz; 11-H),
7.25-7.42 (5H, m; Ph), 8.98 (1H, br s; N1-H), 9.58 (1H, t, J=1.5 Hz; 20-H). 13C NMR δC (CDCl3): 23.40
(C17), 33.33 (C14), 42.13 (C6), 45.79 (C15), 50.28 (C5), 51.03 (OCH3), 55.10 (C7), 57.79 (NCH2Ph),
70.81 (C3), 90.67 (C16), 109.28 (C12), 120.72 (C9), 122.31 (C10), 127.97 (C11),
127.07+128.31+129.02+138.84 (Ph), 137.45 (C8), 142.88 (C13), 164.83 (C2), 168.81 (16-COOCH3),
.
201.45 (C20). Anal. Calcd for C25H26N2O3 3/4CH3OH: C, 72.51; H, 6.38; N, 6.56. Found C, 72.53; H,
6.33; N 6.53.
(±)-Deethylibophyllidine (2)
Method III.: A mixture of the amino aldehyde (20) (0.50 g, 1.24 mmol) and 10 % palladium/charcoal
catalyst (0.1 g) in 10 mL of CH3COOH was stirred for 48 h under hydrogene at atmospheric pressure.
The reaction mixture was filtered and the filtrate was poured into ice-water (40 mL) and neutralized with
saturated Na2CO3 solution. The mixture was extracted with CH2Cl2 (3×50 mL) and the combined organic
phases were dried (MgSO4) and evaporated in vacuo. The residue was purified by preparative TLC
(eluent: AcOEt/CH3OH=1:1, Rf=0.15) to yield 0.31 g (82 %) of deethylibophyllidine (2) as a yellow oil.
The analytical data were identified in the previous method.
ACKNOWLEDGEMENTS
The authors are grateful to the National Scientific Research Foundation (OTKA T046060) for financial
support of this work.
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