Synthesis of vinca alkaloids and related compounds. Part 105: Efficient convergent synthetic pathway to the ibophyllidine skeleton and synthesis of (±)-19-hydroxy-ibophyllidine and (±)-19-hydroxy-20-epiibophyllidine

Article abstract of DOI:10.1016/j.tet.2006.09.079

Starting from methyl-5-oxohexanoate we produced the appropriately functionalized aldehyde, which, after having been allowed to react with the tryptamine derivative in a [4+2] cycloaddition reaction as the final step, yielded the molecule containing a D-se

Full text of DOI:10.1016/j.tet.2006.09.079

Tetrahedron 62 (2006) 12011–12016
Synthesis of vinca alkaloids and related compounds. Part 105:
Efficient convergent synthetic pathway to the ibophyllidine
skeleton and synthesis of (± ±)1ꢀ)hydroxy)ibophyllidine
*
and (± ±)1ꢀ)hydroxy)20)epiibophyllidine
a
a,*
b
c
c
ꢀ
Fl ꢀo ri ꢀa n T ꢀo th, Gy €o rgy Kalaus, Istv ꢀa n Greiner, M ꢀa ria Kajt ꢀa r-Peredy, Agnes G €o m €o ry,
a
a,
*
L ꢀa szl ꢀo Hazai and Csaba Sz ꢀa ntay
a
Department for Organic Chemistry, Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences,
Budapest University of Technology and Economics, Gelle´rt te´r 4, H-1111 Budapest, Hungary
b
Chemical Works of Gedeon Richter Ltd, Gy o€ mrTi uꢀ t 19-21, H-1103 Budapest, Hungary
Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri uꢀ t 59-67, H-1025 Budapest, Hungary
c
Received 27 June 2006; revised 2 September 2006; accepted 21 September 2006
Available online 18 October 2006
Abstract—Starting from methyl-5-oxohexanoate we produced the appropriately functionalized aldehyde, which, after having been allowed
to react with the tryptamine derivative in a [4+2] cycloaddition reaction as the final step, yielded the molecule containing a D-seco-aspido-
spermane skeleton. From the latter we could successfully produce a 1:1 mixture of protected epimers, the desilylation reaction of the protected
molecules gave the alkaloids (ꢀ)-19-hydroxy-ibophyllidine and (ꢀ)-19-hydroxy-20-epiibophyllidine in good yield.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The ibophyllidine alkaloids, as pentacyclic monoterpenoid
indole alkaloids, can be biogenetically classified into the
c-aspidospermane skeleton group. The precursors of their
In the present synthesis we again used the well-proven trypt-
amine derivative 3. We anticipated that aldehyde 4, used as
a reaction partner would yield in a reaction with 3 a molecule
with a D-seco-aspidospermane skeleton from which penta-
cyclic alkaloids can be easily formed (Fig. 2).
6
2
,3
4
biosynthesis are pandoline (1a) and 20-epipandoline (1b)
(
Fig. 1). The title alkaloids were isolated in 1980 by French
5
researchers from the trunk of Tabernaemontana albiflora.
In our earlier publications we described an efficient conver-
gent synthetic pathway to build up the aspidospermane
and c-aspidospermane skeletons, in the course of which
compounds with a D-seco-aspidospermane skeleton were
The starting material for the preparation of 4 was methyl-5-
oxohexanoate (5) (Scheme 1). In the first step, 5 was
8
obtained from an N -benzyltryptamine derivative (3) and
b
appropriately built up aldehydes (or aldehyde equivalents),
respectively. In the final reaction step involving intramolec-
ular acylation or alkylation, the synthesis of several alkaloids
6
,7
and alkaloid-like molecules was achieved.
*
See Ref. 1.
Keywords: 19-Hydroxy-ibophyllidine; 19-Hydroxy-20-epiibophyllidine;
Indole alkaloids; Natural products.
*
Corresponding authors. Tel.: +361 463 1285; fax: +361 463 3297 (Gy.K.);
tel.: +361 463 1195; fax: +361 463 3297 (Cs.S.); e-mail addresses:
kalaus@mail.bme.hu; szantay@mail.bme.hu
Figure 1. Biosynthesis of 2a and 2b.
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.079

12012
F. T oꢀ th et al. / Tetrahedron 62 (2006) 12011–12016
Figure 2. Planned synthesis of 2a and 2b.
Scheme 3. Reagents and conditions: (a) 10% Pd/C, H
b) toluene, xylene or decalin, D.
2 3
, CH COOH, (92%);
(
ꢁ
Scheme 1. Reagents and conditions: (a) Br
ꢁ
2
, (C
2
H
5
)
2
O, 0 C (67%); (b)
OH, 0 C (86%); (c) TBDMSCl, imidazole, CH Cl , D
a mixture of the quaternary salts 13a and 13b, accompanied
NaBH
(78%); (d) (i-Bu)
4
, CH
3
2
2
1
0
ꢁ
AlH, CH
Cl
2 2
, ꢂ60 C (72%).
by the earlier described full epimerization. The salt mix-
ture was catalytically debenzylated and in this step a mixture
of the alcohols containing the protecting group (11a and
2
brominated to give 6, then the ketone group was reduced
with sodium borohydride to 7. Subsequently, we protected
the alcohol 7 in dichloromethane with tert-butyldimethyl-
silyl chloride in the presence of imidazole 8. In the next
step, ester 8 containing the protecting group was converted
into aldehyde 4 in a good yield. The secondary amine 3
was allowed to react with aldehyde 4 in toluene in the pres-
ence of p-toluenesulfonic acid monohydrate (Scheme 2).
From the reaction mixture the D-seco-aspidospermane ꢀ
was isolated. As a continuation of the synthesis we intended
to form the D-ring of the ibophyllidine skeleton. The benzyl
group was removed from the tertiary amine ꢀ by catalytic
hydrogenolysis, then 10 was boiled in toluene, xylene, or
decalin, but the expected pentacyclic molecules (11a and
1
1b) was obtained as a product. By removing the protecting
group in the final step, (ꢀ)-19-hydroxy-ibophyllidine (2a)
and (ꢀ)-19-hydroxy-20-epiibophyllidine (2b) can be iso-
lated from the reaction mixture with a good yield.
1
1b) were not obtained in any of the cases (Scheme 3).
2
Scheme 2. Reagent and conditions: (a) p-TsOH$H O, toluene, D (47%).
Modifying our synthesis strategy, we intended to create the
p-toluenesulfonyloxy group instead of the bromine function
in the intramolecular alkylation reaction. We wished to
achieve the halogen/tosyloxy change by boiling com-
pound ꢀ in acetonitrile with silver p-toluenesulfonate, which
9
is a method known in the literature (Scheme 4). Surpris-
ingly, the reaction did not result in the expected product
mixture (12). In our opinion, during conversion, the tosyloxy
group attaches to molecule 12, resulting under the applied
reaction conditions in the formation via alkylation of
Scheme 4. Reagents and conditions: (a) AgOTs, CH
H
3
CN, D; (b) 10% Pd/C,
3
, CH COOH (48%); (c) 1 M HCl, THF (2a, 42%, 2b, 39%).
2

F. T oꢀ th et al. / Tetrahedron 62 (2006) 12011–12016
12013
3
. Conclusion
4.1.2. Methyl 4)bromo)5)hydroxyhexanoate (7±. NaBH4
(0.40 g, 9 mmol) was added to a solution of 6 (2.00 g,
ꢁ
We have worked out a new, biomimetic synthesis pathway
for the construction of the ibophyllidine skeleton. Starting
from methyl-5-oxohexanoate 5, we produced aldehyde 4,
which was then used as a reaction partner in the course of the
planned synthesis. In the final step the [4+2] cycloaddition
reaction of the tryptamine derivative 3 and the aldehyde 4
resulted in ꢀ with a D-seco-aspidospermane skeleton. The
hydrogenolysis of the tertiary amine ꢀ led to a mixture of
the secondary amine epimers 10 from which the pentacyclic
alkaloid skeleton was attempted to be formed by intramolec-
ular alkylation. Due to lack of formation of the D-ring of the
ibophyllidine skeleton we modified our strategy as a result of
which a 1:1 mixture of the molecules containing the protec-
tive groups (11a and 11b) was produced. As a final step, fol-
lowing removal of the protective group, we arrived at the
9 mmol) in dry methanol (50 mL) at 0 C. After the addition,
the reaction mixture was allowed to warm up to rt, and was
stirred for 1 h. It was then poured into brine (20 mL) and
extracted with dichloromethane (2ꢃ50 mL). The combined
organic phases were dried (MgSO ) and the solvent was
4
evaporated in vacuo. The residue was purified by column
chromatography (eluting with acetone/hexane¼1:2, R ¼
f
0.4) to afford 1.74 g (86%) of the product 7 as a colorless
oil (8:2 mixture of the diastereoisomers): IR (neat) n 3472,
2952, 1736, 1440, 1260, 1200 cm ; H NMR (CDCl )
ꢂ1
1
3
d 1.31 (3H, d, J¼6.1 Hz; CHCH ), 2.01 (1H, d, J¼7.0 Hz;
3
OH), 2.10–2.32 (2H, m; CHCH CH ), 2.48–2.68 (2H, m;
2
2
CH COOCH ), 3.69 (3H, s; OCH ), 3.77 (1H, m; CHOH),
2
3
3
1
3
4.07 (1H, td, J¼10.0+4.0 Hz; CH–Br); C NMR (CDCl3)
d 21.3 (CH CH), 30.6 (CHCH CH ), 32.1 (CH COOCH ),
3
3
2
2
2
(
2
ꢀ)-19-hydroxy-ibophyllidine (2a) and (ꢀ)-19-hydroxy-
51.8 (OCH ), 64.8 (CH–Br), 70.3 (CHOH), 173.2
3
+
0-epiibophyllidine (2b) alkaloids.
(COOCH ); MS m/z (relative intensity) 227 (21.0, [M] ),
3
+
2
25 (21.0, [M] ), 209 (35.0), 207 (35.0), 181 (25.0), 179
(25.0), 127 (33.0), 74 (100.0); HRMS (EI) calcd for
C H
7
14 3
9
+
4
. Experimental
BrO 225.0126, found for [M+H ] 225.0143.
7
4
.1. General
4.1.3. Methyl 4)bromo)5)(tert)butyl)dimethyl)silanyloxy±
hexanoate (8±. Imidazole (1.21 g, 17.8 mmol) was added to
a solution of 7 (2.00 g, 8.9 mmol) in dry dichloromethane
(40 mL). Then tert-butyldimethylsilyl chloride (2.68 g,
17.8 mmol) in 10 mL dry dichloromethane was added drop-
wise to a stirred solution at rt. After the addition the mixture
was refluxed over 24 h. Then it was cooled, the salts were
separated by filtration and the organic phase was washed
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 INOVA-400 instrument at
4
were recorded at rt. Chemical shifts are reported relative to
1
13
00 MHz for H and 100 MHz for C. All NMR spectra
1
1
Me Si (d¼0 ppm). Mutual H– H couplings are given only
with water (2ꢃ15 mL) and brine (15 mL), dried (MgSO ),
4
4
once. 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 spec-
trometer (high resolution mass spectra). Preparative TLC
analyses were performed on silica gel F254 plates, and col-
umn chromatography was carried out on Merck Kieselgel
and concentrated in vacuo. The residue was purified by
column chromatography (eluting with ether/hexane¼1:1,
R ¼0.9) to afford 2.35 g (78%) of the product 8 as a colorless
f
oil (8:2 mixture of the diastereoisomers): IR (neat) n 2952,
2936, 1744, 1440, 1256, 1176 cm ; H NMR (CDCl )
ꢂ1
1
3
d 0.07 (6H, s; Si(CH ) ), 0.90 (9H, s; C(CH ) ), 1.26 (3H,
3
2
3 3
6
0 (0.063–0.200 mm).
d, J¼6.2 Hz; CH CH), 2.01+2.28 (2ꢃ1H, 2ꢃm;
3
CHCH CH ), 2.49+2.63 (2ꢃ1H, 2ꢃddd, J ¼16.4 Hz,
2
2
gem
4
.1.1. Methyl 4)bromo)5)oxohexanoate (6±. Compound 5
2.00 g, 17.5 mmol) was dissolved in ether (50 mL) and it
J ¼8.0+7.5 and 8.5+5.5 Hz; CH COOCH ), 3.68 (3H, s;
vic
2
3
(
was cooled to 0 C. Bromine (3.19 g, 20 mmol, 1.02 mL)
OCH ), 3.92 (1H, td, J¼10.6+3.5 Hz; CHBr), 3.98 (1H,
3
ꢁ
was added to the solution at 0 C over 20 min period. After
13
qd, J¼6.2 and 3.5 Hz; CHO–); C NMR (CDCl ) d ꢂ4.8
3
ꢁ
and ꢂ4.4 (Si(CH ) ), 18.1 (C(CH ) ), 19.6 (CH CH), 25.8
3
2
3 3
3
the addition, the reaction mixture was allowed to warm up to
rt and then stirred for 30 min. The suspension was extracted
(C(CH ) ), 28.6 (CHCH CH ), 32.5 (CH COOCH ), 51.7
3 3 2 2 2 3
(OCH ), 60.5 (CH–Br), 71.1 (CHO–), 173.3 (COOCH );
3
3
+
with 5% aqueous solution of NaHCO (2ꢃ10 mL) and brine
MS m/z (relative intensity) 341 (2.0, [M] ), 339 (2.0,
[M] ), 309 (18.0), 307 (18.0), 283 (69.0), 281 (39.0), 259
3
+
(
centrated in vacuo. The residue was purified by column chro-
2ꢃ10 mL). The organic phase was dried (MgSO ) and con-
4
(31.0), 209 (67.0), 207 (67.0), 159 (79.0), 127 (55), 85
BrO Si 339.0991,
7
13 28 3
9
matography (eluting with ether/hexane¼1:2, R ¼0.45) to
(100.0); HRMS (EI) calcd for C H
found for [M+H ] 339.0986.
f
+
afford 1.33 g (67%) of the product 6 as a yellow oil: IR
neat) n 2961, 1736, 1714, 1440, 1273, 1178 cm ; H
ꢂ1
1
(
NMR (CDCl ) d 2.19+2.35 (2ꢃ1H, 2ꢃm; CH–CH –CH ),
4.1.4. 4)Bromo)5)(tert)butyl)dimethyl)silanyloxy± hexa)
nal (4±. The ester 8 (2.00 g, 5.9 mmol) was dissolved in
3
2
2
2
1
3
.39 (3H, s; COCH ), 2.51+2.55 (2ꢃ1H, 2ꢃddd, J
¼
3
gem
ꢁ
6.6 Hz, J ¼7.0+7.0 and 7.6+6.4 Hz; CH COOCH ),
50 mL dry dichloromethane and cooled to ꢂ60 C. A solu-
vic
2
3
.70 (3H, s; OCH ), 4.43 (1H, dd, J¼8.4+5.6 Hz; CH–Br);
tion of 1.0 M diisobutyl aluminum hydride in hexane
(7.1 mL, 7 mmol) was added dropwise, and the resulting
3
1
3
C NMR (CDCl ) d 26.28 (COCH ), 28.19+31.22
3
3
ꢁ
aqueous NH Cl was added, and the solution was allowed
(
CH CH COOCH ), 51.86 (OCH3), 52.75 (CH–Br),
2
solution was stirred at ꢂ60 C for 45 min. Then saturated
2
3
1
72.74 (COOCH ), 201.30 (CH CO); MS m/z (relative in-
3
3
4
+
+
tensity) 223 (40.0, [M] ), 221 (41.0, [M] ), 209 (29.0),
07 (29.0), 191 (26.0), 121 (45.0), 42 (100.0); HRMS
to warm up to rt. After stirring for 30 min the white precip-
itate was filtered, and the solvent was extracted with water
(2ꢃ20 mL) and brine (15 mL). The combined organic
2
7
9
+
(
EI) calcd for C H14 BrO3 223.0658, found for [M ]
7
2
23.0654.
phases were dried (MgSO ) and concentrated in vacuo.
4

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F. T oꢀ th et al. / Tetrahedron 62 (2006) 12011–12016
The residue was purified by column chromatography (elut-
ing with ether/hexane¼1:4, R ¼0.6) to afford 1.31 g (72%)
glacial acetic acid (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 Na CO solu-
f
of the product 4 as a colorless oil (8:2 mixture of the dia-
stereoisomers): IR (neat) n 2952, 2944, 1732, 1468, 1152,
2
3
tion. The mixture was extracted with dichloromethane
(3ꢃ50 mL) and the combined organic phases were dried
ꢂ1
1
1
092 cm ; H NMR (CDCl ) d 0.07+0.08 (2ꢃ3H, 2ꢃs;
3
Si(CH ) ), 0.90 (9H, s; C(CH ) ), 1.26 (3H, d, J¼6.2 Hz;
(MgSO ) and evaporated in vacuo. The main component
4
3
2
3 3
CH CH), 2.00+2.32 (2ꢃ1H, 2ꢃm; CHCH CH ),
was separated by preparative TLC (eluting with dichloro-
methane/methanol¼20:1, R ¼0.35) to yield 10 (0.39 g,
3
2
2
2
.66+2.77 (2ꢃ1H, 2ꢃm; CH COOCH ), 3.89 (1H, td,
2
3
f
J¼10.6+3.5 Hz; CHBr), 3.99 (1H, qd, J¼6.2 and 3.5 Hz;
92%) as a yellow oil: IR (neat) n 3376, 2952, 1680, 1608,
1464, 1440, 1248, 1204, 744 cm ; H NMR (CDCl3)
1
3
ꢂ1
1
CHO–), 9.81 (1H, t, J¼1.0 Hz; HC]O); C NMR
(
1
CDCl ) d ꢂ4.8 and ꢂ4.4 (Si(CH ) ), 18.1 (C(CH ) ),
d ꢂ0.18, ꢂ0.09, ꢂ0.07, and ꢂ0.03 (6H, 4ꢃs; Si(CH ) ),
3 3
3
3 2
3 3
9.5 (CH CH), 25.8 (C(CH ) ), 25.8 (CHCH CH ), 42.5
3
0.68 and 0.78 (9H, 2ꢃs; C(CH ) ), 1.11 and 1.12 (3H,
3 3
3 3
2
2
(
MS m/z (relative intensity) 309 (4.0, [M] ), 307 (4.0,
CH CHO), 60.4 (CHBr), 71.1 (CHO–), 201.1 (HC]O);
2ꢃd, J¼6.3 Hz; CH CH), 1.14+1.41 (2ꢃ1H, 2ꢃm; 14-
2
3
+
CH ), 1.82+1.92 (2ꢃ1H, 2ꢃm; 6-H ), 2.13 (1H, m;14-H),
2
2
+
[
M] ), 283 (15.0), 281 (15.0), 253 (25.0), 251 (32.0), 209
56.0), 207 (56.0), 171 (23.0), 159 (82.0), 73 (100.0);
2.33 and 2.43+2.64 and 2.70 (2ꢃ1H, 2ꢃdd; 17-H ), 3.10–
2
(
HRMS (EI) calcd for C H
3.20 (2H, m; 5-H ), 3.47 and 3.49 (1H, 2ꢃs; 3-H), 3.76
2
7
9
BrO Si 307.0729, found for
2
and 3.78 (3H, 2ꢃs; OCH ), 3.78–3.94 (2H, m; CH–
1
2
24
3
+
[
MꢂH ] 307.0744.
O+CH–Br), 6.75–6.95 (2H, m; 12-H+10-H), 7.10–7.20
(1H, m; 11-H), 7.20–7.25 (1H, m; 9-H), 8.96 and 9.01
1
3
4
.1.5. 3)Benzyl)4)[2)bromo)3)(tert)butyl)dimethyl)sil)
(1H, s; N1-H). C NMR (CDCl ) d ꢂ5.0, ꢂ4.9, ꢂ4.8, and
3
anyloxy±)butyl])2,3,3a,4,5,7)hexahydro)1H)pyrrolo [2,3)
d]carbazole)6)carboxylic acid methyl ester (ꢀ±. A solution
of 1.00 g (2.85 mmol) of 3, 1.08 g (3.45 mmol) 4, and 10 mg
ꢂ4.7 (Si(CH ) ), 17.8 (C(CH ) ), 19.1 (CH CH), 20.4 and
3
3
3 3
3
24.4 (C17), 25.6 and 25.7 (C(CH ) ), 32.8 and 35.4 (C14-
3
3
CH ), 39.1 and 39.8 (C14), 44.1 and 44.5 (C6), 45.1 and
2
(
5
0.06 mmol) of p-toluenesulfonic acid monohydrate in
0 mL of dry toluene was refluxed under argon over 24 h.
45.4 (C5), 51.0 (OCH ), 55.9 and 56.0 (C7), 59.0 and 59.3
3
(CH–Br), 65.4 and 67.1 (C3), 70.6 and 70.9 (CH–O), 89.5
and 90.5 (C16), 109.2 and 109.3 (C12), 120.8 and 120.9
(C10), 121.9 (C9), 127.9 and 128.0 (C11), 137.5 (C8),
The reaction mixture was extracted with brine (2ꢃ40 mL),
and the combined aqueous phases were extracted with di-
chloromethane (2ꢃ40 mL). The combined organic phases
143.1 (C13), 165.2 and 165.6 (C2), 168.6 and 168.9
(COOCH ); MS m/z (relative intensity) 536 (3.0, [M] ),
+
were dried (MgSO ) and evaporated in vacuo. The residue
4
3
+
was purified by column chromatography (eluent: ethyl-
acetate/hexane¼1:4, R ¼0.6) to yield 0.84 g (47%) ꢀ as a
534 (3.0, [M] ), 456 (53.0), 295 (78.0), 242 (55.0), 215
(85.0), 168 (15.0), 154 (15.0), 110 (100.0); HRMS (EI)
f
7
9
39 2 3
+
yellow oil: IR (neat) n 3381, 2928, 1680, 1612, 1464,
440, 1248, 744 cm ; H NMR (CDCl ) d ꢂ0.19, ꢂ0.08,
calcd for C H
2
BrN O Si 534.1913, found for [M ]
6
ꢂ1
1
1
534.1897.
3
ꢂ0.03, and 0.07 (6H, 4ꢃs; Si(CH ) ), 0.69 and 0.77 (9H,
3
3
2
ꢃs; C(CH ) ), 1.10 and 1.12 (3H, 2ꢃd, J¼6.5 Hz;
4.1.7. 1ꢀ)(tert)Butyl)dimethyl)silanyloxy±)ibophyllidine
(11a± and 1ꢀ)(tert)butyl)dimethyl)silanyloxy±)20)epi)
ibophyllidine (11b±. Silver p-toluenesulfonate (0.45 g,
1.6 mmol) was added to a solution of ꢀ (0.5 g, 0.8 mmol)
in acetonitrile (10 mL), and the mixture was refluxed for
48 h. After heating the solvent was evaporated in vacuo.
The residue was dissolved in glacial acetic acid (10 mL)
and 0.25 g 10% palladium/charcoal was added. The reaction
mixture was hydrogenated for 4 h at rt and then filtrated. The
filtrate was poured into ice-water (50 mL) and neutralized
with saturated Na CO solution. The mixture was extracted
3
3
CH CH), 1.17–1.57 (2H, m; 14-CH ), 1.68+2.05 (2ꢃ1H,
3
2
2
1
3
ꢃm; 6-H ), 2.22–2.40 (1H, m; 14-H), 2.50–2.75 (3H, m;
2
7-H +5-H ), 2.85–3.03 (2H, m; 5-H +3-H), 3.76 and
2
A
B
.78 (3H, 2ꢃs; OCH ), 3.65–3.90 (3H, m; CH–O+
3
CH-Br+NCH CH ), 4.18–4.32 (1H, 2ꢃd; NCH CH ),
A
B
A
B
6
7
.76–6.86 (2H, m; 12-H+10-H), 6.95 (1H, br; 9-H),
.09–7.16 (1H, m; 11-H), 7.26–7.45 (5H, m; Ph), 8.88
1
3
and 8.95 (1H, 2ꢃbr s; N1-H).
C NMR (CDCl3)
d ꢂ4.9, ꢂ4.9, ꢂ4.8, and ꢂ4.7 (Si(CH ) ), 17.9 and 17.9
3
3
(
C(CH ) ), 18.9 and 19.1 (CH CH), 20.7 and 24.8 (C17),
3 3 3
2
3
2
5.6 and 25.7 (C(CH ) ), 32.6 and 34.1 (C14–CH ), 36.8
3
with dichloromethane (3ꢃ50 mL) and the combined organic
3
2
and 37.4 (C14), 42.3 and 42.5 (C6), 50.1 and 50.4 (C5),
0.9 (OCH ), 55.2 (C7), 57.7 and 58.0 (NCH Ph), 59.3
and 59.6 (CH–Br), 69.9 and 72.3 (C3), 70.9 and 71.1
phases were dried (MgSO ) and evaporated in vacuo. The
4
5
residue was purified by column chromatography (eluting
with acetone/hexane¼1:2, R ¼0.75) to afford 0.17 g (48%)
3
2
f
(
CH–O), 90.1 and 91.3 (C16), 109.2 and 109.3 (C12),
of the mixture of 11a and 11b as a colorless oil: IR (neat)
n 3376, 2952, 2912, 1680, 1612, 1468, 1440, 1248,
0
27.9 (C11), 128.4 (C3 +C5 ), 129.0 (C2 +C6 ), 137.7
1
1
20.6 and 120.7 (C10), 122.2 (C9), 127.1 (C4 ), 127.9 and
0
0
0
0
ꢂ1
1
744 cm ; 11a component (w 45%): H NMR (CDCl3)
d 0.092 and 0.10 (2ꢃ3H, 2ꢃs; Si(CH ) ), 0.90 (9H, s;
0
C2), 168.7 and 168.9 (COOCH ); MS m/z (relative inten-
(
(
C8), 139.1 (C1 ), 142.9 and 143.0 (C13), 164.9 and 165.3
3
3
C(CH ) ), 1.38 (3H, d, J¼6.0 Hz; 18-H ), 1.50 (1H, ddd,
3
3 3
3
+
+
sity) 626 (12.0, [M] ), 624 (12.0, [M] ), 412 (40.0), 410
J
¼12.0 Hz, J ¼11.8+6.7 Hz; 15-H ), 1.82+3.15 (2ꢃ
gem vic 2
gem vic A
(
HRMS (EI) calcd for C H
31.0), 295 (11.0), 171 (16.0), 127 (45.0), 91 (100.0);
BrN O Si 624.2382, found
1H, 2ꢃdd, J ¼15.0 Hz, J ¼11.0 and 7.00 Hz; 17-H ),
7
45
9
2.04 (1H, m; 14-H), 2.10–2.32 (3H, m; 6-H +15-H ),
2 B
3
3
2
3
+
for [M ] 624.2397.
2.83 (1H, m; 5-H ), 3.08–3.15 (2H, m; 5-H +20-H), 3.51
A B
(
1H, br d, J¼8.3 Hz; 3-H), 3.76 (3H, s; OCH ), 3.99 (1H,
3
4
.1.6. 4)[2)Bromo)3)(tert)butyl)dimethyl)silanyloxy±)
m; 19-H), 6.81 (1H, d, J¼8.0 Hz; 12-H), 6.93 (1H, m;
butyl])2,3,3a,4,5,7)hexahydro)1H)pyrrolo[2,3)d] carb)
azole)6)carboxylic acid methyl ester (10±. A mixture of ꢀ
10-H), 7.14 (1H, m; 11-H), 7.51 (1H, br d, J¼7.0 Hz;
1
3
9-H), 9.11 (1H, br s; N1-H); C NMR (CDCl ) d ꢂ4.6
3
(
0.5 g, 0.8 mmol) and 10% palladium/charcoal (0.25 g) in
and ꢂ3.8 (Si(CH ) ), 18.1 (C(CH ) ), 23.4 (C18), 25.9
3
2
3 3

F. T oꢀ th et al. / Tetrahedron 62 (2006) 12011–12016
12015
(
4
(
1
(
(
1
J
1
C(CH ) ), 31.9 (C17), 32.6 (C15), 37.4 (C14), 41.7 (C6),
3
8.0 (C5), 50.9 (OCH ), 55.4 (C7), 70.4 (C19), 70.8
3
5-H ), 3.11 (1H, ddd, J¼6.0+7.1+8.0 Hz; 20-H ), 3.67
3
2
b
(1H, d, J¼8.0 Hz; 3-H), 3.77 (3H, s; OCH ), 3.84 (1H, qd,
3
C20), 76.1 (C3), 92.2 (C16), 108.8 (C12), 121.4 (C10),
23.3 (C9), 127.7 (C11), 138.7 (C8), 143.3 (C13), 164.9
J¼6.1 and 6.0 Hz; 19-H), 6.82 (1H, dm, J¼8.0 Hz; 12-H),
13
6.98 (1H, m; 10-H), 7.14 (1H, m; 11-H), 7.38 (1H, d,
J¼7.5 Hz; 9-H), 9.05 (1H, br s; N1-H); C NMR (CDCl3)
1
C2), 168.6 (COOCH ); 11b component (w55%): H NMR
3
CDCl ) d 0.10 (6H, s; Si(CH ) ), 0.90 (9H, s; C(CH ) ),
d 22.2 (C18), 24.9 (C17), 34.6 (C15), 38.8 (C14), 41.7
(C6), 50.7 (OCH ), 51.2 (C5), 55.4 (C7), 71.5 (C19), 73.4
3
3 3
3 3
.23 (3H, d, J¼6.2 Hz; 18-H ), 1.64+2.04 (2ꢃ1H, 2ꢃddd,
3
3
¼12.0 Hz, J ¼5.2+w1 and 7.2+12.0 Hz; 6-H ),
(C20), 74.3 (C3), 90.3 (C16), 109.5 (C12), 120.8 (C10),
122.4 (C9), 128.1 (C11), 136.9 (C8), 143.2 (C13), 164.5
(C2), 169.1 (COOCH ); MS (FAB) m/z (relative intensity)
gem
vic
2
.86–2.00 (4H, m; 17-H +15-H +14-H), 2.74 (1H, dd,
A 2
Jgem¼14.4 Hz, J ¼4.6 Hz; 17-H ), 2.85 (1H, ddd,
vic
B
3
+
J¼6.0+7.1+8.1 Hz; 20-H ), 2.98+3.36 (2ꢃ1H, 2ꢃddd,
341 (100.0, [M+H ]), 327 (35.0), 149 (38.0); HRMS
(FAB) calcd for C H N O 341.1782, found for [M+H ]
341.1778.
b
+
J
(
3
1
(
(
2
(
(
¼12.4 Hz, J ¼7.2+w1 and 5.2+12.0 Hz; 5-H ), 3.70
gem
vic
2
20 25 2 3
1H, qd, J¼6.2 and 6.0 Hz; 19-H), 3.76 (3H, s; OCH ),
3
.84 (1H, d, J¼6.2 Hz; 3-H), 6.83 (1H, d, J¼8.0 Hz;
2-H), 6.89 (1H, m; 10-H), 7.16 (1H, m; 11-H), 7.32
1
3
1H, d, J¼7.3 Hz; 9-H), 9.05 (1H, br s; N1-H); C NMR
Acknowledgements
CDCl ) d ꢂ4.4 and ꢂ4.3 (Si(CH ) ), 18.2 (C(CH ) ),
3
3 2
3 3
1.9 (C18), 25.9 (C(CH ) ), 26.8 (C17), 34.9 (C15), 38.9
3 3
The authors are grateful to the National Scientific Research
Foundation (OTKA T046060) for financial support of this
work.
C14), 39.4 (C6), 50.9 (OCH ), 53.2 (C5), 57.9 (C7), 73.0
3
C19), 73.3 (C20), 74.1 (C3), 91.9 (C16), 109.1 (C12),
1
(
20.9 (C10), 122.6 (C9), 127.9 (C11), 136.9 (C8), 143.6
C13), 164.9 (C2), 168.6 (COOCH ); MS m/z (relative inten-
3
+
sity) 454 (6.0, [M] ), 296 (22.0), 295 (100.0), 263 (9.0);
HRMS (EI) calcd for C H N O Si 454.2652, found for
[
Supplementary data
2
6 38 2 3
+
M ] 454.2652.
1
13
Supplementary data contains H, C, and 2D NMR spectra
of 6, 7, 8, 4, ꢀ, 10, 11a, 11b, 2a, and 2b. Supplementary data
associated with this article can be found in the online ver-
sion, at doi:10.1016/j.tet.2006.09.079.
4
.1.8. 1ꢀ)Hydroxy)ibophyllidine (2a± and 1ꢀ)hydroxy)20)
epiibophyllidine (2b±. Aqueous HCl solution (2N, 0.5 mL)
was added to a solution of 11a and 11b (0.20 g, 0.44 mmol)
in tetrahydrofuran (5 mL), and the mixture was stirred for
30 min at rt. After stirring the mixture was concentrated in
vacuo, then the residue was dissolved in dichloromethane
References and notes
(
(
20 mL) and worked with water (10 mL) and brine
10 mL). The organic phase was dried (MgSO ) and the sol-
1. For part 104, see: Moldvai, I.; G ꢀa ti, T.; Sz ꢀa ntay, Cs., Jr.;
Sz ꢀa ntay, Cs. J. Org. Chem. 2006, 71, 3768.
4
vent was evaporated in vacuo. The two main components
were separated by preparative TLC (eluting with acetone/
2. Saxton, J. E. The Ibogamine-Catharanthine Group. In
Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; The
Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.;
Wiley: New York, NY, 1994; Supplement to Vol. 25, Part 4,
pp 487–521.
3. (a) Kisak €u rek, M. V.; Leewenberg, A. J. M.; Hesse, M. A.
Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Wiley: New York, NY, 1983; Vol. 1, pp 211–376;
(b) Van Beek, T. A.; Verpoorte, R.; Baerheim Svendsen, A.;
Leewenberg, A. J. M.; Bisset, N. G. J. Ethnopharmacol.
1ꢀ84, 10, 1; (c) Van Beek, T. A.; Van Gessel, M. A. J. T.
Alkaloids of Tabernaemontana Species. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, NY, 1988; Vol. 6, pp 75–226.
hexane¼2:1). The less polar compound (2a, R ¼0.53) was
f
obtained (60 mg, 42%) as a colorless oil: IR (neat) n 3376,
952, 1672, 1612, 1480, 1464, 1248, 1224, 744 cm ; H
ꢂ1
1
2
NMR (CDCl ) d 1.28 (3H, d, J¼7.5 Hz; 18-H ), 1.74+2.13
3
3
(
(
(
2ꢃ1H, m; 15-H ), 1.71+2.08 (2ꢃ1H, m; 6-H ), 1.83+2.88
2
2
2ꢃ1H, dm, dd, J ¼11 Hz, J ¼6.9 Hz; 17-H ), 2.10
gem
vic
2
1H, m; 14-H), 2.95+3.28 (2ꢃ1H, 2ꢃdd, J ¼11.5 Hz,
gem
J ¼6.9 Hz; 5-H ), 3.06 (1H, ddd, J¼6.1+7.1+8.0 Hz; 20-
vic
2
H ), 3.81 (1H, br d, J¼8.0 Hz; 3-H), 3.76 (3H, s; OCH ),
a
3
3
(
.89 (1H, m; 19-H), 6.85 (1H, d, J¼8.0 Hz; 12-H), 7.01
1H, m; 10-H), 7.19 (1H, m; 11-H), 7.49 (1H, br d,
1
3
J¼7.1 Hz; 9-H), 9.07 (1H, br s; N1-H); C NMR (CDCl3)
d 23.0 (C18), 29.5 (C17), 33.1 (C15), 37.8 (C14), 41.7
(
(
1
C6), 48.2 (C5), 50.7 (OCH ), 55.4 (C7), 70.8 (C19), 76.1
3
C3), 91.5 (C16), 108.9 (C12), 121.4 (C10), 123.3 (C9),
4. (a) Scott, A. I. Bioorg. Chem. 1ꢀ74, 3, 398; (b) Kuehne, M. E.;
Pitner, J. M. J. Org. Chem. 1ꢀ8ꢀ, 54, 4553; (c) Le Men, J.;
Taylor, W. I. Experientia 1ꢀ65, 21, 508.
5. Kan, C.; Husson, H.; Kan, S.; Lounasmaa, M. Tetrahedron Lett.
1ꢀ80, 21, 3363.
28.0 (C11), 138.5 (C8), 143.2 (C13), 164.8 (C2), 168.7
COOCH ); MS (FAB) m/z (relative intensity) 341 (100.0,
(
[
3
+
M+H ]), 327 (37.0), 149 (46.0). HRMS (FAB) calcd for
+
C H N O 341.1782, found for [M+H ] 341.1772. The
2
6. Kalaus, Gy.; Greiner, I.; Kajt ꢀa r-Peredy, M.; Brlik, J.; Szab ꢀo , L.;
Sz ꢀa ntay, Cs. J. Org. Chem. 1ꢀꢀ3, 58, 1434.
0 25 2 3
more polar component (2b, R ¼0.55) was obtained
f
(
1
55 mg, 39%) as a colorless oil: IR (neat) n 3368, 2928,
688, 1612, 1480, 1456, 1248, 1228, 744 cm ; H NMR
7. (a) Kalaus, Gy.; Greiner, I.; Kajt ꢀa r-Peredy, M.; Brlik, J.;
Szab ꢀo , L.; Sz ꢀa ntay, Cs. J. Org. Chem. 1ꢀꢀ3, 58, 6076;
(b) Kalaus, Gy.; V ꢀa g ꢀo , I.; Greiner, I.; Kajt ꢀa r-Peredy, M.;
Brlik, J.; Szab ꢀo , L.; Sz ꢀa ntay, Cs. Nat. Prod. Lett. 1ꢀꢀ5, 7,
197; (c) Kalaus, Gy.; Greiner, I.; Sz ꢀa ntay, Cs. Synthesis
of Some Aspidosperma and Related Alkaloids. In Studies
in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
ꢂ1
1
(
(
1
CDCl ) d 1.22 (3H, d, J¼8.0 Hz; 18-H ), 1.66+2.14
3
3
2ꢃ1H, m; 15-H ), 1.81+2.90 (2ꢃ1H, dm, dd, J
2 gem
¼
2.0 Hz, J ¼7.0 Hz; 17-H ), 1.83+2.27 (2ꢃ1H, 2ꢃdd,
vic 2
vic
2
J
2
¼11.9 Hz, J ¼8.0 Hz; 6-H ), 2.07 (1H, m; 14-H),
gem vic
gem
.64+2.93 (2ꢃ1H, 2ꢃdd, J ¼12.0 Hz, J ¼7.0 Hz;

12016
F. T oꢀ th et al. / Tetrahedron 62 (2006) 12011–12016
Structure and Chemistry (Part E); Elsevier: Amsterdam,
997; Vol. 19, pp 89–116; (d) Kalaus, Gy.; Juh ꢀa sz, I.;
Greiner, I.; Kajt ꢀa r-Peredy, M.; Brlik, J.; Szab ꢀo , L.; Sz ꢀa ntay,
Cs. J. Org. Chem. 1ꢀꢀ7, 62, 9188.
9. For examples of halogen/tosyloxy change, see: Harikisan,
R. S.; Nanjundiah, S. B.; Nazeruddin, G. M. Tetrahedron
1ꢀꢀ5, 51, 11281.
1
ꢀ
10. Kalaus, Gy.; Juh ꢀa sz, I.; Eles, J.; Greiner, I.; Kajt ꢀa r-Peredy, M.;
8
. (a) Albertson, N. F. J. Am. Chem. Soc. 1ꢀ48, 70, 669; (b) Bates,
H. A. J. Am. Chem. Soc. 1ꢀ82, 104, 2490.
Brlik, J.; Szab ꢀo , L.; Sz ꢀa ntay, Cs. J. Heterocycl. Chem. 2000,
37, 245.