Total synthesis of (-)-vallesamidine

Article abstract of DOI:10.1016/S0040-4039(02)00256-3

A new synthetic method of (-)-vallesamidine, including a unique 2,2,3-trialkylindoline skeleton, is developed by reductive radical cyclization reaction from the 2,3-dialkylindole derivative, which has been known to be an intermediate for the synthesis of

Full text of DOI:10.1016/S0040-4039(02)00256-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2385–2388
Total synthesis of (−)-vallesamidine
Hideo Tanino, Kazuhisa Fukuishi, Mina Ushiyama and Kunisuke Okada*
Faculty of Pharmacy, Meijo University, Tenpaku, Nagoya 468-8503, Japan
Received 26 December 2001; accepted 1 February 2002
Abstract—A new synthetic method of (−)-vallesamidine, including a unique 2,2,3-trialkylindoline skeleton, is developed by
reductive radical cyclization reaction from the 2,3-dialkylindole derivative, which has been known to be an intermediate for the
synthesis of aspidospermidine. © 2002 Elsevier Science Ltd. All rights reserved.
Vallesamidine 1 was isolated from Vallesia dichotoma in
1965 and its structure and absolute configuration were
determined by Djerassii in 1968.1 The defined structure
shows a unique and abnormal indole alkaloid including
2,2,3-trialkylindoline skeleton, which differs from (+)-
aspidospermidine 2, a typical indole alkaloids, having
2,3,3-trialkylindoline chromophore (Scheme 1). The
stereochemistry of vallesamidine at C-5 and C-19 is
identical to that of aspidospermidine, suggesting that
these two alkaloids are possibly biosynthesized from the
same intermediate. A great amount of research has
been reported on the synthesis of 2,3,3-trialkylated
indoline alkaloids such as aspidosperma and strychnos
families,2 but little research has been carried out on the
2,2,3-trialkylated indoline alkaloid.3
succeeded in the synthesis of the aspidosperidine skele-
ton from 3, being used as a key intermediate, in the
cyclization which includes the interesting rearrangement
as mentioned above.
On the other hand, Levy’s first synthesis of valle-
samidine from tabersonine was achieved by treatment
with Zn powder in acetic acid.7 It has been proposed
that 2,2,3-trialkylindoline intermediate 6 is included in
the equilibrium reaction mixture, in addition to 2,3,3-
trialkylindoline 4 and quebrachamine chromophore 5
(Scheme 2). In this way, enanthiomeric (+)-valle-
samidine was obtained in 24% yield.
Because of the above discussion, we have investigated a
new synthetic approach to vallesamidine wherein the
reductive radical cyclization of the known 2,3-dialkylin-
dole derivative 3 provides the 2,2,3-trialkylindoline
skeleton. Although many novel ring systems and natu-
ral products have been synthesized by radical reactions,
a small amount of research has been devoted to the
synthesis of indoline alkaloids.8 In this communication,
we report a successful synthesis of (−)-vallesamidine 1
by the following line (Scheme 3).
In 1990, Heathcock reported the first total synthesis of
( )-vallesamidine via newly developed methodology
wherein the indolenine skeleton is formed in the late
stage of its synthesis.4 In his paper, it is noted that
alkylation at C-2 of a 2,3-disubstituted indole 3 is not
generally useful, because of the propensity of the result-
ing cation to rearrange to the more stable 2,3,3-tri-
alkylindolenium ion. Harley–Mason5 and Fuji6 have
Scheme 1.
Keywords: radical reaction; cyclization; indole; asymmetric synthesis.
* Corresponding author. Tel.: +81-52-832-1781; fax: +81-52-834-8780; e-mail: kokada@ccmfs.meijo-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00256-3

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H. Tanino et al. / Tetrahedron Letters 43 (2002) 2385–2388
Scheme 2.
Scheme 3. Reagents and conditions: (a) 80% AcOH, 80°C, 1 h; (b) (i) 4N-NaOH, dioxane, 100°C, 1 h; (ii) CO2; (iii) aq. NaIO4,
rt, 3 h; (iv) 1N HCl; (c) NaBH4, MeOH, rt, 1 h; (ii) 4N HCl-MeOH, 70°C, 1 h; (d) (i) (1) DIBAL-H, Et2O, −78°C, 1 h; (ii)
CH(OMe)3, p-TsOH, MeOH, 80°C, 2 h; (e) (i) 9-BBN, THF, rt, overnight; (ii) 30% H2O2, aq. NaOH, THF, rt, 1 h; (f) (i) SO3-Py,
DMSO, TEA, CH2Cl2, rt, 30 min; (ii) NaClO2, t-BuOH, aq. NaH2PO4, Me2CꢀCHMe, rt, 1 h; (g) tryptamine, AcOH, 140°C, 6
days.
desired alcohol with a diastereomeric mixture (1:1). The
mixture was easily separated on TLC, to give 3 (31.2%
yield), corresponding to the natural form and its epimer
14. The stereochemistry of each product was character-
ized by comparison with 1H NMR spectra10 of the
authentic samples. Our next approach from 3 to 1 is
outlined in Scheme 4.
The synthesis of the chiral key intermediate 3 was
started from 7, which was obtained from the double
alkylation of (S)-g-trityloxymethyl-g-butyrolactone by
using the method reported by Koga.9 De-tritylation of
7 afforded an alcohol 8 in 93.6% yield, which was
hydrolyzed with 4N-KOH in dioxane followed by neu-
tralization with CO2. The resulting mixture was oxi-
dized with sodium periodate to give hemiacetal 9 in
95.2% yield. Reduction of 9 with sodium borohydride
in methanol gave g-lactones 10 (92.4%). The lactone
was then converted to methylacetal 11 by reduction
with diisobutylaluminum hydride at −78°C, followed by
treatment with methylorthoformate and p-toluenesul-
fonic acid in methanol, in 83.6% yield in two steps.
Transformation of the double bond in 11 into primary
alcohol 12 was performed by following successive reac-
tions of hydroboration with 9-BBN in THF and oxida-
tion with hydrogenperoxide in alkali in 82.6% yield.
The alcohol 12 was further oxidized to carboxylic acid
13 (95.0% yield) in the usual way. Finally, heating the
carboxylic acid 13 with triptamine in AcOH for 6 days
gave a tetracyclic indole lactam derivatives,6 which was
then hydrolyzed by 20% NaOH in MeOH, to afford the
The primary hydroxy group in the side chain of 3 was
converted into mesylate by using MsCl–DMAP in pyri-
dine at 0°C in 92% yield. The resulting mesylate 15 was
treated with diphenydiselenide and NaBH4 in EtOH at
room temperature, giving the desired selenide 16 in 50%
yield together with N-alkylated product11 (13.0% yield,
eburnamonine chromophore). Treatment of the selenide
16 with a mixture of n-Bu3SnH and AIBN in toluene at
100°C gave a single product in 91% yield, the structure
of which was assumed to be pentacyclic compound 1712
based on a following physical data; in 1H NMR (l): the
signal at 4.77 ppm (1H, s) of 16 moved to 3.28 ppm
(1H, s); in 13C NMR (l) : two SP2 carbon signals which
appeared at 126–136 ppm corresponding to a- and
b-carbon in the indole ring of 16 disappeared and in

H. Tanino et al. / Tetrahedron Letters 43 (2002) 2385–2388
2387
Scheme 4. Reagents and conditions: (a) MsCl, DMAP, pyridine, 0°C, 2 h; (b) (PhSe)2, NaBH4, EtOH, 0°C“rt, 3 h; (c) n-Bu3SnH,
AIBN, toluene, 100°C, 0.5 h; (d) HCHO, NaBH3CN, CH3CN, then AcOH, rt, 1 h; (e) LAH, THF, 70°C, 0.5 h.
place of these signals, two new signals were observed at
44.6 ppm (-CH-) and 76.3 ppm (quaternary carbon).
N-Methylation of 17 with the mixture of HCHO–
NaBH3CN–AcOH in acetonitrile gave 18 in 87% yield.
6. Node, M.; Nagasawa, H.; Fuji, K. J. Org. Chem. 1990,
55, 517–521.
7. Levy, J.; Mauperin, P.; Doe, M.; Le Men, J. Tetrahedron
Lett. 1971, 1003–1006.
8. (a) Zhang, W. Tetrahedron 2001, 57, 7237–7262 and
references cited therein; (b) Ziegler, F. E.; Belema, M. J.
Org. Chem. 1994, 59, 7962–7967.
Finally, reduction of lactam 18 was completed by using
LAH in THF under refluxing temperature, providing
(−)-vallesamidine 1 in 82% yield. The structure of the
synthetic material was confirmed by comparison with
the physical data reported by Heathcock.
9. Tomioka, K.; Cho, Y. S.; Sato, F.; Koga, K. Chem. Lett.
1981, 1621–1624.
10. Compound 3: mp 264–268°C decomp.; [h]2D5 +188.1° (c
1
0.15, CH3OH); H NMR (600 MHz, DMSO-d6): l 1.01–
In summary, we have developed a new strategy for
preparation of the 2,2,3-trialkylindoline skeleton via
reductive radical cyclization reaction, which success-
fully transformed into vallesamidine. This methodology
may also be applicable for the synthesis of 2,3,3-tri-
alkylindoline derivatives. Application of this methodol-
ogy to the other indole alkaloids is now in progress.
1.07 (1H, m), 1.06 (3H, t, J=7.3 Hz), 1.39 (1H, ddd,
J=13.9, 10.3, 5.9 Hz), 1.54 (1H, dt, J=13.2, 5.1 Hz),
1.76 (1H, dq, J=14.6, 7.3 Hz), 1.87 (1H, ddd, J=13.2,
10.3, 7.3 Hz), 1.96 (1H, dq, J=14.6, 7.3 Hz), 2.32–2.40
(2H, m), 2.52–2.60 (1H, m), 2.60–2.68 (1H, m), 2.68–2.74
(1H, m), 3.22 (1H, td, J=10.3, 5.9 Hz), 3.30 (1H, td,
J=10.3, 5.5 Hz), 4.83 (1H, s), 4.87–4.93 (1H, m), 6.98
(1H, t, J=7.3 Hz), 7.06 (1H, t, J=7.3 Hz), 7.41 (1H, d,
J=7.3 Hz), 7.45 (1H, d, J=7.3 Hz), 10.30 (1H, br s).
Compound 14: mp 123–127°C; [h]2D5 –141.2° (c 0.24,
1
CH3OH); H NMR (600 MHz, DMSO-d6): l 0.74 (3H, t,
References
J=7.3 Hz), 1.21 (1H, dq, J=14.7, 7.3 Hz), 1.29 (1H, dq,
14.7, 7.3 Hz), 1.52 (1H, ddd, J=13.2, 6.6, 3.7 Hz), 1.79
(1H, dt, J=15.4, 5.9 Hz), 1.94–2.02 (1H, m), 2.05 (1H,
ddd, J=15.4, 8.1, 5.9 Hz), 2.24 (1H, ddd, J=17.6, 11.0,
6.6 Hz), 2.38 (1H, ddd, J=17.6, 6.6, 3.7 Hz), 2.51–2.59
(1H, m), 2.62 (1H, td, J=11.7, 2.2 Hz), (1H, dt, J=13.9,
2.2 Hz), 3.71–3.80 (1H. br m), 3.82–3.90 (1H, br m),
4.87–4.93 (1H, m), 5.03 (1H, br s), 5.06 (1H, s), 6.98 (1H,
t, J=7.3 Hz), 7.06 (1H, t, J=7.3 Hz), 7.41 (1H, d, J=7.3
Hz), 7.43 (1H, d, J=7.3 Hz), 10.29 (1H, br s).
1. (a) Walser, A.; Djerassi, C. Helv. Chim. Acta 1965, 48,
391–404; (b) Brown, S. H.; Djerassi, C.; Simpson, P. G.
J. Am. Chem. Soc. 1968, 90, 2445–2446.
2. (a) Cordell, G. A. In The Alkaloids; Manske, R. H. F.;
Rodrigo, R., Eds.; Academic Press: New York, 1979;
Vol. XVII, pp. 199–384; (b) Smith, G. F. In The Alka-
loids; Manske, R. H. F., Ed.; Academic Press: New
York, 1960; Vol. VIII, pp. 591–671.
3. Padwa, A.; Harring, S. R.; Semones, M. A. J. Org. Chem.
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11. 1H NMR (600 MHz, CDCl3): l 1.01 (3H, t, J=7.3 Hz),
1.46–1.60 (3H, m), 2.03–2.12 (2H, m), 2.13–2.18 (1H, m),
2.26 (1H, ddd, J=17.6, 5.1, 1.5 Hz), 2.45 (1H, ddd,
J=17.6, 13.2, 6.6 Hz), 2.70 (1H, dd, J=15.0, 4.8 Hz),
3.04 (1H, td, 12.5, 4.8 Hz), 3.07–3.14 (1H, m), 3.69 (1H,
td, J=12.5, 4.8 Hz), 4.23 (1H, ddd, J=11.7, 5.9, 1.5 Hz),
4. (a) Dickman, D. A.; Heathcock, C. H. J. Am. Chem. Soc.
1989, 111, 1528–1530; (b) Heathcock, C. H.; Norman, M.
H.; Dickman, D. A. J. Org. Chem. 1990, 55, 798–811.
5. Harley-Mason, J.; Kaplan, M. J. Chem. Soc., Chem.
Commun. 1967, 915–916.

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H. Tanino et al. / Tetrahedron Letters 43 (2002) 2385–2388
4.37 (1H, s), 4.96 (1H, dd, J=12.5, 5.9 Hz), 7.13 (1H, t,
J=5.9 Hz), 3.28 (1H, s), 4.34 (1H, dt, J=12.8, 6.6 Hz),
6.63 (1H, d J=7.3 Hz), 6.78 (1H, t, J=7.3 Hz), 7.06
(1H, t, J=7.3 Hz), 7.17 (1H, 7.3 Hz); 13C NMR (150
MHz, CDCl3): l 9.1 (CH3), 24.6 (CH2), 28.8 (CH2), 29.1
(CH2), 35.2 (CH2), 36.2 (CH2), 36.5 (CH2), 40.1 (CH2),
43.6 (C), 44.6 (CH), 69.7 (CH), 76.3 (C), 109.7 (CH),
119.4 (CH), 123.5 (CH), 127.9 (CH), 130.8 (C), 149.1
(C), 171.0 (C).
J=8.1 Hz), 7.20 (1H, t, J=8.1 Hz), 7.29 (1H, d, J=8.1
Hz), 7.47 (1H, d, J=8.1 Hz).
12. Compound 17: mp 194–195°C; [h]2D5 +26.58° (c 0.23,
CHCl3); 1H NMR (600 MHz, CDCl3): l 0.96 (3H, t,
J=7.3 Hz), 1.63–1.96 (9H, m), 1.96–2.03 (1H, m), 2.27
(1H, ddd, 17.2, 10.6, 5.1 Hz), 2.38 (1H, dt, 17.2, 4.8
Hz), 2.75 (1H, ddd, J=12.8, 8.1, 4.8 Hz), 3.15 (1H, t,