Synthetic Pathway to Strychnos Indole Alkaloids
A R T I C L E S
Table 6. Conversion of Ketone into Enol Triflate
run
base
temp (°C)
17 (%)
18 (%)
13 (%)
1
2
3
4
5
LDA
-78
-78
-50
-35
0
8
21
53
64
54
14
44
trace
55
24
11
KHMDS
KHMDS
KHMDS
KHMDS
Figure 1. (-)-Strychnine.
Scheme 10. Synthesis of (-)-Tubifolin
Scheme 8. Retrosynthetic Analysis of (-)-Tubifoline
spectra of the hydrogenation product agreed with those of (-)-
tubifoline reported in the literature.11,19
Scheme 9. Conversion of Ketone 13 into Olefin 19
The results indicated that the absolute configuration of 7b
obtained by asymmetric allylic substitution was S. Thus, we
succeeded in the total syntheses of (-)-dehydrotubifoline and
(-)-tubifoline from allylamine derivative 7b, which was
synthesized by palladium-catalyzed asymmetric allylic substitu-
tion by 16 steps. All of the steps for the ring constructions were
achieved using palladium catalysts.
Total Synthesis of (-)-Strychnine
(-)-Strychnine,20 which is the most well-known of the
Strychnos alkaloid, has seven rings and six asymmetric centers
in the molecule and is one of the most complex natural products
in its size (Figure 1). Although Woodward succeeded in the
total synthesis of (-)-strychnine in 1954,21 there were no other
reports on the total synthesis of strychnine for about 40 years.
However, tremendous progress has been made recently in
synthetic organic chemistry using organometallic complexes,
and the total syntheses of complicated natural products have
been achieved using novel procedures. In 1992, Magnus22
reported the total synthesis of strychnine, and Overman suc-
ceeded in the first asymmetric total synthesis of (-)- and (+)-
strychnine in 1993.23 Following these reports, several groups
succeeded in the total synthesis of (-)- or (()-strychnine.24,25
Rawal’s synthetic process is particularly remarkable, although
strychnine obtained by his process is in a racemic form.25e Very
recently, Vollhardt succeeded in the total synthesis of (()-
strychnine using an ingenious cobalt-catalyzed [2+2+2]cyclo-
addition as a key step.26 In the past decade, eight synthetic
and 18 in 8% and 14% yields, respectively (Table 6, run 1).
The base was changed to potassium hexamethyldisilazamide
(KHMDS),14 and the reaction was carried out at -78 °C to give
17 and 18 in 65% yield (ratio of 1 to 2, run 2). Because 17 was
considered to be a thermodynamic product, the reaction tem-
perature was raised to -50 °C. As a result, the yield of 17
improved to 53%, and only a small amount of 18 was formed.
At -35 °C, the desired compound 17 was obtained as a sole
product in 64% yield (runs 3 and 4). Treatment of enol triflate
17 with HCO2H and PPh3 in the presence of Pd(OAc)2 and
PPh315 gave the desired olefin 19 in quantitative yield (Scheme
9).
Deprotection of the tosyl group of 19 with sodium naphtha-
lenide followed by treatment with CF3CO2H gave diamine.
Monoalkylation with 2116a in the presence of K2CO3 gave 20
in 49% yield from 19. An intramolecular Heck reaction16a,17
using a palladium catalyst gave a pentacyclic compound in 59%
1
yield, whose H and 13C NMR spectra agreed with those of
(-)-dehydrotubifoline reported in the literature.16 However, the
[R]D value of (-)-dehydrotubifoline is not known. Thus,
hydrogenation of (-)-dehydrotubifoline with PtO2 in EtOH was
carried out (Scheme 10). The [R]D value18 and 1H and 13C NMR
(19) Schumann, D.; Schmid, H. HelV. Chim. Acta 1963, 46, 1996.
(20) Isolation: (a) Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1818, 8,
323. Structural elucidation: (b) Briggs, L. H.; Openshaw, H. T.; Robinson,
R. J. Chem. Soc. 1946, 903. (c) Woodward, R. B.; Brehm, W. J. J. Am.
Chem. Soc. 1948, 70, 2107.
(21) (a) Woodward, R. B.; Cave, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H.
U.; Schenker, K. J. J. Am. Chem. Soc. 1954, 76, 4749. (b) Woodward, R.
B.; Cave, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K.
J. Tetrahedron 1963, 19, 247.
(22) Magnus, P.; Giles, M.; Bonnet, R.; Kim, C. S.; McQuire, L.; Merritt, A.;
Vicker, A. J. Am. Chem. Soc. 1993, 115, 8116.
(23) (a) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1993,
115, 9293. (b) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem.
Soc. 1995, 117, 5776.
(24) For a review of the total synthesis of strychnine, see: Bonjoch, J.; Sole´,
D. Chem. ReV. 2000, 100, 3455.
(14) (a) Stang, P. J.; Dueber, T. E. Org. Synth. 1974, 54, 79. (b) McMurry, J.
E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(15) Cacchi, S.; Morera, E.; Orter, G. Tetrahedron Lett. 1984, 25, 4821.
(16) (a) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc. 1993,
115, 3030. (b) Crawley, G. C.; Harley-Mason, J. Chem. Commun. 1971,
685. (c) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W., Jr.;
Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966.
(17) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
(18) 84% ee, [R]22 -311° (c 0.236, AcOEt).
D
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J. AM. CHEM. SOC. VOL. 125, NO. 32, 2003 9805