neuridine aldehyde (3)8 were first isolated in the early 1960s
from Aspidosperma polyneuron and Aspidosperma dasy-
carpon. The structure of polyneuridine (2) was elucidated
on the basis of 1H and 13C spectroscopic studies,9 in
agreement with earlier studies by mass spectrometry.7 As
illustrated in Figure 1, these two sarpagine bases and the
related macusine A (4)7,10 represented a series of polyneu-
ridine alkaloids, which contained a different exo functional
group at C-16 (S) with the â-axial stereochemistry and an
equatorial carbomethoxy group. Polyneuridine aldehyde (3)
contains the unique C-16 axial aldehyde function and is
located in the middle of the ajmaline biosynthetic pathway.11
A related process is the transformation of 3 to the previously
unknown biogenetic intermediate, the important alkaloid 16-
epi-vellosimine (1),12 and provides a precursor for the
biosynthesis of the ajmaline skeleton.4,11 The biogenetic
connection between the sarpagine- and ajmaline-related
alkaloids proposed earlier13,14 has been detailed by Sto¨ckigt
et al.4,11,12 As illustrated in Figure 2,4 16-epi-vellosimine (1)
Figure 3. Quebrachidine related bisindole alkaloids.
of these alkaloids, as well as their largely unexplored
potential in medicine or as tools for biological studies,
stimulated interest in such systems. On the basis of the above
discussion, cyclization of 1 or 3 at C-7-C-17 would provide
the correct configuration at C-7 of all quebrachidine-related
alkaloids.
Recently, the total synthesis of ajmaline18 and the vinca-
majinine-related alkaloids19 provided direct proof for the
close synthetic relationship of 16-Na-methyl axial aldehydes
to the indolenine group.4 However, it was well-known that
the aldehyde function at C-16 preferred the R-equatorial
stereochemistry.20 The axial aldehyde function of 1 can be
easily epimerized into the sarpagine series of alkaloids.11
Previously, the difficulty in isolation and preparation of
Na-H axial aldehydes at C-16 has prevented use of this
biogenetic-type strategy for the synthesis of ajmaline/
quebrachidine-like alkaloids. To the best of our knowledge,
these two crucial intermediates, 16-epi-aldehydes 1 and 3,
have not previously been synthesized. Facile entry into these
systems and related alkaloids 2 and 4 provided much of the
impetus for this letter. In addition, functions that could be
readily radio-labeled for biogenetic studies are shown in 3
with a box (Figure 1), in regard to their potential biosynthetic
use.
Figure 2. Biogenetic connection between two indole types.4
and polyneuridine aldehyde (3) are proposed important
biogenetic intermediates in the formation of the unique cage-
related quebrachidine alkaloids including (+)-quebrachidine
(6),15 (+)-alstonisidine (7),16 and the antimalarial bisindole,
(+)-alstomacroline (8) (Figure 3).17 The complex architecture
(4) (a) Koskinen, A.; Lounasmaa, M. Planta Med. 1982, 45, 248. (b)
Pfitzner, A.; Sto¨ckigt, J. Tetrahedron Lett. 1983, 24, 5197.
(5) The “biogenetic numbering” of indole alkaloids is used in the text.
See: Le Men, J.; Taylor, W. I. Experientia 1965, 21, 508.
(6) Pfitzner, A.; Sto¨ckigt, J. J. Chem. Soc. Chem. Commun. 1983, 8,
459.
As illustrated in Scheme 1, in a retrosynthetic sense, both
16-epi-vellosimine (1) and polyneuridine aldehyde (3) might
be available via a common intermediate, the E-ethylidene
ketone (9). The synthesis of the axial aldehyde function of
3 could be approached by selective oxidation of the Na-H
diol 10, analogous to the previous (TPAP) approach on the
related Na-methyl diol.19 Although the TPAP-selective oxida-
tion of the â-axial alcohol on the Boc-protected 16-quaternary
diol was used to provide a 16-â-axial aldehyde (dr > 8:1),21,22
synthesis of aldehydes in the Na-H series was more difficult.
(7) Antonaccio, L. D.; Pereira, N. A.; Gilbert, B.; Vorbrueggen, H.;
Budzikiewicz, H.; Wilson, J. M.; Durham, L. J.; Djerassi, C. J. Am. Chem.
Soc. 1962, 84, 2161.
(8) Joule, J. A.; Ohashi, M.; Gilbert, B.; Djerassi, C. Tetrahedron 1965,
21, 1717.
(9) Jokela, R.; Lounasmaa, M. Heterocycles 1996, 43, 1015.
(10) McPhail, A. T.; Roberston, J. M.; Sim, G. A. J. Chem. Soc. 1963,
1832.
(11) Dogru, E.; Warzecha, H.; Seibel, F.; Haebel, S.; Lottspeich, F.;
Sto¨ckigt, J. Eur. J. Biochem. 2000, 267, 1397.
(12) Ruppert, M.; Ma, X.; Sto¨ckigt, J. Curr. Org. Chem. 2005, 9, 1431.
(13) Woodward, R. B. Angew. Chem. 1956, 68, 13.
(14) (a) Bartlett, M. F.; Lambert, B. F.; Werblood, H. M.; Taylor, W. I.
J. Am. Chem. Soc. 1963, 85, 475. (b) van Tamelen, E. E.; Haarstad, V. B.;
Orvis, R. L. Tetrahedron 1968, 24, 687.
(15) Quebrachidine 4 was reported to show psychosedative and adren-
ergic activity. See: Lyon, R. L.; Fong, H. H. S.; Farnsworth, N. R.; Svoboda,
G. H. J. Pharm. Sci. 1973, 62, 218.
(16) Biomimetic synthesis of 7 from 6. See: Burke, D. E.; Cook, J. M.;
Le Quesne, P. W. J. Am. Chem. Soc. 1973, 95, 546.
(17) Antimalarial activity: (a) Keawpradub, N.; Kirby, G. C.; Steele, J.
C.; Houghton, P. J. Planta Med. 1999, 65, 690. (b) Keawpradub, N.;
Houghton, P. J. Phytochemistry 1997, 46, 757.
(18) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens, D.;
Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem. Soc. 1999, 121, 6998.
(19) Yu, J.; Wearing, X. Z.; Cook, J. M. J. Am. Chem. Soc. 2004, 126,
1358.
(20) Bartlett, M. F.; Sklar, R.; Taylor, W. I.; Schlittler, E.; Amai, R. L.
S.; Beak, P.; Bringi, N. V.; Wenkert, E. J. Am. Chem. Soc. 1962, 84, 622.
(21) Yu, J.; Wearing, X. Z.; Cook, J. M. J. Org. Chem. 2005, 70, 3963.
(22) Sarma, P. V. V. S.; Cook, J. M. Org. Lett. 2006, 8, 1017.
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