9160
J . Org. Chem. 1998, 63, 9160-9161
En a n tiosp ecific Tota l Syn th esis of th e
Sa r p a gin e Rela ted In d ole Alk a loid s Ta lp in in e
a n d Ta lca r p in e: Th e Oxya n ion -Cop e
Ap p r oa ch
Peng Yu and J ames M. Cook*
F igu r e 1.
Department of Chemistry, University of WisconsinsMilwaukee,
Milwaukee, Wisconsin 53201
series,16 the cis diester in the NaH series isomerized into
the trans diester 4 so readily that none of the undesired cis
diastereomer was observed on workup. The conditions of
cyclization/isomerization (CH2Cl2, TFA, rt, 48 h)17 at C(1)
were much milder in the Na-H case, as expected. The more
rapid rate of isomerization (at C-1) of the cis diastereomer
in the Na-H series into the desired trans diastereomer 4
(>98% ee) was consistent with previous studies on the
mechanism of this process.13,14 Dieckmann cyclization of 4,
followed by acid-mediated decarboxylation in the second
sequence, provided the desired tetracyclic ketone 5 in 80%
yield. Five steps can now be executed in this two-pot process,
which constitutes an important improvement over previous
methods.17 The reasons for this stem from the unique nature
of Na-H-substituted indoles in comparison to the previously
reported Na-methyl analogues.16
Conversion of the carbonyl function of (-)-5 into the R,â-
unsaturated aldehyde moiety of 6 via the spirooxirano-
phenylsulfoxide18,19 was accomplished in 87% overall yield
by modification of the procedure of Fu.20 The R,â-unsatur-
ated aldehyde (-)-6 contains the desired absolute configu-
ration at C(3) as well as C(5) and serves as the key
intermediate for the total synthesis of both 1 and 2 (see
Scheme 1). From the beginning, an intramolecular sigma-
tropic rearrangement was envisaged to generate the correct
chirality at C(15) for this series of alkaloids. An anionic oxy-
Cope rearrangement would be expected to occur by the
preferred chair transition state21,22 from the bottom face of
the azabicyclononene ring system (from 6) to generate the
correct chirality at C(15). However, the allylic carbanion
required to provide allylic alcohol 8 would be expected to
undergo an allylic rearrangement when stabilized as either
the magnesium or lithium species. This obstacle was over-
come by an important modification of the barium chemistry
of Yamamoto et al.23 Addition of a mixture of trans-1-bromo-
2-pentene (7) and aldehyde 6 to freshly prepared barium
metal at -78 °C generated the desired allylic carbanion. This
barium-stabilized species added in situ at -78 °C in a 1,2-
fashion to 6 in high yield without allylic rearrangement. The
anionic oxy-Cope rearrangement took place in the Na-H
azabicyclononene system 8 almost exclusively from the
Received September 8, 1998
Interest in the macroline/sarpagine alkaloids originated
as a result of folk tales that described the medicinal
properties of the plants from which these alkaloids were
isolated.1-5 A number of alkaloids from Alstonia angustifolia
were reported to possess antiprotozoal activity against
Entamoeba histolytica or Plasmodium falciparum in vitro,6
while other sarpagine alkaloids have been found to possess
sedative, ganglionic blocking, hypoglycemic, or antibacterial
activity.2 Studies were begun to evaluate these alkaloids for
activity against cancer7 and HIV;8,9 however, the paucity of
isolable material from these species has retarded biological
screening.
In 1972, Schmid et al.10 reported the structures of the
alkaloids talpinine 1 and talcarpine 2 (Figure 1), which had
been isolated from the stem bark of Pleiocarpa talbotii
Wernham. LeQuesne reported a series of interconversions
between the Alstonia macroline-related alkaloids and 1 as
well as 2,11 while Sakai12 completed a partial synthesis of
talcarpine 2 from ajmaline. At this time, the assignment of
the chirality of the C(19) methyl group was established in
talcarpine 2 and then related chemically to that in talpinine
1.12
From examination of the transformations carried out by
LeQuesne,11 it was clear the macroline alkaloids2 are related
biosynthetically to the two bases from P. talbotii. The
stereogenic centers of the sarpagine alkaloids at C(3), C(5),
C(15), and C(16) are identical to those in 1 and 2, while both
series are antipodal to ajmaline at C(16). We wish to report
the first stereocontrolled entry into the correct chirality of
the sarpagine alkaloids at C(3), C(5), C(15), and C(16), which
resulted in the enantiospecific total synthesis of 1 and 2.
D-(+)-Tryptophan methyl ester 3 was diastereospecifically
converted (via 4) into azabicyclononone 5 in greater than
98% ee in a two-pot process on a multihundred gram scale.
In contrast to the analogous process in the Na-methyl
(1) Bi, Y.; Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline Related
Alkaloids. In Studies in Natural Products Chemistry, Bioactive Natural
Products, Part A; Basha, F. Z., Rahman, A., Eds.; Elsevier Science:
Amsterdam, 1993; Vol. 13; p 383.
(2) Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline Related
Alkaloids. In Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Elsevier Science: New York, 1995; Vol. 9; p 23.
(3) Wong, W.-H.; Lim, P.-B.; Chuah, C.-H. Phytochemistry 1996, 41, 313.
(4) Cook, J . M.; LeQuesne, P. W. Phytochemistry 1971, 10, 437.
(5) Chatterjee, A.; Banerji, J .; Banerji, A. J . Indian Chem. Soc. 1949,
51, 156.
(6) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J . D.; Said, I. M.; Kirby,
G. C.; Warhurst, D. C. Phytother. Res. 1992, 6, 121.
(7) Leclercq, J .; de Pauw-Gillet, M.-C.; Bassleer, R.; Angenot, L. J .
Ethnopharm. 1986, 15, 305.
(8) Tan, G. T.; Pezzuto, J . M.; Kinghorn, A. D.; Hughes, L. S. H. J . Nat.
Prod. 1991, 54, 143.
(9) Tan, G. T.; Miller, J . F.; Kinghorn, A. D.; Hughes, S. H.; Pezzuto, J .
M. Biochem. Biophys. Res. Commun. 1992, 185, 370.
(10) Naranjo, J .; Pinar, M.; Hesse, M.; Schmid, H. Helv. Chim. Acta 1972,
55, 752.
(11) Garnick, R. L.; LeQuesne, P. W. J . Am. Chem. Soc. 1978, 100, 4213.
(12) Takayama, H.; Phisalaphong, C.; Kitajima, M.; Aimi, N.; Sakai, S.
Tetrahedron 1991, 47, 1383.
(13) Cox, E. D.; Hamaker, L. K.; Li, J .; Yu, P.; Czerwinski, K. M.; Deng,
L.; Bennett, D. W.; Cook, J . M.; Watson, W. H.; Krawiec, M. J . Org. Chem.
1997, 62, 44.
(14) Cox, E. D.; Li, J .; Hamaker, L. K.; Yu, P.; Cook, J . M. J Chem. Soc.,
Chem. Commun. 1996, 2477.
(15) Czerwinski, K. M.; Cook, J . M. Stereochemical Control of the Pictet-
Spengler Reaction in the Synthesis of Natural Products. In Advances in
Heterocyclic Natural Products Synthesis; Pearson, W., Ed.; J AI Press:
Greenwich, CT, 1996; Vol. 3; p 217.
(16) Zhang, L. H.; Bi, Y.; Yu, F.; Menzia, G.; Cook, J . M. Heterocycles
1992, 34, 517.
(17) Yu, P.; Wang, T.; Yu, F.; Cook, J . M. Tetrahedron Lett. 1997, 38,
6819.
(18) Taber, D. F.; Guan, B. P. J . Org. Chem. 1979, 44, 450.
(19) Satoh, T.; Itoh, M.; Ohara, T.; Yamakawa, K. Bull. Chem. Soc. J pn.
1987, 60, 1939.
(20) Fu, X.; Cook, J . M. J . Org. Chem. 1993, 58, 661.
(21) Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609.
(22) Paquette, L. A.; Maynard, G. D. J . Am. Chem. Soc 1992, 114, 5018.
(23) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J . Am. Chem. Soc. 1991,
113, 8955.
10.1021/jo981815h CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/20/1998