General approach for the synthesis of sarpagine/ajmaline indole alkaloids. Stereospecific total synthesis of the sarpagine alkaloid (+)-vellosimine

Article abstract of DOI:10.1021/ol000095+

matrix presented (+)-Vellosimine has been synthesized enantiospecifically in 27% overall yield from commercially available D-(+)-tryptophan methyl ester via the asymmetric Pictet-Spengler reaction and a stereocontrolled intramolecular palladium-coupling reaction as key steps.

Full text of DOI:10.1021/ol000095+

ORGANIC
LETTERS
2
000
Vol. 2, No. 14
057-2059
General Approach for the Synthesis of
Sarpagine/Ajmaline Indole Alkaloids.
Stereospecific Total Synthesis of the
Sarpagine Alkaloid (+)-Vellosimine
2
Tao Wang and James M. Cook*
Department of Chemistry, UniVersity of WisconsinsMilwaukee,
Milwaukee, Wisconsin 53211
capncook@csd.uwm.edu
Received April 18, 2000
ABSTRACT
(+)-Vellosimine has been synthesized enantiospecifically in 27% overall yield from commercially available D-(+)-tryptophan methyl ester via
the asymmetric Pictet−Spengler reaction and a stereocontrolled intramolecular palladium-coupling reaction as key steps.
1
2
The sarpagine alkaloid (+)-vellosimine 1 was first isolated
from the tree Geissospermum Vellosii in 1958 by Rapoport
Chinese medicine for the treatment of neuralgia, migrain,
and hypertension.
8
,10,13
1
,2
et al. Amorphous extracts of this bark, known as pao
The structure of (+)-vellosimine 1 was elucidated on the
basis of NMR spectroscopy as well as a comparison with
the data from other indole alkaloids and confirmed by
3
pereira, have long enjoyed a reputation as a febrifuge in
2
Brazilian folk medicine and have also been reported to have
curare-like activity.4 During the following years, (+)-
vellosimine has also been isolated from various species of
1
1
analysis of its 2D NMR spectrum. Common structural
features of the sarpagine indole alkaloids include the asym-
metric centers at C-3(S), C-5(R), C-15(R), and C-16(R) as
well as the ethylidene double bond at C-19 and C-20 with
the E configuration. No enantiospecific total synthesis of
members of this class has appeared, to date. Sakai14 earlier
reported the partial synthesis (from ajmaline) of (-)-
koumidine, which has a similar skeleton to that of (+)-
vellosimine; however, the double bond is present in the
Z-configuration and the chirality at C-16 is S rather than R.
Establishment of the C(19)-C(20) double bond by Sakai
by an elimination process yielded the Z-configuration
Rauwolfia which are broadly distributed throughout Asia and
5
-12
Africa.
These plants are widely employed in traditional
(1) Rapoport, H.; Onak, T. P.; Hughes, N. A.; Reinecke, M. G. J. Am.
Chem. Soc. 1958, 80, 1601.
(
2) Rapoport, H.; Moore, E. J. Org. Chem. 1962, 27, 2981.
(3) (a) Henry, T. A. The Plant Alkaloids, 4th ed.; The Blakiston Co.:
Philadelphia, PA, 1949. (b) Bertho, A.; Von Schuckmann, G. Chem. Ber.
931, 64, 2278.
1
(4) Ferreira, R. Brazil Med. 1949, 63, 131.
(5) Arthur, H. R.; Johns, S. R.; Lamberton, J. A.; Loo, S. N. Aust. J.
Chem. 1968, 21, 1399.
(
(
(
(
6) Chatterjee, A.; Bandyopadhyay, S. Ind. J. Chem. 1979, 18B, 87.
7) Amer, M. M. A.; Court, W. E. Planta Med. 1980, Supplement, 8.
8) Feng, X. Z.; Fu, F. Y. Acta Pharm. Sin. 1981, 16, 510.
(12) Ponglux, D.; Wongseripipatana, S.; Subhadhirasakul, S.; Takayama,
H.; Yokota, M.; Ogata, K.; Phisalaphong, C.; Aimi, N.; Sakai, S. J. Chem.
Soc., Perkin Trans. 1 1989, 5075.
(13) The editorial board, Academia Sinica: Ann. Chin. Plants 1977, 63,
92.
(14) Kitajima, M.; Takayama, H.; Sakai, S. J. Chem. Soc., Perkin Trans.
1 1991, 1773.
9) Sierra, P.; Novotny, L.; Samek, Z.; Budesinsky, M.; Dolejs, L.; Blaha,
K. Collect. Czech. Chem. Commun. 1982, 47, 2912.
(
(
10) Lin, M.; Yang, B. Q.; Yu, D. Q. Acta Pharm. Sin. 1986, 21, 114.
11) Banerji, J.; Das, B.; Chakrabarti, R. Ind. J. Chem. (Sect. B) 1987,
2
6B, 709.
1
0.1021/ol000095+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

15
required for koumidine in a 5:1 ratio. Magnus reported the
total synthesis of the enantiomer of (-)-koumidine (from
D-tryptophan); however, establishment of the double bond
Scheme 1
(Z:E ) 1:5.7) was still not stereospecific. Several other
groups have encountered a similar problem during the
enantiospecific synthesis of the C(19)-C(20) related alkaloid
geissoschizine; the ratio of E to Z was very good but not
reported as stereospecific.1 Recently, Martin reported the
total synthesis of geissoschizine with stereoselective estab-
6,17
1
8
lishment of the double bond by an elimination process.
Furthermore Rawal and Bosch reported the total synthesis
of Strychnos alkaloids with stereocontrolled establishment
19,20
of the double bond by a Heck coupling reaction.
a
See reference 23 for details.
illustrated briefly in Scheme 1. Benzylation of the N
moiety of D-tryptophan methyl ester 5 provided N
benzyl D-tryptophan methyl ester, which was easily converted
without isolation and purification) into the trans diastere-
b
-amino
a
-H, N
b
-
(
omer 6 with 100% diastereoselectivity under the improved
conditions of the Pictet-Spengler reaction (83% yield for
the complete process on 400 g scale). The trans diester 6
was subjected to a Dieckmann cyclization on scales above
the 100 g level to provide the â-ketoester which (without
a b
isolation) was hydrolyzed to furnish the (-)-N -H, N -benzyl
tetracyclic ketone 7 in >98% ee (80% yield for this
process).
2
3
We report an efficient, enantiospecific total synthesis of
(
+)-vellosimine 1 with the stereospecific establishment of
Incorporation of the E-ethylidene function into the sarpagine
skeleton required the Z-1-bromo-2-iodo-2-butene 9 employed
the double bond by a key palladium (enolate-mediated)
carbon-carbon bond forming process.2 This approach
should provide a route to other sarpagine indole alkaloids
1
20
19,24
25
earlier by Bosch, Rawal,
and Kuehne. The ketone 7
was subjected to the conditions of catalytic hydrogenation
including N
a
-methylsarpagine 3 (10-hydroxy-N
a
-methyl-
to provide the N -H, N -H ketone 8 in 80% yield which
a
b
vellosimine) required for the total synthesis of the bisindole
alkaloid macralstonidine 4 synthesized in biomimetic fashion
by LeQuesne et al.22
underwent alkylation with Z-1-bromo-2-iodo-2-butene 9 to
provide N -Z-2′-iodo-2′-butenyl ketone 10 in 87% yield.
b
Ketone 10 was then successfully converted into R,â-
unsaturated aldehyde 11 in high yield, according to the
The chirality at C-3 and C-5 was established by the
asymmetric Pictet-Spengler reaction and Dieckmann reac-
tion in a two-pot process as reported previously and
procedure earlier reported from our laboratory in a different
system.
2
3
23
Several attempts to convert 11 into (+)-1 by Michael
reactions were unsuccessful; however, treatment of 11 with
(
15) Magnus, P.; Mugrage, B.; Deluca, M. R.; Cain, G. A. J. Am. Chem.
Soc. 1990, 112, 5220.
16) (a) Hachmeister, B.; Thielke, D.; Winterfeldt, E. Chem. Ber. 1976,
09, 3825. (b) Bohlmann, C.; Bohlmann, R.; Rivera, E. G.; Vogel, C.;
Manandhar, M. D.; Winterfeldt, E. Liebigs Ann. Chem. 1985, 1752.
17) Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989, 111,
00.
(
Bu
accompanied by the undesired Z-olefinic isomer 12 (1:12 )
:3), as illustrated in Scheme 2. The radical-mediated
3
SnH/AIBN/∆/benzene did provide (+)-vellosimine 1,
1
1
(
3
coupling had taken place with loss of stereochemistry as
expected, but did provide (+)-vellosimine for characteriza-
tion.
(
(
18) Martin, S. F.; Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1, 79.
19) Rawal, V. H.; Michoud, C.; Monested, R. J. Am. Chem. Soc. 1993,
1
15, 3030.
(20) (a) Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1995, 117,
Attempts to couple the R,â-unsaturated aldehyde 11 with
1
1017. (b) Bonjoch, J.; Sole, D.; Garcia-Rubio, S.; Bosch, J. J. Am. Chem.
0
a Pd catalyst under basic conditions furnished the interesting
Soc. 1997, 119, 7230.
21) (a) Piers, E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454. (b) Piers,
(
insertion product 13 (Scheme 3) presumably via the enolate
E.; Renaud, J. J. Org. Chem. 1993, 58, 11. (c) Muratake, H.; Natsume, M.
Tetrahedron Lett. 1997, 38, 7581. (d) Palucki, M.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 11108. (e) Kawatsura, M.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 1473. (f) Fox, J. M.; Huang, X.; Chieffi, A.;
Buchwald, S. L. J. Am. Chem. Soc., 2000, 122, 1360.
1
1*. A similar insertion reaction has been observed in other
2
6
systems by Miura et al. However, this result led to a
solution to the problem of the stereochemistry of the C(19)-
C(20) E ethylidene function.
(22) Garnick, R. L.; LeQuesne, P. W. J. Am. Chem. Soc. 1978, 100,
4
213.
(
23) (a) Yu, P.; Wang, T.; Yu, F.; Cook, J. M. Tetrahedron Lett. 1997,
(24) Birman, V. B.; Rawal, V. H. Tetrahedron Lett. 1998, 39, 7219.
(25) Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61,
7873.
3
3
8, 6819. (b) Wang, T.; Yu, P.; Li, J.; Cook, J. M. Tetrahedron Lett. 1998,
9, 8009. (c) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens,
Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem. Soc. 1999, 121, 6998.
d) Yu, P.; Cook, J. M. J. Org. Chem. 1998, 63, 9160.
(26) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998,
39, 6203.
(
2058
Org. Lett., Vol. 2, No. 14, 2000

Scheme 2a
Scheme 3a
a
(
a) Pd/C, H
2
, 5% HCl-ethanol, rt, 12 h, 80%. (b) Z-1-Bromo-
2
-iodo-2-butene 9, THF, K
2
CO
3
, rt, 24 h, 87%. (c) PhSOCH
2
Cl/
/dioxane, reflux,
3
SnH, AIBN, benzene, 80 °C, syringe pump,
LDA/THF, -78 °C, KOH(aq), 12 h, rt; LiClO
4 h, 87%. (d) Bu
0%.
4
2
4
a
(
a) Pd(OAc)
5 h, 71% (13); 80% (14). (b) H
h; HCl (2 N, aq), 4, 6 h, 73%.
2
, PPh
3
, Bu
4
NBr, K
2
CO
3
, DMF-H
2
O (9:1), 70 °C,
When the ketone 10 was subjected to the same conditions
3
COCH
2
PPh , KOt-Bu, PhH, rt, 24
3
0
19-21,24,26
as 11, (Pd , base)
the intramolecular palladium
(enolate-mediated) coupling reaction took place stereospe-
cifically in 80% yield. Ketone 14 was then converted into
vellosimine 1 via a Wittig reaction, followed by hydrolysis.
The latter process was possible since it was known that the
sarpagine stereochemistry at C(16) was favored thermo-
dynamically from other work in our laboratory.2
This approach provides the first stereospecific solution to
the problem of the stereochemistry of the C(19)-C(20)
E-ethylidene function in the sarpagine alkaloids. This route
should also provide easy access to other sarpagine alkaloids
3c,d
In summary, the first stereospecific total synthesis of the
a
including that of N -methyl sarpagine 3 required for the
N
a
-H substituted indole alkaloid (+)-vellosimine 1 has been
synthesis of the bisindole macralstonidine 4.
accomplished from commercially available D-(+)-tryptophan
methyl ester 5 in seven reaction vessels in 27% overall yield
via the asymmetric Pictet-Spengler reaction and a stereo-
controlled intramolecular palladium (enolate-mediated) cou-
pling reaction.
Acknowledgment. The authors thank the NIMH and the
Graduate School (UWsMilwaukee) for financial support.
OL000095+
Org. Lett., Vol. 2, No. 14, 2000
2059