An enantioselective total synthesis of (+)-geissoschizine

Article abstract of DOI:10.1021/ol990554a

(equation presented) A concise asymmetric synthesis of the indole alkaloid (+)-geissoschizine (1) has been completed. The synthesis features the highly diastereoselective vinylogous Mannich reaction of 3 with 4 to give 5, which is elaborated into the key

Full text of DOI:10.1021/ol990554a

ORGANIC
LETTERS
1
999
Vol. 1, No. 1
9-81
An Enantioselective Total Synthesis of
(
+)-Geissoschizine†
7
Stephen F. Martin,* Kevin X. Chen, and C. Todd Eary
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received April 1, 1999
ABSTRACT
A concise asymmetric synthesis of the indole alkaloid (+)-geissoschizine (1) has been completed. The synthesis features the highly
diastereoselective vinylogous Mannich reaction of 3 with 4 to give 5, which is elaborated into the key tetracyclic intermediate 7 in two steps.
Following the stereoselective introduction of the ethylidene moiety to give 9, reduction of the lactam and radical decarboxylation via an acyl
selenide gave 12, which was converted into (+)-geissoschizine by formylation. The synthesis requires only 11 chemical operations and proceeds
in an overall yield of 17%.
1
The corynantheoid alkaloid geissoschizine (1), which has
been isolated from a number of plant species, is a pivotal
intermediate in the biosynthesis of the monoterpenoid indole
alkaloids of the Corynantheine-Yohimbine, Aspidosperma,
Iboga, Strychnos, Sarpagine, Picraline, and Ajmaline fami-
lies.2 The solution structure of 1 has been studied exten-
hydrogen bond between the enol hydroxyl group and the
4e
nitrogen lone pair. Its structure, coupled with its importance
as a key biosynthetic intermediate and lack of availability,
has inspired numerous synthetic investigations. Since the first
total synthesis of racemic geissoschizine by van Tamelen, a
,3
4
sively (Figure 1), and recent work suggests that the preferred
(2) For general reviews of the structure and synthesis of indole alkaloids
of the Corynantheine-Heteroyohimbine group, see: (a) Brown, R. T. In
Indoles; Saxton, J. E., Ed.; Wiley-Interscience: New York, 1983; Part Four
(The Monoterpenoid Indole Alkaloids), Chapter 3. (b) Sz a´ ntay, C.; Blask o´ ,
C.; Honty, K.; D o¨ rnyei, G. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1986; Vol. 27, p 131. (c) Lounasmaa, M.; Tolvanen, A.
In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; Wiley-Interscience:
New York, 1994; Supplement to Vol. 25, Part 4, Chapter 3.
(3) For reviews of the biosynthesis of the indole alkaloids, see: (a)
Cordell, G. A. In Introduction to Alkaloids: a Biogenetic Approach; Wiley-
Interscience: New York, 1981; pp 574-832. (b) Herbert, R. B. In Indoles;
Saxton, J. E., Ed.; Wiley-Interscience: New York, 1983; Part Four (The
Monoterpenoid Indole Alkaloids), Chapter 1. (c) Rahman, A.-ur; Basha,
A. Biosynthesis of Indole Alkaloids; Clarendon Press: Oxford, U.K., 1983.
(
d) Herbert, R. B. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.;
Figure 1. Geissoschizine.
Wiley-Interscience: New York, 1994; Supplement to Vol. 25, Part 4,
Chapter 1. See also: (e) Schmidt, D.; St o¨ ckigt, J. Planta Med. 1995, 61,
2
54.
conformation is one in which the CD ring is a trans-
quinolizidine with a twist-boat D-ring and an intramolecular
(4) (a) Rakur, G.; Winterfeldt, E. Chem. Ber. 1976, 109, 3837. (b) Damak,
M.; Ahond, A.; Potier, P.; Janot, M. M. Tetrahedron Lett. 1976, 4731. (c)
Hofle, G.; Heinstein, P.; St o¨ ckigt, J.; Zenk, M. H. Planta Med. 1980, 40,
1
26. (d) Goutarel, R.; Pais, M.; Gottlieb, H. E.; Wenkert, E. Tetrahedron
†
Dedicated to the memory of Dr. Ta-shue Chou (1950-1999).
Lett. 1978, 1235. (e) Takayama, H.; Watanabe, T.; Seki, H.; Aimi, N.; Sakai,
S.-I. Tetrahedron Lett. 1992, 33, 6831. See also: (f) Jokela, R.; Halonen,
M.; Lounasmaa, M. Tetrahedron 1993, 49, 2567. (g) Lounasmaa, M.; Jokela,
R.; Hanhinen, P.; Laine, C.; Anttila, U. Heterocycles 1996, 43, 1699.
(1) (a) Rapoport, H.; Windgassen, R. J.; Hughes, N. A.; Onak, T. P. J.
Am. Chem. Soc. 1960, 82, 4404. (b) Janot, M. M. Tetrahedron 1961, 14,
13.
1
1
0.1021/ol990554a CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/17/1999

5
number of syntheses have been completed, but only two
4 proceeded with a high degree of stereoselectivity via attack
asymmetric syntheses of 1 have been reported by the
Winterfeldt and Overman groups.6
at C(3) from the face opposite the carboxyl group at C(5) to
give 5 as the only observed product. Although it was not
11
We were attracted some years ago to geissoschizine (1)
as a consequence of our interest in designing general
strategies for the synthesis of indole alkaloids, and we
developed one facile entry to this target in which a vinylo-
gous Mannich reaction and an intramolecular hetero Diels-
necessary to esterify the acid function in 3 prior to this
addition, subsequent transformations required protection of
the carboxyl group; therefore, 5 was treated with isobutylene
in the presence of acid to give 6 in 59% overall yield from
3. N-Acylation of 6 with diketene followed by a base-
induced, intramolecular Michael reaction gave 7 (86%), in
which the correct relative and absolute stereochemistries at
C(3) and C(15) have been established. The equatorial
orientation of the two substituents at C(15) and C(20) is
presumably subject to thermodynamic control, but this issue
has not been explicitly addressed.
5
e,g,7
Alder reaction were exploited as key constructions.
In
that synthesis, the relative stereochemistry between C(3) and
C(15) and the geometry of the ethylidene side chain were
controlled, thereby addressing two of the standing problems
in the area. However, this route to geissoschizine could not
be readily modified for an asymmetric synthesis of 1, and it
could not be adapted to provide intermediates related to
geissoschizine that could be transformed along biogenetic
pathways into the more complex indole alkaloids of the
Having assembled the requisite skeletal framework, it then
remained to refunctionalize 7 to give geissoschizine. Hydride
reduction of the ketone moiety in 7 gave the alcohol 8, which
was characterized by X-ray crystallographic analysis, as the
only product. The stereochemical outcome of this reduction
is consistent with that observed in closely related systems.7
Treatment of 8 with sodium methoxide in methanol induced
â-elimination and stereoselective introduction of the (E)-
ethylidene side chain. The resulting acid was esterified with
acetyl chloride, producing 9 in 85% overall yield from 7.
The lactam function was selectively reduced by the Borch
8
Sarpagine, Ajmaline, and Picraline groups. We now report
a novel entry to geissoschizine that provides a concise
solution to these two problems.
b,12
The synthesis commenced with the conversion of D-
tryptophan (2) into the dihydrocarboline 3 in a single
9
operation by a modification of a known procedure to set
the stage for the key vinylogous Mannich reaction (Scheme
7b,10
1).
In the event, reaction of 3 with the vinyl ketene acetal
1
3
protocol to furnish the ester 10 in 92% yield.
(
5) (a) Yamada, K.; Aoki, K.; Kato, T.; Uemura, D.; van Tamelen, E.
Scheme 1
E. J. Chem. Soc., Chem. Commun. 1974, 908. (b) Hachmeister, B.; Thielke,
D.; Winterfeldt, E. Chem. Ber. 1976, 109, 3825. (c) Wenkert, E.; Vankar,
Y. D.; Yadav, J. S. J. Am. Chem. Soc. 1980, 102, 7971. (d) Banks, B. J.;
Calverley, M. J.; Edwards, P. D.; Harley-Mason, J. Tetrahedron Lett. 1981,
2
1
2, 1631. (e) Martin, S. F.; Benage, B.; Hunter, J. E. J. Am. Chem. Soc.
988, 110, 5925. (f) Wenkert, E.; Guo, M.; Pesthanker, M. J.; Shi, Y. J.;
Vanker, Y. D. J. Org. Chem. 1989, 54, 1166. (g) Martin, S. F.; Benage, B.;
Geraci, L. S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc. 1991, 113,
1
. (h) Lounasmaa, M.; Jokela, R.; Miettinen, J.; Halonen, M. Heterocycles
1992, 34, 1497. (i) Lounasmaa, M.; Jokela, R.; Anttila, U.; Hanhinen, P.;
Laine, C. Tetrahedron 1996, 52, 6803. (j) Bennasar, M.-L.; Jimenez, J.-
M.; Sufi, B. A.; Bosch, J. Tetrahedron Lett. 1996, 37, 9105. (k) Takayama,
H.; Watanabe, F.; Kitajima, M.; Aimi, N. Tetrahedron Lett. 1997, 38, 5307.
(
6) (a) Bohlmann, C.; Bohlmann, R.; Rivera, E. G.; Vogel, C.;
Manandhar, M. D.; Winterfeldt, E. Liebigs Ann. Chem. 1985, 1752. (b)
Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989, 111, 300.
(
7) For other recent applications of vinylogous Mannich reactions to
alkaloid synthesis, see: (a) Martin, S. F.; Liras, S. J. Am. Chem. Soc. 1993,
1
1
3
15, 10450. (b) Martin, S. F.; Clark, C. W.; Corbett, J. W. J. Org. Chem.
995, 60, 3236. (c) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118,
299. (d) Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M.J. Am. Chem.
Soc. 1996, 118, 9804.
8) For example, see: (a) van Tamelen, E. E.; Oliver, L. K. Bioorg. Chem.
976, 5, 309. (b) Herlem, D.; Flor e´ s-Parra, A.; Khuong-Huu, F.; Chiaroni,
(
1
A.; Riche, C. Tetrahedron 1982, 38, 271. (c) Lounasmaa, M.; Hanhinen,
P. Tetrahedron 1996, 52, 15225.
(
9) Previero, A.; Coletti-Previero, M.-A.; Barry, L.-G. Can. J. Chem.
968, 46, 3404.
10) For a recent review of the Mannich reaction, see: Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 1045.
11) The numbering of all synthetic intermediates corresponds to that
shown in 1 for geissoschizine. The structure assigned to each compound
1
(
(
1
13
was in accord with its spectral ( H and C NMR, IR, MS) characteristics.
Analytical samples of all new compounds were obtained by distillation,
recrystallization, or preparative HPLC or TLC and gave satisfactory
combustion analysis (C, H) and/or identification by high-resolution mass
spectrometry. All yields are based on isolated, purified materials.
(
12) (a) Winterfeldt, E.; Radunz, H.; Korth, T. Chem. Ber. 1968, 101,
3
172. (b) Winterfeldt, E.; Gaskell, A. J.; Korth, T.; Radunz, H.-E.;
Walkowiak, M. Chem. Ber. 1969, 102, 3558. (c) Naito, T.; Kojima, N.;
Miyata, O.; Ninomima, I. J. Chem. Soc., Perkin Trans. 1 1990, 1271.
(
13) Borch, R. F. Tetrahedron Lett. 1968, 61.
(14) Evans, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1989, 111, 1063.
80
Org. Lett., Vol. 1, No. 1, 1999

1
9
Acid-catalyzed cleavage of the tert-butyl ester in the
yield from 11. Formylation of 12 according to the procedure
of Winterfeldt then delivered (+)-geissoschizine (1) in 48%
yield; 50% of starting 12 was also recovered. The synthetic
geissoschizine thus obtained was spectroscopically identical
with an authentic sample of racemic geissoschizine prepared
14
presence of thioanisole, an essential additive, provided the
acid 11. Removal of the carboxyl group at C(5) proved to
be more difficult than anticipated. For example, application
of the classical Barton radical decarboxylation procedures
15
5g
to 11 provided 12 in low and inconsistent yields (0-15%).
Radical decarboxylation of the benzophenone oxime ester
independently in our group, and the optical rotation
compared favorably with naturally obtained material.20
In summary, a concise and practical asymmetric synthesis
of geissoschizine (1) has been developed that involves only
11 chemical operations from commercially available D-
tryptophan and proceeds in 17% overall yield, based upon
recovered 12 in the last step. In this synthesis the relative
stereochemistries at C(3) and C(15) and the geometry of the
ethylidene array are controlled completely. The approach
highlights the utility of vinylogous Mannich reactions as key
constructions in alkaloid synthesis. The utility of acyl
selenides as intermediates for efficient radical decarboxyla-
tion has also been further validated.
1
6
derived from 11 was also examined without reward.
Methods involving generation and reduction of the iminium
ion generated by the reaction of 11 with phosphorus
oxychloride were also unsuccessful.17 Ultimately we found
that the acyl selenide derived from 11, which was best
prepared by sequential reaction with isobutyl chloroformate
and then sodium phenylselenide,18 underwent facile and
efficient radical decarbonylation to give 12 in 79% overall
(15) (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun. 1983, 939. (b) Barton, D. H. R.; Herve, Y.; Potier, P.;
Thierry, J. J. Chem. Soc., Chem. Commun. 1984, 1298. (c) Barton, D. H.
R.; Crich, D.; Herve, Y.; Potier, P.; Thierry, J. Tetrahedron 1985, 41, 4347.
(
(
16) Hasebe, M.; Tsuchiya, T. Tetrahedron Lett. 1987, 28, 6207.
17) (a) Dean, R. T.; Padgett, H. C.; Rapoport, H. J. Am. Chem. Soc.
Acknowledgment. We thank the National Institutes of
Health and The Robert A. Welch Foundation for their
generous support of this research.
1
976, 98, 7448. (b) Johansen, J. E.; Christie, B. D.; Rapoport, H. J. Org.
Chem. 1981, 46, 4914.
18) For leading references to acyl selenides, see: (a) Boger, D. L.;
(
Mathvink, R. J. J. Org. Chem. 1992, 57, 1429. (b) Evans, P. A.; Roseman,
J. D.; Garber, L. T. J. Org. Chem. 1996, 61, 4880.
Supporting Information Available: Complete charac-
1
13
(
19) (a) Pfenninger, J.; Heuberger, C.; Graf, W. HelV. Chim. Acta 1980,
3, 2328. (b) Ireland, R. E.; Norbeck, D. W.; Mandel, G. S.; Mandel, N. S.
J. Am. Chem. Soc. 1985, 107, 3285.
20) The optical rotation for synthetic geissoschizine was [R] D ) +109°
c ) 0.58, EtOH), and the value for a previous asymmetric synthesis of
terization data ( H and C NMR and mass spectral data)
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
6
21
(
(
2
5
6b
geissoschizine was [R] D ) +113° (c ) 0.43, EtOH).
OL990554A
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