A biomimetic approach to the Strychnos alkaloids. A novel, concise synthesis of (±)-akuammicine and a route to (±)-strychnine

Full text of DOI:10.1021/ja962577f

9804
J. Am. Chem. Soc. 1996, 118, 9804-9805
Scheme 1
A Biomimetic Approach to the Strychnos Alkaloids.
A Novel, Concise Synthesis of (()-Akuammicine
and a Route to (()-Strychnine
Stephen F. Martin,* Cameron W. Clark, Masayuki Ito, and
Michael Mortimore
Department of Chemistry and Biochemistry
The UniVersity of Texas, Austin, Texas 78712
ReceiVed July 26, 1996
Strychnine (1)1 and akuammicine (2)2 are representative
members of the Strychnos family of indole alkaloids and have
been targets of synthetic investigations since the elucidation of
their structures nearly 50 years ago.3-9 The total synthesis of
1 by Woodward more than 40 years ago arguably marked the
genesis of modern synthetic organic chemistry.4 Today, the
Woodward approach still exemplifies how ingenuity and careful
planning may be exploited in the design of short and efficient
syntheses of complex targets. With the exception of protecting
groups, each carbon atom introduced into an intermediate was
retained in the final product, therefore, the strategy represents
the first example of atom economy in organic synthesis.10
Subsequent to the seminal achievement of Woodward, strych-
nine did not succumb again to total synthesis until 1992 with
the elegant syntheses by Magnus,5 Stork,6 Overman,7 Kuehne,8
and Rawal.9 Three total syntheses of akuammicine (2) have
been recorded by Overman,11 Kuehne,12 and Bonjoch and
Bosch.13 Herein we report the implementation of a novel
biomimetic strategy to a facile total synthesis of akuammicine
(2) and an oxygenated analogue that is a potential intermediate
in a formal synthesis of strychnine (1). The critical element in
the design of the synthetic plan was inspired by a transformation
in the proposed biogenetic conversion of indole alkaloids
possessing the corynantheoid skeleton, which may be repre-
sented by 4 and 5, into alkaloids of the Strychnos family such
as 2 and 1, respectively (Scheme 1).14
We recently reported a general entry to indole alkaloids of
the heteroyohimboid and corynantheoid families that featured
a vinylogous Mannich reaction followed by an intramolecular
hetero-Diels-Alder reaction to assemble the pentacyclic mo-
lecular framework of these alkaloids.15 For example, reaction
of 6, which was prepared in two steps from tryptamine, with
1-((trimethylsilyl)oxy)butadiene in the presence of crotonyl
chloride (7a) gave 8a that underwent cyclization upon heating
to give the pentacyclic adduct 9a in 70% overall yield from 6
(Scheme 2).
To apply the retrosynthetic analysis adumbrated in Scheme
1 to a concise synthesis of akuammicine (2), it was first
necessary to convert 9a into deformylgeissoschizine (12a),
which is a well-known intermediate in the syntheses of
corynantheoid alkaloids. In the event, hydration of the enol
ether moiety of 9a followed by oxidation16 of the intermediate
lactol gave the lactone 10a in 79% yield. When 10a was
exposed to sodium methoxide, â-elimination ensued to give an
acid that was esterified in situ to give 11a in 79% yield.
Selective reduction of the amide moiety of 11a proceeded in
91% yield to furnish 12a in only eight steps from tryptamine.
A similar sequence of reactions was performed to prepare the
oxygenated analogue 12b in comparable overall yield.
(1) Robinson, R. Experientia 1946, 2, 28.
(2) (a) Millson, P.; Robinson, R.; Thomas, A. F. Experientia 1953, 9,
89. (b) Edwards, P. N.; Smith, G. F. J. Chem. Soc. 1961, 152.
(3) For representative synthetic efforts toward Strychnos alkaloids, see:
(a) van Tamelen, E. E.; Dolby, L. J.; Lawton, R. G. Tetrahedron Lett. 1960,
30. (b) Harley-Mason, J. Pure Appl. Chem. 1975, 41, 167. (c) Takano, S.;
Hirama, M.; Ogasawara, K. Tetrahedron Lett. 1982, 23, 881. (d) Belgacem,
L.; Henin, J.; Massiot, G.; Vercauteren, J. Tetrahedron Lett. 1987, 28, 3573.
(e) Bosch, J.; Bonjoch, J. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Elsevier: Amsterdam, 1988; Vol. 1, p 31. (f) Nkiliza, J.;
Vercautern, J.; Le´ger, J.-M. Tetrahedron Lett. 1991, 32, 1787. (g) Amat,
M.; Linares, A.; Bosch, J. J. Org. Chem. 1990, 55, 6299. (h) Bonjoch, J.;
Sole´, D.; Bosch, J. J. Am. Chem. Soc. 1993, 115, 2064. (i) Rawal, V. H.;
Michoud, C.; Monestel, R. F.; J. Am. Chem. Soc. 1993, 115, 3030. (j) Diez,
A.; Vila, C.; Sinibaldi, M.-E.; Troin, Y.; Rubiralta, M. Tetrahedron Lett.
1993, 34, 733. (k) Kraus, G. A.; Bougie, D. Tetrahedron 1994, 50, 2681.
(l) Bonjoch, J.; Sole´, D.; Bosch, J. J. Am. Chem. Soc. 1995, 117, 11 017.
(4) (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.;
Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749. (b)
Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.;
Schenker, K. Tetrahedron 1963, 19, 247.
With the key intermediates 12a,b in hand, we examined the
feasibility of mimicking the biogenetic reorganization of a
corynantheoid intermediate into the pentacyclic skeleton of the
Strychnos family. Treatment of 12a with tert-butylhypochlorite
in the presence of SnCl4 gave a mixture of epimeric chloroin-
dolenines 13a that were not isolated but rather treated directly
with lithium hexamethyldisilazide to give a mixture from which
(()-akuammicine (2) was isolated in 30-35% yield (Scheme
1
3). The synthetic 2 thus obtained was identical (TLC, H and
13C NMR) with an authentic sample.17 The oxygenated
analogue 12b underwent a similar conversion to give 16 in about
25-30% yield.
(5) (a) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.;
Merritt, A.; Vicker, N. J. Am. Chem. Soc. 1992, 114, 4403. (b) Magnus,
P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt,
A.; Kim, C. S.; Vicker, N. J. Am. Chem. Soc. 1993, 115, 8116.
(6) Stork, G. Reported at the Ischia Advanced Scool of Organic
Chemistry, Ischia Porto, Italy, September 21, 1992.
The mechanism of this novel biogenetically-patterned trans-
formation has not been fully established. However, the initial
(7) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.
1993, 115, 9293.
(14) (a) Wenkert, E.; Wickberg, B. J. Am. Chem. Soc. 1965, 87, 1580.
(b) Battersby, A. R.; Hall, E. S. J. Chem. Soc., Chem. Commun. 1969, 793.
(c) Scott, A. I.; Cherry, P. C.; Qureshi, A. A. J. Am. Chem. Soc. 1969, 91,
4932. (d) Heimberger, S. I.; Scott, A. I. J. Chem. Soc., Chem. Commun.
1973, 217. (e) Rahman, A.-ur; Basha, A. Biosynthesis of Indole Alkaloids;
Clarendon Press: Oxford, 1983; p 45.
(15) Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore,
M. P. J. Am. Chem. Soc. 1991, 113, 6161 and references therein.
(16) Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S.
Tetrahedron Lett. 1983, 24, 2677.
(8) Kuehne, M. E.; Xu, F. J. Org. Chem. 1993, 58, 7490.
(9) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
(10) For a review of more recent applications of this concept, see: Trost,
B. M. Science 1991, 254, 1471.
(11) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W., Jr.;
Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966.
(12) Kuehne, M. E.; Xu, F.; Brook, C. S. J. Org. Chem. 1994, 59, 7803.
(13) (a) Sole´, D.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1996, 61, 4194.
(b) Sole´, D.; Bonjoch, J.; Garcia-Rubio, S.; Suriol, R.; Bosch, J. Tetrahedron
Lett. 1996, 37, 5213.
(17) We thank Professor Larry E. Overman (University of California,
Irvine) for supplying a generous sample of authentic (()-akuammicine (2).
S0002-7863(96)02577-2 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 40, 1996 9805
Scheme 2
Scheme 3
hydrogenolysis have been accompanied by significant reduction
of the double bond; an alternate hydroxyl protecting group is
thus indicated. Although difficulties encountered in deprotecting
16 to give 17 temporarily preclude the claim of a formal
synthesis of strychnine, the facile synthesis of 16 provides clear
evidence that this route constitutes a novel entry to this complex
alkaloid.
oxidation of the indole ring with electropositive halogen to give
the chloroindolenines as 13a,b is well precedented.18 Treatment
of 13a,b with base is then envisioned to give intermediates
related to 14a,b or 15a,b, which undergo skeletal reorganization
to give 2 and 16. This hypothesis is based upon the related
rearrangements of substituted tetrahydrocarbolines to the As-
pidosperma skeleton that are also promoted upon sequential
reaction with hypochlorite and base.19 Furthermore, the base-
induced rearrangement of strictamine, which is one of the
epimeric forms of 15a, into akuammicine is known.20 We are
presently undertaking experiments to unravel the details of this
interesting transformation anticipating that some insights may
lead to increased efficiency.21
An extraordinarily concise synthesis of (()-akuammicine (2)
has been developed that requires only 10 steps from com-
mercially available starting materials. The approach is also
applicable to the facile synthesis of strychnine (1) as evidenced
by the preparation of the oxygenated analogue 16. The synthetic
strategy features a biomimetically-patterned transformation of
the corynantheoid framework via oxidation and base-induced
rearrangement to give the Akuamma skeleton as illustrated by
the conversions 12a f 2 and 12b f 16. The applications of
this and related biomimetic transformations to the syntheses of
other indole alkaloids is currently being investigated on a broad
front, and the results of these investigations will be reported in
due course.
The unprotected alcohol 17 has been converted by Overman
in four steps into strychnine (1),7 but several attempts to
selectively remove the benzyl protecting group from 16 by
(18) Martin, S. F.; Mortimore, M. Tetrahedron Lett. 1990, 31, 4557 and
references therein. Also, see: ref 15.
(19) For example, see: (a) Vercauteren, J.; Massiot, G.; Le´vy, J. J. Org.
Chem. 1984, 49, 3230. (b) Feldman, P. L.; Rapoport, H. J. Am. Chem. Soc.
1987, 109, 1603.
Acknowledgment. We thank the National Institutes of Health (GM
25439) and the Robert A. Welch Foundation for their generous support
of this research program.
(20) Ahmad, Y.; Fatima, K.; Rahman, A.; Occolowitz, J. L.; Solheim,
B. A.; Clardy, J.; Garnick, R. L.; Le Quesne, P. W. J. Am. Chem. Soc.
1977, 99, 1943.
(21) As evidenced by following the course of the rearrangement by TLC,
it appears that only one of the diastereoisomeric chloroindolenines 12a,b
undergoes the rearrangement with the other remaining unchanged during
the course of the reaction. This observation suggests that if the stereochem-
istry of the chlorination step could be controlled, the overall efficiency of
this biomimetic conversion might be significantly improved.
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