Synthesis of (±)-3H-epivincamine via a Rh(II)-triggered cyclization/cycloaddition cascade

Article abstract of DOI:10.1021/ol071173x

A synthesis of (±)-3H-epivincamine is reported. Important steps include (1) a Rh(II)-catalyzed intramolecular [3+2]-cycloaddition of an α-diazo indolo amide, (2) a reductive ring opening of the cycloadduct, (3) a decarboethoxylation reaction, and (4) a base-induced keto-amide ring contraction.

Full text of DOI:10.1021/ol071173x

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3249-3252
Synthesis of (±)-3H-Epivincamine via a
Rh(II)-Triggered Cyclization/
Cycloaddition Cascade
Dylan B. England and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received May 18, 2007
ABSTRACT
A synthesis of (±)-3H-epivincamine is reported. Important steps include (1) a Rh(II)-catalyzed intramolecular [3+2]-cycloaddition of an r-diazo
indolo amide, (2) a reductive ring opening of the cycloadduct, (3) a decarboethoxylation reaction, and (4) a base-induced keto-amide ring
contraction.
Vinca alkaloids comprise a large group of biologically active,
naturally occurring bases, isolated from several plants of the
Vinca genus.1 Members of this family of alkaloids have been
used for the treatment of cognitive and behavioral symptoms
associated with vascular and degenerative disorders of the
central nervous system.2 (+)-Vincamine (1) and (-)-ebur-
namonine (2) as well as (()-3H-epivincamine (3) all exhibit
strong vasodilation activity which brings about an enhance-
ment of the overall cerebral blood flow.3,4 Thus, these
compounds along with their semisynthetic derivatives have
recently been the subject of intense pharmacological and
synthetic studies.5 These natural products all share a common
pentacyclic framework which generally contain a cis-fused
D/E ring system (Figure 1), although there are some
examples of related alkaloids possessing the trans-fused
junction.6 Several strategies for the synthesis of vincamine
(1) and its structural analogues have been reported.7 The most
common feature of these approaches is to first establish the
[ABCD]-type octahydroindolo[2,3-a]quinolizine system (i.e.,
4) starting from an indole subunit and then complete the
(1) (a) Atta-ur-Rahman, Sultana, M. Heterocycles 1984, 22, 841. (b)
Saxton, J. E. Nat. Prod. Rep. 1996, 13, 327. (c) Node, M.; Nagasawa, H.;
Fuji, K. J. Org. Chem. 1990, 55, 517.
(2) Desmae¨le, D.; Mekouar, K.; d’Angelo, J. J. Org. Chem. 1997, 62,
3890.
(3) Taylor, W. I., Farnsworth, N. R., Eds. The Vinca Alkaloids; Marcel
Dekker: New York, 1973.
(4) Hagstadius, S.; Gustafson, L.; Risberg, J. Psychopharmacology 1984,
83, 321.
(5) (a) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H. J.
Org. Chem. 1990, 55, 3068. (b) Takano, S.; Yonaga, M.; Morimoto, M.;
Ogasawara, K. J. Chem. Soc., Perkin Trans. 1 1985, 305. (c) Schultz, A.
G.; Malachowski, W. P.; Pan, Y. J. Org. Chem. 1997, 62, 1223. (d)
Lounasmaa, M.; Jokela, R. Heterocycles 1986, 24, 1663. (e) Kuehne, M.
E. J. Am. Chem. Soc. 1964, 86, 2949.
Figure 1. Common pentacyclic framework of vinca alkaloid
family.
10.1021/ol071173x CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/21/2007

synthesis of the specific target by appending the final E-ring.2
Methods for building up the requisite gem-disubstituted
tetracyclic [ABCD]-framework 4 usually involve a Pictet-
Spengler/Bischler-Napieralski cyclization,8 a Michael-type
alkylation of the so-called “Wenkert enamine”,9 or an
annulation reaction of a dihydro-â-carboline derivative.10
Our approach to the Vinca alkaloids was guided by a long
standing interest in the intramolecular [3+2]-cycloaddition
of carbonyl ylide dipoles.11 The generation of onium ylides
by a transition-metal-promoted cyclization reaction has
emerged in recent years as an important and efficient method
for the assembly of ring systems that are difficult to prepare
by other means.12,13 In earlier work from our laboratory, we
had described the formation of push-pull dipoles from the
Rh(II)-catalyzed reaction of R-diazo amides and noted that
a smooth intramolecular 1,3-dipolar cycloaddition occurred
across alkenyl π-bonds to provide novel pentacyclic com-
pounds in good yield and in a stereocontrolled fashion.14
Herein we report a concise synthesis of (()-3H-epivincamine
(3), first isolated by Cava in 19686 according to the plan
outlined in Scheme 1. The key intermediate 6 is readily
assembled by a Rh(II)-catalyzed cyclization/dipolar cycload-
dition sequence starting from R-diazo indolo amide 5.
Reductive ring opening of the resulting cycloadduct 6 is then
marshalled to create the trans-pentacyclic skeleton found in
(()-3H-epivincamine (3). Finally, a base-induced ring
contraction is exploited to complete the synthesis of 3. The
Scheme 1
successful completion of this synthesis demonstrates the
utility of our cascade methodology for the construction of
complex indole-containing natural products.
For the initial investigations into the tandem process, we
chose to examine the reactivity under Rh(II) catalysis
conditions of R-diazo amide 11, a test substrate. Compound
11 was readily prepared by treating carboline 9 with acetic
anhydride under refluxing conditions followed by reaction
of the resulting N-acetyl carboline 10 with sodium hydride
and ethyl 2-diazomalonyl chloride15 (Scheme 2). Heating
(6) Cava, M. P.; Tjoa, S. S.; Ahmed, Q. A.; Da Rocha, A. I. J. Org
Chem. 1968, 33, 1055.
(7) (a) Hugel, G.; Le´vy, J. Tetrahedron 1984, 40, 1067. (b) Hakam, K.;
Thielmann, M.; Thielmann, T.; Winterfeldt, E. Tetrahedron 1987, 43, 2035.
(c) Ge´nin, D.; Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. J. Org.
Chem. 1987, 52, 353. (d) Kaufman, M. D.; Grieco, P. A. J. Org Chem.
1994, 59, 7197. (e) Wenkert, E.; Hudlicky, T.; Showalter, H. D. J. Am.
Chem. Soc. 1978, 100, 4893.
Scheme 2
(8) (a) Herrmann, J. L.; Cregge, R. J.; Richman, J. E.; Semmelhack, C.
L.; Schlessinger, R. H. J. Am. Chem. Soc. 1974, 96, 3702. (b) Pfa¨ffli, P.;
Oppolzer, W.; Wenger, R.; Hauth, H. HelV. Chim. Acta 1975, 58, 1131. (c)
Herrmann, J. L.; Cregge, R. J.; Richman, J. E.; Kieczykowski, G. R.;
Normandin, S. N.; Quesada, M. L.; Semmelhack, C. L.; Poss, A. J.;
Schlessinger, R. H. J. Am. Chem. Soc. 1979, 101, 1540. (d) Langlois, Y.;
Pouilhe´s, A.; Ge´nin, D.; Andriamialisoa, R. Z.; Langlois, N. Tetrahedron
1983, 39, 3755. (e) Lounasmaa, M.; Tolvanen, A. J. Org. Chem. 1990, 55,
4044.
(9) (a) Rossey, G.; Wick, A.; Wenkert, E. J. Org. Chem. 1982, 47, 4745.
(b) Wenkert, E.; Wickberg, B. J. Am. Chem. Soc. 1965, 87, 1580. (c) Szabo,
L.; Sapi, J.; Kalaus, G.; Argay, G.; Kalman, A.; Baitz-Gacs, E.; Tamas, J.;
Szantay, C. Tetrahedron 1983, 39, 3737. (d) Nemes, A.; Czibula, L.; Visky,
G.; Farkas, M.; Kreidl, J. Heterocycles 1991, 32, 2329.
(10) (a) Oppolzer, W.; Hauth, H.; Pfa¨ffli, P.; Wenger, R. HelV. Chim.
Acta 1977, 60, 1801. (b) Hugel, G.; Le´vy, J.; Le Men, J. C. R. Acad. Sci.
1972, 274, 1350. (c) Danieli, B.; Lesma, G.; Palmisano, G. J. Chem. Soc.,
Chem Commun. 1981, 908. (d) Magnus, P.; Pappalardo, P.; Southwell, I.
Tetrahedron 1986, 42, 3215.
(11) For some leading references, see: Padwa, A. HelV. Chim. Acta 2005,
88, 1357.
(12) (a) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. (b)
Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223. (c) Padwa, A.
Pure Appl. Chem. 2004, 76, 1933.
(13) (a) Hodgson, D. M.; LeStrat, F.; Avery, T. D.; Donohue, A. C.;
Bru¨kl, T. J. Org. Chem. 2004, 69, 8796. (b) Hodgson, D. M.; LeStrat, F.
Chem. Commun. 2004, 822. (c) Chiu, P. Pure Appl. Chem. 2005, 77, 1183.
(d) Chen, B.; Ko, R. Y. Y.; Yuen, M. S. M.; Cheng, K.-F.; Chiu, P. J. Org.
Chem. 2003, 68, 4195. (e) Chiu, P.; Chen, P. Org. Lett. 2001, 3, 1721. (f)
Graening, T.; Bette, V.; Neudo¨rfl, J.; Lex, J.; Schmalz, H. G. Org. Lett.
2005, 7, 4317.
(14) (a) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60, 6258. (b) Padwa,
A.; Price, A. T. J. Org. Chem. 1998, 63, 556. (c) Padwa, A.; Lynch, S. M;
Mej´ıa-Oneto, J. M.; Zhang, H. J. Org. Chem. 2005, 70, 2206. (d) Mej´ıa-
Oneto, J. M.; Padwa, A. Org. Lett. 2006, 8, 3275.
compound 11 with catalytic Rh2(OAc)4 generates a rhodium
carbenoid intermediate which undergoes cyclization with the
neighboring amido carbonyl group to form a transient
carbonyl ylide dipole 12. Subsequent bimolecular trapping
of the dipole with various common dipolarophiles led to the
expected [3+2]-cycloadducts.12 Table 1 illustrates the scope
of the cycloaddition by showcasing the reaction with a variety
of commercially available dipolarophiles. In a typical experi-
ment, heating a sample of 11 with catalytic amounts of Rh2-
(OAc)4 in benzene at 80 °C in the presence of an equivalent
(15) Marino, J. P.; Osterhout, M. H.; Price, A.; Sheehan, S. M.; Padwa,
A. Tetrahedron Lett. 1994, 35, 849.
3250
Org. Lett., Vol. 9, No. 17, 2007

Scheme 3
Table 1. Bimolecular Cycloadditions of Diazo Amide 11
Using Various Dipolarophiles
its 1H NMR spectrum. The relative sterochemical configura-
tions within 6 are a consequence of endo cycloaddition with
regard to the dipole, and this is in full accord with the lowest-
energy transition state.16
The uniquely functionalized oxapolycyclic adduct 6 con-
tains a “masked” N-acyliminium ion which can be released
by treatment with a Lewis acid.17 However, our initial
attempts to reduce the resulting iminium ion with Et3SiH
and other hydride reagents afforded only recovered starting
material. We suspected that removal of the lactam carbonyl
group would help promote the reduction by enhancing the
nucleophilicity of the nitrogen atom thereby facilitating
oxabicyclic ring opening. Accordingly, cycloadduct 6 was
converted into the corresponding thiolactam 14 with Lawes-
son’s reagent in 95% yield. Reductive removal of the
thiocarbonyl group with Raney-Ni followed by treatment
of the resulting piperidine with Zn/AcOH gave the ring-
opened amide 7 containing the trans D/E ring fusion of 3H-
epivincamine in 75% yield over the two steps. Reduction of
the transient iminium ion with zinc occurred from the least
hindered face and generated the required trans ring junction.18
Next, the carboethoxy group was selectively removed
following experimental conditions previously developed in
our laboratory.19 Thus, treatment of 7 with MgI2 in refluxing
acetonitrile containing trace amounts of water resulted in the
formation of an R-hydroxy lactam in 62% yield. The reaction
was shown to proceed via a novel R-hydroxy-â-dicarbonyl
to R-ketol ester rearrangement via a transient carbonate
intermediate.19,20 Oxidation of the secondary alcohol to the
corresponding keto amide 8 was performed using Dess-
Martin periodinane in 50% yield. The conversion of related
of a trapping agent affords cycloadducts 13a-13d in 75-
85% yield and with complete diastereoselectivity. In general,
the cascade reaction sequence produced only the endo-
cycloaddition product isolated as a single diastereomer.
An optimized sequence for the diastereoselective synthesis
of (()-3H-epivincamine (3) following the above-mentioned
strategy is shown in Scheme 3. The readily available
carboline 9 was treated with the mixed anhydride of
4-methylenehexanoic acid to give 2-(4-methylenehexanoyl)-
2,3,4,9-tetrahydro-1H-pyrido-[3,4-b]indol-1-one. Deproto-
nation of the indole N-H with sodium hydride followed by
reaction with ethyl 2-diazo malonyl chloride gave R-diazo
indolo amide 5 in 60% yield. The critical intramolecular
dipolar-cycloaddition was achieved by heating a solution of
5 with Rh2(OAc)4 (1 mol %) in refluxing benzene. Under
these conditions, the key intermediate 6 was obtained in 95%
yield and with complete diastereoselectivity as evidenced by
(16) Weingarten, M. D.; Prein, M.; Price, A. T.; Snyder, J. P.; Padwa,
A. J. Org. Chem. 1997, 62, 2001.
(17) Padwa, A.; Zhang, H. J. Org. Chem. 2007, 72, 2570.
(18) All of our efforts using a variety of reducing agents only resulted
in the formation of the trans-ring sterochemistry. Studies are currently
underway toward an enantioselective synthesis of 3 using a chiral catalyst
in the iminium ion reduction step.
(19) Hong, X.; Mej´ıa-Oneto, J. M.; Padwa, A. Tetrahedron Lett. 2006,
47, 8387.
(20) (a) Rubin, M. B.; Inbar, S. Tetrahedron Lett. 1979, 5021. (b) Davis,
F. A.; Clark, C.; Kumar, A.; Chen, B.-C. J. Org. Chem. 1994, 59, 1184.
Org. Lett., Vol. 9, No. 17, 2007
3251

oxolactams to vincamine derivatives has been reported in
the literature.10a,21 In our hands, methanolysis of 8 with
sodium carbonate as base gave, after 1 h of stirring at room
temperature, a 95% yield of (()-3H-epivincamine (3) as the
only diastereomer.
In summary, a concise synthesis of the Vinca alkaloid (()-
3H-epivincamine (3) is reported. A central step in the
synthesis consists of an intramolecular [3+2]-cycloaddition
reaction of an R-diazo indolo amide which delivers the
pentacyclic skeleton of the natural product in excellent yield.
The acid lability of the oxabicyclic structure was exploited
to establish the trans D/E ring fusion. Finally, a base induced
keto-amide ring contraction was utilized to generate the
E-ring of the natural product. The short sequence of reactions
used to synthesize (()-3H-epivincamine (3) should also
provide a rapid entry into other Vinca alkaloids and is
currently under active investigation in our laboratories.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (Grant GM
059384) and the National Science Foundation (Grant CHE-
0450779).
Supporting Information Available: Complete descrip-
tion of experimental details and product characterization of
all new compounds together with photocopies of spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) (a) Sza`ntay, C.; Szabo´, L.; Kalaus, G. Tetrahedron 1977, 33, 1803.
(b) Szabo, L.; Kablaus, G.; Sza´ntay, C. Arch. Pharm. (Weinheim, Ger.)
1983, 316, 629.
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