Sequential acid/base-catalyzed polycyclization of tryptamine derivatives. A rapid access to Buechi's ketone

Article abstract of DOI:10.1021/ol0521127

(Chemical Equation Presented) The development of an efficient and diastereoselective methodology that allows the rapid construction of the tetracyclic core of the Aspidosperma and Strychnos alkaloid families is decribed. Our approach relies upon two key steps: a sequential silica gel/potassium tert-butoxide polycyclization of a tryptamine precursor and a tandem oxidative decarboxylation/ring-closing reaction. The assembly of Buechi's ketone, a key intermediate in the synthesis of vindorosine, has been accomplished using this approach.

Full text of DOI:10.1021/ol0521127

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5245-5248
Sequential Acid/Base-Catalyzed
Polycyclization of Tryptamine
Derivatives. A Rapid Access to Bu
1chi’s
Ketone§
Nicolas Heureux,† Johan Wouters,‡ and Istva´n E. Marko´*,†
Department of Chemistry, UniVersite´ Catholique de LouVain,
LouVain-la-NeuVe, Belgium, and Department of Chemistry,
Faculte´s UniVersitaires Notre-Dame de la Paix, Namur, Belgium
marko@chim.ucl.ac.be
Received September 2, 2005
ABSTRACT
The development of an efficient and diastereoselective methodology that allows the rapid construction of the tetracyclic core of the Aspidosperma
and Strychnos alkaloid families is decribed. Our approach relies upon two key steps: a sequential silica gel/potassium tert-butoxide polycyclization
of a tryptamine precursor and a tandem oxidative decarboxylation/ring-closing reaction. The assembly of Bu1chi’s ketone, a key intermediate
in the synthesis of vindorosine, has been accomplished using this approach.
Indole alkaloids, such as strychnine 1, vindoline 3, and
vindorosine 2, have attracted considerable attention over the
years, due to their enticing structures and biological activities.
For decades, the construction of strychnine1 has represented
a formidable synthetic challenge that has only been met a
few times. Vindoline, though possessing a simpler architec-
tural framework,2 is a key component in the preparation of
the antitumor drugs vincristine and vinblastine.3 These
alkaloids share the same tetracyclic core 4, known as the
Bu¨chi ketone (R2 ) H),4 from which their complex structures
could be elaborated. In this communication, we wish to report
our results on the establishment of an efficient route toward
4 that hinges upon two key steps: an anionic polycyclization
reaction and an oxidative ring-regression process (Figure 1).5
† Universite´ Catholique de Louvain.
‡ Faculte´s Universitaires Notre-Dame de la Paix.
§ Dedicated with deep respect and affection to Professor Martin E.
Kuehne.
(2) (a) Gorman, M.; Neuss, N.; Biemann, K. J. Am. Chem. Soc. 1962,
84, 1058. (b) Moza, B. K.; Troja´nek, J. Collect. Czech. Chem. Commun.
1963, 28, 1427.
(3) (a) Noble, R. L.; Beer, C. T.; Cutts, J. H. Ann. N. Y. Acad. Sci. 1958,
76, 882. (b) Svoboda, G. H.; Neuss, N.; Gorman, M. J. Am. Pharm. Assoc.
Sci. Ed. 1959, 48, 659.
(4) (a) Buchi, G.; Matsumoto, K.; Nishimura, H. J. Am. Chem. Soc. 1971,
93, 3299. (b) Ando, M.; Buchi, G.; Ohnuma, T. J. Am. Chem. Soc. 1975,
97, 6880.
(1) (a) Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1818, 8, 323.
(b) Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1819, 810, 142. (c)
Openshaw, H. T.; Robinson, R. J. Nature 1946, 157, 438. (d) For a review
of strychnine total syntheses until 2000, see: Bonjoch, J.; Sole, D. Chem.
ReV. 2000, 100, 3455. (e) Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.;
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9801.
10.1021/ol0521127 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/21/2005

Scheme 2
Figure 1.
overall yields. To prepare more activated enaminones, the
same coupling reaction was performed with 3-methoxy-
methylene-2,4-pentanedione 18, affording in 98% yield the
corresponding di-keto derivative 15. Finally, the construction
of the cyclic precursor 16, which could directly lead to a
pentacyclic adduct by anionic polycyclization, was ac-
complished using the ꢀ-bromoester 178 in 97% yield (Scheme
3).
As part of our ongoing efforts directed toward the
preparation of highly functionalized tetracyclic indolino-
compounds, akin to the core of various natural products, we
have developed a novel, one-pot, three-component anionic
polycyclization reaction, depicted in Scheme 1.6 This process
Scheme 1
Scheme 3
involves the Michael addition of gramine derivative 5 to
acrolein, followed by a Horner-Emmons condensation and
an intramolecular anionic polycyclization sequence.
Our retrosynthetic analysis of 8, based upon this anionic
polycyclization retron, is depicted in Scheme 2. Thus, the
tetracyclic ketone 8 could be derived from an appropriate
enaminone precursor 9, which would in turn originate from
the condensation of a protected tryptamine 10 and a Michael
acceptor bearing a suitable leaving group at the â-position
11.
Our approach toward 8 began with the condensation of
N-benzyltryptamine 13, prepared almost quantitatively from
tryptamine 12,7 with 3-butyn-2-one leading to 14 in excellent
With a ready access to these three key precursors, we next
turned our attention to the crucial anionic polycyclization
cascade.9 Disappointingly, no reaction was observed under
a wide range of conditions, including Brønsted bases,
combination of Brønsted bases and Lewis acids or ambident
(5) For alternative strategies for the synthesis of vindoline and vindor-
osine, see: (a) Ban, Y.; Sekine, Y.; Oishi, T. Tetrahedron Lett. 1978, 2,
151. (b) Takano, S.; Shishido, K.; Matsuzaka, J.; Sato, M.; Ogasawara, K.
Heterocycles 1979, 13, 307. (c) Veenstra, S. J.; Speckamp, W. N. J. Am.
Chem. Soc. 1981, 103, 4645. (d) Andriamialisoa, R. Z.; Langlois, N.;
Langlois, Y. J. Org. Chem. 1985, 50, 961. (e) Danieli, B.; Lesma, G.;
Palmisano, G.; Riva, R. J. Chem. Soc., Perkin Trans. 1 1987, 155. (f)
Feldman, P. L.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 1603. (g)
Kuehne, M. E.; Podhorez, D. E.; Mulamba, T.; Bornmann, W. G. J. Org.
Chem. 1987, 52, 347. (h) Winkler, J. D.; Scott, R. D.; Williard, P. G. J.
Am. Chem. Soc. 1990, 112, 9871. (i) Kobayashi, S.; Ueda, T.; Fukuyama,
T. Synlett 2000, 6, 883. (j) Zhou, S.; Bommezijn, S.; Murphy, J. A. Org.
Lett. 2002, 4, 443. (k) Guo, Z.; Schultz, A. G. Tetrahedron Lett. 2004, 45,
919.
(7) Boumendjel, A.; Nuzillard, J.-M.; Massiot, G. Tetrahedron Lett. 1999,
40, 9033.
(8) Kalaus, G.; Greiner, I.; Kajta´r-Peredy, M.; Eles, J.; Szabo´, L.; Szabo´,
P.; Sza´ntay, C. Tetrahedron 2002, 58, 8921.
(9) For some selected examples of anionic cyclisations, see ref 1 and
references therein and (a) Marko´, I. E.; Southern, J. M.; Adams, H.
Tetrahedron Lett. 1992, 33, 4657. (b) Solberghe, G.; Marko´, I. E.
Tetrahedron Lett. 2002, 43, 5061.
(6) Turet, L.; Marko´, I. E.; Tinant, B.; Declercq, J.-P.; Touillaux, R.
Tetrahedron Lett. 2002, 43, 6591.
5246
Org. Lett., Vol. 7, No. 23, 2005

reagents combining these two properties, and the starting
materials were recovered. Using more forcing conditions only
resulted in extensive decomposition. It thus transpires that
the poor electrophilicity of the enaminone function hampers
the addition of the indolinyl anion to the conjugated system
(Scheme 4).
overall yield of 79%. Finally, base-catalyzed imino-aldol
cyclization proceeded at -78 °C and afforded the long-
sought-after tetracycle 23, in excellent yield and as a single
diastereoisomer. The high reactivity of compound 22 was
thus bypassed using an efficient two-step sequence, involving
a silica gel mediated cyclization followed by an anionic ring
closure11 (Scheme 5).
The structure of the spirocyclic adduct 24 was determined
by 2D-NMR experiments and unambiguously established by
single-crystal X-ray diffraction analysis. The piperidine ring
system adopts a halfchair-like conformation in which the
chain bearing the ketone function occupies an equatorial
position anti to the imine portion of the indolenine nucleus
(Figure 2).
Scheme 4
To circumvent this problem, a more potent Michael
acceptor is required. It was decided to introduce an electron-
withdrawing group between the nitrogen atom and the enone
system and 22 became our next objective. Tryptamine
derivative 22 was efficiently prepared by coupling N-
benzyltryptamine 13 with (E)-4-oxo-2-pentenoic acid, in the
presence of BOP-Cl.10 Unfortunately, attempted purification
of 22 using classical methods repeatedly failed and extensive
degradation was observed in all cases. However, when crude
22 was treated directly with tBuOK in THF, at -78 °C, the
corresponding polycyclic adduct 23 could be isolated for the
first time, as a single diastereoisomer, albeit in rather modest
yield (Scheme 5). It appears that the exacerbated reactivity
Figure 2.
Although readily available in only two operations from
tryptamine 13, tetracycle 23 possesses one carbon too many
and a ring contraction is required to reach the core of the
Aspidosperma and Strychnos alkaloids. It was envisioned that
hydrolysis of the amide bond of 23, followed by an oxidative
decarboxylation, would afford the desired product 4. How-
ever, the robust nature of the N-benzyl amide precluded its
hydrolysis and its conversion into the N-Boc derivative
became mandatory. Initially, the indolino nitrogen of 23 was
methylated using excess methyl iodide and potassium
carbonate in refluxing acetonitrile. Although several hydro-
genation conditions failed to deprotect the N-benzyl amide
25, sodium, in a mixture of ammonia and tetrahydrofuran,
selectively cleaved the benzyl group. Amine 26 was then
transformed into the corresponding Boc-protected amide 27
in excellent overall yield. According to a procedure described
by Potier et al.,12 the N-Boc amide 27 opened smoothly, when
treated with an aqueous 1 M solution of lithium hydroxide,
affording the free carboxylic acid 28 in 87% yield (Scheme
6).
Scheme 5
At this juncture, all that remained to complete the synthesis
of the tetracyclic core of the Aspidosperma and Strychnos
alkaloid families was a tandem oxidative decarboxylation-
Michael addition reaction. The oxidative removal of a
carboxylic acid can be accomplished using various proce-
dures, including lead chemistry developed by Kochi,13 radical
of 22 now leads, under the usual basic conditions required
for the polycyclization, to the formation of numerous
undesired side products. Therefore, milder reaction conditions
were explored. Unexpectedly, when treated overnight with
silica gel in CH2Cl2, the unstable enone 22 was smoothly
converted into the unique imino-spiro compound 24 in a good
(11) This sequence can also be performed as a one-pot operation by
t
directly adding an excess of BuOK to the heterogeneous mixture (60%
yield).
(12) (a) Sagnard, I.; Sasaki, N. A.; Chiaroni, A.; Riche, C.; Potier, P.
Tetrahedron Lett. 1995, 36, 3149.
(10) Diago-Messeguer, J.; Palomo-Coll, A. L.; Ferna´ndez-Lizarbe, J. R.;
Zugaza-Bilbao, A. Synthesis 1980, 547.
(13) (a) Kochi, J. K. J. Am. Chem. Soc. 1965, 87, 2500. (b) Sheldon, R.
A.; Kochi, J. K. Org. React. 1972, 19, 279.
Org. Lett., Vol. 7, No. 23, 2005
5247

Scheme 6
Scheme 7
In summary, we have developed an efficient and diaste-
reoselective methodology that enables the rapid construction
of the tetracyclic indolino-derivative 30, the core of the
Aspidosperma and Strychnos alkaloid families (8 steps, 17%
overall yield). This approach hinges upon two key steps: a
one-pot silica gel/tBuOK polycyclization sequence and an
oxidative decarboxylation-Michael addition reaction. Cur-
rent efforts are now directed toward expending the scope of
this novel methodology, developing an enantioselective
version, and applying it to the synthesis of strychnine and
vindoline.
decomposition of thiohydroxamic derivatives,14 or PdII-
catalyzed decarboxylation of pivaloyl mixed anhydrides.15
While the last two methods only led to regeneration of our
tetracyclic amide 27, the use of Pb(OAc)4 resulted in
complete degradation of the starting material. We believe
that the two oxidizible nitrogen atoms present in 28 interfere
with the normal oxidative-decarboxylation pathway, leading
to the generation of numerous byproducts. Fortunately,
modified Kochi’s conditions, initially introduced by Suarez
et al. and employing hypervalent iodine-based reagent instead
of lead tetraacetate,16 afforded a crude product containing
mostly the desired compound 30, presumably through the
intermediacy of enone 29. Crude product 30 was immediatly
converted, in two steps, into Bu¨chi’s ketone 4, identical in
all respects to previously reported material (50% overall
yield).17 (Scheme 7).
Acknowledgment. Financial support by the Universite´
catholique de Louvain and the Fond National de la Recherche
Scientifique is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data, including spectra copies,
for all new compounds; crystallographic data in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Barton, D. K.; Crich, D.; Motherwell, W. B. Tetrahedron 1985,
41, 3901.
OL0521127
(15) Gooben, L. J.; Rodr´ıguez, N. Chem. Commun. 2004, 724.
(16) Concepcion, J. I.; Francisco, C. G.; Freire, R.; Hernandez, R.;
Salazar, J. A.; Suarez, E. J. Org. Chem. 1986, 51, 402.
(17) We are grateful to Prof. J. D. Winkler for kindly providing us wih
spectroscopic data for this compound.5j
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