An aza-wittig/π-furan cyclization approach toward the homoerythrina alkaloid (±)-selaginoidine

Article abstract of DOI:10.1021/ol0501323

(Chemical Equation Presented) A one-pot procedure was developed to efficiently prepare hexahydroindolinones containing a tethered furan ring. Reaction of a furanyl azide with Bu₃P delivered the iminophosphorane, which was allowed to react with

Full text of DOI:10.1021/ol0501323

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1339-1342
An Aza-Wittig/
Approach Toward the Homoerythrina
Alkaloid ( )-Selaginoidine
π-Furan Cyclization
±
Michael P. Cassidy, Ayse Daut O2zdemir, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received January 20, 2005
ABSTRACT
A one-pot procedure was developed to efficiently prepare hexahydroindolinones containing a tethered furan ring. Reaction of a furanyl azide
with Bu3P delivered the iminophosphorane, which was allowed to react with 1-methyl-(2-oxocyclohexyl)acetic acid to give the desired
hexahydroindolinone ring system. Further treatment with trifluoroacetic acid afforded the tetracyclic lactam skeleton found in the alkaloid
(±)-selaginoidine.
The taxodeaceous plant Athrotaxis selaginoides is well-
known in Tasmania under the name of King Billy Pine and
is highly valued as a source of softwood timber.1,2 Some
specimens of the tree attain a height of 40 m and are over
1000 years old. A number of alkaloids are present in all of
its plant materials, including the bark and leaves.3 One of
the compounds isolated was assigned the structure of (()-
selaginoidine (1), which corresponds to a unique nonben-
zenoid member of the homoerythrina alkaloid family.4 On
the basis of our earlier work using hexahydroindolinone
derivatives for the synthesis of various erythrina alkaloids,5
we felt that a suitably substituted hexahydroindolinone
precursor might allow for a facile entry to the tetracyclic
core of selaginoidine (1). The formation of the homoerythrina
skeleton of 1 was envisioned to come about from either a
Heck or radical-induced cyclization of the bromo-furanyl
hexahydroindolinone 2 (Scheme 1). A convenient way to
construct 2 would involve condensation of furanylamine 3
with a (1-substituted-2-oxo-cyclohexyl)acetic acid derivative
(i.e., 4) under Dean-Stark conditions.6
Scheme 1
Accordingly, 2,3-dibromo-5-carbomethoxyfuran (5)7 was
subjected to a Pd(0)-catalyzed coupling with allyl alcohol.8
This resulted in exclusive reaction at the 2-bromo position
(1) Curtis, W. M. The Student’s Flora of Tasmania, Part I; Tasmanian
Government Printer: Hobart, 1956; p 6.
(2) Bick, I. R. C.; Bremner, J. B.; Razak, A.; Thuc, L. V. Experientia
1980, 36, 1135.
(3) Panichanun, S.; Bick, I. R. C. Tetrahedron 1984, 40, 2685.
(4) Tsuda, Y.; Sano, T. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, 1996; Vol. 48, pp 249-337.
(5) Lee, H. I.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. Org. Lett.
2003, 5, 5067.
(6) (a) Ragan, J. A.; Claffey, M. C. Heterocycles 1995, 41, 57. (b) Ennis,
M. D.; Hoffman, R. L.; Ghazal, N. B.; Old, D, W.; Mooney, P. A. J. Org.
Chem. 1996, 61, 5813.
10.1021/ol0501323 CCC: $30.25
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and delivered aldehyde 6 in 70% yield.9 A subsequent
reduction of 6 with sodium borohydride afforded the
expected alcohol 7, which in turn was converted into the
corresponding mesylate 8. Treatment of 8 with NaN3 in DMF
furnished furanyl azide 9 in 93% yield (Scheme 2).
heterocycles.12 The aza-Wittig reaction corresponds to the
nitrogen analogue of the Wittig olefination process and
involves the reaction of an iminophosphorane with a carbonyl
group. The reaction has been used to prepare various cyclic
imines and its synthetic relevance has been summarized in
several review articles.13 The intramolecular version of this
reaction has drawn considerable attention in recent years
because of its high potential for heterocyclic synthesis.14
Since we were having a great deal of difficulty in converting
azide 9 into amine 10 for subsequent condensation with
ketoacid 4 (R ) Me), we wondered whether it might be
possible to use azide 9 directly without the intervention of
10. Thus, an aza-Wittig type reaction of 11 with ketoacid 4
should generate imine 12, which we expected to rapidly
cyclize and furnish the desired hexahydroindolinone system
13 (Scheme 3).15 Indeed, this proved to be the case, especially
Scheme 2
Scheme 3
The reduction of azides to amines is a reaction of
paramount importance in organic synthesis; therefore, a great
many reagents have been reported to effect this transforma-
tion.10 Indeed, there has always been a considerable interest
in searching for more efficient and chemoselective azide
reducing agents.11 In our hands, however, the reduction of
azide 9 to amine 10 proved somewhat problematic due to
the presence of both the ester and bromo groups. Our
attempts to hydrogenate the azide group were complicated
as a result of the simultaneous reduction of the bromo group.
The Staudinger reaction12 using the iminophosphorane
derived from 9 also proved troublesome, as we could only
obtain amine 10 as an impure oil in low yield.
when microwave technology was applied to the condensation
reaction.
Iminophosphoranes were first prepared at the beginning
of the last century by Staudinger and have become extremely
useful reagents for the construction of nitrogen containing
The advent of single mode microwave reactors, which
enable precise control of reaction conditions, has opened the
way for the exploration of microwave-assisted methods for
organic synthesis.16 With this in mind, we used microwave
irradiation employing several different azides to rapidly
access a number of heterocyclic frameworks with abbreviated
reaction times and yields far exceeding those of conventional
thermal methods. In a typical example, the reaction of azide
9 with tributylphosphine (Bu3P) was carried out at 25 °C
using xylene as a solvent. Preformation of the iminophos-
phorane intermediate was necessary. Addition of ketoacid 4
followed by microwave irradiation in a sealed 10-mL vial
(7) Chadwick, D. J.; Chambers, J.; Meakins, G. D.; Snowden, R. L. J.
Chem. Soc., Perkin Trans. 1 1973, 1766.
(8) Diederich, F., Stang, P. J., Eds.; Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH; Weinheim, Germany, 1998.
(9) Bach, T.; Kru¨ger, L. Synlett 1998, 1185.
(10) (a) Marson, C. M.; Hobson, A. D. In ComprehensiVe Organic
Functional Group Transformations; Ley, S. V., Ed.; Pergamon-Elsevier:
Oxford, U.K., 1995; Vol. 2, pp 297-332. (b) Gilchrist, T. L. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, U.K., 1991; Vol. 8, pp 381-402. (c) Hassner, A. In
Houben-Weyl Methods of Organic Chemistry, 4th ed.; Georg-Thieme
Verlag: Stuttgart, Germany, 1990; Vol. E16a, Part 2, pp 1243-1290. (d)
Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 298.
(11) For some recent methods, see: (a) Rao, H. S. P.; Siva, P. Synth.
Commun. 1994, 24, 549. (b) Ranu, B. C.; Sarkar, A.; Chakraborty, R. J.
Org. Chem. 1994, 59, 4114. (c) Alvarez, S. G.; Fisher, G. B.; Singaram, B.
Tetrahedron Lett. 1995, 36, 2567. (d) Salunkhe, A. M.; Brown, H. C.
Tetrahedron Lett. 1995, 36, 7987. (e) Capperucci, A.; Degl’Innocenti, A.;
Funicello, M.; Mauriello, G.; Scafato, P.; Spagnolo, P. J. Org. Chem. 1995,
60, 2254. (f) Goulaouic-Dubois, G.; Hesse, M. Tetrahedron Lett. 1995, 36,
7427. (h) Ramesha, A. R.; Bhat, S.; Chandrasekaran, S. J. Org. Chem. 1995,
60, 7682. (i) Baruah, M.; Boruah, A.; Prajapati, D.; Sandhu, J. S.; Ghosh,
A. C. Tetrahedron Lett. 1996, 37, 4559. (j) Peters, R. G.; Warner, B. P.;
Burns, C. J. J. Am. Chem. Soc. 1999, 121, 5585.
(13) (a) Wamhoff, H.; Richardt, G.; Sto¨lben, S. AdV. Heterocycl. Chem.
1995, 64, 159. (b) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep.
Proced. Int. 1992, 24, 209. (c) Barluenga, J.; Palacios, F. Org. Prep. Proced.
Int. 1991, 23, 1. (d) Fresneda, P. M.; Molina, P. Synlett 2004, 1.
(14) (a) Molina, P.; Vilaplana, M. J. Synthesis 1994, 1917. (b) Gusari,
N. I. Russ. Chem. ReV. (Engl. Transl.) 1991, 60, 146.
(15) Unfortunately, all of our attempts to induce a Heck or radical
cyclization of 13 failed. We are currently investigating a Lewis acid induced
cyclization of the debrominated furan derived from 13.
(16) Loupy, A., Ed.; MicrowaVes in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2002.
(12) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635.
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Org. Lett., Vol. 7, No. 7, 2005

(200 W, 150 °C, 30 min) gave the best results, producing
hexahydroindolinone 13 in 63% yield. This optimized
method was then applied to a number of related condensation
reactions where the azide, ketone, and acid chloride were
varied (Scheme 4). Heating a 1:1 mixture of furanyl azide
skeleton of the erythrina/homoerythrina family of alkaloids.
Furanyl azide 23 was easily converted into the desired
enamide sulfide (i.e., 24) following the azide/iminophos-
phorane/ethylthioacetyl chloride protocol already established
(Scheme 5). A subsequent sodium periodate oxidation
Scheme 4
Scheme 5
afforded sulfoxide 26, which on treatment with trifluoroacetic
acid furnished the tetracyclic lactam 28 in 76% yield as the
exclusive product. The preferential formation of 28 is
consistent with our earlier stereochemical observations,
suggesting that a 4π-Nazarov type electrocyclization controls
the direction of closure from the R-acylthionium ion inter-
mediate.21 The Pictet-Spengler step involves attack of the
proximal furanyl ring from the less hindered side of the
iminium ion.
20 with ketoacid 4 in a microwave reactor at 180 °C for 30
min delivered not only the desired hexahydroindolinone 21
(80%) but also the tetracyclic furan 22 (15%) derived from
a N-acyliminium ion promoted cyclization of 21 under the
reaction conditions.17 Further experimentation showed that
treating 21 with either trifluoroacetic acid or trifluoromethane
sulfonic acid gave lactam 22 in >90% yield.
Earlier work in our laboratory has shown that the Pum-
merer reaction followed by a π-cyclization represents an
effective and general method for the preparation of many
diverse azapolycyclic skeletons.18 Since the combination of
a Pummerer/Mannich cyclization sequence offers unique
opportunities for the assemblage of complex target mol-
ecules,19 we decided to study the acid-induced cyclization
of enamides 27 (n ) 1) and 28 (n ) 2) to determine whether
these systems could also be used to assemble the core
To demonstrate that this methodology could also be used
for assembling the homoerythrina skeleton, the homologous
enamido furanyl sulfoxide 27 was subjected to the acid-
catalyzed cyclization conditions (Scheme 5). The major
product isolated (40%) corresponded to the cyclized lactam
29. Presumably, the lower yield of product is related to the
entropically more demanding seven-membered ring cycliza-
tion onto the resulting N-acyliminium ion formed from the
initial Pummerer reaction. Further studies need to be carried
out in order to maximize the yield of 29.
In summary, we have shown that a variety of vinylogous
amides and hexahydroindolinones can be prepared using an
aza-Wittig reaction of iminophosphoranes derived from
furanyl azides and 1-methyl-(2-oxo-cyclohexyl)acetic acid.
Intramolecular electrophilic substitution on the furan ring
occurs when the hexahydroindolinone is treated with acid.
Further studies on the synthesis of selaginoidine (1) and
(17) (a) Ito, K.; Suzuki, F.; Haruna, M. J. Chem. Soc., Chem. Commun.
1978, 733. (b) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T.
Chem. Pharm. Bull. 1993, 41, 2087. (c) Hosoi, S.; Nagao, M.; Tsuda, Y.;
Isobe, K.; Sano, T.; Ohta, T. J. Chem. Soc., Perkin Trans. 1 2000, 1505.
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(19) (a) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J. Org. Chem.
1998, 63, 1144. (b) Padwa, A.; Kappe, C. O.; Reger, T. S. J. Org. Chem.
1996, 61, 4888. (c) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.; McClure,
M. S. J. Org. Chem. 1998, 63, 6778.
(20) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.; McClure, M. S.;
Wang, Q. J. Org. Chem. 2002, 67, 5928.
(21) Denmark, S. E. In ComprehensiVe Organic Synthesis; Trost, B. M.;
Fleming, I.; Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 751-784.
Org. Lett., Vol. 7, No. 7, 2005
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related homoerythrinane alkaloids are in progress and will
be reported in due course.
ship. We thank Mickea Rose for some experimental as-
sistance.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge the sup-
port of this work by the National Institutes of Health (GM
59384) and the University Research Committee of Emory
University for funds to acquire a microwave reactor. A.D.O.
thanks Istanbul Technical University for a Visiting Scholar-
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