Application of the Rh(II) cyclization/cycloaddition cascade for the total synthesis of (±)-aspidophytine

Article abstract of DOI:10.1021/ol061137i

A new strategy for the synthesis of (±)-aspidophytine has been developed and is based on a Rh(II)-catalyzed cyclization/dipolar cycloaddition sequence. The resulting [3+2]-cycloadduct undergoes an efficient Lewis acid mediated cascade that rapidly provide

Full text of DOI:10.1021/ol061137i

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3275-3278
Application of the Rh(II) Cyclization/
Cycloaddition Cascade for the Total
Synthesis of (±)-Aspidophytine
Jose´ M. Mej´ıa-Oneto and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received May 9, 2006
ABSTRACT
A new strategy for the synthesis of (
sequence. The resulting [3 2]-cycloadduct undergoes an efficient Lewis acid mediated cascade that rapidly provides the complete skeleton
of aspidophytine. The synthesis also features a mild decarbomethoxylation reaction.
±)-aspidophytine has been developed and is based on a Rh(II)-catalyzed cyclization/dipolar cycloaddition
+
The Aspidosperma alkaloids occupy a central place in natural
product chemistry because of their wide range of complex
structural variations and diverse biological activity.1 This
family of indole alkaloids contains over 250 members that
share in their molecular structure a common pentacyclic
ABCDE framework, with the C-ring being of critical
importance because all six stereocenters and most of the
functionalities are located in this ring.2 Individual members
differ mainly in functionality and stereochemistry. Over the
years, efficient and elegant routes to this molecular frame-
work have been developed.3,4
cleavage of haplophytine (4) led to aspidophytine (5),7 a
lactonic aspidospermine type of alkaloid which has been
suggested to be not only a biosynthetic precursor of 4 but
also a possible intermediate to be used in its synthesis.8,9
Because of its intriguing structure, aspidophytine has attracted
the attention of two major research groups. In 1999 Corey
et al.8 and four years later Fukuyama et al.9 accomplished
the synthesis of aspidophytine utilizing completely different
(2) (a) Saxton, J. E. Indoles, Part 4: The Monoterpenoid Indole
Alkaloids; Wiley: Chichester, 1983. (b) Herbert, R. B. In The Monoter-
penoid Indole Alkaloids; Supplement to Vol. 25, part 4 of The Chemistry
of Heterocyclic Compounds; Saxton, J. E., Ed.; Wiley: Chichester, 1994;
Chapter 1. (c) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 327 and
references therein.
In 1973, Cava and Yates reported on the structural
determination of haplophytine (4), a dimeric indole alkaloid
isolated from the leaves of Haplophyton cimicidum.5,6 Acid
(3) For the first synthesis of aspidospermine and vindoline, see: (a) Stork,
G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872. (b) Ando, M.; Buchi,
G.; Ohnuma, T. J. Am. Chem. Soc. 1975, 97, 6880.
(1) Saxton, J. E. In The Alkaloids: Chemistry and Biology; Cordell, G.
A., Ed.; Academic Press: San Diego, CA, 1998; Vol. 51, pp 1-197.
10.1021/ol061137i CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/22/2006

strategies. The Corey approach hinged on a creative cascade
reaction between dialdehyde 7 and indole 6, synthesized from
vanillin acetate in 10 steps (Scheme 1). The Fukuyama group
Sonogashira coupling11 with alkyne 9 and then an effective
amine-aldehyde condensation cascade to furnish the aspi-
dosperma skeleton.9
Our approach to aspidophytine was guided by a long-
standing interest in developing new applications of the Rh-
(II) cyclization/cycloaddition cascade for the synthesis of
complex natural products, particularly alkaloids.12 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.13,14 In
earlier work from our laboratory, we had described the
formation of push-pull dipoles from the Rh(II)-catalyzed
reaction of R-diazo imides and noted that a smooth intramo-
lecular 1,3-dipolar cycloaddition occurred across both alkenyl
and heteroaromatic π-bonds to provide novel pentacyclic
compounds in good yield and in a stereocontrolled fashion.15
Our plan for the synthesis of aspidophytine is shown in
retrosynthetic format in Scheme 2 and is centered upon the
Scheme 1
used their signature radical cascade chemistry10 to construct
Scheme 2
indole 8 from vanillin acetate (11 steps), followed by a
(4) For some select methods to synthesize the pentacyclic framework of
aspidospermidine (1), see: (a) Camerman, A.; Camerman, N.; Kutney, J.
P.; Piers, E.; Trotter, J. Tetrahedron Lett. 1965, 637. (b) Harley-Mason, J.;
Kaplan, M. J. Chem. Soc., Chem. Commun. 1967, 915. (c) Laronze, J.-Y.;
Laronze-Fontaine, J.; Le´vy, J.; Le Men, J. Tetrahedron Lett. 1974, 491. (d)
Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am. Chem. Soc. 1981, 103,
6990. (e) Gallagher, T.; Magnus, P.; Huffman, J. J. Am. Chem. Soc. 1982,
104, 1140. (f) Wenkert, E.; Hudlicky, T. J. Org. Chem. 1988, 53, 1953. (g)
Mandal, S. B.; Giri, V. S.; Sabeena, M. S.; Pakrashi, S. C. J. Org. Chem.
1988, 53, 4236. (h) Meyers, A. I.; Berney, D. J. Org. Chem. 1989, 54,
4673. (i) Node, M.; Nagasawa, H.; Fugi, K. J. Org. Chem. 1990, 55, 517.
(j) Le Menez, P.; Kunesch, N.; Lui, S.; Wenkert, E. J. Org. Chem. 1991,
56, 2915. (k) Desmae¨le, D.; d’Angelo, J. J. Org. Chem. 1994, 59, 2292. (l)
Wenkert, E.; Lui, S. J. Org. Chem. 1994, 59, 7677. (m) Forns, P.; Diez,
A.; Rubiralta, M. J. Org. Chem. 1996, 61, 7882. (n) Schultz, A. G.; Pettus,
L. J. Org. Chem. 1997, 62, 6855. (o) Callaghan, O.; Lampard, C.; Kennedy,
A. R.; Murphy, J. A. J. Chem. Soc., Perkin Trans. 1 1999, 995. (p) Iyengar,
R.; Schildknegt, K.; Aube´, J. Org. Lett. 2000, 2, 1625. (q) Toczko, M. A.;
Heathcock, C. H. J. Org. Chem. 2000, 65, 2642. (r) Patro, B.; Murphy, J.
A. Org. Lett. 2000, 2, 3599. (s) Kozmin, S. A.; Iwama, T.; Huang, Y.;
Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628. (t) Banwell, M. G.; Smith,
J. A. J. Chem. Soc., Perkin Trans. 1 2002, 2613. (u) Marino, J. P.; Rubio,
M. B.; Cao, G.; de Dios, A. J. Am. Chem. Soc. 2002, 124, 13398. (v)
Gnecco, D.; Va´zquez, E.; Galindo, A.; Tera´n, J. L.; Berne`s, S.; Enr´ıquez,
R. G. ArkiVoc 2003, 11, 185. (w) Tanino, H.; Fukuishi, T.; Ushiyama, M.;
Okada, K. Tetrahedron 2004, 60, 3273. (x) Banwell, M. G.; Lupton, D.
W. Org. Biomol. Chem. 2005, 3, 213.
construction of the key cycloadduct 11 by making use of
R-diazo imide 10. The successful completion of this synthesis
demonstrates the utility of this cascade methodology for the
construction of complex indole-containing natural products.
(5) Yates, P.; MacLachlan, F. N.; Rae, I. D.; Rosenberger, M.; Szabo,
A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M.
V.; Ziegler, W. J. Am. Chem. Soc. 1973, 95, 7842.
(11) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(6) (a) Saxton, J. E. Alkaloids 1965, 8, 673. (b) Cheng, P.-T.; Nyburg,
S. C.; MacLachlan, F. N.; Yates, P. Can. J. Chem. 1976, 54, 726.
(7) (a) Cava, M. P.; Talapatra, S. K.; Nomura, K.; Weisbach, J. A.;
Douglas, B.; Shoop, E. C. Chem. Ind. (London) 1963, 1242. (b) Cava, M.
P.; Talapatra, S. K.; Yates, P.; Rosenberger, M.; Szabo, A. G.; Douglas,
B.; Raffuaf, R. F.; Shoop, E. C.; Weisbach, J. A. Chem. Ind. (London)
1963, 1875. (c) Rae, I. D.; Rosenberger, M.; Szabo, A. G.; Willis, C. R.;
Yates, P.; Zacharias, D. E.; Jeffrey, G. A.; Douglas, B.; Kirkpatrick, J. L.;
Weisbach, J. A. J. Am. Chem. Soc. 1967, 89, 3061.
(8) He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 6771.
(9) (a) Sumi, S.; Matsumoto, S.; Tokuyama, H.; Fukuyama, T. Org. Lett.
2003, 5, 1891. (b) Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T.
Tetrahedron 2003, 59, 8571.
(10) (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994,
116, 3127. (b) Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T.
Synthesis 2000, 429. (c) Tokuyama, H.; Watanabe, M.; Hayashi, Y.;
Kurokawa, T.; Peng, G.; Fukuyama, T. Synlett 2001, 1403. (d) Kobayashi,
S.; Peng, G.; Fukuyama, T. Tetrahedron Lett. 1999, 40, 1519. (e) Kobayashi,
S.; Ueda, T.; Fukuyama, T. Synlett 2000, 883.
(12) For some leading references, see: (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. Top. Curr. Chem. 1997, 189, 121. (d)
Padwa, A. Pure Appl. Chem. 2004, 76, 1933. (e) Padwa, A.; Brodney, M.
A.; Lynch, S. M.; Rashatasakhon, P.; Wang, Q.; Zhang, H. J. Org. Chem.
2004, 69, 3735.
(13) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; John Wiley & Sons: New
York, 1998.
(14) Boger and co-workers have recently described an alternate approach
to onium ylides based on a [4+2]-cycloaddition of 1,3,4-oxadiazoles
followed by a thermal extrusion of nitrogen and have elegantly exploited
this chemistry for the construction of a variety of aspidosperma alkaloid
targets. See: Choi, Y.; Ishikawa, H.; Velcicky, J.; Elliott, G. I.; Miller, M.
M.; Boger, D. L. Org. Lett. 2005, 7, 4539 and references therein.
(15) (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) Mej´ıa-Oneto, J. M.; Padwa,
A. Org. Lett. 2004, 6, 3241. (d) Padwa, A.; Lynch, S. M.; Mej´ıa-Oneto, J.
M.; Zhang, H. J. Org. Chem. 2005, 70, 2206.
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Org. Lett., Vol. 8, No. 15, 2006

Construction of the required R-diazo imide 10 entailed the
synthesis of two building blocks, the substituted 2-(indol-
3-yl)acetic acid 16 and the diazo lactam 20. The preparation
of 16 was carried out in five steps in 36% overall yield
starting from aniline 13 and is summarized in Scheme 3.
dure17 to furnish â-keto ester 19 in 54% overall yield. Finally,
the requisite R-diazo lactam 20 was easily obtained using
standard diazo transfer conditions18 and was isolated in 96%
yield.
At this point, we joined the two synthesized fragments by
treating acid 16 with (COCl)2 and allowing the resulting acid
chloride to react with the stable N-H diazo lactam in the
presence of 4 Å molecular sieves. The desired R-diazo imide
10 was obtained in 92% yield. Formation of the push-pull
dipole 21 was achieved by reaction of 10 with Rh2(OAc)4,
which afforded a rhodium carbenoid species that readily
underwent cyclization onto the neighboring imido carbonyl
to form the carbonyl ylide dipole 21.12 Subsequent intramo-
lecular cycloaddition across the tethered indolyl group
furnished cycloadduct 11 in 97% yield.19 The acid lability
of cycloadduct 11 was exploited in the next step of the
synthesis. Treatment of 11 with a Lewis acid such as BF3‚
OEt2 resulted in cleavage of the oxabicyclic ring and
formation of a transient N-acyl iminium ion which was
captured by the adjacent carbonyl group of the tert-butyl ester
(Scheme 5). Loss of isobutylene from the resulting oxonium
Scheme 3
Commercially available aniline 13 was iodinated using ICl
(73%), and the resulting iodoaniline 14 was subsequently
alkylated with methyl bromocrotonate to give the secondary
amine 15 in 75% yield based on recovered starting material.
Intramolecular Heck cyclization (90%) of 15 afforded the
expected indole ring16 which was easily converted to 16 by
N-methylation with CH3I (80%) followed by a subsequent
hydrolysis step (94%).
Scheme 5
Preparation of the diazo lactam unit 20 commenced with
commercially available δ-valerolactam 17 which was depro-
tonated with excess base and allowed to react with tert-butyl
bromoacetate to give lactam 18 in 80% yield (Scheme 4).
Scheme 4
ion resulted in the isolation of 23 in 70% yield. The relative
stereochemistry of 23 was assigned on the basis of its
spectroscopic properties which were essentially identical to
the related ring-opened product 24 (R ) H) whose structure
was confirmed by a single-crystal X-ray analysis.20
The completion of the synthesis of aspidophytine (5) from
23 is outlined in Scheme 6. First, the carbomethoxy and
(17) Brooks, D. W.; Lu, D. L.; Masamune, S. Angew. Chem., Int. Ed.
Engl. 1979, 18, 72.
(18) (a) Regitz, M. Chem. Ber. 1966, 99, 3128. (b) Regitz, M.; Hocker,
J.; Liedhegener, A. Org. Synth. 1973, 5, 179.
The ethyl ester portion of 18 was converted to the methyl
3-oxopropanoate group using a modified Masamune proce-
(19) In contrast to a previous finding,15 the exo cycloadducts 11 and 22
were the exclusive products isolated from the Rh(II)-catalyzed reaction.
We assume that the bulky tert-butyl ester functionality blocks the endo
approach thereby resulting in cycloaddition taking place from the less-
congested exo face.
(16) (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 1037. (b)
Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S. J. Org. Chem. 1980, 45,
2709. (c) Aubert, K. M.; Heathcock, C. H. J. Org. Chem. 1999, 64, 16.
Org. Lett., Vol. 8, No. 15, 2006
3277

with a halide ion and loss of CO2 to give 26.23 Acetylation
of 26 with acetyl chloride/NEt3 afforded the corresponding
acetate which was subsequently reduced using SmI2 to give
27 in 90% yield from both steps. The carbonyl group of 27
was transformed into the corresponding enol triflate which,
upon treatment with Pd(Ph3P)4 and n-Bu3SnH according to
Corey’s experimental conditions,8 gave 28 (72%). Treatment
of 28 with P2S5 furnished thiolactam 29 in 95% yield.24
Although not investigated in detail, our attempts to reduce
29 with Raney-Ni were not successful. Instead, S-ethylation
of thiolactam 29 with Meerwein’s reagent followed by
LiAlH(OtBu)3/nBu3SnH reduction25 provided (()-aspido-
phytine (5) in 61% yield from 29. Confirmation of the
structure was obtained by comparison of the spectral data
with that of an authentic sample of aspidophytine provided
by Professor Fukuyama.
Scheme 6
In conclusion, a concise total synthesis of (()-aspidophy-
tine was achieved featuring a Rh(II) cyclization/cycloaddition
cascade of a suitably substituted R-diazo imide as the key
step. We are currently refining this strategy and further
applying the methodology toward other aspidosperma alka-
loids.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM 059384)
and the National Science Foundation (CHE-0450779). We
wish to thank Professor Tohru Fukuyama and Dr. Hidetoshi
Tokuyama (University of Tokyo) for an authentic sample
of aspidophytine for comparison purposes.
hydroxyl groups next to the keto group were sequentially
removed to produce compound 27. Treatment of 23 with
MgI2 in refluxing acetonitrile containing a small quantity of
water resulted in the formation of alcohol 26 in 75% yield.
Although a cursory analysis of the conditions suggests a
Krapcho dealkoxycarbonylation reaction,21 the isolation of
carbonate 25 from the reaction is more consistent with an
unexpected carbomethoxy group migration22 to the adjacent
hydroxyl group followed by further reaction of the carbonate
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds together with an ORTEP drawing for compounds
24 and 25. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL061137I
(22) For some related examples, see: (a) Rubin, M. B.; Inbar, S.
Tetrahedron Lett. 1977, 1037. (b) Davis, F. A.; Clark, C.; Kumar, A.; Chen,
B.-C. J. Org. Chem. 1994, 59, 1184.
(23) Structure 25 was established on the basis of an X-ray crystal structure
analysis. A more detailed study of this unusual rearrangement is currently
underway in our laboratory.
(20) The authors have deposited coordinates for structure 24 with the
Cambridge Crystallographic Data Centre. The coordinates can be obtained,
on request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, B2 1EZ, U.K.
(21) For a review of dealkoxycarbonylations, see: Krapcho, A. P.
Synthesis 1982, 805 and 893.
(24) Curphey, T. J. J. Org. Chem. 2002, 67, 6461.
(25) Raucher, S.; Klein, P. Tetrahedron Lett. 1980, 21, 4061.
3278
Org. Lett., Vol. 8, No. 15, 2006