A synthesis of the welwistatin core

Article abstract of DOI:10.1021/ol0620747

An approach to the core structure of the microtubule-targeting agent welwistatin is described. The approach utilizes the type 2 intramolecular Diels-Alder reaction, with indole serving as the tether between diene and dienophile, to form the natural produc

Full text of DOI:10.1021/ol0620747

ORGANIC
LETTERS
A Synthesis of the Welwistatin Core§
2006
Vol. 8, No. 23
5287-5289
Ryan Lauchli and Kenneth J. Shea*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, IrVine, California 92697-2025
kjshea@uci.edu
Received August 22, 2006
ABSTRACT
An approach to the core structure of the microtubule-targeting agent welwistatin is described. The approach utilizes the type 2 intramolecular
Diels Alder reaction, with indole serving as the tether between diene and dienophile, to form the natural product’s characteristic bicyclo-
−
[4.3.1]decane skeleton.
Despite the success of microtubule-targeting agents pacli-
taxel, vinblastine, and colchicine as cancer therapeutics, the
effectiveness of these treatments is diminished in many
instances by multiple drug resistance (MDR).1 The mecha-
nism of MDR is thought to be overexpression of P-
glycoprotein, which acts as a drug efflux pump. The
antimicrotubule agent welwistatin has shown the unique
characteristic of maintaining its antimicrotubule properties
in laboratory cell lines, even when those cell lines had MDR
and overexpressed P-glycoprotein. This enhanced cytotoxic
action demonstrates that welwistatin may be effective as an
anticancer drug.
dolinone A has been synthesized by impressive efforts of
two groups, no members of the welwistatin structural class
have yielded to total synthesis to date.3 Recently, several
core structure syntheses have been disclosed, emphasizing
the significant interest in synthesizing this challenging
molecule.4 The complex architecture of welwistatin com-
prises 4 stereocenters, 3 quaternary carbons including 2
which are vicinal, a sensitive vinyl chloride, and an imbedded
bicyclo[4.3.1] ring system. We hypothesized that this bicyclo-
[4.3.1] system could be accessed through a type 2 intramo-
lecular Diels-Alder (T2IMDA) cyclization by using the
indole framework to tether the diene and dienophile (Scheme
(2) (a) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem.
Soc. 1994, 116, 9935. (b) Jimenez, J. I.; Huber, U.; Moore, R. E.; Patterson,
G. M. L. J. Nat. Prod. 1999, 62, 569.
(3) (a) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394.
(b) Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L.
J. Am. Chem. Soc. 2006, 128, 1448.
(4) (a) Konopelski, J. P.; Deng, H.; Scheimann, K.; Keane, J. M.;
Olmstead, M. M. Synlett 1998, 1105. (b) Wood, J. L.; Holubec, A. A.;
Stoltz, B. M.; Weiss, M. M.; Dixon, J. A.; Doan, B. D.; Shamji, M. F.;
Chen, J. M.; Heffron, T. P. J. Am. Chem. Soc. 1999, 121, 6326. (c) Kaoudi,
T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem., Int. Ed. 2000,
39, 731. (d) Konopelski, J. P.; Deng, H. Org. Lett. 2001, 3, 3001. (e) Jung,
M. E.; Slowinski, F. Tetrahedron Lett. 2001, 42, 6835. (f) Lo´pez-Alvarado,
P.; Garc´ıa-Granda, S.; AÄ lvarez-Ru´a, C.; Avendan˜o, C. Eur. J. Org. Chem.
2002, 1702. (g) Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss, M. M.;
Tamaki, K.; Ovaska, T. V.; Wood, J. L. Angew. Chem., Int. Ed. 2004, 43,
1270. (h) MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7,
3421. (i) Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org. Lett. 2005, 7,
4087. (j) Greshock, T. J.; Funk, R. L. Org. Lett. 2006, 8, 2643. (k) For a
review, see: Avendan˜o, C.; Mene´ndez, J. C. Curr. Org. Synth. 2004, 1,
65.
Welwistatin is an alkaloid isolated from blue-green algae,
along with several related compounds.2 Though welwitin-
§ Dedicated to the memory of the late Dr. Vinayak Kane.
(1) (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G.; Moore,
R. E. Mol. Pharm. 1995, 47, 241. (b) Zhang, X.; Smith, C. D. Mol. Pharm.
1996, 49, 288. (c) Jordan, M. A.; Wilson, L. Nature ReV. Cancer 2004, 4,
253.
10.1021/ol0620747 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/13/2006

1).5 Our interest is to develop a concise entry to the
second generation catalyst at 80 °C under a balloon filled
with ethylene.8
The N-tosyl protecting group was also critical for the
following step, the addition of vinylmagnesium bromide to
aldehyde 9 to form the allylic alcohol 10. With the N-methyl
group, the allylic alcohol rapidly decomposed.9 Tosyl protec-
tion disfavored carbocation formation, and permitted isolation
of the allylic alcohol 10 in 81% yield. MnO2 was used to
oxidize the allylic alcohol to the corresponding vinyl ketone
3, the T2IMDA cyclization precursor. The indole group had
not previously been incorporated as part of the tether in the
T2IMDA reaction. It was anticipated, however, that this
group could reduce the conformational freedom of the Diels-
Alder precursor, resulting in milder conditions for the
cycloaddition. Previous experience had shown that a simple
C4-alkyl chain tether required a temperature of 200 °C for
15 min to induce cyclization to the bicyclo[4.3.1] cycloadduct
(Scheme 3).10
Scheme 1. The T2IMDA Strategy for Constructing the
Welwistatin Core
welwistatin core structure, and investigate the potential of
the indole group as a tether in the T2IMDA and its effects
on stereochemistry and reactivity on the cycloaddition step.
To establish the feasibility of this approach, we targeted
the parent 1,3-butadiene and unsubstituted enone as the
DielssAlder components to access the core structure of
welwistatin.Our synthetic route began with 4-bromoindole.6
Scheme 3. A Comparison of the Reactivities of T2IMDA
Precursors
Scheme 2. Synthesis of the Diels-Alder Precursor
Our attempt at the T2IMDA reaction was conducted at
120 °C. Gratifyingly, the reaction was complete after 1 h at
this temperature, and the product was isolated in 50% yield
overall from 10. Connectivity in the cycloadduct was
established by 2D NMR experiments. Mass spectrometry
revealed the monomeric nature of the product, eliminating
the possibility that a bimolecular cycloaddition between two
indole molecules had occurred. These data confirmed the
synthesis of the welwistatin core.
Following the success of the indole moiety as a tether in
the T2IMDA cyclization in forming the welwistatin core
structure, we endeavored to introduce functionality at key
positions. One possibility was the use of furan as the diene.
Though furan has been used as a diene in many Diels-Alder
reactions, the need to overcome its aromatic stabilization
usually limits its use in cycloadditions.11 Strategies to increase
the reactivity of furan have included high pressure, the
introduction of heteroatoms at the 1-position, and tethering
Vilsmeier-Hack formylation of this compound gave a
quantitative yield of aldehyde 6.7 A Sonagashira coupling
was used to install the TMS-protected acetylene at the
4-position of the indole. Deprotection of the acetylene
proceeded cleanly, and the indole nitrogen was protected at
this stage with tosyl chloride. Tosyl protection of the indole
was found to be necessary for the subsequent metathesis step,
as this protecting group improved the toluene solubility of
the compound. The ene-yne metathesis in toluene was
subsequently accompished in 94% yield by using Grubbs
(8) (a) Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002, 43, 2235. (b)
Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317.
(9) Similar results were observed previously: Bennasar, M. L.; Zulaica,
E.; Tummers, S. Tetrahedron Lett. 2004, 45, 6283.
(10) Shea, K. J.; Wise, S. Tetrahedron Lett. 1979, 20, 1011.
(11) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179.
(5) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001,
40, 820.
(6) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51,
5106.
(7) Somei, M.; Kizu, K.; Kunimoto, M.; Yamada, F. Chem. Pharm. Bull.
1985, 33, 3696.
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Org. Lett., Vol. 8, No. 23, 2006

the dienophile to the 1-position for type 1 intramolecular
Diels-Alder reactions. To the best of our knowledge, no
examples of T2IMDA cyclizations with furan dienes have
been reported. Installing furan as the diene began with
opening the oxo bridge can allow for elaboration to these
functionalities in a synthesis of welwistatin. In summary, a
Scheme 4. The Furan Diene to Access a Functionalized Core
of Welwistatin
Figure 1. ORTEP of cycloadduct 18.
3,4-substituted indole has served as a tether in the T2IMDA
cyclization to form the core structure of welwistatin. The
unfuntionalized core was accessed in 8 steps from 4-bro-
moindole. The unprecedented use of furan as a diene in the
T2IMDA reaction provided an appropriately functionalized
welwistatin core from 4-bromoindole in 6 steps. Elaboration
of this core is underway.
aldehyde 6. Suzuki coupling with 3-furan boronic acid gave
4-furylindole 14 quantitatively. Protection of the indole with
tosylate and additon of vinyl magnesium bromide to give
the allylic alcohol 16 proceeded as in the unfunctionalized
diene case. Oxidation with MnO2 gave the cyclization
precursor, which was immediately dissolved in toluene and
heated to 120 °C. This relatively low temperature for the
cycloaddition was deemed necessary to disfavor retrocy-
cloadditon. Surprisingly, cycloadduct 18 was obtained after
3 h in 69% yield. The cycloadduct proved to be stable
indefinitiely at ambient temperature, and its structure was
confirmed through X-ray crystallography.
Acknowledgment. This research was supported by the
National Institutes of Health. We are grateful to Dr. Joseph
W. Ziller (UCI) for X-ray crystallographic work, Dr. Phil
Dennison (UCI) for NMR expertise, and Dr. John Greeves
(UCI) for mass spectral data. R.L. thanks the National
Institutes of Health for a predoctoral fellowship.
Supporting Information Available: Experimental details
and spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Cycloadduct 18 incorporates oxygen at both ketone and
vinyl chloride positions in the natural product, and thus
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