Rapid synthesis of the N-methylwelwitindolinone skeleton

Article abstract of DOI:10.1021/ol051043t

(Chemical Equation Presented) An efficient, convergent synthesis of the core bicyclo[4.3.1]decane ring system of welwitindolinones is described. Key steps in the synthesis include an intramolecular palladium-catalyzed enolate arylation reaction to create

Full text of DOI:10.1021/ol051043t

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3421-3424
Rapid Synthesis of the
N-Methylwelwitindolinone Skeleton
James A. MacKay, Raynauld L. Bishop, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchicago.edu
Received May 5, 2005
ABSTRACT
An efficient, convergent synthesis of the core bicyclo[4.3.1]decane ring system of welwitindolinones is described. Key steps in the synthesis
include an intramolecular palladium-catalyzed enolate arylation reaction to create the desired bicyclic skeleton and a Curtius rearrangement
to install the bridgehead isocyanate unit.
A 1994 report described the isolation of a new class of indole
alkaloids from the lipophilic extracts of both Hapalosiphon
welwitschii and Westiella intricata.1 The extracts from these
cyanobacteria were found to have potent biological activities,
including antifungal, larvacidal, and insecticidal properties.
Significantly, the major component from each of these
extracts, N-methylwelwitindolinone C isothiocyanate (1), was
shown to reverse multidrug resistance (MDR) in chemo-
therapeutic cancer treatment.2
centers, three quaternary carbons, and a unique bicyclo[4.3.1]-
decane ring system about an oxindole. While no total syn-
thesis of 1 or any other member of this family of compounds
exists to date, there are several reports describing strategies
for their synthesis.3,4 Herein, we report a rapid, convergent
synthesis of the core skeleton of 1. The route features a Lewis
acid-mediated alkylative coupling to assemble the carbon
framework, a Pd-catalyzed intramolecular enolate arylation
reaction5 to assemble the tetracyclic ring system, and a
Curtius rearrangement to install the isocyanate moiety.
Scheme 1
In addition to its striking biological activity, N-methyl-
welwitindolinone C isothiocyanate (1) exhibits daunting
structural complexity that arises from four stereogenic
(1) (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.
(2) (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.;
Moore, R. E. Mol. Pharmacol. 1995, 47, 241. (b) Zhang, X. Q.; Smith, C.
D. Mol. Pharmacol. 1996, 49, 288.
10.1021/ol051043t CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/12/2005

Scheme 2
The strategy for the synthesis of welwitindolinones is
promoted reaction of a ketone-TMS-enol ether with tertiary
or benzylic alkyl halides.7 For the problem at hand, it was
more desirable to use the readily synthesized tertiary alcohol
(10) directly. When the coupling of cyclohexanone-TMS-
enol ether and tertiary alcohol 10′, lacking the bromine at
the 4-position of the indole, was carried out under Natsume’s
conditions, using SnCl4 as the Lewis acid,7d,e the desired
alkylation product (11′) was obtained in >80% yield. Unfor-
tunately, under the same conditions, the corresponding halo-
genated indole (10) afforded the alkylated product (11) in
only 66% yield. On the other hand, when the reaction was
performed with TiCl4 in toluene, the yield increased to 76%.
shown in Scheme 1. The key step in the plan involves
assembly of the challenging bridged-bicyclic ring system
through an intramolecular Pd-catalyzed enolate arylation
reaction (4 f 3).6 Although several reports describe the
construction of the seven-membered ring of 1 by formation
of the C4-C11 bond,4c,e-g no one to date has successfully
constructed the bicyclo[4.3.1]decane ring skeleton through
this means. Our plan was to use a â-keto ester in the
cyclization event to allow the arylation reaction to proceed
under mild conditions.5 Importantly, the bridgehead methyl
ester in the resulting product would serve as a masked
form of the required isothiocyanate. The latter function-
ality could be revealed when needed via a Curtius rearrange-
ment (3 f 2). Finally, enolate arylation precursor 4
would be prepared convergently, through the alkylative
coupling of the indole subunit (6) to the cyclohexanone
unit (5).
To test the strategy toward welwitindolinones, we first set
out to create the cyclization precursor 14 (Scheme 2).
Commercially available 4-bromoindole (7) was acylated
under Friedel-Crafts conditions to afford ketone 8 (95%).
Subsequent tosylation gave protected indole 9 in quantitative
yield, which was then treated with MeMgBr, affording
tertiary alcohol 10 in 84% yield.
Although the natural product (1) contains an N-methyl
indole, the N-tosyl-protected indole was used for the alkyl-
ation reaction to minimize reaction at the indole 2-position.
Deprotection of the tosyl group proceeded uneventfully with
potassium hydroxide in ethanol and afforded the free indole
12 in quantitative yield. Methylation under phase transfer
conditions then gave 13, containing the requisite N-methyl
group. Finally, treatment of 13 with LDA generated the
kinetic lithium enolate, which was carboxylated using the
Mander reagent8 to afford 14 in 96% yield.9
(6) For examples of intramolecular Pd-catalyzed enolate arylations, see:
(a) Ciufolini, M. A.; Qi, H. B.; Browne, M. E. J. Org. Chem. 1988, 53,
4149. (b) Muratake, H.; Hayakawa, A.; Natsume, M. Tetrahedron Lett. 1997,
38, 7577. (c) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581.
(d) Muratake, H.; Nakai, H. Tetrahedron Lett. 1999, 40, 2355. (e) Muratake,
H.; Natsume, M.; Nakai, H. Tetrahedron 2004, 60, 11783. (f) Shaughnessy,
K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546.
(g) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (h) Honda, T.;
Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631. (i) Gaertzen, O.; Buchwald,
S. L. J. Org. Chem. 2002, 67, 465. (j) Zhang, T. Y.; Zhang, H. B.
Tetrahedron Lett. 2002, 43, 1363. For examples of intramolecular Pd-
catalyzed vinylations, see: (k) Piers, E.; Marais, P. C. J. Org. Chem. 1990,
55, 3454. (l) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11. (m) Sole´,
D.; Peidro, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225. (n) Yu, J. M.; Wang,
T.; Liu, X. X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X. B.; Cook, J.
M. J. Org. Chem. 2003, 68, 7565. For an example from our lab of a Pd-
catalyzed phenolate arylation, see: (o) Hennings, D. D.; Iwasa, S.; Rawal,
V. H. J. Org. Chem. 1997, 62, 2.
The next task was to introduce the cyclohexanone unit at
the benzylic position of 10. Such couplings are typically
carried out by an SN1-type process through the Lewis acid-
(3) For a review on studies toward 1 and related structures, see:
Avendan˜o, C.; Mene´ndez, J. C. Curr. Org. Synth. 2004, 1, 65.
(4) (a) Konopelski, J. P.; Deng, H. B.; Schiemann, K.; Keane, J. M.;
Olmstead, M. M. Synlett 1998, 1105. (b) Deng, H.; Konopelski, J. P. Org.
Lett. 2001, 3, 3001. (c) 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. (d) 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. (e) Kaoudi, T.; Quiclet-Sire, B.; Seguin,
S.; Zard, S. Z. Angew. Chem., Int. Ed. 2000, 39, 731. (f) Jung, M. E.;
Slowinski, F. Tetrahedron Lett. 2001, 42, 6835. (g) Lo´pez-Alvarado, P.;
Garc´ıa-Granda, S.; AÄ lvarez-Ru´a, C.; Avendan˜o, C. Eur. J. Org. Chem. 2002,
1702.
(7) (a) Chan, T. H.; Paterson, I.; Pinsonnault, J. Tetrahedron Lett. 1977,
18, 4183. (b) Reetz, M. T.; Maier, W. F. Angew. Chem. 1978, 90, 50.
(c) Reetz, M. T.; Schwellnus, K. Tetrahedron Lett. 1978, 19, 1455.
(d) Muratake, H.; Natsume, M. Tetrahedron 1990, 46, 6331. (e) Sakagami,
M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 1393.
(8) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(5) For recent reviews on Pd-catalyzed enolate arylation, see: (a) Lloyd-
Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953. (b) Miura, M.; Nomura,
M. Top. Curr. Chem. 2002, 219, 211. (c) Culkin, D. A.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234.
3422
Org. Lett., Vol. 7, No. 16, 2005

With ketoester 14 in hand, the key intramolecular Pd-
catalyzed enolate arylation was examined next (Scheme 3).
15 were examined. To our surprise, 15 proved to be quite
resistant toward basic hydrolysis, affording the acid in low
conversions and yields, even under forcing conditions.11 The
low reactivity of ester 15 to basic hydrolysis can be
understood by considering the structural constraints in the
molecule. Inspection of the X-ray crystal structure of 15 shows
that the conformation of the bicyclic ring system forces the
ester to occupy a position where both faces of the carbonyl
are inaccessible to hydrolytic attack (Figure 1). The top face
is blocked by the ketone carbonyl group, the bottom by the
indole C5 carbon. For this reason, we decided to employ
nucleophilic dealkylation conditions to remove the methyl
group.12 Refluxing the ester in pyridine with an excess of
LiI cleanly afforded the desired acid 16 in 95% yield, with
no evidence of the decarboxylation product (Scheme 4).
Scheme 3
A variety of experimental conditions were screened, includ-
ing different bases, solvents, and Pd sources, in an effort to
optimize the reaction.10 The highest yield was obtained using
Pd(OAc)2/PtBu3 (0.3:0.6 equiv) in the presence of KOtBu
(2 equiv) in toluene at 70 °C. The best results were obtained
when palladium acetate, the ligand, and the base were
premixed at room temperature, followed by the addition of
a solution of 14. The reaction proceeded quickly (less than
4 h) and afforded the product (15) as a crystalline solid in
74% yield. While the 1H NMR and 13C NMR spectra of 15
were consistent with the assigned structure, definitive proof
of the structure was ultimately secured through X-ray
crystallography, which clearly confirmed the presence of the
desired bicyclo[4.3.1]decane ring system (Figure 1).
Scheme 4
Keto acid 16 was treated with diphenylphosphoryl azide
(DPPA), triethylamine, and 4-methoxy benzyl alcohol in
refluxing THF, with the expectation that the intermediate
isocyanate would be intercepted by the benzylic alcohol.13
Remarkably, even after the reaction mixture was heated for
24 h, the major product of the reaction was the isocyanate.
With a view toward optimizing the isocyanate formation,
the Curtius rearrangement was performed in the absence of
an alcohol and provided the desired isocyanate 17 in a 78%
isolated yield.
The success of the arylation reaction followed by a Curtius
rearrangement to form the bridgehead isocyanate lays the
groundwork for our synthetic plan toward N-methyl-
welwitindolinone C isothiocyanate (1) and presents an
attractive method for rapidly building up the highly complex
welwitindolinone skeleton in a convergent manner. The
model structure is conveniently synthesized in 10 steps
from 4-bromoindole and contains the majority of the
structural complexity of 1. Additionally, this route high-
lights the power of the Pd-catalyzed enolate arylation
reaction, which should prove useful in other alkaloid
synthesis problems. While new challenges will likely await
us in the synthesis of welwitindolinone 1, we expect this
strategy to be amenable to assembling the core of the natural
product.
Figure 1. ORTEP of compound 15.
What remained to be established through these studies was
the feasibility of installing a nitrogen on the bridgehead (C11)
carbon. The plan was to perform the Curtius rearrangement
of the acyl azide derived from ester 15 in the presence of an
alcohol and thus generate a carbamate that could be depro-
tected to reveal a functionalizable amine. In preparation for
acyl azide formation, conditions for the hydrolysis of ester
(11) Refluxing in MeOH/H2O with 60 equiv of LiOH for 22 h gave
incomplete conversion and partial decomposition of the product.
(12) McMurry, J. Org. React. 1976, 24, 187.
(13) Shioiri, T.; Yamada, S.; Ninomiya, K. J. Am. Chem. Soc. 1972, 94,
6203.
(9) Although the carbomethoxylation proceeded cleanly; the product
proved elusive to rigorous purification, most likely due to facile enolization
and epimerization of the â-ketoester functionality.
(10) See Supporting Information.
Org. Lett., Vol. 7, No. 16, 2005
3423

Acknowledgment. We thank Professor Chong Zheng
(Northern Illinois University) for solving the X-ray crystal
structure of 15. We thank the National Cancer Institute of
the NIH (CA101438) for financial support. J.A.M gratefully
acknowledges postdoctoral fellowship support (#PF-04-016-
01-CDD) from the American Cancer Society.
crystallographic data for 15. This material is available free
of charge via the Internet at http://pubs.acs.org. Crystal-
lographic data for the structural analysis of 15 has also been
deposited with the Cambridge Crystallographic Data Centre
(CCDC 271206). These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds and
OL051043T
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Org. Lett., Vol. 7, No. 16, 2005