Approaches to N-methylwelwitindolinone C isothiocyanate: Facile synthesis of the tetracyclic core

Article abstract of DOI:10.1021/ol1006373

The synthesis of a functionalized, tetracyclic core of N- methylwelwitindolinone C isothiocyanate is reported. The approach features a convergent coupling between an indole iminium ion and a highly functionalized vinylogous silyl ketene acetal followed by

Full text of DOI:10.1021/ol1006373

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2492-2495
Approaches to N-Methylwelwitindolinone
C Isothiocyanate: Facile Synthesis of
the Tetracyclic Core
Richard W. Heidebrecht, Jr.,† Brian Gulledge,§ and Stephen F. Martin*,§
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received March 18, 2010
ABSTRACT
The synthesis of a functionalized, tetracyclic core of N-methylwelwitindolinone C isothiocyanate is reported. The approach features a convergent
coupling between an indole iminium ion and a highly functionalized vinylogous silyl ketene acetal followed by an intramolecular palladium-
catalyzed cyclization that proceeds via an enolate arylation.
A series of novel indole alkaloids were isolated in 1994 by
Moore and co-workers from the extracts of blue-green
cyanobacteria Hapalosiphon wetwitschii and Westiella in-
tracta.1 These compounds, which were collectively named
welwitindolinones, possess a unique skeletal framework and
were isolated along with the structurally related fischerindoles
and hapalindoles. A putative biogenetic relationship among
these alkaloids has been proposed.1 These natural products
exhibit diverse biological activities, perhaps the most exciting
of which is the ability of some to reverse multiple drug
resistance (MDR) during chemotherapeutic treatment of
cancer.2
reported by Baran4 and Wood5 and of welwitindolinone A
isothiocyanate (2) by Baran (Figure 1).6 Another important
As a result of their novel structures and exciting biological
activities, the various welwitindolinones have captured the
attention of many groups, whose efforts have been chronicled
in a number of accounts.3 Noteworthy are the elegant
syntheses of welwitindolinone A isonitrile (1) independently
Figure 1. Structures of welwitindolinone A isocyanate (1), wel-
witindolinone A isothiocyanate (2), and N-methylwelwitinolidone
C isothiocyanate (3).
member of this family is N-methylwelwitindolinone C
isothiocyanate (3). Numerous efforts directed toward the
synthesis of this challenging target have not yet reached
fruition,7 but the tetracyclic core has been prepared by several
groups.7b,g-k,m-o We now report the details of some of our
work in the area.
† The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142.
§ The University of Texas at Austin.
(1) 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, 9935–9942.
(2) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.; Moore,
R. E. Mol. Pharmacol. 1995, 47, 241–247.
10.1021/ol1006373  2010 American Chemical Society
Published on Web 05/06/2010

Our initial approach to N-methylwelwitindolinone C
isothiocyanate (3) is outlined in retrosynthetic format in
Scheme 1. We envisioned that the late-stage intermediate
tive. The crossed Claisen condensation of 9 with the enolate
of tert-butyl acetate afforded ketoester 10. Because the tert-
butyl ketoester group was prone to decarboxylation in
subsequent reactions, it was converted to the methyl ester
6. The overall yield of 6 from 9 via this two-step procedure
was superior to that obtained using methyl acetate in the
crossed Claisen condensation with 9.
Scheme 1. Initial Retrosynthetic Proposal
Scheme 3. Attempted Preparation of Tetracycle 15
4, which might be elaborated into 3 by a series of
refunctionalizations and alkylations, might be accessible
via a novel double allylic alkylation of the tricyclic
ketoester 5. The synthesis of 5 would then involve the
cyclization of 6 via an enolate arylation, and compound
6 might be readily prepared by a Michael addition of
N-methyl-4-bromooxindole (7).
In the event, 4-bromooxindole (8), prepared via a known
procedure,8 was selectively N-methylated using a method
developed by Bordwell (Scheme 2).9 Warming oxindole 7
The next stage of the synthesis required the palladium-
catalyzed cyclization of the enolate of the ketoester 6
(Scheme 3). Although use of bis-tert-butyl-2-biphenylphos-
phine as a ligand10 provided the cyclized ꢀ-keto ester, which
existed in its enol form 11, in 58% yield, significant amounts
of unreacted 6 were invariably recovered; the structure of
11 was established by X-ray crystallography. On the other
hand, use of a combination of commercially available tri-
tert-butylphosphine palladium dimer11 and either palladium
bis-dibenzylideneacetone or chlorobisallylpalladium dimer
in a ratio of 2:1 as suggested by Fu12 gave the enol 11 in
88% yield. These reactions are sensitive to the presence of
oxygen, and the best results were obtained with a freeze-
pump-thaw protocol.
Scheme 2. Preparation of Ketoester 6
The synthetic plan then anticipated the conversion of 11
into the tetracyclic intermediate 15 via a palladium-catalyzed
(3) Reviews: (a) Avendano´, C.; Mene´dez, J. C. Curr. Org. Synth. 2004,
1, 65–82. (b) Menendez, J. C. Top. Heterocycl. Chem. 2007, 11, 63–101.
(c) Brown, L. E.; Konopelski, J. P. Org. Prep. Proced. Int. 2008, 40, 411–
445.
(4) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394–
15396.
(5) (a) Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood,
J. L. J. Am. Chem. Soc. 2006, 128, 1448–1449. (b) Reisman, S. E.; Ready,
J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Ovaska, T. V.;
Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087–2100.
(6) Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.; Llamas,
T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17938–
17954.
in degassed sodium methoxide in methanol with excess
methyl 3-methylcrotonate provided the adduct 9 in 74%
yield. It was essential to rigorously exclude air in order to
avoid extensive formation of the corresponding isatin deriva-
Org. Lett., Vol. 12, No. 11, 2010
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double allylic alkylation using the known bis-allylic carbon-
ate 12. However, when 11 was allowed to react with 12 in
the presence of base and a number of Pd(0) catalysts, none
of the desired 15 was obtained. Somewhat surprisingly, 14
was the only product isolated.13 This alternate mode of
cyclization is presumably the consequence of the more acidic
proton on the oxindole ring. A change of strategy that would
obviate this deleterious cyclization was thus warranted.
Reasoning that the undesired cyclization mode would not
be accessible to the indole analogue of 13, 11 was tranformed
into 16, which like 11 existed in its enolic form as confirmed
via X-ray crystallography, in modest yield by reduction and
dehydration (Scheme 4). Palladium-catalyzed alkylation of
Interestingly, when 17 was treated with ZnCl2 in the presence
of a Pd(0) catalyst, 18 was formed in 51% yield.14 When
this reaction was performed in the absence of the palladium
catalyst, 18 was again isolated, albeit in only 28% yield.
Because the problem we encountered involved forming
the C(14)-C(15) bond after forming the C(11)-C(12) bond,
it occurred to us that reversing the order of these two bond
constructions might be a viable alternative. This revised
approach then dictated the intermediacy of a substrate such
as 19, which could be formed by cyclization of the ꢀ-keto
ester 20 (Scheme 5). Our first attempts to prepare 20 involved
Scheme 5. Revised Retrosynthetic Analysis
Scheme 4. Attempted Preparation of an Indolic Tetracycle
the alkylation of the dianion of 10 with a suitably substituted
allyl halide (path A), but these efforts were to no avail. We
also envisioned that 20 might be accessed by path B, a
process that would involve capture of the stabilized carboca-
tion generated from 21 with a π-nucleophile such as 22. At
the time we conceived of this approach there was little
precedent for such a construction.15 Shortly after we had
conducted this reaction, Rawal reported a similar process
using a N-protected indole in his work directed toward the
welwitindolinones.7g,m Since our original discovery, we have
found this reaction to be more generally useful for preparing
heteroaryl propanoic acid derivatives.16
16 with 12 afforded allylic carbonate 17; however, all
attempts using various bases to enolize the ketone function
in 17 under the reaction conditions were unsuccessful.
(7) (a) Konopelski, J. P.; Deng, H.; Schiemann, K.; Keane, J. M.;
Olmstead, M. M. Synlett 1998, 1105–1107. (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, 6326–6327. (c)
Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3, 3001–3004. (d) Jung, M. E.;
Slowinski, F. Tetrahedron Lett. 2001, 42, 6835–6838. (e) Lo´pez-Alvarado,
`
P.; Garc´ıa-Granda, S.; Alvarez-Ru´a, C.; Avendan˜o, C. Eur. J. Org. Chem.
2002, 1702–1707. (f) Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss,
M. M.; Tamaki, K.; Ovaska, T. O.; Wood, J. L. Ang. Chem. Int. Ed. 2004,
43, 1270–1272. (g) MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett.
2005, 7, 3421–3424. (h) Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org.
Lett. 2005, 7, 4087–4089. (i) Greshock, T. J.; Funk, R. L. Org. Lett. 2006,
8, 2643–2645. (j) Lauchli, R.; Shea, K. J. Org. Lett. 2006, 8, 5287–5289.
(k) Boissel, V.; Simpkins, N. S.; Bhalay, G. Tetrahedron Lett. 2009, 50,
3283–3286. (l) Boissel, V.; Simpkins, N. S. Chem. Commun. 2009, 1398–
1400. (m) Tian, X.; Huters, A. D.; Douglas, C. J.; Garg, N. K. Org. Lett.
2009, 11, 2349–2351. (n) Trost, B. M.; McDougall, P. J. Org. Lett. 2009,
11, 3782–3785. (o) Brailsford, J. A.; Lauchli, R.; Shea, K. J. Org. Lett.
2009, 11, 5330–5333.
In order to examine the feasibility of forming 20 via path
B, the vinylogous silyl ketene acetal 22 was first prepared
Scheme 6. Preparation of Vinylogous Silyl Ketene Acetal 22
(8) Kosuge, T.; Ishida, H.; Inaba, A.; Nukaya, H. Chem. Pharm. Bull.
1985, 33, 1414–1418.
(9) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218–4223.
(10) Fox, J. M.; Huang, S.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360–1370.
(11) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473–
1478.
(12) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
6343–6348.
(13) The conversion of enol 11 into 14 under similar conditions has
been previously reported. Holubec, A. A. Ph.D. Dissertation, 2000, Yale
University. We thank a reviewer for calling this reference to our atten-
tion.
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Org. Lett., Vol. 12, No. 11, 2010

(Scheme 6). Accordingly, the bis-anion of tert-butyl acetoac-
etate (23) was alkylated with the allylic bromide 24, which
was easily prepared in two steps from the corresponding diol
to furnish 25. Dioxanone formation to give 26 and subsequent
silylation of the dienolate derived from 26 gave 22, which
because of its instability was used without further purification
as an inconsequential mixture (1.5:1) of isomeric olefins.
The requisite indole fragment 29 was then prepared from
4-bromoindole (27) by a procedure developed by Rapoport
(Scheme 7).17 N-Methylation of 27 with dimethyl carbonate18
presence of TMSOTf to form 29 in 35% yield over two steps.
Heating 29 with methanol unveiled an intermediate ketoester
20 (R ) TBDPS), which underwent palladium-catalyzed
cyclization to give 30 in 71% yield from 29. The silyl ether
was cleaved with triethylamine hydrofluoride, but the
subsequent acetylation of the resulting alcohol was compli-
cated by competing reaction with the enolized ketone to give
an enol acetate. After some experimentation, we discovered
that selective acetylation of the alcohol could be achieved
by the action of acetyl chloride in the presence of collidine
at -78 °C to furnish 31 in 52% overall yield from 30.
Cyclization of the sodium enolate derived from 31 was
achieved by utilizing Pd2(dba)3 to deliver the desired
tetracycle 32 in 71% yield. Oxidative cleavage of the
exocyclic olefin under Johnson-Lemieux conditions gave
the dione 33.
Scheme 7. Preparation of the Welwitindolinone C Skeleton
In preparing 33, we have thus developed a facile entry to
the tetracyclic scaffold found in N-methylwelwitindolinone
C isothiocyanate (3). The synthesis features the coupling of
an indole-stabilized carbocation with a vinylogous silyl
ketene acetal as a π-nucleophile together with a palladium-
catalyzed enolate arylation and a palladium-catalyzed allylic
alkylation. Efforts toward the application of this approach
and variants thereof to the total synthesis of 3 are in progress
and will be reported in due course.
Acknowledgment. We thank the National Institutes of
Health (GM 25439), the Robert A. Welch Foundation, Pfizer,
Inc., Merck Research Laboratories, and Boehringer Ingelheim
Pharmaceuticals for their generous support of this research.
We are also grateful to Vince Lynch (The University of
Texas) for X-ray crystallography, Steve Sorey (The Univer-
sity of Texas) for NMR spectroscopy, and Bob Fu (The
University of Texas) for helpful discussions and technical
assistance.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for all new compounds,
plus X-ray coordinates for compounds 11 and 16 (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL1006373
(14) For related cyclizations of 4-substituted indoles, see: Fillion, E.;
Dumas, A. M. J. Org. Chem. 2008, 73, 2920–2923, and references therein.
(15) For examples, see: (a) Comins, D. L.; Stroud, E. D. Tetrahedron
Lett. 1986, 27, 1869–1872. (b) Muratake, H.; Natsume, M. Tetrahedron
1990, 46, 6331–6342. (c) Grieco, P. A.; Handy, S. T. Tetrahedron Lett.
1997, 38, 2645–2648.
(16) Fu, T.-H.; Bonaparte, A.; Martin, S. F. Tetrahedron Lett. 2009,
50, 3253–3256.
(17) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986,
51, 5106–5110. This material is also commercially available.
(18) Jiang, X.; Tiwari, A.; Thompson, M.; Chen,; Chem, Z.; Cleary,
T. P.; Lee, T. B. K. Org. Process Res. DeV. 2001, 5, 604–608.
(19) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino,
H. Org. Lett. 2000, 2, 1485–1487.
followed by acetylation at C(3) of 27 afforded ketone 28.19
Reaction of 28 with methylmagnesium bromide provided the
unstable tertiary alcohol 21, which was immediately treated
with the crude vinylogous silyl ketene acetal 22 in the
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