Concise synthesis of the bicyclic scaffold of n-methylwelwitindolinone c isothiocyanate via an indolyne cyclization

Article abstract of DOI:10.1021/ol9007684

A concise synthesis of the N-methylwelwitindolinone C isothiocyanate scaffold is disclosed. The approach relies on an indolyne cyclization to construct the [4.3.1]-bicyclic ring system present in the natural product. Subsequent oxidation of the indole cor

Full text of DOI:10.1021/ol9007684

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2349-2351
Concise Synthesis of the Bicyclic
Scaffold of N-Methylwelwitindolinone C
Isothiocyanate via an Indolyne
Cyclization
Xia Tian, Alexander D. Huters, Colin J. Douglas, and Neil K. Garg*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
Los Angeles, California 90095-1569
neilgarg@chem.ucla.edu
Received April 9, 2009
ABSTRACT
A concise synthesis of the N-methylwelwitindolinone C isothiocyanate scaffold is disclosed. The approach relies on an indolyne cyclization
to construct the [4.3.1]-bicyclic ring system present in the natural product. Subsequent oxidation of the indole core occurs with excellent
diastereoselectivity to afford oxindole 2, the structure of which was confirmed by X-ray crystallographic analysis.
N-Methylwelwitindolinone C isothiocyanate (1, Figure 1),
was first isolated from the blue-green algae Hapalosiphon
welwitschii in 1994 by Moore and co-workers.1,2 1 was found
to reverse multiple drug resistance (MDR) to a variety of
anticancer drugs, thus rendering it an attractive agent for the
treatment of drug-resistant tumors.3,4 The unique structural
framework of 1, coupled with its impressive biological
profile, has attracted considerable attention from the synthetic
community over the past decade.5 Although numerous
Figure 1. N-Methylwelwitindolinone C isothiocyanate (1).
(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
.
approaches to 1 have been reported,6-13 a total synthesis of
this unique target has remained elusive. In this communica-
tion, we disclose a concise approach to the [4.3.1]-bicyclic
core of 1 using an indolyne cyclization.
With the aim of developing a concise route to the bicycle
present in 1, oxindole 2 was selected as a suitable model
system target (Scheme 1). It was envisioned that oxindole 2
could be derived from indole precursor 3 through a diaste-
reoselective oxidation reaction. In the key retrosynthetic
(2) 1 has sometimes been referred to as “welwistatin”; however, as
originally defined in ref 3b, “welwistatin” refers to the des-N-methyl
analogue of 1
.
(3) (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M.;
Moore, R. E. Mol. Pharmacol. 1995, 47, 241–247. (b) Zhang, X.; Smith,
C. D. Mol. Pharmacol. 1996, 49, 288–294. (c) Avendan˜o, C.; Mene´ndez,
J. C. Curr. Med. Chem. 2002, 9, 159–193
.
(4) At concentrations as low as 0.1 µM, 1 was found to greatly decrease
the IC50 of vinblastine, taxol, actinomycin D, cochicines, and daunomycin
in MCF-7/ADR drug-resistant breast carcinoma cells.
(5) For a review, see: Avendan˜o, C.; Mene´ndez, J. C. Curr. Org. Synth.
2004, 1, 65–82
.
10.1021/ol9007684 CCC: $40.75
Published on Web 05/11/2009
 2009 American Chemical Society

Scheme 1
.
Indolyne Approach to the Synthesis of 1
Scheme 2. Synthesis of Bromoindole Substrates 5 and 6
Our synthetic routes to the desired cyclization precursors
5 and 6 are depicted in Scheme 2. To access 5-brominated
substrate 5, readily available 5-bromo-N-methylindole
(7)18 was allowed to react with enone 819 in the presence
of I2 in MeOH following the general method described
by Wang and co-workers.20 This approach led to the
single-step formation of the 5-brominated cyclization
substrate 5 in 85% yield. Unfortunately, the analogous
route to 4-brominated substrate 6 was less fruitful.21
Nonetheless, substrate 6 could be prepared in six steps
from 4-bromoindole following the robust approach de-
veloped by Rawal.9 Thus, 4-bromoindole (9) was elabo-
rated to known tertiary alcohol 10 over three steps.9 Upon
treatment of 10 with TiCl4 and enoxysilane 11,22 Ts-indole
12 was obtained. Subsequently, a two-step detosylation/
methyl protection sequence provided the desired substrate
6.
disconnection, the C4-C11 bond of bicycle 3 would arise
via a cyclization of an enolate onto an electrophilic indole,
or indolyne14-16 (see transition structure 4). Although the
enolate participating in this reaction would be adjacent to
the congested C12 quaternary center, the desired cyclization
seemed favorable given that the intermediate indolyne would
be extremely reactive. Furthermore, the stereoelectronics for
bicycle formation appeared optimal, as suggested in Scheme
1. Inspired by classic methods for aryne generation,17 it was
envisioned that the desired indolyne intermediate could be
accessed in situ from either 5- or 4-brominated substrates, 5
or 6, respectively.
(6) (a) 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. (b) 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, 1270–1272
.
(7) Jung, M. E.; Slowinski, F. Tetrahedron Lett. 2001, 42, 6835–6838
.
(8) (a) Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3, 3001–3004. (b)
Xia, J.; Brown, L. E.; Konopelski, J. P. J. Org. Chem. 2007, 72, 6885–
6890
.
(9) MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421–
Table 1. Indolyne Cyclization Experiments
3424
.
(10) (a) Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org. Lett. 2005, 7,
4087–4089. (b) Boissel, V.; Simpkins, N. S.; Bhalay, G.; Blake, A. J.; Lewis,
W. Chem. Commun. 2009, 1398–1400
.
(11) Greshock, T. J.; Funk, R. L. Org. Lett. 2006, 8, 2643–2645
.
(12) Lauchli, R.; Shea, K. J. Org. Lett. 2006, 8, 5287–5289
(13) 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
.
(14) For seminal studies involving indolynes, see: (a) Julia, M.; Huang,
Y.; Igolen, J. C. R. Acad. Sci., Ser. C 1967, 265, 110–112. (b) Igolen, J.;
Kolb, A. C. R. Acad. Sci., Ser. C 1969, 269, 54-56. For related studies,
see: (c) Julia, M.; Le Goffic, F.; Igolen, J.; Baillarge, M. C. C. R. Acad.
Sci., Ser. C 1967, 264, 118–120. (d) Julia, M.; Igolen, J.; Kolb, A. C. R.
substrate
temperature
yielda
ratio (3:13)
1.2:1
Acad. Sci., Ser. C 1971, 273, 1776–1777
.
5
6
6
23 °C
23 °C
50 °C
56% (62%)
no reaction
64%
(15) In a previous study, we demonstrated that indolynes function as
practical electrophilic indole surrogates and can also be accessed from
indolylsilyltriflate species under mild fluoride-mediated conditions, see:
Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007–
1:1
a Combined isolated yield of 3 and 13. Yield in parentheses reflects
yield based on recovered substrate.
1010
.
(16) For the preparation of indolynes from dihaloindoles and butyllithium
reagents, and subsequent Diels-Alder studies, see: (a) Buszek, K. R.; Luo,
D.; Kondrashov, M.; Brown, N.; VanderVelde, D. Org. Lett. 2007, 9, 4135–
4137. (b) Brown, N.; Luo, D.; VanderVelde, D.; Yang, S.; Brassfield, A.;
Buszek, K. R. Tetrahedron Lett. 2009, 50, 63–65. (c) Buszek, K. R.; Brown,
Table 1 highlights the results of our efforts to effect the
indolyne cyclization of substrates 5 and 6. Gratifyingly, both
substrates could be converted to the desired bicycle 3 upon
reaction with NaNH2/t-BuOH23 in THF.24 Although the yield
is modest, several significant aspects of our cyclization results
N.; Luo, D. Org. Lett. 2009, 11, 201–204
.
(17) For reviews regarding the chemistry of arynes, see: (a) Pellissier,
H.; Santelli, M. Tetrahedron 2003, 59, 701–730. (b) Wenk, H. H.; Winkler,
M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502–528. (c) Sanz, R.
Org. Prep. Proced. Int. 2008, 40, 217–291
.
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Org. Lett., Vol. 11, No. 11, 2009

should be noted: (a) the desired C-arylated product 3 is the
major compound produced in the cyclizations, albeit with
O-arylated product 13 being formed competitively;25-27 (b)
4-brominated substrate 6 requires higher temperatures to
induce product formation; this result may be explained by
the greater acidity of the C4 proton of substrate 5 in
comparison to the C5 proton of 6;28 (c) whereas the
dehydrohalogenation of 5-bromo substrate 5 could plausibly
lead to undesirable mixtures of 4,5- and 5,6-indolyne
intermediates, formation of the desired 4,5-indolyne appears
to be favored; (d) the use of 5-brominated substrate 5 to
access bicycle 3 is generally preferred, as the synthesis of 5
is concise, high-yielding, and ultimately begins with inex-
pensive 5-bromoindole.29 Moreover, it is notable that a
5-substituted substrate could be used as the synthetic
precursor to the desired 4-substituted product. Our studies
are the first to describe direct formation of the [4.3.1]-bicycle
of 1 through assembly of the C4-C11 bond with an adjacent
quaternary center at C12.
nantly afforded the undesired epimers of the corresponding
oxindole products. After extensive experimentation, we have
found that bicyclic indole 3 can be cleanly converted to
oxindole 2 through a two-step sequence involving treatment
with NBS to afford the corresponding C-2 brominated indole,
followed by HCl-promoted hydrolysis (Scheme 3). Fortu-
nately, a single diastereomer of product was obtained. X-ray
diffraction studies revealed that 2 possessed the desired
stereochemical configuration at C3, as depicted.
Scheme 3. Oxidation of 3 and X-ray Structure of Oxindole 2
To date, most of the disclosed approaches to N-methyl-
welwitindolinone C isothiocyanate (1) plan for a late-stage
diastereoselective indole oxidation to furnish the oxindole
found in the natural product.8-12 However, only two studies
toward this goal have been documented,10a,30 whereby
attempted oxidation of model system substrates predomi-
In summary, we have developed a concise approach to
the bicyclic scaffold of N-methylwelwitindolinone C isothio-
cyanate (1). Our strategy involves an expedient synthesis of
bromoindole 5, an indolyne cyclization to forge the congested
C4-C11 bond of bicycle 3, and a diastereoselective oxidation
to deliver oxindole 2. Efforts to access related structures that
possess a C11 nitrogen substituent are currently underway
in our laboratory, in addition to studies aimed at completing
the total synthesis of 1.
(18) 7 is commercially available or can be easily prepared in one step
from inexpensive 5-bromoindole on a multigram scale, see: Jiang, X.;
Tiwari, A.; Thompson, M.; Chen, Z.; Cleary, T. P.; Lee, T. B. K. Org.
Proc. Res. DeV. 2001, 5, 604–608.
(19) Thulasiram, H. V.; Gadad, A. K.; Madyastha, M. K. Drug Metab.
Dispos. 2000, 28, 833–844.
Acknowledgment. The authors are grateful to the Uni-
versity of California, Los Angeles, and Boehringer Ingelheim
for financial support. We thank Professor Jung (UCLA),
Professor Houk (UCLA), and Dr. Jason Rohde (Ironwood
Pharmaceuticals) for pertinent discussions, the Garcia-
Garibay laboratory (UCLA) for access to instrumentation,
and Dr. John Greaves (UC Irvine) for mass spectra.
(20) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. Synlett 2003, 15, 2377–2379.
(21) The reaction of 4-bromo-N-methylindole with enone 8 was unsuc-
cessful under a variety of reaction conditions, likely because of steric
hinderance imposed by the C4 substituent.
(22) Aggarwal, V. K.; Daly, A. M. Chem. Commun. 2002, 2490–2491.
(23) Caubere, P. Acc. Chem. Res. 1974, 7, 301–308.
(24) Alternative basic conditions commonly used to promote aryne
formation were unsuccessful (e.g., LDA, LHMDS, Me2Zn(TMP)Li).
(25) Prolonged reaction times led to olefin isomerization of enol ether
13 to afford the corresponding tetrasubstituted olefin.
(26) Utilization of the TBS or TIPS enol ether derivatives of 5 did not
lead to improvements in yield or selectivity for C-arylation.
(27) Variations in temperature, stoichiometry, and counterion did not
lead to improvements in the conversion of 5 to 3.
Supporting Information Available: Detailed experimen-
tal details and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(28) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007,
63, 1568–1576.
OL9007684
(29) 5-Bromoindole is commercially available from Combi-Blocks, Inc.
at a cost of $24 per 25 grams; the cost of 4-bromoindole is $195 per 25
grams.
(30) Greshock, T. J. Ph.D. Dissertation. Pennsylvania State University,
University Park, PA, 2006.
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