Synthesis and preliminary biological studies of 3-substituted indoles accessed by a palladium-catalyzed enantioselective alkene difunctionalization reaction

Article abstract of DOI:10.1021/ja103472a

A unique alkene difunctionalization reaction that allows rapid construction of molecular complexity around the biologically relevant indole framework has been developed. The reaction proceeds with up to 87% yield, 99:1 er, and >20:1 dr. Evaluation of several of the compounds revealed promising anticancer activity against MCF-7 cells.

Full text of DOI:10.1021/ja103472a

Published on Web 05/20/2010
Synthesis and Preliminary Biological Studies of 3-Substituted Indoles
Accessed by a Palladium-Catalyzed Enantioselective Alkene
Difunctionalization Reaction
Tejas P. Pathak,† Keith M. Gligorich,‡ Bryan E. Welm,‡ and Matthew S. Sigman*,†,‡
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, and Department of
Surgery, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, Utah 84112
Received April 23, 2010; E-mail: sigman@chem.utah.edu
The indole framework represents a “privileged” structural motif
commonly found in pharmaceutical drugs and natural products.1
Therefore, new methods for accessing unique indole derivatives is of
importance for drug lead synthesis. For this reason, we became
interested in using indoles as nucleophiles in the enantioselective alkene
difunctionalization reactions recently disclosed by our laboratory.2,3
Herein we report the successful development of such a reaction and
preliminary biological studies showcasing both the activity toward
breast cancer cell lines and differential phenotypes for two related
derivatives.
ever, high diastereoselectivity and enantioselectivity were observed
in all cases (Table 1, entries 1a-f). Both tetrahydrofuran and
tetrahydropyran ring systems were formed in good yields with excellent
er and dr (Table 1, entries 1g and 1h). A substrate containing an ether
linkage was cyclized to yield a 1,4-dioxane product, albeit in modest
yield (Table 1, entry 1i).
Various indoles were next submitted to the reaction conditions, and
it was found that N-alkyl-protected indoles were well-tolerated,
including an indole containing a removable protecting group (Table
1, entries 2a and 2b). Various 2-substituted indoles with different steric
and electronic parameters were also found to be compatible, again
leading to good yields and excellent er (Table 1, entries 2c-e). The
electronic nature of indole substitution had little effect on the reaction
outcome (Table 1, entries 2f-i). Furthermore, 5-bromoindole was
tolerated, giving a 62% yield and an excellent er of 98:2 (Table 1,
entry 2g), which showcases the potential for further functionalization
of these compounds with Pd(0) catalysis. The chemistry presented is
not limited to only indole nucleophiles, as demonstrated by the
successful use of N-methylpyrrole (Table 1, entry 2j). However, it
should be noted that N-protection of the indole is required and that
electron-poor groups (such as Ts or Boc) on the indole nitrogen
substantially decrease the yield.
Scheme 1. Proposed Mechanism for the Tandem Oxypalladation/
Electrophilic Aromatic Substitution Process
To illustrate the utility of this method to rapidly access relatively
complex structures, processing of several derivatives was examined
(Scheme 2). Treatment of 1g with NBS resulted in rapid oxidative
cyclization, affording 3a as the fused tetracyclic product in 92% yield.6
Additionally, treatment of 1g with DMDO resulted in the formation
of the tertiary alcohol 3b in good yield, albeit with low dr.7 Compound
3b, which has homology with the core structure of the communesin
class of natural products,8 contains four contiguous stereocenters and
can be synthesized from salicylaldehyde in just four steps.
Previously, substrate 1 was found to undergo a highly enantiose-
lective, Pd-catalyzed sequential intra- and intermolecular alkene
difunctionalization reaction using mainly alcohols as exogenous
nucleophiles.3 We envisioned a scenario in which Pd would catalyze
an intramolecular nucleopalladation, with the proposed subsequent
formation of a quinone methide intermediate. To this intermediate,
addition of electron-rich heteroaromatic derivatives could be ac-
complished via electrophilic aromatic substitution (Scheme 1).4a
However, we were concerned that the indole would not be compatible
with the Pd(II) catalysis because of the ability of these compounds to
undergo C-H activation.4b To our delight, the combination of substrate
1 and N-methylindole under previously reported conditions successfully
led to the formation of the desired product. Modest changes were made
to these conditions,3,5a including a decrease in the concentration of
the indole nucleophile (from 50 to 15 equiv), resulting in a high yield
of the desired product (81% isolated yield) with excellent dr (>20:1)
and er (97:3).5 It should be noted that a 60% yield can be obtained
using 5 equiv of N-methylindole without any influence on dr or er,
with recovery of the remaining nucleophile in >95% yield.5a
Scheme 2. Accessing Interesting Indole Core Structures
In view of the ease with which we were able to access diverse
analogues and the unique architecture of the products formed, we
decided to evaluate the biological activity of several racemic variants
using a luminal-type breast cancer cell line (MCF-7, Figure 1).
Excitingly, several of the analogues, including 2c and 2f, were found
The nature of the phenol was first explored, and it was found that
electron-withdrawing substituents generally gave higher yields; how-
† University of Utah.
‡ Huntsman Cancer Institute.
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7870 J. AM. CHEM. SOC. 2010, 132, 7870–7871
10.1021/ja103472a  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. 3-Substituted Indoles Formed by the Pd-Catalyzed Enantioselective Alkene Difunctionalization Reactiona
a Reaction conditions: 4 mol % Pd(MeCN)2Cl2, 8 mol % CuCl, 14 mol % iPrQuinox, 1 equiv of KHCO3, 15 equiv of NuH, Balloon O2, r.t., 0.1-0.05 M
4:1 toluene/THF. The er for the major diastereomer was determined by supercritical fluid chromatography using a column equipped with a chiral stationary
1
phase. The dr was >20:1 for all compounds, as determined by H NMR spectroscopy. The major diastereomer was determined by X-ray crystal analysis of
entry 2g. The absolute configuration was assigned by comparison with a previous report.3
to reduce the cell count in comparison with a DMSO control in this
whole-cell assay. The differential activity was evaluated for these two
analogues and their corresponding enantiomers in MCF-7 and MCF-
10A (normal breast) cell lines, wherein the compounds were modestly
more effective at killing tumor cells.5a Of particular interest, cell-cycle
analysis was performed using flow cytometry with a bromodeoxyuri-
dine pulse.5a The results of this experiment were quite revealing in
that 2c caused a G1 arrest while 2f caused a G2 arrest similar to that
of Taxol. This finding suggests that modest structural changes in the
indole framework have a significant bearing on the molecular target
of these compounds.
further development of the chemical methodology and exploration of
the molecular origin of the antitumor activity.
Acknowledgment. This work was supported by the National
Institutes of Health (NIGMS RO1GM3540 and R01CA140296).
Crystal structure analysis was performed by Dr. Atta Arif. We thank
Dr. Ryan Looper for insightful discussions. K.M.G. thanks the DOD
BreastCancerResearchProgramforapostdoctoralfellowship(W81XWH-
09-1-0431).
Supporting Information Available: Experimental procedures and
full spectroscopic data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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Figure 1. (a) Relative activity of new compounds in MCF-7 cells. (b)
Cell-cycle analysis of 2c and 2f at 48 h.
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In conclusion, we have developed a highly enantioselective and
diastereoselective Pd-catalyzed alkene difunctionalization reaction that
is proposed to proceed by intramolecular oxypalladation followed by
the addition of indole to a quinone methide. The chemistry tolerates a
wide range of substitution on both the alkene and indole substrates,
and the resulting products can easily be processed to form relatively
complex structures. Several of the new indole compounds were found
to have modestly selective activity in MCF-7 tumor cells in comparison
with MCF-10A normal breast cells. Cell-cycle analysis of two of these
compounds revealed distinct phenotypes, providing a foundation for
(5) (a) See the Supporting Information for more details. (b) See the Table 1
footnote for detailed optimized conditions.
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(7) (a) Schwaebisch, D.; Tchabanenko, K.; Adlington, R. M.; Cowley, A. M.;
Baldwin, J. E. Chem. Commun. 2004, 2552. (b) The diastereomers were
readily separated.
(8) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47,
8170.
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