Rhodium-catalyzed [3 + 2] annulation of indoles

Article abstract of DOI:10.1021/ja9078094

(Chemical Equation Presented) An effective Rh₂(S-DOSP) ₄-catalyzed asymmetric cyclopentannulation of indolyl rings has been developed. Depending on the substitution pattern of the indole, two distinct regioisomeric products can be ge

Full text of DOI:10.1021/ja9078094

Published on Web 12/21/2009
Rhodium-Catalyzed [3 + 2] Annulation of Indoles
Yajing Lian and Huw M. L. Davies*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia 30322
Received September 21, 2009; E-mail: hmdavie@emory.edu
Fused indolines are common subunits in a wide range of alkaloid
NOE analysis, and 6 had an exo configuration and 7 an endo
configuration. Vinylcarbenoids are known to be reactive at either the
carbenoid or the vinylogous site,13 and at this stage it was uncertain
whether the two products were derived from competition between
reaction at these two sites or between initial attack of the carbenoid at
the C2 or C3 position of the indole.
natural products.1 Many methodologies have been developed for the
synthesis of this skeleton.2 Strategies based on the annulation of indoles
are particularly useful because indoles are readily available.3,4 Methods
for conversion of indoles into fused indolines have been reported,3
but enantioselective variants are limited.4 Recently, Barluenga et al.5
developed an asymmetric C2-C3 cyclopentannulation of 2-substituted
indoles with Fisher carbenes containing (S)-menthol as a chiral
auxiliary. Herein, we describe a catalytic enantioselective [3 + 2]
annulation of indoles using Rh-stabilized vinylcarbenoids.
Scheme 2
For some time we have studied the enantioselective reactions of
donor/acceptor-substituted carbenoids. Several highly enantioselective
C-C bond-forming reactions have been developed, including cyclo-
propanation,6 [3 + 2] cycloaddition,7 [4 + 3] cycloaddition,8 and C-H
functionalization.9 A series of chiral dirhodium tetracarboxylate
catalysts have been used, of which the most notable is the prolinate
catalyst Rh2(S-DOSP)4.6 This study was part of our program directed
toward generating new types of enantioselective transformations of
donor/acceptor carbenoids that proceed via zwitterionic intermediates.10,11
It is well-established that the reaction of carbenoids with N-
alkylindoles generates zwitterionic intermediates.12 This pathway is
favored because the positive charge of the intermediate is stabilized
by the electron-rich indole while the negative charge is stabilized by
the carbenoid component. We began our studies with methyl phenyl-
diazoacetate (1) as the precursor to the donor/acceptor carbenoid. Even
though the Rh2(S-DOSP)4-catalyzed reaction of 1 with 1,2-dimeth-
ylindole (2) is very efficient, generating the alkylation product 3 in
95% yield, negligible asymmetric induction (<5% ee) was observed
(Scheme 1). The lack of asymmetric induction in the formation of 3
presumably occurs because the zwitterionic intermediate A could
undergo a rapid proton transfer to generate the achiral enol B, which
then would tautomerize to the observed product 3. We reasoned that
if the indoles were to react with a vinylcarbenoid intermediate,
alternative pathways avoiding achiral intermediates would be possible.
Our exploration of this chemistry, which led to a highly enantioselective
entry to cyclopenta[b]indoles, is described in this paper.
In order to determine the cause of the formation of the two
regioisomers, the reaction was extended to 1,2-disubstituted indoles,
as these would be expected to undergo initial electrophilic attack only
at C3. With these substrates, only a single regioisomer of each fused
indoline was formed. The Rh2(S-DOSP)4-catalyzed [3 + 2] annulation
is applicable to a range of (E)-arylvinyldiazoacetates and 1,2-
disubstituted indoles (Table 1), producing the fused indolines 8-17
with very high asymmetric induction (90-98% ee) exclusively as the
exo diastereomers. The absolute configurations of 10 and 16 were
unambiguously assigned by X-ray crystallography.14 The relative
configurations of 6, 8, 9, 11-15, and 17 were assigned by NOE, while
their absolute configurations were tentatively assigned by assuming a
similar mode of asymmetric induction for all of the substrates.
When the reaction was extended to 1,3-disubstituted indolyl
derivatives, the opposite regioisomeric series of fused indolines was
formed (Table 2). As was observed in the reaction with 5, the
asymmetric induction for this series of compounds was exceptionally
high (99% ee) and only the endo diastereomer was observed. The
absolute configuration of 20 was unambiguously assigned by X-ray
crystallography,14 while the relative configurations of 7, 18, and 19
were assigned by NOE and the absolute configurations tentatively
assigned by analogy.
Scheme 1
A remarkable feature of the [3 + 2] cycloaddition is that exo isomers
are produced from 1,2-disubstituted indoles while endo isomers are
produced from 1,3-disubstituted indoles. Furthermore, the two types
of indoles give opposite absolute configurations at the ring-fusion
stereocenters. Although the detailed mechanism of the transformation
is not well understood, a plausible mechanism that rationalizes the
observed relative and absolute stereochemistries is shown in Figure
1. A model for the high asymmetric induction generated by Rh2(S-
DOSP)4 has the catalyst adopting a D2-symmetric conformation in
which a blocking group is in front of the ester and behind the vinyl
group.6,9b In cyclopropanation reactions, the alkene approaches over
the vinyl group, and it would be reasonable to assume that a similar
arrangement occurs here, even though the reaction proceeds via a
zwitterionic intermediate and never reaches the cyclopropane stage.
The difference in the ring-fusion stereochemistry can be rationalized
in terms of whether the initial attack occurs at C2 or C3 of the
indole.12b,c Similar changes in the absolute configurations of the
The Rh2(R-DOSP)4-catalyzed reaction of methyl (E)-phenylvinyl-
diazoacetate (4) with N-methylindole (5) in CH2Cl2 resulted in a very
efficient transformation, but in this case the products were the two
regioisomeric fused indoline derivatives 6 and 7 (Scheme 2). Unlike
the reaction with 1, these products were formed with high asymmetric
induction (80% ee for the major isomer 6 and >99% ee for the minor
isomer 7). The relative configurations of 6 and 7 were determined by
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440 J. AM. CHEM. SOC. 2010, 132, 440–441
10.1021/ja9078094  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Annulation of 1,2-Disubstituted Indoles
Figure 1. Proposed reaction mechanism.
Acknowledgment. This research was supported by the National
Science Foundation (CHE-0907936). We thank Dr. Ken Hardcastle
for the X-ray crystallographic structure determination.
Supporting Information Available: Full experimental data for the
compounds described in the paper and X-ray crystallographic data (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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cyclopentannulation of indolyl rings has been developed. Depending
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reactions of donor/acceptor carbenoids proceeding by means of
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induction.
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(14) The crystal structures of 10, 16, and 20 have been deposited at the
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747614, 747615, and 747616, respectively.
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