Highly efficient hydrogen-bonding catalysis of the diels-alder reaction of 3-vinylindoles and methyleneindolinones provides carbazolespirooxindole skeletons

Article abstract of DOI:10.1021/ja203812h

Carbazolespirooxindole derivatives were synthesized in a high-yielding, atypically rapid, stereocontrolled Diels-Alder reaction catalyzed by a C ₂-symmetric bisthiourea organocatalyst. Simple precursors and mild conditions were used to construc

Full text of DOI:10.1021/ja203812h

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Highly Efficient Hydrogen-Bonding Catalysis of the DielsÀAlder
Reaction of 3-Vinylindoles and Methyleneindolinones Provides
Carbazolespirooxindole Skeletons
Bin Tan,† Gloria Hernꢀandez-Torres,†,‡ and Carlos F. Barbas, III*,†
†The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, United States
‡Departamento de Química Orgꢀanica, Universidad Autꢀonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
S Supporting Information
b
ABSTRACT: Carbazolespirooxindole derivatives were syn-
thesized in a high-yielding, atypically rapid, stereocon-
trolled DielsÀAlder reaction catalyzed by a C2-symmetric
bisthiourea organocatalyst. Simple precursors and mild
Figure 1. Natural products containing tetrahydrocarbazole or spiroox-
indole scaffolds.
conditions were used to construct carbazolespirooxindole
derivatives with high enantiopurity and structural diversity
under H-bonding catalysis. The practical approach recycles
the organocatalyst and solvent. This simple and efficient
operational procedure will allow diversity-oriented synth-
eses of this intriguing class of compounds.
Scheme 1. Carbazolespirooxindole Scaffold Synthesis
espite rapid progress in organocatalyst development,1 prac-
D
tical and efficient asymmetric approaches remain in high
demand. An ideal asymmetric reaction would be atom-econom-
ical and rapid, performed under mild conditions to yield quanti-
tative and enantiomerically pure products with catalyst and
solvent recycling. Since the DielsÀAlder (DÀA) reaction2 is
arguably the most powerful organic transformation available for
the synthesis of complex molecules, development of efficient
organocatalytic approaches to this reaction is significant.3 Orga-
nocatalytic asymmetric DÀA reactions have been approached
using iminium,4 enamine,5 and bifunctional acidÀbase catalysis6
as well as hydrogen-bonding catalysis.7 Here we describe an
unusually efficient organocatalytic asymmetric DÀA reaction of
3-vinylindoles and methyleneindolinones that uses the readily
accessible bisthiourea catalyst I as a H-bonding catalyst.
Scheme 2. Catalyst Structures
Spirooxindole8 and tetrahydrocarbazole9 scaffolds are present
in many natural and unnatural compounds that exhibit important
biological activities (Figure 1). Recently, methyleneindolinones
were used as highly reactive Michael acceptors10 and as
dipolarophiles11 in domino reactions12 and [2 + 3] cycloaddi-
tions.11d 3-Vinylindoles have been used as dienes in an organo-
catalytic DÀA reaction;6d however, only moderate yields were
obtained after long reaction times at low temperature (À55 °C).
We envisioned that carbazolespirooxindole skeletons with multi-
ple stereocenters could be constructed through simple DÀA
reactions between 3-vinylindoles (1) and methyleneindolinones
(2) with suitable organocatalysts (Scheme 1).
with methyleneindolinones through H-bonding. Therefore, the
DÀA reaction between 1a and 2a at room temperature in toluene
with 20 mol % catalyst I was investigated. In the absence of any
other additive, the reaction proceeded smoothly in quantitative
yield with moderate stereoselectivity15 [see Supporting Informa-
tion (SI) Table 1, entry 1]. As expected, lower enantioselectivity
was obtained using the phenyl-derivatized thiourea catalyst II (SI
Table 1, entry 2), since this catalyst should not effectively H-bond
with the substrate. Considering the poor asymmetric induction
Inspired by the pioneering work of Schreiner7a,b and Rawal7cÀe
on the use of H-bonding catalysts13 in DÀA reactions, we
envisioned that bisthiourea catalyst I14 (Scheme 2) should interact
Received: April 25, 2011
Published: July 22, 2011
r
2011 American Chemical Society
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|

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Table 1. Generality of the DÀA Reactionsa
Scheme 3. Effect of Substituents on the 3-Vinylindole
Scheme 4. Preparative-Scale Experiment
To determine the substrate generality and limitations of this
strategy, a number of donors and acceptors were evaluated
(Table 1). Only one diastereomer was detected for each product,
1
as determined from H NMR spectra of the crude reaction
mixtures, although 3À4 stereogenic centers were generated in
these DÀA reactions. Modifying the acceptor structure with
substituents that altered its electronic nature had little effect on
the yields and stereoselectivities (entries 1À6). Ester and ketone
groups did not substantially impact the yield or stereoselectivity
(entries 7À12). Furthermore, activating cyano and tosyl groups
were good substrates for the reaction (entries 13 and 14). The
wide scope of methyleneindolinone derivatives supports the
generality of the reaction and makes possible subsequent trans-
formations of the final products. The current system does have
limitations: for example, a phenyl-substituted methyleneindoli-
none provided the corresponding product with lower chemical
and optical yield (entry 15). Pharmacological agents often have
chlorine or bromine atoms on the indole moiety. As shown in
Table 1 and Scheme 3, halogenated carbazolespirooxindoles
were obtained in excellent yields and diastereo- and enantios-
electivities. In addition, substituted dienes served as substrates. In
the case of 3s, a new stereocenter was selectively created from the
E vinylindole. The absolute configuration of 3p was unambigu-
ously assigned by X-ray analysis, and this result together with
NMR analysis was used to establish the relative and absolute
configurations of our compounds (see the SI).
To investigate recycling of the organocatalyst, the reaction of 1a
(0.15 mmol, 1.5 equiv) and 2a (0.1 mmol, 1 equiv) in hexane was
used as a model (see the SI). Reaction completion was accom-
panied by a color change of the reaction mixture from yellow to
colorless. Because of the difference in the solubilities of the
reagents and the DÀA adduct, the final product was isolated by
simple centrifugation. The catalyst and the excess 1a remained in
the filtrate, whereas the productwas recovered asa whitesolidafter
filtration. 1a (0.13 mmol) and 2a (0.10 mmol) were then added to
the solution for the next cycle of the DÀA reaction. This
procedure was repeated several times with only a marginal loss
of performance in each cycle. Almost quantitative yield and
excellent enantioselectivity were obtained after five cycles (see SI
Table 2). When the reaction was carried out on a gram scale, there
was no change in reactivity or stereoselectivity (Scheme 4). As the
a Unless otherwise specified, all reactions were carried out using
3-vinylindole 1a (0.15 mmol, 1.5 equiv) and methyleneindolinone 2a
(0.1 mmol, 1.0 equiv) in hexane (4 mL) with 15 mol % catalyst at room
temperature (22 °C). b Isolated yields. Almost quantitative yields were
obtained except for entry 15, as shown by 1H NMR analysis of the crude
product. c Determined by 1H NMR analysis of the crude product.
d Determined by chiral-phase HPLC analysis of the [1,3]-H shift
e
f
product. The reaction was carried out at À20 °C. Using 20 mol %
catalyst I gave only 80% conversion after 12 h.
observed when the bisthiourea moiety was replaced by other
common H-bond donor groups (SI Table 1, entries 3À8), we
assumed that catalyst I acted to simultaneously activate both the
diene and the dienophile and that the bisthiourea functionality was
essential. To our surprise, catalyst VIII,16 which efficiently cata-
lyzes Michael reactions and FriedelÀCrafts alkylations, provided
only moderate stereoselectivity (SI Table 1, entry 8). It is
noteworthy that bifunctional tertiary amineÀthiourea catalysts17
that might activate both the diene and the dienophile through
H-bonding interactions gave rise to the desired product with
moderatediastereoselectivityandlow enantioselectivity(<10% ee;
SI Table 1, entries 9 and 10).
Reactions catalyzed by I were further optimized (for more
details, see the SI). The asymmetric induction was sensitive to
solvent (SI Table 1, entries 11À14). Of those tested, hexane
provided the best exo/endo selectivity (>99:1 dr) and enantio-
selectivity (93% ee) (SI Table 1, entry 14). In contrast to
previously reported data for DÀA reactions with vinylindoles,
the exo cycloadduct 3a was obtained as the only diastereoi-
somer under our reaction conditions. Moreover, the DÀA
adduct precipitated as a white solid when hexane was used as
the solvent. The stereoinduction was not improved when the
temperature was decreased to À20 °C (SI Table 1, entry 16).
Optimal results were obtained in the reaction performed in
hexane with 15 mol % catalyst at room temperature (SI Table 1,
entry 15).
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Scheme 6. Transformation of the Product
Figure 2. Chemical shift changes (Δδ) observed for the 13C NMR signals
of methyleneindolininone 2a complexed with catalyst I. No changes were
observed in the spectra of 3-vinylindole 1a after addition of catalyst I.
shift can be performed directly under acidic conditions without
affecting the ester functionalities or changing the enantioselectivity
(Scheme 6).
Scheme 5. Control Experiment for Mechanism Studies
In summary, we have developed a highly rapid and efficient
organocatalytic DielsÀAlder reaction for the direct construction
of carbazolespirooxindole derivatives containing three or four
stereocenters, including one spiro quaternary chiral center. A
simple bisthiourea was used as the organocatalyst, and this
straightforward process provided the products in almost quanti-
tative yield with excellent stereoselectivity (>99:1 dr, up to 99% ee)
from simple starting materials. Very mild reaction conditions
were used, and the reaction was scalable. Furthermore, the
catalyst and solvent were recyclable. The bisthiourea activates
methyleneindolinones though H-bonding interactions, and the
mechanism we have proposed will serve as a useful model for
development of other reactions catalyzed by H-bonding.
Further synthetic application of this transformation and me-
chanistic studies are underway in our laboratory.
catalyst was readily recycled and the reaction was scalable, this
method should be suitable for large-scale chemical production. This
procedure is not limited to the synthesis of 3a, since all products
with the exception of 3c precipitated from the reaction mixture.
Although the mechanism of this reaction has not been com-
pletely elucidated, we believe that the thiourea groups direct the
stereoselectivity.18 We initially hypothesized that the catalyst forms
H-bonds with both the 3-vinylindole and the methyleneindolinone.
However, in 1H and 13C NMR experiments, no evidence of catalyst
interactions with 3-vinylindole alone was found, while strong
interactions with the methyleneindolinone were observed in the
13C NMR spectra, where H-bonding induced a downfield shift of
up to 0.98 ppm (Figure 2). It remains possible that the 3-viny-
lindole is activated in a later tertiary complex. For more details, see
the SI. The poor stereocontrol obtained in the reaction with
1-methyl-3-vinylindole (Scheme 5) indicated that the NÀH group
of the vinylindole is essential. This and the unusual exo selectivity
obtained in the DÀA product suggested that additional interactions
between the oxindole and vinylindole reagents must be involved in
the stereoselectivity. Furthermore, the effects of the N-methyle-
neoxindole protecting group on the ee were striking. A bulky
electron-acceptor group at the 3-position was necessary, since only
Boc-protected 3-methyleneoxindole derivatives provided a stereo-
controlled product; the unprotected derivative and the Bn-protected
derivative showed no stereoinduction. In the absence of catalyst, the
reaction was significantly slower and required several hours to reach
completion. On the basis of these data, we hypothesize that the
vinylindole might be directed or oriented by interactions between
the NÀH group of the diene and the Boc group of the dienophile via
πÀπ and weak H-bonding interactions prior to CÀC bond
formation. This would provide a well-organized environment for
asymmetric induction as well as a pocket to enable this reaction to
proceed smoothly. However, more studies are needed to support
such a model. While most organocatalytic DÀA reactions require
several hours to several days to reach completion, the H-bonding-
accelerated reactions disclosed here are completed within minutes.
Finally, the Boc-protected carbazolespirooxindoles were success-
fully deprotected by treatment with trifluoroacetic acid. The [1,3]-H
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization data, and crystallographic data (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
carlos@scripps.edu
’ ACKNOWLEDGMENT
This work is dedicated to Prof. K. Barry Sharpless on the
occasion of his 70th birthday. Research support from the Skaggs
Institutefor ChemicalBiologyisgratefullyacknowledged. Wethank
Dr. A. L. Rheingold for the X-ray crystallographic analysis. G.H.-
T. thanks Universidad Autꢀonoma de Madrid for financial
support.
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(15) The product was stable during NMR analysis but not during
chiral-phase chromatography. Thus, a [1,3]-H shift transformation was
performed prior to HPLC analyses.
(16) (a) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew.
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(e) Bui, T.; Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009, 131, 8758.
(18) (a) Rampalakos, C.; Wulff, W. D. Adv. Synth. Catal. 2008,
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