Stereodivergent Synthesis of Tetrahydrofuroindoles through Pd-Catalyzed Asymmetric Dearomative Formal [3+2] Cycloaddition

Article abstract of DOI:10.1002/anie.201711873

A stereodivergent synthesis of tetrahydrofuroindoles through palladium-catalyzed asymmetric dearomative formal [3+2] cycloaddition of nitroindoles with epoxybutenes was developed. The polarity of the solvent was found to play a key role in the diastereoselectivity. In toluene, good to excellent yields (70–99 %), diastereoselectivity (87/13->95/5 d.r.), and enantioselectivity (85/15–94/6 e.r.) were obtained, regardless of the properties of the substituents on nitroindoles. In acetonitrile, tetrahydrofuroindoles of a different diastereoisomer were produced with good to excellent yields (75–98 %) and stereoselectivity (78/22–93/7 d.r., 93/7–99/1 e.r.). Mechanistic studies were conducted to illustrate the origin of the diastereodivergency. The kinetic experiments indicate that the rate-determining step of this reaction is different in different solvents. ESI-MS experiments also support the existence of key palladium complex intermediates and the catalytic cycle of the reaction.

Full text of DOI:10.1002/anie.201711873

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Accepted Article
Title: Stereodivergent Synthesis of Tetrahydrofuroindoles via Pd-
Catalyzed Asymmetric Dearomative Formal [3+2] Cycloaddition
Reactions
Authors: Shuli You, Qiang Cheng, Fang Zhang, Yue Cai, and Yin-Long
Guo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711873
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10.1002/anie.201711873
Angewandte Chemie International Edition
COMMUNICATION
Stereodivergent Synthesis of Tetrahydrofuroindoles via Pd-
Catalyzed Asymmetric Dearomative Formal [3+2] Cycloaddition
Reactions
Qiang Cheng[a], Fang Zhang[a], Yue Cai[a], Yin-Long Guo[a]*, and Shu-Li You[a,b]
*
Dedication ((optional))
Abstract: Stereodivergent synthesis of tetrahydrofuroindoles via
palladium-catalyzed asymmetric dearomative formal [3+2]
cycloaddition of nitroindoles with epoxybutenes was developed.
Polarity of solvent was found to play as the key role on the switch of
diastereoselectivity. In toluene, good to excellent yields (70-99%),
diastereo- (87/13->95/5 dr) and enantioselectivity (85/15-94/6 er)
were obtained regardless of the properties of substituents on
nitroindoles. In acetonitrile, tetrahydrofuroindoles of another
diastereoisomer were produced with good to excellent yields (75-
98%) and stereoselectivity (78/22-93/7 dr, 93/7-99/1 er). Mechanistic
studies were conducted to illustrate the origin of the
diastereodivergency. The kinetic experiments indicate that the rate-
determining step of this reaction has been altered in different
solvents. The ESI-MS experiments also support the existence of the
key palladium-complex intermediates and the catalytic cycle of the
reaction.
achieved for this goal, investigations for more convenient and
reliable methods are still urgent.[5]
Asymmetric construction of polysubstituted fused rings provides
convenient accesses to various natural products and
pharmaceuticals, and their analogs.[1] Thus methodologies have
been developed for the synthesis of polycyclic systems, among
which catalytic asymmetric dearomatization (CADA) reactions
have recently emerged as a powerful tool to convert simple
arenes to fused and spiro ring structures.[2] However, most of the
reported CADA reactions are based on the nucleophilicity of
electron-rich arenes,[3] which leads to substrate scope limitation
that arenes with electron-deficient substituents are frequently
unreactive. Reversing the electronic properties of arenes by
decorating with electron-withdrawing substituents, by converting
arenes to Michael acceptors, will bring with novel reactivity.
Scheme 1. Dearomatization of 3-nitroindoles via palladium-catalyzed [3+2]
cycloaddition reactions.
Recently, 3-nitroindole was reported as a suitable substrate
for
several
dearomative
transformations.[6]
Merging
dearomatization of 3-nitroindole with palladium-catalyzed
asymmetric [3+2] cycloaddition would lead to multiple
substituted fused indolines (Scheme 1a). However, challenges
such as the high energetic barrier for dearomatization, as well as
the control of enantio- and diastereoselectivity, will be
encountered. Two recent elegant examples using vinylaziridines
and vinylcyclopropanes were reported in racemic form.[6k,6l]
Another pioneering example by Trost and coworkers provided a
trial of asymmetric catalysis, albeit with moderate
enantioselectivity (83/17 er).[6b] Recently, our group reported a
Pd-catalyzed asymmetric dearomative formal [3+2] cycloaddition
reaction of nitrobenzofurans, while stereodivergent process
could not be realized yet.[7] Herein, we report an asymmetric
dearomatization of 3-nitroindoles via palladium-catalyzed formal
[3+2] cycloaddition reactions, solvent induced stereodivergency,
and related mechanistic studies (Scheme 1b).
We initiated our studies with 1-tert-butyloxycarbonyl-3-
nitroindole 1a and racemic 2-vinyloxirane 2a as model
substrates combined with Pd2dba3/L as the catalyst and toluene
as solvent. The detailed ligand screening can be found in the
supporting information (Table S1). It should be noted that
phosphinooxazoline (PHOX) ligands[8] were found to be efficient
for this reaction. To our delight, ligand L1 decorated with fluorine
and trifluoromethyl groups provided the best results (Table S1,
Stereodivergent synthesis performs as a powerful tool for the
access to the full set of stereoisomers of multiple stereogenic
center containing compounds from the same substrate, which
has attracted much attention recently.[4] Although strategies
including dual catalysis, switching of solvents or additives,
change of substrates, and using different catalysts have been
[a]
Q. Cheng, Dr. F. Zhang, Y. Cai, Prof. Dr. Y.-L. Guo, Prof. Dr. S.-L.
You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn; or ylguo@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
[b]
Prof. Dr. S.-L. You
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin (China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201711873
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COMMUNICATION
entry 11; Table 1, entry 1). Next, a detailed optimization of
reaction conditions was conducted. Examination of solvents
such as p-xylene, Et2O, THF, dioxane and DCM showed
comparable or no better results (Table 1, entries 2-6). To our
surprise, when acetonitrile, a much polar solvent, was used, the
diastereoselectivity was reversed compared to that in toluene
(Table 1, entry 7). To further illustrate the relationship between
1d). Attention was then paid to the groups on the indole ring. To
our delight, all reactions with substrates bearing substituents on
different positions proceeded smoothly in good to excellent
yields (70-99%) and stereoselectivity (86/14->95/5 dr, 85/15-
94/6
er).
4-Substituted
nitroindoles
displayed
lower
enantioselectivity, but better diastereoselectivity (Scheme 2,
3ua-3wa). On the other hand, substituents with varied electronic
the polarity of the solvent and diastereoselectivity of the reaction, properties ranging from electron-donating methyl and methoxyl
polar solvents like DMF and DMSO were also applied. As
expected, 4aa was obtained as the major product in these two
solvents (Table 1, entries 8, 9). Thus, a diastereodivergent
phenomenon induced by polarity of solvent was discovered, and
is further discussed later (vide infra). Finally, toluene was proved
to be the best solvent for the formation of 3aa (Table 1, entry 1),
while acetonitrile was favorable for the formation of 4aa (90%
yield, 15/85 dr, 99/1 er, Table 1, entry 7). It is noteworthy that
the best result was observed for 3aa when [Pd(η3-C3H5)Cl]2 was
group to electron-withdrawing ester and even nitro group were
well tolerated, indicating a wider group tolerance than traditional
dearomatization reactions of indoles functioning as nucleophiles.
In addition, halides, including the bromide group, survived in this
palladium-catalyzed process (Scheme 2, 3fa-3ha, 3oa, 3pa, 3ua,
3hb). To further explore scope, substituted vinyl epoxides were
applied. We are pleased to obtain products bearing vicinal
quaternary stereogenic carbon centers with good to excellent
yields, diastereo- and enantioselectivity (Scheme 2, 3ab, 3hb,
used (89% yield, >95/5 dr, 94/6 er, Table 1, entry 10). In addition, 3nb). Furthermore, the absolute configuration of 3ra was
Cs2CO3 was an indispensable additive for the reaction favoring
the formation of 3aa (Table 1, entry 11). With acetonitrile as
solvent, palladium sources made no much difference, and
Pd2dba3 gave better results (Table 1, entries 7 and 12).
Furthermore, additive was not essential for the formation of 4aa,
while Cs2CO3 promoted the reaction obviously (Table 1, entry
13).
determined as 3S,3aS,8aR by an X-ray crystallographic analysis
of a single crystal of the enantiopure sample.[9]
Table 1. Effect of solvents and optimization of other reaction conditions.[a]
entry
solvent
yield (%)[b]
dr[c]
er[d]
3aa
4aa
1
2
3
4
5
6
7
8
toluene
p-xylene
Et2O
THF
Dioxane
DCM
80
93
82
77
96
84
90
45
47
89
0
91/9
89/11
94/6
94/6
90/10
91/9
78/22
88/12
79/21
33/67
42/58
31/69
94/6
98/2
99/1
99/1
97.5/2.5
95/5
92/8
99/1
94/6
97.5/2.5
n.d.
62/38
89/11
52/48
15/85
28/72
18/82
>95/5
n.d.
MeCN
DMF
9
DMSO
toluene
toluene
MeCN
MeCN
10[e]
11[e,f]
12[e]
13[f]
n.d.
35/65
30/70
n.d.
98/2
99/1
75
70
20/80
15/85
[a] Reaction conditions: 5 mol% of Pd2dba3, 11 mol% of L1, 0.1 mmol of 1a,
0.13 mmol of 2a, 0.1 mmol of Cs2CO3 in solvent (1 mL), sealed tube, rt. [b]
Isolated yield of 3aa and 4aa. [c] Determined by 1H NMR of crude reaction
mixture. [d] Determined by HPLC analysis. [e] [Pd(η3-C3H5)Cl]2 was used as
Pd source. [f] Reaction without Cs2CO3. n.d. = not determined.
With the optimal conditions established for 3aa (Table 1, entry
10) and 4aa (Table 1, entry 7), we launched the substrate scope
investigation. In toluene, various electron-withdrawing groups on
N-1 of nitroindole could be accommodated, leading to good to
excellent yields, diastereo- and enantioselectivity (Scheme 2,
3aa-3ca), while electron-donating benzyl group failed (Scheme 2,
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10.1002/anie.201711873
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COMMUNICATION
Scheme 2. Reaction scope in toluene. Reaction conditions: 5 mol% of [Pd(η3-
C3H5)Cl]2, 11 mol% of L1, 0.2 mmol of 1, 0.26 mmol of 2, 0.2 mmol of Cs2CO3
in toluene (2 mL), sealed tube , rt.
of 3aa with methyl acrylate in the presence of Zhan-1B catalyst
occurred smoothly with other functional groups untouched
(Scheme 4, equation (3)). It is worth noting that all reactions
proceeded without erosion of stereomeric purity.
Compared with toluene, reactions in acetonitrile occurred
faster to produce the diastereoisomer
4
with higher
enantioselectivity (Scheme 3). Of particular note, methyl
substituted epoxybutene 2b produced dearomatized products
with higher diastereoselectivity. Substrates bearing either an
EWG (CO2Me, NO2, CN, F, Cl, Br) or EDG (Me, OMe) provided
4 with good to excellent yields (75-98%), moderate to good
diastereoselectivity
(78/22-93/7
dr),
and
excellent
enantioselectivity (93/7-99/1 er). In addition, the absolute
configuration of 4pb was determined as 3R,3aR,8aR by an X-
ray crystallographic analysis of
enantiopure sample.[9]
a single crystal of the
Scheme 4. Transformations of 3aa.
Although palladium-catalyzed [3+2] cycloaddition reaction has
been studied extensively, its mechanism is still not fully
understood. The challenge lied on the difficulty in isolation of the
unstable intermediates that are essential for drawing a possible
catalytic cycle. Nevertheless, ESI-MS is a direct and reliable
method for the characterization of reaction intermediates in situ,
which benefits from the gentle ionization process that delivers
minimal fragmentation.[10] We next tried to capture the key
reaction intermediates by monitoring the reaction with SAESI-
MS instrument in the cation mode (Figure S5, see the supporting
information for details). When the reaction in toluene was
monitored after ten minutes, an ion of m/z 854.0680 was
obtained (Figure S5a), indicating the existence of intermediate A
or B (Figure 2). The SAESI-MS/MS spectra further support the
structure of this ion (Figure S5b). In addition, a relatively weak
signal of m/z 1116.1650 was also observed (Figure S5a). The
SAESI-MS/MS spectra showed unambiguously the constituents
of this ion (Figure S5c), indicating the existence of intermediate
C (Figure 2). In addition, the experimental isotopic distributions
of the palladium-containing species matched the theoretical
isotopic distributions (Figure S5d). To our surprise, the positive
ions of the intermediates in both solvents were observed with
barely no difference (Figure S6), indicating that two reaction
systems might share the same reaction intermediates.
With these key intermediates identified (Figure 2), a Hammett
plot was put forward as a tool to investigate the rate determining
steps. Under the optimal reaction conditions, various substituted
nitroindoles were applied as substrates. The reactions were
monitored by 1H NMR or HPLC to determine the kinetic
behaviors (Figure 1, see the supporting information for details).
The observed Hammett plots strongly suggest that in toluene
(Figure 1a), as ρ > 0, the rate limiting step is an anion building
step, that is the Michael addition process. Oppositely, in
acetonitrile (Figure 1b), allylic cyclization step is supported as
the rate limiting step, as ρ < 0.
Scheme 3. Reaction scope in acetonitrile. Reaction conditions: 5 mol% of
Pd2dba3, 11 mol% of L1, 0.2 mmol of 1, 0.26 mmol of 2, 0.2 mmol of Cs2CO3
in acetonitrile (2 mL), sealed tube, rt.
To illustrate the potential application of this reaction, several
transformations of product 3aa were carried out. Firstly, the Boc
group on nitrogen was easily removed by TMSCl in MeOH at
room temperature (Scheme 4, equation (1)). In addition, the nitro
o
group could also be readily reduced with Zn and TMSCl at 0 C
to afford 6 (Scheme 4, equation (2)). Cross-metathesis reaction
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10.1002/anie.201711873
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Finally, with all the mechanistic information in hand, a possible
catalytic cycle was proposed (Figure 2). Coordination and
oxidative addition of a palladium catalyst to the epoxybutene 2a
leads to ring-opened intermediate B. The following steps varied
depending on the solvent. In toluene, as drawn in red (path a), a
rate determining Michael addition type dearomatization process,
which may be derived from a decreased nucleophilicity due to
the formation of a tight ion pair in a nonpolar solvent, leads to
intermediate C followed by a fast cyclization to form the final
product 3aa. On the other hand, in acetonitrile, intermediate C is
easy to be formed, while the next ring closing becomes rate
limiting step due to the stabilization of the zwitterion by the polar
solvent. This provides time for π-σ-π inversion of the allylic
palladium complex and leads to the formation of diastereoisomer
4aa, where the configuration of the allylic stereogenic center is
inversed compared with 3aa.
Figure 2. Proposed reaction mechanism.
In summary, we have developed a palladium-catalyzed
diastereo- and enantioselective dearomative formal [3+2]
Acknowledgements
cycloaddition reaction.
A
stereodivergent synthesis of
We thank the National Key R&D Program of China
(2016YFA0202900), the National Basic Research Program of
China (2015CB856600), NSFC (21332009, 21572252), Program
of Shanghai Subject Chief Scientist (16XD1404300), the
Strategic Priority Research Program (XDB20000000), and Key
Research Program of Frontier Sciences (QYZDYSSWSLH012)
of CAS for generous financial support.
tetrahydrofuroindoles was realized via tuning the polarity of
solvents in this kind of reactions. The mechanistic studies
supported that reactions in different solvents would proceed in
the same pathway with different rate limiting steps, leading to a
reversed stereocontrol. The ESI-MS studies have been carried
out to present a full picture of the reaction processes. These
results indicate some general explanation of stereoselectivity for
palladium-catalyzed asymmetric [3+2] cycloaddition reactions.
Keywords: cycloaddition • dearomatization • indole •
mechanism • stereodivergent
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Qiang Cheng, Fang Zhang, Yue Cai,
Yin-Long Guo*, Shu-Li You*
Page No. – Page No.
Stereodivergent Synthesis of
Tetrahydrofuroindoles via Pd-
Catalyzed Asymmetric Dearomative
Formal [3+2] Cycloaddition Reactions
Stereodivergent synthesis of tetrahydrofuroindoles via palladium-catalyzed
asymmetric dearomative formal [3+2] cycloaddition of nitroindoles with
epoxybutenes was developed. Polarity of solvent was found to play as the key role
on the switch of diastereoselectivity. In toluene, good to excellent yields (70-99%),
diastereo- (87/13->95/5 dr) and enantioselectivity (85/15-94/6 er) were obtained
regardless of the properties of substituents on nitroindoles. In acetonitrile,
tetrahydrofuroindoles of another diastereoisomer were produced with good to
excellent yields (75-98%) and stereoselectivity (78/22-93/7 dr, 93/7-99/1 er).
Mechanistic studies were conducted to illustrate the origin of the
diastereodivergency. The kinetic experiments indicate that the rate-determining
step of this reaction has been altered in different solvents. The ESI-MS experiments
also support the existence of the key palladium-complex intermediates and the
catalytic cycle of the reaction.
This article is protected by copyright. All rights reserved.