Catalytic Asymmetric Four-Component Reaction for the Rapid Construction of 3,3-Disubstituted 3-Indol-3′-yloxindoles

Article abstract of DOI:10.1021/acs.orglett.5b02160

A Rh(II)/chiral phosphoric acid cocatalyzed four-component reaction of indoles, 3-diazooxindoles, arylamines, and ethyl glyoxylate is developed, offering an extremely efficient strategy for the construction of 3,3-disubstituted 3-indol-3′-yloxindoles with

Full text of DOI:10.1021/acs.orglett.5b02160

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Four-Component Reaction for the Rapid
Construction of 3,3-Disubstituted 3‑Indol-3′-yloxindoles
Changcheng Jing, Dong Xing,* and Wenhao Hu*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical
Engineering, East China Normal University, Shanghai, 200062, China
S
* Supporting Information
ABSTRACT: A Rh(II)/chiral phosphoric acid cocatalyzed four-
component reaction of indoles, 3-diazooxindoles, arylamines, and
ethyl glyoxylate is developed, offering an extremely efficient strategy
for the construction of 3,3-disubstituted 3-indol-3′-yloxindoles with
excellent diastereoselectivities and high to excellent enantioselectiv-
ities. This transformation is proposed to proceed through a Mannich-
type trapping of the zwitterionic intermediate generated from a metal
carbene and an indole with an iminoester derived from an arylamine
and a glyoxylate.
3,3-Disubstituted 3-indol-3′-yloxindoles (mixed 3,3′-bisindoles)
that contain an all-carbon quaternary stereogenic center at the
C3 position of the oxindole rings (Figure 1, A) belong to an
Michael-type reactions, offering alternative ways for the
synthesis of enantioenriched mixed 3,3′-bisindoles.
In recent years, catalytic asymmetric multicomponent
reactions (MCRs) have emerged as powerful synthetic tools
over traditional methods for their high efficiency and step-
economic feature.8 When disconnecting the mixed 3,3′-
bisindole skeleton A into three parts: the oxindole ring, the
C3-indolyl substituent, and the C3-carbon substitution (Z),
catalytic asymmetric MCRs that may efficiently assemble these
three parts in one single step, ideally from readily accessible
starting materials, into the desired mixed 3,3′-bisindole skeleton
with excellent stereoselective controls, would be highly
desirable and would offer an ideal platform for diversity-
oriented synthesis (DOS) of mixed 3,3′-bisindole derivatives
for potential biological evaluations.9
Figure 1. Mixed 3,3′-bisindoles as key intermediates for the total
synthesis of natural hexahydropyrroloindoline alkaloids.
Under transition metal catalysis, 3-diazooxindole reacted
with indole to provide 3-indol-3′-yloxindole,10 which has been
used as the key precursor for asymmetric synthesis of 3,3-
disubstituted mixed 3,3′-bisindoles.3,4,11 This process is
believed to proceed through active zwitterionic intermediate
formation followed by rapid proton transfer (Scheme 1, path
a). Very recently, Gong’s research group has merged this
process with a one-pot subsequent Michael addition with
nitroalkenes via relay catalysis, thus offering an efficient way for
the construction of mixed 3,3′-bisindoles (Scheme 1, path a′).12
As part of our continuous efforts in exploring catalytic
asymmetric MCRs via electrophilic trapping of active
zwitterionic intermediates generated from metal carbenes,13
we envisioned that the use of an in situ generated iminoester
from an arylamine and a glyoxylate would act as an efficient
trapping agent to intercept the zwitterionic intermediate,
followed by delayed proton transfer (rather than a stepwise
important class of indole structural motifs, which show
significant biological and pharmaceutical activities.1 Such
skeletons also serve as key intermediates for the total synthesis
of a number of hexahydropyrroloindoline alkaloids (Figure 1).2
These characteristics have promoted the development of an
array of catalytic asymmetric transformations to access such
molecules. Overman developed an elegant Mukaiyama-aldol
reaction of 2-siloxyindole with enantioenriched aldehydes and
further applied this method to the total synthesis of
(+)-gliocladin C.3 Trost reported an efficient Pd(0)-catalyzed
enantioselective hydrocarbonation of allenes with 3-indol-3′-
yloxindoles and furnished the synthesis of the pyrrolidinoline
core of the gliocladin family.4 Guo, Peng5 and the research
group of Gong6 developed organocatalyzed asymmetric α-
alkylation of cyclic ketones or aldehydes with 3-hydroxy-3-
indol-3′-yloxindoles to afford 3,3-disubstituted oxindoles. On
the other hand, by starting from oxindole-derived nitroalkenes1c
or α,β-unsaturated aldehydes7 to react with indoles, Arai’s and
Zhang’s research group developed efficient catalytic asymmetric
Received: July 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02160
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Organic Letters
Letter
a
Scheme 1. Design of MCRs via Electrophilic Trapping of the
Zwitterionic Intermediate Generated from 3-Diazooxindole
and Indole
Table 1. Optimization of the Reaction Conditions
b
c
d
entry
6
solvent
t, °C
yield, %
dr
ee, %
1
6a
−
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
43
<5
40
34
60
59
62
61
59
60
80
74
72
75
20
57
>95:5
−
−
−
2
3
6b
6c
6d
6e
6f
6g
6h
6i
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
28
71
59
73
38
62
64
56
86
66
86
92
91
74
4
C−H functionalization/Mannich reaction pathway), to estab-
lish new MCRs (Scheme 1, path b). By introducing chiral
phosphoric acids as cocatalysts, the formation of an iminoester
can be facilitated and meanwhile efficient stereoselective
control could be achieved during the electrophilic trapping
process. However, the existence of four components and two
catalysts makes the desired transformation relatively compli-
cated, and a series of competitive reactions may occur. For
example, the glyoxylate may undergo aldol-type trapping of the
zwitterionic intermediate.14 Yet, arylamine may react with metal
carbene to generate ammonium ylide, which could be further
trapped by either the glyoxylate15 or iminoester. Furthermore,
an indole may directly react with the glyoxylate16 or
iminoester17 in the presence of chiral phosphoric acid catalysts.
Nonetheless, herein we demonstrate a rhodium(II)/chiral
phosphoric acid cocatalyzed four-component reaction of
indoles, 3-diazooxindoles, anilines, and ethyl glyoxylate for
the rapid construction of mixed 3,3′-bisindoles with high
diastereo- and enantioselectivities. Control experiments re-
vealed that this catalytic asymmetric four-component reaction
proceeded through electrophilic trapping of active zwitterionic
intermediates rather than a stepwise C−H functionalization/
Mannich reaction pathway.
Initially, we started our investigation by examining the
reaction of N-Boc 3-diazooxindole 1a, N-benzyl indole 2a,
aniline 3a, and ethyl glyoxylate 4 in the presence of both
[Rh2(OAc)4] (2 mol %) and racemic BINOL-derived
phosphoric acid 6a (5 mol %). To our delight, the desired
four-component product 5a was formed in 43% yield with
>95:5 diastereoselectivity (Table 1, entry 1). In contrast, in the
absence of 6a, this four-component reaction became very messy
and the formation of 5a was not observed (Table 1, entry 2),
indicating the indispensable role of phosphoric acid (PPA) for
this transformation. To improve the reactivity as well as fulfill
catalytic asymmetric control, a series of chiral BINOL-derived
PPA catalysts were evaluated. Among them, (S)-3,3′-bis-
(triphenylsilyl)-BINOL phosphoric acid (6j) gave the best
result, yielding 5a in 80% yield with >95:5 dr and 86% ee
(Table 1, entries 3−11). Different solvents were then screened,
and the use of xylene as the solvent gave a further improved
result, yielding 5a in 75% yield with >95:5 dr and 92% ee
(Table 1, entries 12−14). Decreasing the reaction temperature
to 0 °C caused reduced the yield of 5a while the
stereoselectivity remained almost unaffected (Table 1, entry
15). Increasing the reaction temperature to 40 °C resulted in
both reduced yield and enantioselectivity of 5a (Table 1, entry
16).
5
6
7
8
9
10
11
12
13
14
15
16
6j
6j
6j
CH2Cl2
xylene
6j
6j
xylene
6j
xylene
40
a
Reactions were conducted in 0.10 mmol scale of 3a. 1a:2a:3a:4 =
b
c
1.1:1.0:1.1:1.2. Isolated yield after column chromatography. Deter-
d
mined by 1H NMR of crude mixture. Determined by chiral HPLC of
major diastereomer.
With the optimized reaction conditions in hand, the substrate
scope of this transformation was investigated (Scheme 2). A
variety of substituted anilines were first examined. For all
substituted anilines being tested, the desired four-component
products were obtained in good yields with excellent
diastereoselectivities (>95:5 for all cases). While electron-
deficient anilines generally provided the products with excellent
enantioselectivities (5b, 5c, 5f, and 5g), electron-rich ones such
as p-toluidine gave the desired products with much lower
enantioselectivity (5d, 49% ee). This poor enantioselectivity
might be caused by the relatively higher reactivity of the in situ
generated iminoester from p-toluidine and ethyl glyoxylate.
Next, the generality for indoles and 3-diazooxindoles was
investigated. For C5-substituted indoles, electron-withdrawing
substituents gave higher enantioselectivities than electron-
donating ones (5h and 5j vs 5i). C6- and C7-substituted
indoles were also tolerated, yielding 5k and 5l in good yields
with excellent diastereoselectivities and high enantioselectiv-
ities. Substituents on C5, C6, and C7 positions of N-Boc 3-
diazooxindoles also gave the desired four-component products
in good yields with excellent diastereoselectivities and high to
excellent enantioselectivities (5m−5p). Different N-substitu-
ents on indoles and 3-diazooxindoles were also examined.
Replacing the N-benzyl substituent of indole to N-methyl
caused apparently reduced enantioselectivity (5b vs 5q). Yet,
N-benzyl 3-diazooxindoles gave the desired products with
comparably high enantioselectivities (5r−5t). Finally, the
absolute configuration of the four-component product was
unambiguously determined as 2S,3S by X-ray analysis of 5t.18
B
DOI: 10.1021/acs.orglett.5b02160
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Organic Letters
Letter
a
Scheme 2. Substrate Scope
Scheme 3. Plausible Reaction Pathways
stepwise transformation from 7a could be completed in 20 h,
yielding 5b in 92% yield with 67% ee (Scheme 4). The poor
Scheme 4. Control Experiments
a
dr >95:5 for all cases.
enantioselectivity observed for the stepwise transformation
further illustrated the advance of the electrophilic trapping
pathway for more efficient control of the enantioselectivity,
presumably through a metal/chiral PPA cooperatively activat-
ing manner.21 Yet, the possibility of a pathway involving
demetalation of zwitterionic intermediate B′ into enol C, which
further underwent tautomerization to give 7 or reacted with the
PPA-activated iminoester to afford the desired four-component
product 5, could not be excluded at the current stage.
To gain some insight into the pathway of this catalytic
asymmetric four-component reaction, several control experi-
ments were conducted. First, in view of the indispensable role
of chiral phosphoric acid for this transformation (Table 1, entry
1 vs 2), p-bromoaniline 3b was allowed to react with ethyl
glyoxylate 4 either with or without PPA 6j (5 mol %). As
1
monitored by H NMR, in the presence of 6j, 3b and 4 were
An interaction model was proposed to explain the stereo-
selective outcome of this four-component reaction (Figure 2).
fully converted into the iminoester immediately; in contrast, in
the absence of 6j, only a trace amount of the iminoester was
observed in 10 min.19 These results suggest that the chiral PPA
catalyst not only provides efficient stereoselective control but
also regulates the reaction pathway in the desired four-
component manner by efficiently facilitating the formation of
the iminoester. With the rapid generation of the iminoester, this
four-component reaction undergoes either a stepwise C−H
functionalization/Mannich reaction pathway with 3-indol-3′-
yloxindoles 7 as the intermediates or an electrophilic trapping
of the active zwitterionic intermediates followed by a delayed
proton transfer. A control experiment starting from the C−H
functionalization product 7a was conducted with 3b and 4.
After reaction for 1 h, 5b was formed in 13% yield with 14% ee
(Scheme 4).20 In contrast, under identical conditions, the four-
component reaction between indole 1a, 3-diazooxindole 2a, 3b,
and 4 gave 5b in 94% yield with 97% ee (Scheme 2, 5b). When
starting from N-benzyl-substituted 3-indol-3′-yloxindole 7r, the
formation of 5r was not observed after reacting for 1 h (Scheme
4), while the corresponding four-component transformation
gave 5r in 83% yield with 87% ee (Scheme 2, 5r). These results
clearly indicated that this four-component reaction proceeded
through electrophilic trapping of the zwitterionic intermediate
(Scheme 3, path b) rather than a stepwise C−H functionaliza-
tion/Mannich reaction pathway (Scheme 3, path a). The
Figure 2. Proposed transition state.
Chiral PPA (S)-6j first facilitates the formation of the
iminoester in its energetically favored E configuration from
aniline and ethyl gloyxylate. The imino group is protonated by
PPA while the iminoester maintains its E form.22 The N-phenyl
group of the iminoester is oriented toward the empty pocket of
the PPA catalyst. Meanwhile, weak hydrogen bonding between
the Lewis basic phosphoryl oxygen atom and the acidic C−H
proton at the C3 position of the indole ring in the zwitterionic
intermediate through the sterically favored configuration is
C
DOI: 10.1021/acs.orglett.5b02160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) For selected reviews on asymmetric MCRs, see: (a) Ramon, D. J.;
́
Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (b) de Graaff, C.;
Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969.
(9) For selected reviews on the application of MCRs to DOS, see:
(a) Sunderhaus, J. D.; Martin, S. F. Chem. - Eur. J. 2009, 15, 1300.
(b) Biggs-Houck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem. Biol.
2010, 14, 371. (c) O'Connor, C. J.; Beckmann, H. S. G.; Spring, D. R.
Chem. Soc. Rev. 2012, 41, 4444.
formed (the N-benzyl substituent on the indole ring is away
from the ester group of the iminoester; see Figure 2, TS1).
With subsequent proton transfer through the PPA catalyst, the
four-component product is formed with efficient asymmetric
control through this dual hydrogen bonding activation mode.
In summary, we have developed an extremely efficient
strategy for the construction of 3,3-disubstituted mixed 3,3′-
bisindoles by a Rh(II)/chiral phosphoric acid cocatalyzed
enantioselective four-component reaction of indoles, 3-
diazooxindoles, arylamines, and ethyl glyoxylate. With this
method, a series of highly valuable 3-(2-arylamino-)-3-indol-3′-
yloxindoles were synthesized in good yields with excellent
diastereoselectivities and high to excellent enantioselectivities.
This transformation is proposed to proceed through electro-
philic trapping of zwitterionic intermediates generated from
metal carbenes and indoles with iminoesters derived from
arylamines and ethyl glyoxylate. With its high efficiency in
accessing complicated chiral products in one step, this
transformation may have great potential in the synthesis of
related natural products and diversity-oriented synthesis of
complicated chiral compounds.
(10) Muthusamy, S.; Gunanathan, C.; Babu, S. A.; Suresh, E.;
Dastidar, P. Chem. Commun. 2002, 824.
(11) DeLorbe, J. E.; Jabri, S. Y.; Mennen, S. M.; Overman, L. E.;
Zhang, F.-L. J. Am. Chem. Soc. 2011, 133, 6549.
(12) Chen, D.-F.; Zhao, F.; Hu, Y.; Gong, L.-Z. Angew. Chem., Int. Ed.
2014, 53, 10763.
(13) For reviews, see: (a) Guo, X.; Hu, W. Acc. Chem. Res. 2013, 46,
2427. (b) Xing, D.; Hu, W. Tetrahedron Lett. 2014, 55, 777. (c) Qiu,
H.; Li, M.; Jiang, L.-Q.; Lv, F.-P.; Zan, L.; Zhai, C.-W.; Doyle, M. P.;
Hu, W.-H. Nat. Chem. 2012, 4, 733. (d) Jia, S.; Xing, D.; Zhang, D.;
Hu, W. Angew. Chem., Int. Ed. 2014, 53, 13098.
(14) Xing, D.; Jing, C.; Li, X.; Qiu, H.; Hu, W. Org. Lett. 2013, 15,
3578.
(15) Ren, L.; Lian, X.-L.; Gong, L.-Z. Chem. - Eur. J. 2013, 19, 3315.
(16) Zhuang, W.; Poulsen, T. B.; Jorgensen, K. A. Org. Biomol. Chem.
2005, 3, 3284.
(17) Kang, Q.; Zhao, Z.-A.; You, S.-L. Tetrahedron 2009, 65, 1603.
(18) CCDC 1044173 (5t) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02160.
■
S
(19) The formation of the iminoester was appraently incomplete
even after reacting 3b and 4 for 20 h. For a detailed monitoring of the
1
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
Crystallographic data for 5t (CIF)
iminoester formation by H NMR spectroscopy, see Scheme S1 of
theSupporting Information. See also: Xu, X. F.; Zhou, J.; Yang, L. P.;
Hu, W. H. Chem. Commun. 2008, 6564.
(20) The reaction time of the control experiment was set to 1 h to
keep in line with the reaction time of the four-component reaction.
(21) For a theoretical calculation of the Rh-enolated form of a similar
active intermediate, see: Ma, X.; Jiang, J.; Lv, S.; Yao, W.; Yang, Y.; Liu,
S.; Xia, F.; Hu, W. Angew. Chem., Int. Ed. 2014, 53, 13136.
(22) For a computational modelling study of chiral PPA-catalyzed
transfer hydrogenation of α-iminoesters, see: Shibata, Y.; Yamanaka,
M. J. Org. Chem. 2013, 78, 3731.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dxing@sat.ecnu.edu.cn.
*E-mail: whu@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial supports from NSF of China
(21125209, 21332003, and 21402051), the MOST of China
(2011CB808600), and STCSM (12JC1403800).
REFERENCES
■
(1) (a) Bindra, J. S. The Alkaloids, Vol. 14; Manske, R. H. F., Ed.;
Academic Press: New York, 1973; pp 84−121. (b) Kobayashi, M.;
Aoki, S.; Gato, K.; Matsunami, K.; Kurosu, M.; Kitagawa, I. Chem.
Pharm. Bull. 1994, 42, 2449. (c) Arai, T.; Yamamoto, Y.; Awata, A.;
Kamiya, K.; Ishibashi, M.; Arai, M. A. Angew. Chem., Int. Ed. 2013, 52,
2486.
(2) For reviews, see: (a) Steven, A.; Overman, L. E. Angew. Chem.,
Int. Ed. 2007, 46, 5488. (b) Ruiz-Sanchis, P.; Savina, S. A.; Albericio,
́
F.; Alvarez, M. Chem. - Eur. J. 2011, 17, 1388. (c) Zhou, F.; Liu, Y.-L.;
Zhou, J. Adv. Synth. Catal. 2010, 352, 1381.
(3) Overman, L. E.; Shin, Y. Org. Lett. 2007, 9, 339.
(4) Trost, B. M.; Xie, J.; Sieber, J. D. J. Am. Chem. Soc. 2011, 133,
20611.
(5) Song, L.; Guo, Q.-X.; Li, X.-C.; Tian, J.; Peng, Y.-G. Angew.
Chem., Int. Ed. 2012, 51, 1899.
(6) Guo, C.; Song, J.; Huang, J.-Z.; Chen, P.-H.; Luo, S.-W.; Gong,
L.-Z. Angew. Chem., Int. Ed. 2012, 51, 1046.
(7) Liu, R.; Zhang, J. Org. Lett. 2013, 15, 2266.
D
DOI: 10.1021/acs.orglett.5b02160
Org. Lett. XXXX, XXX, XXX−XXX