Asymmetric triple relay catalysis: Enantioselective synthesis of spirocyclic indolines through a one-pot process featuring an asymmetric 6π electrocyclization

Article abstract of DOI:10.1002/anie.201407677

A rare example of a one-pot process that involves asymmetric triple relay catalysis is reported. The key step is an asymmetric [1,5] electrocyclic reaction of functionalized ketimines. The substrates for this process were obtained in situ in a two-step process that involved the hydrogenation of nitroarenes with a Pd/C catalyst to yield aryl amines and their subsequent coupling with isatin derivatives in a Bronsted acid catalyzed ketimine formation reaction. The electrocycli-zation was catalyzed by a bifunctional chiral Bronsted base/ hydrogen bond donor catalyst. The one-pot process gave the desired products in good yields and with excellent enantiose-lectivity.

Full text of DOI:10.1002/anie.201407677

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DOI: 10.1002/anie.201407677
Asymmetric Catalysis
Asymmetric Triple Relay Catalysis: Enantioselective Synthesis of
Spirocyclic Indolines through a One-Pot Process Featuring an
Asymmetric 6p Electrocyclization**
Xiao-Ping Yin, Xing-Ping Zeng, Yun-Lin Liu, Fu-Min Liao, Jin-Sheng Yu, Feng Zhou, and
Jian Zhou*
Abstract: A rare example of a one-pot process that involves
asymmetric triple relay catalysis is reported. The key step is an
asymmetric [1,5] electrocyclic reaction of functionalized
ketimines. The substrates for this process were obtained
in situ in a two-step process that involved the hydrogenation
of nitroarenes with a Pd/C catalyst to yield aryl amines and
their subsequent coupling with isatin derivatives in a Brønsted
acid catalyzed ketimine formation reaction. The electrocycli-
zation was catalyzed by a bifunctional chiral Brønsted base/
hydrogen bond donor catalyst. The one-pot process gave the
desired products in good yields and with excellent enantiose-
lectivity.
distinct catalysts to exploit asymmetric triple relay catalysis is
still underdeveloped, although it has already exhibited its
powerfulness in tackling some synthetic challenges.[7]
On the other hand, the ever-increasing demand in
chemical biology and medicinal research for synthetic libra-
ries derived from privileged scaffolds requires the develop-
ment of new synthetic methods that enable the construction
of libraries of optically active compounds with polycyclic
structures.[8] In particular, efficient stereoselective syntheses
of spirocyclic compounds are very much in demand.[9] There-
fore, the exploration of asymmetric triple relay catalysis for
the facile construction of spirocyclic compounds from simple
materials is highly desirable. Herein, we report an unprece-
dented example of asymmetric triple replay catalysis, which
integrates palladium, Brønsted acid, and bifunctional chiral
Brønsted base/hydrogen bond donor catalysis, and we dem-
onstrate its effectiveness in the highly enantioselective syn-
thesis of oxindole-based spirocyclic indolines through a one-
pot sequence that involves hydrogenation, ketimine forma-
tion, and an asymmetric 6p electrocyclization (Scheme 1).
As we are interested in the catalytic asymmetric synthesis
of chiral spirocyclic compounds,[10] we wished to construct
spirocyclic compounds through a [1,5] electrocyclic reaction
of an imine as its catalytic asymmetric version is still in its
infancy.[11] In 2009, the groups of List and Smith independ-
I
nspired by the multienzymatic tandem catalytic processes
that nature uses for the efficient synthesis of complex
molecules, the development of multi-catalyst-promoted
asymmetric tandem reactions (MPATR) is of current inter-
est.[1] Aside from the general advantages of tandem cataly-
sis,[2] namely the effectiveness in minimizing waste produc-
tion, the consumption of energy, labor, and time, and yield
losses associated with the purification of intermediates, the
use of multiple catalysts, rather than a single catalyst, offers
the promise to incorporate more substrates and reaction types
to design novel cascade reactions, which are very attractive
for building up molecular complexity from simple materials.[1]
Over the past decade, much progress has been made in this
area, and asymmetric relay catalysis (or sequential catalysis)
has been established as a major type of MPATR,[1,3] which
refers to the sequential combination of catalytic reactions,
each of which is independently operated by a distinct catalyst,
into a one-pot process. Nevertheless, despite remarkable
advances in the development of tandem reactions that were
achieved by using two metal catalysts,[4] two organocatalysts,[5]
or a metal and an organocatalyst,[6] the combination of three
[*] X.-P. Yin, X.-P. Zeng, Y.-L. Liu, F.-M. Liao, J.-S. Yu, Dr. F. Zhou,
Prof. Dr. J. Zhou
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry
East China Normal University
3663N, Zhongshan Road, Shanghai 200062 (China)
E-mail: jzhou@chem.ecnu.edu.cn
[**] We appreciate financial support from the 973 program
(2015CB856600), the NSFC (21172075, 21222204), the Program of
SSCS (13XD1401600), and the Ministry of Education (NCET-11-
0147, PCSIRT).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407677.
Scheme 1. One-pot reaction sequence involving hydrogenation, keti-
mine formation, and an asymmetric 6p electrocyclization.
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ently pioneered the catalytic asymmetric 6p electrocycliza-
tion.[12] Whereas List et al. developed a highly enantioselec-
tive cycloisomerization of a,b-unsaturated hydrazones to
pyrazolines catalyzed by a chiral phosphoric acid,[12a] Smith
and co-workers used functionalized aldimines as precursors to
2-aza-pentadienyl anions while employing phase transfer
catalysis (PTC) to generate a tight ion pair featuring
a chiral ammonium cation to achieve excellent enantioselec-
tivity.[12b] Smith et al. further used their method to develop
cascade syntheses of polycyclic compounds.[12c] Despite sig-
nificant advances, the use of functionalized ketimines for such
reactions is still unknown, and the identification of new
catalysts for this interesting reaction is still very much in
demand.
a ratio of approximately 10:1. Nevertheless, it was directly
used for the optimization of the reaction conditions. First, we
attempted the electrocyclization of 4a under Smithꢀs con-
ditions using chiral ammonium catalyst C1 along with K2CO3
as the base and toluene as the solvent at À158C; however, the
desired product 5a was obtained in only 6% ee, albeit in 89%
yield (Table 1, entry 1). This result further suggested the
Table 1: Optimization of the reaction conditions.[a]
Considering the versatility of bifunctional tertiary amine/
hydrogen bond donor catalysts,[13] we speculated that such
a dual activation mode would be suitable for the asymmetric
[1,5] electrocyclic reaction of aniline-derived ketimine 4,
which might be activated to produce 2-aza-pentadienyl anion
intermediates through activation of the ketimine moiety
through hydrogen bonding and simultaneous activation of the
methine moiety through deprotonation. The hydrogen bond-
ing interactions might organize a favorable transition state to
control the sense of the disrotatory electrocyclization process
(Scheme 1).
Entry
Catalyst
Solvent
t [d]
Yield[b] [%]
ee[c] [%]
1[d]
2
3
4
5
6
7
8
9
C1
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
EtOH
toluene
THF
1
6
6
4
3
3
3
3
3
3
2
89
trace
trace
78
63
88
94
93
46
90
6
49
16
98
95
97
65
98
97
99
98
(DHQD)2PYR
C2
C3
C4
C4
C4
C4
C4
C4
C4
10
Et2O
Et2O
11[e]
88
Importantly, with bifunctional tertiary amines as the
catalyst, catalyst quenching, a major obstacle in the develop-
ment of the desired tandem process, may be avoided.[1] We
were also concerned that the Brønsted acid required for the
synthesis of the aniline-derived ketimines might be detrimen-
tal to the electrocyclization, as it might protonate the tertiary
amine moiety of the chiral catalyst. However, recent results
from Wang and co-workers and our group revealed that
bifunctional chiral tertiary amines could tolerate the coex-
istence of some acidic additives.[14] Furthermore, bifunctional
tertiary amines are known to be able to tolerate some metal
species,[6k–n] and might be compatible with the palladium
species we wished to use for the hydrogenation of nitroarenes
1 to obtain malonate-anilines 3. It is important to conduct the
ketimine formation and the cyclization process in a one-pot
fashion as the purification of such sensitive imines often
incurs yield losses.[15] Based on the above analyses, it is
worthwhile to combine the three distinct catalytic reactions
into the one-pot process shown in Scheme 1.
[a] Reactions run on a 0.1 mmol scale in 1.0 mL of solvent. [b] Yield of
isolated product. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] With 0.2 mL of aqueous K2CO3 (33%). [e] At 408C.
importance of identifying a new catalyst motif for this
valuable cyclization. In the following, various tertiary amine
catalysts were evaluated at 258C using CH2Cl2 as the solvent.
Not surprisingly, simple chiral tertiary amines proved to be
incapable of catalyzing this transformation. For example,
(DHQD)2PYR (hydroquinidine-2,5-diphenyl-4,6-pyrimidine-
diyl diether) gave only trace amounts of 5a in 49% ee even
after six days (entry 2). On the other hand, it was also
important for the desired reactivity and enantioselectivity
that the amine catalyst featured a suitable hydrogen bond
donor moiety. Cinchona alkaloid derivatives with a single
hydrogen bond donor were inferior as well, and derivative C2,
for instance, afforded product 5a in trace amounts and 16%
ee (entry 3). Fortunately, cinchona alkaloid derivatives with
a dual hydrogen bond donor moiety, squaramide C3[19] or
thiourea C4,[20] were promising, giving 5a in reasonable yield
and ꢀ 95% ee (entries 4 and 5; for the full catalyst evaluation,
see the Supporting Information, Table S1). Encouraged by
these results, we chose the more easily available thiourea
catalyst C4 for further optimization. By replacing CH2Cl2
With our interests in oxindole chemistry,[10,16] we first
designed isatin-derived malonate-ketimine 4a as a starting
point for the study of the asymmetric 6p electrocyclization, to
pave the way for the subsequent development of the tandem
reaction. It should be noted that whereas the catalytic
asymmetric synthesis of spirocyclic oxindoles, a prominent
structural motif in natural products, drugs, and bioactive
products,[17] has been extensively studied, the asymmetric
synthesis of spirocyclic oxindole-indoline derivatives is
unprecedented.
The synthesis of ketimine 4a from malonate-aniline
derivative 1a and N-methylisatin (2a) required the use of
a stronger acid catalyst,[18] namely para-toluenesulfonic acid
(p-TsOH; see Supporting information). Ketimine 4a was
prepared as an inseparable mixture of the Z and E isomers in
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with Et2O as the solvent, product 5a could be obtained in
90% yield and 99% ee (entries 5–10). When the temperature
was increased to 408C, the reaction in Et2O could reach
completion within two days, affording product 5a in 88%
yield and 98% ee (entry 11).
C4 by p-TsOH with a pKa value of up to À2.8. Gratifyingly, it
turned out that the cyclization of 4a catalyzed by 10 mol% of
C4 could tolerate the coexistence of up to 4 mol% of p-
TsOH, without obvious erosion in enantioselectivity and
reactivity (Scheme 3). Not surprisingly, the addition of
Next, the scope of the asymmetric 6p electrocyclization
was examined using 10 mol% of quinine-derived bifunctional
thiourea C4 in Et2O at 408C. Avariety of malonate-ketimines
4 with different substituents on the isatin framework provided
the desired spirocyclic oxindole derivatives 5 in good yield
and with excellent ee values (Scheme 2), which highlights the
Scheme 3. Studies of the catalyst compatibility.
10 mol% p-TsOH greatly decreased the yield and ee value
of product 5a. However, the presence of both Pd/C and
4 mol% of p-TsOH had little effect on the performance of C4
in the cyclization reaction, and product 5a was obtained in
98% yield with 98% ee, which is comparable to the result
obtained with C4 alone (Table 1, entry 11). Noticeably, the
use of 4 mol% of p-TsOH was enough to catalyze the
ketimine formation at 608C, whilst the racemic background
reaction was minimized.
The above control experiments confirmed the prerequi-
site catalyst compatibility; however, the merging of three
distinct catalytic reactions into a one-pot process with
minimal extra procedures was not as trivial as first antici-
pated. Attention should be paid to three issues. First, it was
better to run all three steps in the same solvent to obviate the
need for changing the solvent for each cycle. We chose to use
the best solvent for the asymmetric step to optimize the
conditions for the non-enantioselective reactions, a tactic
useful for further studies of asymmetric triple relay catalysis.
Fortunately, Et2O proved to be a suitable solvent for all three
steps. Second, the concentration should be adjusted to
maximize the efficiency of each step. In this sequence,
whereas the ketimine formation required a high substrate
concentration (0.3m), the asymmetric cyclization achieved
higher enantioselectivity at a lower concentration (0.1m).
Last, the reaction time of the ketimine formation catalyzed by
p-TsOH (4 mol%) should be limited to eight to ten hours, and
no background racemic reaction was observed during this
time. The full optimization of the tandem process is detailed
in Table S2. Finally, a simple one-pot procedure was devel-
oped. The initial palladium-catalyzed hydrogenation of nitro-
arene 1 (0.3 mmol) using a H2 balloon was run in a screw-
capped pressure tube at 258C in Et2O (1 mL). After 1 had
been consumed (as confirmed by TLC analysis), isatin 2,
molecular sieves (M.S.; 5 ꢁ), and p-TsOH (4 mol%) were
added, and the reaction was heated at 608C for 8–10 hours.
Then, the mixture was cooled down, and Et2O (2 mL) and
thiourea C4 (10 mol%) were added for the following [1,5]
electrocyclic reaction at 408C. According to this procedure,
which only involves sequential addition steps and a single
purification, all of the oxindole-indoline derivatives 5a–
l shown in Scheme 2 were obtained in reasonable yield with
Scheme 2. Scope of the asymmetric 6p electrocyclization. Yields of
isolated products are given. All ee values were determined by HPLC
analysis on a chiral stationary phase.
potential of bifunctional tertiary amine/hydrogen bond donor
catalysis in this type of electrocyclization. The absolute
configuration of product 5e was assigned to be S by X-ray
analysis,[21] and those of others were tentatively assigned.
Noticeably, although ketimines 4 were all prepared as
mixtures of the Z and E isomers, the desired products 5
were all obtained in > 94% ee. We are currently investigating
the origin of this high selectivity.
Having established the highly enantioselective 6p elec-
trocyclization of ketimines 4, we next tried to develop the
triple relay sequence shown in Scheme 1. The development of
this process is justified by the inconvenience in purifying 4,
which involves a flash column chromatography followed by
a recrystallization, as 4 underwent partial racemic cyclization,
either owing to the presence of p-TsOH in the reaction
mixture or during the column chromatography (see the
Supporting Information). Obviously, a prerequisite for the
success of this sequence was to prevent the p-TsOH catalyzed
background cyclization and the quenching of chiral catalyst
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Table 2: Scope of the cascade process.[a]
process without taking special care except for adding the
reagents in a sequential fashion. The finding that bifunctional
tertiary amines could tolerate the presence of a stronger
Brønsted acid such as p-TsOH and Pd species was also
unprecedented and should be useful for developing new
tandem sequences that feature these catalysts, in particular
considering the usefulness of bifunctional chiral tertiary
amines in ketimine addition reactions.[23]
Apart from (aza)isatins, a,a-difluoro-1,3-indandione (6)
could also be integrated into this tandem sequence [Eq. (1)].
However, possibly owing to the negative influence of the
difluoromethylene group on the catalyst–substrate interac-
tion,[23a,24a] ketimine 7 failed to cyclize, both in the presence of
thiourea C4 or in the presence of PTC catalyst C1 and K2CO3.
Nevertheless, a combination of C4 and K2CO3 (20 mol%
each) could catalyze the cyclization to give the desired
product 8 in 45% yield and 16% ee through the cascade
process. Despite the moderate ee value, this represents a new
method to prepare novel difluorinated spirocyclic indoline
derivatives.[24]
Entry
Product
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5 f
5g
5h
5i
85
83
81
55
66
79
53
76
78
75
45
54
92
96
92
92
97
91
93
97
92
94
86
80
10
11
12
5j
5k
5l
The triple sequence described above could be modularly
varied by using other asymmetric imine addition reactions.[25]
For example, an analogous sequence involving hydrogena-
tion, ketimine formation, and a Mannich reaction starting
from 3-alkenyl-oxindole 9 and N-methyl isatin (2a) readily
gave bis(spirooxindole) 12 in 47% yield, > 20:1 d.r., and 67%
ee [Eq. (2)]. The structure and relative configuration of 12
were confirmed by X-ray analysis.[21] In this case, the ketimine
formation was promoted by 5 ꢁ molecular sieves, and the use
of p-TsOH should be avoided as it led to severe background
reactions. Despite ample room for improvement, this
sequence constitutes a new strategy for the synthesis of
bis(spirooxindoles), which are privileged scaffolds with very
limited synthetic methods known for their preparation.[26]
In conclusion, we have developed a rare example of
asymmetric triple relay catalysis through the sequential use of
[a] Run on a 0.3 mmol scale. [b] Yield of isolated product. [c] Determined
by HPLC analysis on a chiral stationary phase. For details, see the
Supporting Information.
high to excellent ee values from simple starting materials
(Table 2, entries 1–12).
The importance of the asymmetric tandem process was
further highlighted by the efficient synthesis of spirocyclic
indolines 5m–t, as the corresponding malonate-ketimine
precursors were either difficult to purify or prepared from
expensive substrates. For example, owing to the reduced steric
hindrance of the methyl ester group, it was difficult to purify
the ketimine precursor of product 5m owing to rapid racemic
cyclization during column chromatography. However, with
the one-pot process, the desired product 5m was obtained in
76% yield and 92% ee. The low yield of product 5q was due
to the steric hindrance imposed by the ortho fluorine
substituent at the aryl ring. Furthermore, the one-pot
method greatly improved the efficiency of the syntheses of
products 5r–t by avoiding yield losses during the purification
of the ketimine precursors derived from 7-azaisatin, which are
expensive and difficult to prepare.[22]
We were pleased to find that the three distinct catalytic
reactions could be effectively incorporated into a one-pot
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Received: July 23, 2014
Revised: September 2, 2014
Published online: October 14, 2014
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