Catalytic [4+2] cyclization of α,β-unsaturated acyl chlorides with 3-alkylenyloxindoles: Highly diastereo- and enantioselective synthesis of spirocarbocyclic oxindoles

Article abstract of DOI:10.1002/anie.201207405

Cinchona alkaloids were used as Lewis base catalysts in the title reaction. The [4+2] cyclization of α,β-unsaturated acyl chlorides with electron-deficient alkenes derived from oxindole gave the corresponding spirocarbocyclic oxindoles. Copyright

Full text of DOI:10.1002/anie.201207405

Angewandte
Chemie
DOI: 10.1002/anie.201207405
Carbocycles
Catalytic [4+2] Cyclization of a,b-Unsaturated Acyl Chlorides with
3-Alkylenyloxindoles: Highly Diastereo- and Enantioselective
Synthesis of Spirocarbocyclic Oxindoles**
Li-Tao Shen, Wen-Qiang Jia, and Song Ye*
The spirooxindole is a privileged structure moiety found in
many biologically active natural products and pharmaceuti-
cally active compounds.[1] Thus, many elegant approaches
have been developed for its construction.[2] Typical intra-
molecular approaches are the oxidative rearrangement of
tetrahydro-b-carbolines,[3] and the palladium-catalyzed Heck
reaction.[4] The intermolecular cyclization, which forms two or
À
more C C bonds in one pot, is very interesting for the
construction of cyclic compounds, because it is a step-
economic approach and the starting materials are relatively
readily available.[5] Trost and co-workers reported a palla-
dium-catalyzed [3+2] cyclization of 3-alkenyloxindole with
trimethylenemethane, leading to the spirocyclic oxindolic
cyclopentanes in good yields with high enantioselectivities.[6]
Scheme 1. Lewis base catalyzed cyclization of a,b-unsaturated acyl
chlorides.
A facile synthesis of spirooxindole, developed by Carreira
and co-workers, involves the formal [3+2] cyclization of
spirocyclopropane with aldimines.[7] Recently, several effi-
cient routes to spirocyclic oxindole by the chiral amine-
catalyzed cascade process were reported, including the
[4+2] cyclization through double Michael addition,[8] the
[4+2] or [3+2] cyclization through Michael–aldol process,[9]
and the three-component [2+2+2] cyclization.[10] Moreover,
Lu and co-workers reported an interesting phosphine-cata-
lyzed highly enantioselective [3+2] cyclization of 3-alkenyl-
oxindoles with Morita–Baylis–Hillman adducts.[11]
Recently, the cyclization reaction of a,b-unsaturated acyl
chlorides catalyzed by chiral Lewis bases emerges as a power-
ful tool for the construction of cyclic compounds (Scheme 1).
In 2007, Peters and co-workers reported the pioneering
cinchona alkaloids catalyzed [4+2] cyclization of unsaturated
acyl halides with aldehydes (Scheme 1, reaction a).[12] Our
group reported the N-heterocyclic carbene catalyzed cycliza-
tion of a,b-unsaturated acyl chloride and activated ketones or
nitroso compounds.[13,14] Lately, the highly enantioselective
[4+2] cyclization of a,b-unsaturated acyl chlorides with
azodicarboxylates was realized in our group (Scheme 1,
reaction b).[15] Compared to the well-established catalytic
cyclizations of a,b-unsaturated acyl chlorides with unsatu-
À
À
rated C O or N N bonds, the corresponding reaction with
À
unsaturated C C bonds remains a challenge (Scheme 1,
reaction c). Herein, we report a catalytic [4+2] cyclization
that includes only carbon atoms of a,b-unsaturated acyl
chlorides with electron-deficient alkenes derived from oxin-
dole for the construction of spirocarbocyclic oxindoles.
Initially, the N-heterocyclic carbene (NHC)-catalyzed
[4+2] cyclization of a,b-unsaturated acyl chloride 1a and 3-
alkylenyloxindole 2a was investigated. We are happy to find
that NHC 4a could catalyze the reaction to give the desired
cycloadduct 3a in good yield with high diastereoselectivity
(Table 1, entry 1). However, the reaction catalyzed by chiral
NHC 5a gave cycloadduct 3a in nearly racemate form
(Table 1, entry 2). Several chiral NHCs, derived from l-
pyroglutamic acid and aminoindanol, were tested but without
notable enantioselectivity observed.
The cinchona alkaloids were then chosen as Lewis base
catalyst for the reaction. We were happy to find that
cycloadduct 3a was obtained in 90% yield with 15:1 d.r. for
the reaction catalyzed by O-TMS quinidine 6a (TMS-QD;
Table 1, entry 3). Other quinidine derivatives 6b (Bn-QD)
and 6c (tBu-QD) also worked well but led to low enantio-
selectivity (Table 1, entries 4 and 5). Solvent screening
revealed that THF is the best choice compared to ethyl
ether, CH2Cl2, DMF, and toluene (Table 1, entries 3, 6–9).
When the reaction temperature was lowered from À108C to
À788C, better diastereoselectivity and enantioselectivity
were obtained and the yield was not affected (Table 1,
[*] Dr. L.-T. Shen, W.-Q. Jia, Prof. Dr. S. Ye
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
E-mail: songye@iccas.ac.cn
[**] Financial support from the Ministry of Science and Technology of
China (2011CB808600), National Natural Science Foundation of
China (No. 21072195), and the Chinese Academy of Sciences is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207405.
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Table 1: Optimization of reaction conditions.
Entry Cat.[a,b] Solvent
T [8C] Yield [%][c] d.r.[d]
ee [%][e]
1
2
3
4
5
6
7
8
4a
5a
6a
6b
6c
6a
6a
6a
6a
6a
6a
THF
THF
THF
THF
THF
À10
À10
À10
À10
À10
80
87
90
89
86
32
78
17
35
90
90
15:1
18:1
15:1 83
8:1 26
15:1 53
2:1 56
5:1 45
3:1 65
2:1 32
>20:1 89
>20:1 93
/
2
ethyl ether À10
CH2Cl2
DMF
À10
À10
À10
À78
À78
9
toluene
THF
THF
10
11[f]
[a] NHCs 4a–5a were freshly generated from the corresponding azolium
salt in the presence of Cs2CO3 at room temperature for 30 min, and used
immediately. [b] The hydrochloride salt of quinidine derivative was used
for easy manipulation. [c] Yield of isolated product. [d] Determined by
1H NMR spectroscopy (300 MHz). [e] Determined by HPLC using
a chiral stationary phase. TMS=trimethylsilyl. [f] Acyl chloride was
added over four hours by using a syringe pump.
Scheme 2. Enantioselective [4+2] annulation of a,b-unsaturated acyl
chlorides and 3-alkylenyloxindoles. The yields of isolated products 3
and the ee values determined by HPLC are given. Unless otherwise
noted d.r. >20:1.
entry 10). The enantioselectivity was further improved to
93% ee when the acyl chloride was added slowly (Table 1,
entry 11).
With the optimized reaction conditions in hand, the scope
of a,b-unsaturated acyl chlorides and 3-alkylenyloxindoles
was briefly investigated (Scheme 2). It was found that both b-
aryl-a,b-unsaturated acyl chlorides with electron-withdraw-
ing groups (Ar= 4-Cl, 4-BrC6H4) and with electron-donating
groups (Ar= 4-Me, 4-MeOC6H4) all worked well to give the
desired cycloadducts (3a–3j) in good yields with high
diastereoselectivities and enantioselectivities. 3-Substituted
(Ar= 3-Cl, 3-MeC6H4,) and 2-substituted (Ar= 2-ClC6H4)
phenyl groups were also tolerable for the reaction (3k–3m)
albeit with some decreased enantioselectivities for cyclo-
adducts 3l and 3m. Furthermore, a,b-unsaturated acyl
chlorides with b-heteroaryl groups, such as 2-furyl and 2-
thienyl, also worked very well (3n–3q) to give the desired
cycloadduct in good yields with high diastereo- and enantio-
selectivity.
bromooxindole derivative gave the corresponding cycload-
duct 3r in good yield with 15:1 d.r. and 84% ee.
The scope of the reaction was further expanded for more
varied substrates (Scheme 3). It was found that reaction of b-
isopropyl-a,b-unsaturated acyl chloride 7 went smoothly to
give the corresponding cycloadduct 8 in 72% yield with
excellent diastereoselectivity and 65% ee. The enantiopurity
of 8 could be improved to 86% ee after one recrystallization.
Furthermore, doubly activated alkenes 9 derived from
oxindole and malononitrile also worked well to afford the
corresponding cycloadduct 10 in 76% yield with 85% ee.
The structures of spirocarbocyclic oxindole (+)-3a and
rac-3i were unambiguous established by the X-ray analysis of
their crystals (Figures S1 and S2 in the Supporting Informa-
tion).[16]
The plausible catalytic cycle of this cinchona alkaloid
catalyzed all-carbon-[4+2] annulations is depicted in
Scheme 4. Dienolate A is generated from a,b-unsaturated
acyl chloride 1 and tertiary amine catalyst in the presence of
base. The dienolate A reacts with 3-alkylenyloxindole 2 in
a Diels–Alder-type reaction or a stepwise vinylogous aldol
reaction with subsequent intramolecular cyclization, to give
Several 3-alkylenyloxindole derivatives have also been
tested for the reaction. Beside 5-chlorooxindole derivative
2a, other 5-substituted derivatives, such as 5-fluoro- and 5-
methyl-3-alkylenyloxindoles, also worked well to give the
desired cycloadducts (3c, 3e, 3g, and 3p) in high yields with
high diastereo- and enantioselectivities. Reaction of the 6-
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Scheme 4. Plausible catalytic cycle.
zwitterionic intermediate B. The observed exclusive or very
high trans selectivity suggests that the Diels–Alder reaction
pathway is favored over the stepwise pathway.[17] The collapse
of zwitterion B furnishes final cycloadduct 3 and regenerates
the catalyst.
In conclusion, the cinchona alkaloids catalyzed all-
carbon-[4+2] cyclization of a,b-unsaturated acyl chlorides
with electron-deficient alkenes derived from oxindole was
developed to give the corresponding spirocarbocyclic oxin-
doles in good yields with high diastereo- and enantioselectiv-
ities. Studies of more Lewis bases catalyzed cyclization
reactions of a,b-unsaturated acyl chlorides are under way.
Received: September 13, 2012
Published online: November 13, 2012
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Keywords: acyl chlorides · cyclization · enantioselectivity ·
.
spiro compounds
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ethyl acetate, with a trace of chloroform. CCDC 900492
((+)-3a), 892111 (rac-3i) contain 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.
[17] The epimerization of trans-3 to cis-3 under the reaction
conditions was observed with elongated reaction time, which
accounts for the presence of some cis-product in some cases.
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