Chiral spirooxindole-butenolide synthesis through asymmetric N-heterocyclic carbene-catalyzed formal (3 + 2) annulation of 3-bromoenals and isatins

Article abstract of DOI:10.1021/ol502365r

By using an N-heterocyclic carbene catalyst bearing a hydroxyl moiety, the asymmetric formal (3 + 2) cyclization of aryl 3-bromoenals and isatins was achieved to produce a series of chiral spirooxindole-butenolides including an alkenyl-substituted compound, which underwent benzannulations with benzynes to form intriguing spirocyclic scaffolds.

Full text of DOI:10.1021/ol502365r

Letter
pubs.acs.org/OrgLett
Chiral Spirooxindole−Butenolide Synthesis through Asymmetric
N‑Heterocyclic Carbene-Catalyzed Formal (3 + 2) Annulation of
3‑Bromoenals and Isatins
Chenguang Zheng, Weijun Yao, Yucheng Zhang, and Cheng Ma*
Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027, China
S
* Supporting Information
ABSTRACT: By using an N-heterocyclic carbene catalyst bearing
a hydroxyl moiety, the asymmetric formal (3 + 2) cyclization of aryl
3-bromoenals and isatins was achieved to produce a series of chiral
spirooxindole−butenolides including an alkenyl-substituted com-
pound, which underwent benzannulations with benzynes to form
intriguing spirocyclic scaffolds.
nucleophiles.8 Upon the nucleophilicity of species II,9 the She
he formal [3 + 2] annulation of the umpoled β-acylvinyl
Tanionic synthon (I) with carbonyls constitutes a group9a realized the formal [3 + 2] annulation between alkynals
and β,γ-unsaturated α-ketoesters to butenolide products by
NHC/Lewis acid catalysis10 (Scheme 1, top). Independently,
Snyder shed light on the potential application of the allenoate
reactivity in a diastereoselective cycloisomerization to the
securinega family of alkaloids.9b Very recently, Du and Lu
reported the NHC/Lewis-acid-catalyzed annulation of alkynyl
aldehydes and isatins to spirooxindoles in moderate to good
yield.9c On the other hand, in 2010, we displayed that the
combination of NHCs and β-haloenals provided access to 3-
halogen-substituted homoenolates III (Scheme 1, bottom).11
After the reaction with a variety of electrophiles and subsequent
elimination of the halogen, a series of butenolides and
analogues were obtained. Thereafter, the groups of Ye, Jiao,
and Yao independently uncovered the formation of 2-halogen-
substituted homoenolates, which were easily transformed into
α,β-unsaturated acyl azoliums via tautomerization and halogen
elimination and thereby facilitated a set of fascinating cascade
reactions.12
promising approach for the construction of butenolide
scaffolds1,2 because this reaction enables formation of the
unsaturated five-membered ring and a stereogenic center in a
single-step process, which remarkably possesses the ability to
form spirocyclic frameworks with a butenolide moiety by using
cyclic ketone substrates (Scheme 1, middle).3
Scheme 1. NHC-Catalyzed Formal [3 + 2] Annulation of
Alkynals (Top) and 3-Bromoenals (Bottom) to Butenolides
Despite these advances, the development of efficient and
highly enantioselective methods through the [3 + 2] annulation
strategy involving the umpoled β-acylvinyl anionic synthon (I)
for the synthesis of spirocyclic butenolide products has
remained elusive.13 We herein wish to report an asymmetric
formal [3 + 2] annulation of aryl 3-bromoenals and isatins to
furnish spirooxindole−butenolides in excellent yield with high
enatioselectivity by hydrogen-bonding activation-assisted chiral
NHC catalysis.14
We initiated our studies by examining the reaction of 3-
bromoenal 1a and N-allyl-substituted isatin 2a in the presence
of NHC precursors C and stoichiometric base (Table 1). Upon
treatment with DBU (1.5 equiv), racemic spirooxindole−
butenolide 3a was isolated in 99% yield by using imidazolium
salt C1 as the NHC precursor (Table 1, entry 1). Therefore, a
Over the past decade, N-heterocyclic carbene (NHC)-
catalyzed umpolung reactions of aldehydes have become a
quickly growing field and have found a wide range of
applications in synthetic chemistry.4 Following the conceptual
studies of NHC-homoenolate formation reported by the groups
of Bode and Glorius,5,6 two sorts of Breslow-type species,7 II
and III, have been exploited as potential β-acylvinyl anionic
synthon equivalents. In 2006, Zeitler8a disclosed that the
addition of NHCs to alkynyl aldehydes resulted in the
generation of NHC-bound allenoate intermediates II, which
would be protonated and allowed the formation of α,β-
unsaturated acyl azoliums for further reactions with different
Received: August 10, 2014
© XXXX American Chemical Society
A
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Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of the Reaction
temp
yield
b
c
entry
C/base/solvent
C1/DBU/THF
(°C)
t (h)
(%)
er
1
2
0
−78
0
1
1
99
C2/DBU/THF
95
50:50
3
C3/DBU/THF
24
24
24
12
48
24
5
NR
NR
trace
90
4
C4/DBU/THF
0
5
C3/Cs2CO3/THF
C4/Cs2CO3/THF
C4/K2CO3/THF
C4/Li2CO3/THF
C4/Cs2CO3/THF
C4/Cs2CO3/dioxane
C4/Cs2CO3/DCM
C4/Cs2CO3/toluene
0
6
0
95:5
95:5
d
7
0
47(45)
trace
99
8
0
9
20
20
20
20
20
95:5
96:4
95:5
93:7
90:10
10
11
12
13
2.5
10
22
2
99
98
85
C4/Cs2CO3/DCM-tBuOH
(10:1)
99
a
Unless otherwise noted, reactions were conducted on a 0.2 mmol
a
Unless otherwise noted, 1 (0.4 mmol), 2 (0.2 mmol), C4 (10 mol
scale of 2a with 1a (0.4 mmol), catalyst C (10 mol %), and base (0.3
b
b
c
%), and Cs2CO3 (0.3 mmol) in solvent (4 mL) under N2. C1 as the
catalyst. Using 0.6 mmol of aldehydes at 40 °C. The yields are of the
isolated products. The er value is determined by chiral HPLC analysis.
mmol) in solvent (4 mL) under N2. Isolated yield. Determined by
c
d
chiral HPLC analysis. Recovery of 2a is in parentheses.
set of chiral azolium salts C2−C4 was tested to carry out this
reaction enantioselectively. Unfortunately, Rovis’s triazolium
catalyst C2,15 a common chiral catalysts in typical NHC-
homoenolate additions, was not suitable for this reaction and
afforded 3a as a racemic mixture even at −78 °C in 95% yield
(Table 1, entry 2). Moreover, C3 and its free hydroxyl
counterpart C4 could not yield any desired product with DBU
as the base (Table 1, entries 3 and 4).16 Switching DBU to
Cs2CO3, while C3 was still ineffective, the triazolium C4 gave
3a in 90% yield and 95:5 er at 0 °C after 12 h (Table 1, entries
5 and 6). Screening of inorganic bases revealed that Cs2CO3
was the best choice (Table 1, entries 6−8), suggesting that Cs+
ions might play some distinct role arising from the inherent
coordination ability to accelerate this reaction.17 Performing the
reaction at 20 °C or increasing the polarity of solvents could
accelerate this conversion (Table 1, entries 9−12). Never-
theless, the use of protic solvents resulted in a diminished er,
presumably due to erosion of the possible H-bonding between
the substrates and the free hydroxyl moiety of the catalyst C4
(Table 1, entry 11 vs 13).
With the optimized reaction conditions in hand, we explored
the scope of this transformation (Scheme 2). The reaction of 3-
bromoenal 1a proceeded smoothly for a wide scope of N-
substituted isatins 2 bearing a set of groups (−F, −Cl, −Br, and
−OMe) at different positions (4-, 5-, 6-, and 7-positions) of the
isatin scaffold and gave the corresponding products 3b−3g in
excellent yields and high enantioselectivities (94:6−96:4 er).
Electron-rich isatin (R2 = OMe) underwent the reaction slowly
and required extended reaction times (5.5 h) to yield 3d (91%,
95:5 er). Moreover, N-Bn- and N-Me-substituted isatins 2 were
also suitable for the outlined reaction, producing the desired
butenolides 3h (96:4 er) and 3i (94:6 er) in nearly quantitative
yield.
On the other hand, as shown in Scheme 2, the reaction of
isatin 2a with a variety of aryl β-bromoenals 1 bearing either
electron-withdrawing (−NO2) or electron-donating groups
(−OMe) at the para- or meta-position of benzene rings
occurred smoothly to furnish products 3k−3n in 91−99% yield
and 94:6 to 96:4 er. Although racemic 3j could be delivered in
99% yield by using the salt C1, enantioselective synthesis of 3j
was unsuccessful by chiral NHC catalyst C4, probably due to
the steric hindrance of the methyl group at the ortho-position. It
was found that the reaction rate of this process decreased with
increasing electron richness of the aldehyde substrates, and
elevated temperature (40 °C) was required to accomplish
conversions to 3m, 3o, and 3p, yet in high yields and
stereoinduction. The absolute configuration of the produced
stereocenter was unambiguously established by a single-crystal
X-ray analysis of 3b to be R. Notably, the optically pure product
3k (>99.5:0.5 er) could be obtained through a single
recrystallization from CH2Cl2/hexane in 83% yield. Never-
theless, alkyl-substituted bromoenals are not suitable substrates
to form the corresponding chiral products.
A proposed reaction pathway for this annulation is depicted
in Scheme 3. Initial addition of in situ generated NHC I to β-
bromoenal 1a and subsequent 1,2-H-migration would produce
Breslow-type intermediate II.18 Species II may undergo
nucleophilic addition to the ketone moiety of 2 presumably
through a postulated transition state of III, wherein the
substrate 2 (R = Me, R2 = H) could be activated and
approached to the enolate with its Si face because of potential
B
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Letter
In conclusion, we have reported an asymmetric NHC-
catalyzed formal [3 + 2] annulation of aryl 3-bromoenals and
isatins, giving rise to a set of chiral spirooxindole−butenolides
in excellent yield and high enantioselectivity. The resulting
butenolides are of potential synthetic interest as they can be
converted to various chiral spirocyclic scaffolds. This study
extends the synthetic potentiality of functionalized homoeno-
late azoliums in asymmetric catalytic synthesis.
Scheme 3. Proposed Reaction Pathway
ASSOCIATED CONTENT
* Supporting Information
■
S
X-ray crystallographic data of (R)-3b and (2R,3S)-4a;
experimental procedures and characterization data of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mcorg@zju.edu.cn.
Notes
hydrogen bonds and π−π stacking effects. Nevertheless, in view
of the distinguished positive effect of cesium carbonate as the
base, we assume that the Cs+ ion may be involved in III as a
Lewis acid to facilitate this conversion rather than a standby
cation. Carbon−carbon bond formation followed by proton
transfer would afford azolium IV along with the elimination of
bromide anions. Finally, base-prompted O-acylation would
occur to form the butenolide product 3i and regenerate the
NHC catalyst.
Treatment of N-allyl-substituted butenolides 3a and 3m with
a NaBH4/NiCl2 system19 afforded spirocyclic lactones 4a and
4m with almost complete transfer of chirality and excellent
diastereoselectivities (>21:1 dr) in good yields (eq 1). On the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from NSFC (21072166) and the Program for
New Century Excellent Talents in University is gratefully
acknowledged.
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