A Unified Catalytic Asymmetric (4+1) and (5+1) Annulation Strategy to Access Chiral Spirooxindole-Fused Oxacycles

Article abstract of DOI:10.1002/anie.202105282

A unified catalytic asymmetric (N+1) (N=4, 5) annulation reaction of oxindoles with bifunctional peroxides has been achieved in the presence of a chiral phase-transfer catalyst (PTC). This general strategy utilizes peroxides as unique bielectrophilic four- or five-atom synthons to participate in the C?C and the subsequent umpolung C?O bond-forming reactions with one-carbon unit nucleophiles, thus providing a distinct method to access the valuable chiral spirooxindole-tetrahydrofurans and -tetrahydropyrans with good yields and high enantioselectivities under mild conditions. DFT calculations were performed to rationalize the origin of high enantioselectivity. The gram-scale syntheses and synthetic utility of the resultant products were also demonstrated.

Full text of DOI:10.1002/anie.202105282

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How to cite:
International Edition: doi.org/10.1002/anie.202105282
German Edition: doi.org/10.1002/ange.202105282
Asymmetric Catalysis
A Unified Catalytic Asymmetric (4 + 1) and (5 + 1) Annulation
Strategy to Access Chiral Spirooxindole-Fused Oxacycles
Min Gao+, Yanshu Luo+, Qianlan Xu, Yukun Zhao, Xiangnan Gong, Yuanzhi Xia,* and
Lin Hu*
Abstract: A unified catalytic asymmetric (N + 1) (N = 4, 5)
annulation reaction of oxindoles with bifunctional peroxides
has been achieved in the presence of a chiral phase-transfer
catalyst (PTC). This general strategy utilizes peroxides as
unique bielectrophilic four- or five-atom synthons to partic-
ꢀ
ꢀ
ipate in the C C and the subsequent umpolung C O bond-
forming reactions with one-carbon unit nucleophiles, thus
providing a distinct method to access the valuable chiral
spirooxindole-tetrahydrofurans and -tetrahydropyrans with
good yields and high enantioselectivities under mild condi-
tions. DFT calculations were performed to rationalize the
origin of high enantioselectivity. The gram-scale syntheses and
synthetic utility of the resultant products were also demon-
strated.
Introduction
Optically active five and six-membered oxygenated
heterocycles are abundant in numerous biologically active
natural products and drugs.[1,2] Catalytic asymmetric annula-
tion reactions provide a powerful tool to access such scaffolds
in a single step. In this context, Pd or Lewis acid-catalyzed
(3 + 2) cycloadditions of carbonyl compounds with trimethy-
lenemethanes and donor-acceptor cyclopropanes are leading
strategies to access chiral tetrahydrofurans[3] (path a, Sche-
me 1A). In addition, Lewis acid or Brønsted acid-catalyzed
asymmetric (4 + 2) cycloadditions of carbonyl compounds
with 1,3-dienes provide another powerful tool for the syn-
thesis of chiral dihydropyrans with high enantioselectivity.[4]
Despite these achievements, the complementary catalytic
asymmetric (4 + 1) or (5 + 1) annulation reactions[5] featuring
the direct coupling of one-carbon unit nucleophiles with
[*] M. Gao,[+] Q. Xu, Y. Zhao, Prof. Dr. L. Hu
Chongqing Key Laboratory of Natural Product Synthesis and Drug
Research, School of Pharmaceutical Sciences, Chongqing University
Chongqing 401331 (China)
Scheme 1. Background and our synthetic strategy.
appropriate bifunctional electrophiles via new bond discon-
nections, however, remain underdeveloped (path b, Sche-
me 1A).
E-mail: lhu@cqu.edu.cn
X. Gong
Analytical and Testing Center, Chongqing University
Chongqing 401331 (China)
Y. Luo,[+] Prof. Dr. Y. Xia
College of Chemistry and Materials Engineering, Wenzhou University
Wenzhou 325035 (China)
E-mail: xyz@wzu.edu.cn
The enantioenriched spirooxindoles bearing five- or six-
membered oxacycle moieties are privileged scaffolds that
have been extensively investigated in the medicinal programs
for new drug development.[6] Many catalytic asymmetric (3 +
2) cyclization reactions have been reported for the prepara-
tion of chiral g-butyrolactone-based spirooxindoles in the
presence of N-heterocyclic carbene or other organocata-
lysts.[7] Surprisingly, few precedents are available for the
catalytic asymmetric synthesis of chiral tetrahydrofuran- or
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202105282.
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[15]
ꢀ
pyran-based spirocyclic systems (Scheme 1B). Recently, Trost
and Franz reported the Pd- and Lewis acid-catalyzed
asymmetric (3 + 2) cycloadditions of isatin with trifluorome-
thylallyl carbonate and allyl silane to access spirooxindole-
fused tetrahydrofurans with high enantioselectivities.[8] Tana-
ka and Feng described the Rh- and Lewis acid-catalyzed
asymmetric (4 + 2) cycloadditions of isatin with 2-alkynyl-
benzaldehydes and Danishefsky diene for the construction of
polarized O O bond are less reactive substrates. Actually,
compared to the well-documented catalytic asymmetric a-
hydroxylation and a-benzoyloxylation of reactive alkyl hy-
droperoxides[16,17] and benzoyl peroxides,[18] the similar cata-
lytic asymmetric a-alkoxylation of dialkyl peroxides has not
been reported yet.
chiral spirocyclic pyranones.[9] However, all these reactions Results and Discussion
required the use of specific 1,3- or 1,4-dipole equivalents as
substrates, thus rendering them only suitable for the prepa-
ration of individual five- or six-membered oxacycle products.
Herein, we report a unified catalytic asymmetric (N + 1) (N =
4, 5) annulation strategy for the general synthesis of chiral
spirooxindole-fused tetrahydrofurans and tetrahydropyrans
by employing simple oxindoles as one-carbon nucleophiles
and bifunctional peroxides as unique four- or five-atom
bielectrophiles under mild phase-transfer catalytic conditions.
Unlike previous cyclization methods, the critical ring-
Bearing these issues in mind, we commenced our inves-
tigation by exploring the reaction of N-Boc-oxindole 1a (Boc:
tert-butoxycarbonyl) with peroxide 2a[19] in the presence of
cinchona alkaloid-derived phase-transfer catalysts 5 and
CsOH base. Indeed, we noticed that the double C-alkylation
was the severe side reaction that needed to be addressed first,
as treatment of 1a with tert-butyl peroxide 2a at ꢀ208C
always produced compound 4 as the major product with
commonly used catalysts 5a–c (3:4 = 1:2, Table 1, entries 1–
3). Notably, catalyst 5d bearing a very bulky triphenyl moiety
could improve the ratio of the desired product 3; however, the
enantioselectivity was found to be very poor (Table 1,
entry 4). In spite of these difficulties, catalyst 5c still
generated the product 3 with 50% ee. This promising result
encouraged us to further investigate the influence of varying
the structure of peroxides on the reaction. We speculated that
ꢀ
closing C O bond in this protocol was constructed via
a umpolung approach.
Electrophilic reactivity of dialkyl peroxides towards
strong carbon nucleophiles such as organolithium and
Grignard reagents for the synthesis of ethers was well
known,[10] but exploiting such umpolung C O bond-forming
ꢀ
strategy for the construction of oxygen heterocycles has only
received less attention.[11,12] Dussault and co-workers first
reported two examples of cyclization reactions of tert-butyl 3-
iodopropyl and tert-butyl 3-iodobutyl peroxides with cyclo-
hexanone under the stronger KOtBu basic conditions[11a]
(Scheme 1C). Recently, our group also developed the general
(4 + 1) and (5 + 1) annulation reactions of b-keto esters and
other active methylene compounds with a wide range of
bifunctional peroxides bearing allylic halide appendages for
the synthesis of 2,2-disubstituted tetrahydrofurans and dihy-
dropyrans in the presence of KOH or Cs2CO3 base.[12]
However, application of such bielectrophilic peroxides to
the asymmetric catalytic annulation process has not been
realized so far.
ꢀ
peroxides possessing enhanced O O bond reactivity may
ꢀ
facilitate the critical ring-closing C O bond formation, thus in
turn improving the chemoselectivity of the reaction. In fact,
the structure of the peroxides had a significant impact on the
reaction. Peroxide 2b bearing a cumenyl group dramatically
improved the chemoselectivity to 5:1 (Table 1, entry 5). More
impressively, peroxides 2c–e bearing ketal moieties com-
pletely suppressed the side product 4. Peroxide 2e even
afforded the product 3 in 80% ee and 75% yield by using 5c
as a catalyst at ꢀ408C (3:4 > 20:1, Table 1, entries 6–9).
To further improve the enantioselectivity of the reaction,
we screened many other phase-transfer catalysts. We found
that incorporation of an amino acid subunit into the catalyst
significantly affected the outcomes of stereoselectivity (Ta-
ble 1, entries 10–14). For example, catalyst 5 f and 5g bearing
N-Boc-D- and L-valine moieties afforded 3 in 86% and 57%
ee, respectively, while catalyst 5i bearing less hindered glycine
structure only produced 3 in 30% ee.
The mild basic conditions of our protocol prompted us to
assemble the chiral spirooxindoles by selecting oxindoles as
one-carbon nucleophiles[13] via asymmetric phase-transfer
catalysis.[14] We envisioned that an intermolecular C C bond
ꢀ
formation, followed by a critical stereoselective intramolec-
ꢀ
ular C O bond formation from the chiral ion pair intermedi-
At this stage, other reaction parameters were then
evaluated. Using toluene or dichloromethane (DCM) as
solvent drastically decreased the ee of 3 (Table 1, entries 15–
16). Lowering the temperature to ꢀ608C led to freezing of the
50% aqueous solution of CsOH, thus product 3 was obtained
in lower ee and yield. Instead, 80% aqueous solution of CsOH
performed well at such cryogenic temperature and improved
the ee of 3 to 90%, albeit with a prolonged reaction time to
reach the full conversion (Table 1, entries 17–19). Mechanis-
tically, one molar of methoxide should be released from the
ate, would generate the chiral spirocyclic oxacycles in a single
step (Scheme 1D). Moreover, by devising the linkage of
peroxides as four- or five-atom components, this tandem
process could be facilely developed into the synthesis of chiral
spirooxindole-fused tetrahydrofurans and tetrahydropyrans
in a unified fashion. Although such design seems straightfor-
ward, several challenges are associated with this catalytic
asymmetric process. First, the competitive double intermo-
lecular C-alkylation or the O-alkylation pathways, which
could terminate the tandem process, are the primary con-
cerns. Second, whether high enantioselectivity could be
consistently obtained for the formation of oxacycles with
different ring size is quite uncertain. Third, dialkyl peroxides
possessing a sterically more hindered and electronically less
ꢀ
peroxy cyclohexyl ketal after the C O bond-forming step.
This in situ generated base should in turn deprotonate the
oxindole substrate for further annulation reaction; however,
the reaction conversion turned out to be low when reducing
the CsOH to 1.0 equivalent, and 3a was obtained in 35%
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Table 1: Optimization of the reaction conditions.
catalyst and 5.0 equiv of CsOH (80% aq.) as base in 5:1
Toluene/DCM co-solvent systems (Table 1, entry 23).
With the optimal conditions in hand, we first probed the
scope of oxindoles for the catalytic asymmetric (4 + 1)
annulation reactions. As shown in Table 2, a wide range of
Table 2: Substrate scope for (4 + 1) annulation reactions.[a]
entry substrates catalyst
T
[8C]
time 3:4[a]
[h]
yield of 3 ee of 3
[%][b]
[%][c]
Initial screening of catalysts
1
2
3
4
1a 2a
1a 2a
1a 2a
1a 2a
5a
5b
5c
5d
ꢀ20
8
1:2
1:2
1:2
2:1
30
25
31
43
24
34
50
8
ꢀ20 10
ꢀ20 12
ꢀ20
8
Impact of peroxide structures on the reaction
5
6
7
8
9
1a 2b
1a 2c
1a 2d
1a 2e
1a 2e
5c
5c
5c
5c
5c
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ40
4
4
4
4
8
5:1
45
61
63
78
75
63
66
68
74
80
>20:1
>20:1
>20:1
>20:1
Further screening of catalysts
10
11
12
13
14
1a 2e
1a 2e
1a 2e
1a 2e
1a 2e
5e
5 f
5g
5h
5i
ꢀ40
ꢀ40
ꢀ40
ꢀ40
8
8
8
8
>20:1
>20:1
>20:1
>20:1
71
70
73
42
33
81
86
57
64
30
ꢀ40 12 >20:1
Optimization of other reaction parameters
15
16
17
18
19
20
21
22
23
1a 2e
1a 2e
1a 2e
1a 2e
1a 2e
1a 2e
1aa 2e
1ab 2e
1a 2e
5 f
5 f
5 f
5 f
5 f
5 f
5 f
5 f
5 f
ꢀ40
8
7
>20:1
>20:1
48
45
50
53
64
35
23
/
64[d]
19[e]
75
ꢀ40
[a] Reaction conditions: 1 (0.2 mmol), 2e (0.24 mmol), catalyst 5 f
(10 mol%), and 80% aq. CsOH (1.0 mmol) in 2.0 mL solvent. [b] 0.05 M
reaction solution. [c] The absolute configuration was determined to be R;
see the Supporting Information for details.
ꢀ60 10 >20:1
ꢀ60
4
>20:1
76[f]
90[g]
90[g,h]
42[g]
ꢀ60 16 >20:1
ꢀ60 36 >20:1
ꢀ60 15 >20:1
[i]
ꢀ60 36
/
/
N-Boc-oxindoles performed well in this reaction (65–85%
yield, 86–93% ee). 5-Substituted substrates bearing either
electron-donating or electron-withdrawing groups on the
phenyl ring uneventfully afforded the products with more
than 90% ee (Table 2, 3a–h). Notably, substrate 1i bearing
ꢀ60 16 >20:1
76
90[g,j]
[a] Determined by 1H NMR. [b] Isolated yield. [c] Determined by chiral
HPLC. [d] Toluene as solvent (low solubility for 5 f). [e] DCM as solvent.
[f] Solid CsOH. [g] 80% aq. CsOH. [h] 1.0 equiv of 80% aq. CsOH.
[i]<10 conversion. [j] 1.2 equiv of 2.
a
strongly electron-donating N,N-dimethylamino group,
which appears to be sensitive to the peroxide reagent, was
still compatible with current conditions and provided the
product 3i in 85% yield and 87% ee. Moreover, substrates
bearing different 4-, and 6-substitutents on the phenyl ring
had slightly influence on the reaction, also consistently
affording the spirocyclic tetrahydrofuran products with good
yields and high enantioselectivities (Table 2, 3j–p).
Next, we found the catalytic asymmetric (4 + 1) annula-
tions could also be applied to the substituted allyl peroxides 6
(Table 3). Under the identical conditions, a range of optically
active spirocyclic tetrahydrofurans including the challenging
tetrasubstituted olefin-containing products, which were diffi-
cult to access from the existing methods, could be directly
prepared with high enantioselectivities. Peroxide substrates
bearing dialkyl and diaryl groups on the terminal olefinic
yield and 90% ee (Table 1, entry 20). Next, oxindole sub-
strates bearing other types of protecting groups such as
benzyloxycarbony (Cbz) and benzyl (Bn) groups were
examined (Table 1, entries 21–22). A severe hydrolysis side
reaction of Cbz-protected substrate 1aa was observed under
the basic conditions, thus leading to much lower yield and ee
of 3, while the Bn-protected substrate 1ab was found to be
less reactive and almost no reaction happened at ꢀ608C.
Upon further optimization (see the Supporting Information
for details), we finally identified the optimal conditions by
conducting the reaction of Boc-protected oxindole 1a and
peroxide 2e (1.2 equiv) at ꢀ608C by using 10 mol% of 5 f as
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Table 3: Substrate scope for peroxides.
Table 4: Substrate scope for (5+1) annulation reactions.
[a] 0.05 M reaction solution. [b] 1:3 E/Z mixture of peroxides was used.
[c] 1:1 E/Z mixture of peroxides was used.
carbon were well tolerated and generally afforded the
products with more than 90% ee (Table 3, 7a–g). In the cases
of 6 f–h, a pair of E/Z peroxides, which were prepared from
the corresponding 1,4-diol precursors as mixtures, could be
directly used for the reaction. The geometry of the double
bond had no noticeable impact on the stereoselectivity of the
reaction (Table 3, 7 f–i). It should be noted that products 7 f
and 7g could be separated as pure forms by simple
chromatography after the reaction. Meanwhile, oxindoles
with substituents at different positions (e.g., 5-Me, 5-MeO, 6-
F) were also compatible for the reaction, which furnished the
corresponding products with good yields and high enantiose-
lectivities (Table 3, 7j–l).
[a] The absolute configuration was determined to be R; see the
Supporting Information for details. [b] 2.0 equivalents of 80% aq. CsOH
were used. [c] 4-bromo-but-2-enyl peroxide was used. [d] 1:3 E/Z mixture
of peroxides was used.
Encouraged by the generality of the reaction, we decided
to expand the above protocol to the (5 + 1) annulation
process. Accordingly, we reinvestigated the catalytic asym-
metric reactions by searching suitable five-atom bielectro-
philic peroxide partners. After extensive experiments, we
found that peroxides 8 bearing benzylic functionality could
cyclize with 1 under the established conditions of the (4 + 1)
process (Table 4). More importantly, a range of oxindole and
peroxide substrates, regardless of the positions and electronic
properties of substituents on each phenyl ring, were well
tolerated for this new (5 + 1) process and successfully
afforded the structurally diverse spirooxindole-tetrahydro-
pyrans 9a–o with high enantioselectivities (Table 4, 85–94%
ee). For example, the interesting tetrafluorophenyl product 9l
as well as the hybrid products 9n,o could be efficiently
generated over 90% ee (Table 4, 9l–o). Meanwhile, other
alkyl substituted bifunctional peroxides were also tested for
current (5 + 1) annulations. We found that 4-bromo-but-2-
enyl peroxides provided better results than the corresponding
iodides. However, the spirooxindole products 9p–s were
generated in moderate enantioselectivities (Table 4, 60–79%
ee). It had to be mentioned that considerable amounts of
double C-alkylation side products were still inevitably formed
in these (5 + 1) reactions, thus giving relatively lower yields of
the desired products compared to the (4 + 1) ones.
To explore the practicality of the newly developed
reaction, scalable (4 + 1) and (5 + 1) annulations of peroxides
2e and 8a were examined under the standard conditions. As
shown in Scheme 2, both processes still performed well at
around 5 mmol scale, affording products 3a and 9a without
noticeable drop of the yields. Interestingly, the enantioselec-
tivity of (5 + 1) process was even improved at large scale.
Owing to the synthetic versatility of the olefin and
carbonyl functionalities, chiral spirocyclic oxacycles prepared
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Scheme 2. Scale-up synthesis and derivatization.
from current method are valuable building blocks for further
transformations. As shown in Scheme 2, compound 3a was
readily converted into chiral 2,2-disubstituted tetrahydrofur-
an 10 in 98% yield and 92% ee by a single step of hydrolysis in
methanol. Similarly, treatment of 3a with CrO3 in DCM
readily furnished the g-lactone 11 in 60% yield and 90% ee.
This spirooxindole-g-butyrolactone compound has been used
as a potent anticancer agent.[6b] Meanwhile, the double bond
in the above products provides an additional handle for
structural variations. For example, compound 3a could be
stereoselectively hydrogenated or oxidized by meta-chloro-
perbenzoic acid (m-CPBA) to give compound 12 and the rigid
bis-spirocyclic epoxide 13 in 5:1 and 6:1 dr, respectively. The
relative configurations of these compounds were unambigu-
ously confirmed by the nuclear Overhauser effect (NOE)
analysis (see the Supporting Information for details).
Finally, to gain insights about this annulation process, we
conducted the following control experiments (Scheme 3A).
We found that adding 1.0 equivalent of 2,2,6,6-tetramethylpi-
peridine 1-oxyl (TEMPO) as radical scavenger to the reaction
mixture of 1a and 6b did not affect the yield and ee of product
7b markedly under the standard conditions. Meanwhile, we
could detect and isolate the C-alkylation intermediate 14 at
the early stage of the reaction. After resubmitting this
intermediate to the standard conditions, the final product
7b was obtained in 73% yield and 81% ee. These data
indicated that the current catalytic annulations probably
Scheme 3. Mechanistic investigations.
gen-bonding between the N-H moiety and the substrate
played an important role in this enhancement, we prepared
the catalyst 5j by replacing the Boc-N-H moiety in 5 f with
Boc-N-Me structure. Under the same conditions as 5 f, this
catalyst promoted the reaction of 1a and 2e in 80% ee
(Scheme 3C). We also synthesized the catalyst 5k bearing two
identical methyl groups on the nitrogen atom. Interestingly,
this new catalyst performed as equally well as the optimal
catalyst 5 f (3a: 89% ee vs. 90% ee). These data implied that
the hydrogen-bonding might not involve in the stereo-
determining transition state. More importantly, we obtained
the X-ray crystal structure of catalyst 5 f, in which the N-H
moiety is far away from the open face of the cinchonium salt
wherein the reaction is most likely to happen. On the basis of
these results, we justified that an additional hydrogen-bond
interaction between the catalyst and substrate could be
reasonably ruled out.
The crystal structure of 5 f also provides insightful
information to rationalize the plausible transition state of
5 f-catalyzed annulation reactions. For chiral quaternary
ammonium salts catalyzed asymmetric phase-transfer reac-
tions, the catalytic efficiency essentially hinges on how the
three of the catalystꢀs tetrahedral faces surrounding the
cationic nitrogen center could be effectively blocked and
while one face is adequately left open for the substrate
docking.[20] As exhibited in Scheme 3D, three tetrahedral
faces in cinchonium salt 5 f, namely C12-C18-C20, C11-C12-C18,
ꢀ
ꢀ
proceeded via a C C ! C O bond-forming sequence,
wherein both bonds were more likely formed via a nucleo-
philic substitution mechanism instead of a radical pathway.
As shown in Table 1, incorporation of a D-N-Boc-valine
subunit into the catalyst 5 f significantly improved the
enantioselectivity of the reaction. To elucidate if a hydro-
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and C11-C18-C20, are sufficiently shielded by the quinuclidine
comparison, an intermolecular a-alkoxylation reaction of 3-
backbone, the naphthalene ring, and the quinoline/ isopropyl/
vinyl components, respectively. Only the C11-C12-C20 face is
accessible for the enolate of C-alkylation intermediate to
approach. The remarkable features of this open face include
a nearly co-planar quinoline and naphthalene rings with
respect to the C11-C21 axis and a rigid quinuclidine backbone
beneath the aryl plane. The isopropyl and N-Boc segments of
D-valine subunit reside at the rear of the quinoline and
allyl oxindole 15 and dialkyl peroxide 16 was conducted under
the similar catalytic conditions, but no reaction occurred at all
(Scheme 3B). This result again proved that catalytic asym-
metric a-alkoxylation of dialkyl peroxides is rather different
from the well-established a-hydroxylation and a-benzoylox-
ylation reactions of reactive hydroperoxides and peresters.
naphthalene rings, respectively. This spacial arrangement Conclusion
provides a well-defined pocket to execute the chiral recog-
nition of the approaching enolate. Moreover, detailed two-
dimensional NMR experiments revealed that catalyst 5 f
adopted the similar conformation in solution (see the
Supporting Information for details).
To better understand the origin of high enantioselectivity
of the 5 f-catalyzed annulation reactions, density functional
In summary, we have developed a unified phase-transfer-
catalyzed asymmetric (N + 1) (N = 4, 5) annulation reaction
of oxindoles with various peroxide bielectrophiles, giving rise
to a wide range of chiral spirooxindole-tetrahydrofurans and
-tetrahydropyrans with good yields and high enantioselectiv-
ities. This general (N + 1) annulation strategy utilized 2-
iodomethylallyl and 2-iodomethylbenzyl peroxides as unique
four- and five-atom umpoled synthons to construct the critical
ꢀ
theory (DFT) calculations were conducted to analyze the C
O bond-forming transition states leading to compound 7a.[21]
As shown in Figure 1, the transition state TS-S that derives
from the si face attack of the oxindolyl enolate by peroxide
would give an (S)-configurated product 7a. The TS-R that is
from the re face attack would yield an (R)-enantiomer. It was
found that the TS-S (13.7 kcalmolꢀ1) was energetically
disfavored due to the steric repulsion between the substrateꢀs
bulky cyclohexyl ketal moiety and the catalystꢀs quinoline
ring, while the TS-R (11.5 kcalmolꢀ1) was more favorable by
placing the bulky peroxy ketal group and various olefinic
substituents at the open naphthalene side. The calculated
energy difference between the two transition states was
2.2 kcalmolꢀ1, which was in line with the experimental
observations of 5 f-catalyzed reactions that generated the
products with R absolute configuration and high enantiose-
lectivity.
ꢀ
ring-closing C O bond via an electrophilic alkoxylation
approach, thus providing a simple and distinct method for
the synthesis of chiral five- and six-membered oxacycles
under mild conditions. A plausible transition state model was
proposed to rationalize the origin of high enantioselectivity of
the reaction based on the DFT calculations. Meanwhile, the
gram-scale synthesis and the flexible transformations of the
resultant spirooxindole-oxacycle products into other biolog-
ically important chiral scaffolds such as highly functionalized
tetrahydrofurans and g-butyrolactones in one step were also
demonstrated.
Acknowledgements
An extra merit of catalyst 5 f is noteworthy to mention.
There could be a favorable entropic effect, which was
endowed by the structurally well-defined chiral pocket of
Financial support from NSFC (21871032 and 21873074), the
Natural Science Foundation of Chongqing (cstc2020jcyj-
msxmX0520), the Fundamental Research Funds for Central
Universities (2020CDJ-LHZZ-007), and the Venture &
Innovation Support Program for Chongqing Overseas Re-
turnees (cx2020080) is acknowledged.
ꢀ
the catalyst 5 f, to facilitate the formation of the C O bond by
reducing the motion of the structured enolate when lining up
[20b]
ꢀ
with the antibonding s* orbital of the O O bond.
For
Conflict of Interest
The authors declare no conflict of interest.
Keywords: annulation reaction · organocatalysis ·
oxygen heterocycles · peroxides · umpolung reaction
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Figure 1. DFT calculated geometries and relative free energies of the
ꢀ
C O bond-forming transition states (for clarity, hydrogen atoms are
omitted).[21]
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[21] Calculations were done at the (SMD)M06/6–311 + G(d,p)//
B3LYP/6-31G(d) level of theory. More details are given in the
Supporting Information.
Cambridge Crystallographic Data Centre and Fachinforma-
tionszentrum Karlsruhe Access Structures service.
[22] Deposition numbers 2034242 (for 3h), 2034243 (for 9h), and
2051539 (for 5f) contain the supplementary crystallographic data
for this paper. These data are provided free of charge by the joint
Manuscript received: April 18, 2021
Revised manuscript received: June 10, 2021
Accepted manuscript online: June 23, 2021
Version of record online: && &&
,
&&&&
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These are not the final page numbers!

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Research Articles
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Research Articles
Asymmetric Catalysis
M. Gao, Y. Luo, Q. Xu, Y. Zhao, X. Gong,
Y. Xia,* L. Hu*
&&&& — &&&&
A Unified Catalytic Asymmetric (4+1)
and (5+1) Annulation Strategy to Access
Chiral Spirooxindole-Fused Oxacycles
Peroxides, which function as umpoled
bielectrophilic synthons, enable the uni-
fied catalytic asymmetric (4+1) and (5+
1) annulation reactions in the presence of
a phase-transfer catalyst (PTC). This new
strategy provides an unconventional
protocol to access the biologically
important chiral spirooxindole-tetrahy-
drofurans and -tetrahydropyrans in good
yields and high enantioselectivities (up to
94% ee).
&&&&
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ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 10
These are not the final page numbers!