Organocatalytic Remote Asymmetric Inverse-Electron-Demand Oxa-Diels-Alder Reaction of Allyl Ketones with Isatin-Derived Unsaturated Keto Esters

Article abstract of DOI:10.1002/adsc.202001242

A remote cascade asymmetric inverse-electron-demand oxa-Diels-Alder reaction of allyl ketones with isatin-derived β,γ-unsaturated α-keto esters has been developed in the presence of a chiral bifunctional squaramide catalyst. Taking advantage of the secondary amide activating group, a series of enantioenriched 3,4’-pyranyl spirooxindole derivatives bearing three contiguous chiral centers were attained in high yields (84 to >99%) with excellent enantioselectivities (96–99% ee). Moreover, the gram-scale synthesis and the construction of 1-benzazepine scaffold by the product were also demonstrated. (Figure presented.).

Full text of DOI:10.1002/adsc.202001242

Title: Organocatalytic Remote Asymmetric Inverse-Electron-Demand
Oxa-Diels−Alder Reaction of Allyl Ketones with Isatin-Derived
Unsaturated Keto Esters
Authors: Ye Lin, Xi-Qiang Hou, Bing-Yu Li, and Da-Ming Du
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001242
Link to VoR: https://doi.org/10.1002/adsc.202001242

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalytic Remote Asymmetric Inverse-Electron-Demand
Oxa-Diels−Alder Reaction of Allyl Ketones with Isatin-Derived
Unsaturated Keto Esters
Ye Lin,a Xi-Qiang Hou,a Bing-Yu Lia and Da-Ming Dua*
a
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, 5 South Zhongguancun Street,
Beijing 100081, People’s Republic of China. Fax: (+86)-10-68914985; E-mail: dudm@bit.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A remote cascade asymmetric inverse-electron- excellent enantioselectivity (96−99% ee). Moreover, the
demand oxa-Diels−Alder reaction of allyl ketones with gram-scale synthesis and the construction of 1-benzazepine
isatin-derived β,γ-unsaturated α-keto esters has been scaffold by the product were also demonstrated.
developed in the presence of
a chiral bifunctional
squaramide catalyst. Taking advantage of the secondary
amide activating group, a series of enantioenriched 3,4’-
pyranyl spirooxindole derivatives bearing three contiguous
chiral centers were attained in high yields (84 to >99%) with
Keywords: Asymmetric catalysis; Benzazepines; Inverse-
electron-demand oxa-Diels−Alder reaction; Spirooxindoles;
Squaramide
unsaturated C–C double bond and C–O double bond
participated in the bond forming reactions, leading to
the construction of 3,4’-pyranyl spirooxindole
Introduction
Spirooxindoles are intriguing synthetic targets in structures. Specifically, the isatin-derived β,γ-
organic and medicinal chemistry owing to their wide unsaturated α-keto esters were served as C3 synthon
spectrum of biological and pharmacological by reaction with bisnucleophiles (Nu–Nu) to facilitate
activities.[1] In particular, 3,4’-pyranyl spirooxindoles the synthesis of 3,4’-pyranyl spirooxindoles (Scheme
with multiple stereocenters have been proven to be a 1a). Although these substantial advances have been
privileged skeleton in a variety of natural products achieved, the novel reaction modes of isatin-derived
and pharmaceutical molecules that possess important β,γ-unsaturated α-keto esters have not been developed
biological activities, such as p38α inhibitor,[2b] and there is still some room to explore them in depth.
antibacterial agent[2c] and trigolutes A–D[2a,d] (Figure
1). Accordingly, considerable efforts have been
devoted to exploit highly efficient methods for the
construction of diverse 3,4’-pyranyl spirooxindole
scaffolds,[3] especially in an asymmetric manner.[4–6]
However, the great majority of the reported protocols
mainly focus on Michael/cyclization of dicyano
alkylidene oxindoles[4] and Michael/hemiketalization
of isatin-derived β,γ-unsaturated α-keto esters.[5] By
contrast, the novel and elegant strategies for
enantioselective
synthesis
of
3,4’-pyranyl
spirooxindoles remain limited as yet and some of
these methods are associated with limitations of low
synthetic efficiency and stereoselectivity.[6] In this
context, it is strongly desired to develop simple and
practical synthetic methodologies for the efficient
Figure 1. Representative examples of biologically active
pyranyl spirooxindoles.
construction
of
enantioenriched
3,4’-pyranyl
On the other hand, catalytic asymmetric inverse-
electron-demand hetero-Diels−Alder (IEDHDA)
reactions have emerged as a powerful strategy for
accessing optically active six-membered heterocycles
especially pyran frameworks, which are a fertile
source of pharmacologically active scaffolds
spirooxindole scaffolds, yet an extreme challenge.
Isatin-derived β,γ-unsaturated α-keto esters
possessing multiple reactive sites have been
successfully developed as efficient synthons to
construct 3,4’-pyranyl spirooxindole frameworks.
Currently, in the existing modes of reaction, [5] the exo
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
andnaturally occurring molecules.[7] On this account,
a vast number of the asymmetric IEDHDA reactions
have been investigated and various efficient creative
substrates or intermediates possessing IEDHDA
reactive activity, such as ketenes,[8] dienamines,[9]
aldehydes,[10] enamines,[11] enolates,[12] and enol
ethers[13] have been extensively exploited to deliver
various chiral six-membered heterocycles. Recently,
the allyl ketones which widely applied to α- or γ-
selective Michael additions or aldol reactions,[14] have
been successfully utilized in a remote asymmetric
inverse-electron-demand (IED) oxa-Diels−Alder
reaction for construction of pyran skeletons.[15]
Nowadays, the development of asymmetric remote
activation via organocatalysis is still a challenging
research topic in the area of organic synthesis because
of the long distance from the activated site (γ- or η-
site) to the chiral center of the catalyst.
Figure 2 Screened bifunctional squaramide catalysts.
Table 1. Screening of organocatalysts and optimization of
the reaction conditions [a]
Time Yield[b]
ee[d]
[%]
Entry Solvent Cat.
dr[c]
[min]
[%]
2
1
CH2Cl2 C1
CH2Cl2 C2
CH2Cl2 C3
CH2Cl2 C4
CH2Cl2 C5
CH2Cl2 C6
CH2Cl2 C7
CH2Cl2 C8
CH2Cl2 C9
93
94
91
96
90
96
92
93
94
95
97
94
91
96
96
95
96
95
16:1
7:1
95
95
94
96
94
95
92
71
-94
88
87
89
60
76
95
95
99
99
2
2
2
3
16:1
>20:1
9:1
2
4
2
5
2
19:1
10:1
5:1
6
Scheme 1 Strategies for the construction of 3,4’-pyranyl
spriooxindole scaffolds
2
7
2
8
Based on this background, as a part of our ongoing
study on bifunctional squaramide organocatalytic
asymmetric cascade strategy on the construction of
spirooxindole scaffolds, we report the remote
asymmetric IED oxa-Diels−Alder reaction of allyl
ketones with isatin-derived β,γ-unsaturated α-keto
esters, which could afford a series of highly
functionalized 3,4’-pyranyl spirooxindoles with three
contiguous chiral carbon centers by using a chiral
squaramide catalyst (Scheme 1b).
2
10:1
9:1
9
5
10
CHCl3
DCE
C4
C4
C4
5
4:1
11
5
PhMe
7:1
12
25
20
5
CH3CN C4
THF C4
5:1
13
5.3:1
19:1
8:1
14
15[e]
16[f]
17[g] CH2Cl2
18[h] CH2Cl2
CH2Cl2 C4
2
CH2Cl2 C4
15
15
C4
C4
>20:1
>20:1
Results and Discussion
[a]
Unless otherwise specified, reactions were carried out
with 1a (0.1 mmol), 2a (0.12 mmol), and catalyst (5
mol %) in solvent (1.0 mL) at room temperature.
Initially, we chose isatin-derived β,γ-unsaturated α-
keto ester 1a and phenyl allyl ketone 2a as the model
substrates in the presence of 5 mol % quinine-derived
squaramide C1 to test the feasibility. To our delight,
the reaction proceeded efficiently to afford the desired
β,γ-regioselective IED oxa-DA cycloadduct 3aa in
excellent yield (93%) and enantioselectivity (95% ee),
albeit with good diastereoselectivity (16:1 dr), when
the dichloromethane (DCM) was used as solvent at
room temperature within 2 minutes (Table 1, entry 1).
To further improve the stereoselectivity, a series of
bifunctional squaramide catalysts C2−C9 (Figure 2)
were subsequently investigated, and the results are
outlined in Table 1. A similar result was acquired
with catalyst C3, while catalysts C2, C5 and C7 gave
[b] Isolated yields.
Determined by 1H NMR analysis.
[c]
[d] Determined by chiral HPLC analysis.
[e] 2.5 mol % catalyst was used.
[f] 10 mol % catalyst was used.
[g] The reaction was performed at 0 °C.
[h] The reaction was performed at −20 °C.
worse reaction outcomes affording product 3aa with
lowerdiastereoselectivities (Table 1, entries 2, 5 and
7). The diastereoselectivity could be improved to 19:1
in the presence of catalyst C6 (Table 1, entry 6).
However, cyclohexanediamine-derived squaramide
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
catalyst C8 furnished 3aa with a significantly
decreased stereoselctivity (5:1 dr, 71% ee). The
pseudo-enantiomer catalyst C9 led to maintained
yield and enantioselectivity, but slightly decreased
diastereoselectivity (Table 1, entry 9). Among these
cinchona alkaloid-derived squaramides, squaramide
C4 gave the best result affording product 3aa in 96%
yield with excellent diastereo- and enantioselectivity
(>20:1 dr, 96% ee, Table 1, entry 4). Moreover,
several thiourea catalysts were also screened and the
diastereoselectivity declined significantly albeit with
higher enantioselectivity (for details, see the
Supporting Information). Accordingly, catalyst C4
was evaluated as the optimal catalyst for further
studies. A survey of the solvent effect showed the
reaction media had a tremendous impact on the
reaction activity and efficiency. Among chloroform,
1,2-dichloroethane (DCE), toluene, tetrahydrofuran
(THF) and acetonitrile, DCM remained the suitable
solvent (Table 1, entries 10−14). Subsequently, no
improvements were obtained when we tested the
effect of catalyst loading with increasing to 10 mol %
and reducing to 2.5 mol % respectively (Table 1,
entries 15 and 16). Striving as much as possible to
further improve the enantioselectivity, lower reaction
temperature was evaluated. To our delight, an
improvement in enantioselectivity (99% ee) was
achieved when the temperature was lowered to 0 °C
(Table 1, entry 17). Further reducing the temperature
to −20 °C, the outcome was unchanged.
With the optimum reaction conditions established,
we then commenced to probe the substrate scope and
limitation of this reaction. As summarized in Table 2,
a variety of isatin-derived β,γ-unsaturated α-keto
esters 1 with different N-protected groups were firstly
tested under the optimized conditions. It was found
that the diastereoselectivity slightly declined when the
N-protected groups of isatin-derived β,γ-unsaturated
α-keto esters were alkyl substituents or without the
substituent (Table 2, 3ba, 3ca and 3fa). There was no
reaction for the N-Boc protected substrate 1e,
probably due to the electronic equalization of
unsaturated bond. Subsequently, various isatin-
derived β,γ-unsaturated α-keto esters 1 with halogens
and electron-donating substituents at the 5-, 6-, or 5,7-
position on the oxindole ring also participated in the
reaction, and the reaction could facilely afford their
corresponding products 3ga−3ma in high yields (84
to >99%) with excellent stereoselectivities (>20:1 dr,
97−99% ee). Besides, isatin-derived β,γ-unsaturated
α-keto ester 1n was also well tolerated and gave the
desired product 3na in high yield (90%) and excellent
enantioselectivity (96% ee), but slightly decreased
diasteroselectivity (16:1 dr).
[a] Reaction conditions: 1 (0.10 mmol), 2a (0.12 mmol), and
catalyst C4 (5 mol %) in CH2Cl2 (1.0 mL) were stirred at
0 ℃ for 15 min. The dr and ee values were determined by
1H NMR and HPLC anslysis, respectively.
[b] No reaction
To further explore the generality of this reaction,
structurally diverse allyl ketones 2 were examined
under the standard conditions by reacting with 1a. As
shown in Table 3, it appeared that the reaction could
proceed smoothly to generate the corresponding
products 3 in high yields (90−98%) with consistently
excellent stereoselectivities (>20:1 dr, 98−99% ee) in
almost all case, regardless of the electronic and steric
properties of the substituents. Methyl, methoxy,
fluoro, chloro, and bromo substituents on the phenyl
ring in 2b−2e and 2g−2i, were all compatible in this
IED oxa-Diels−Alder, affording the corresponding
products in high levels of yield and stereoselectivity.
Also, 2j with a sterically bulky 2-naphthalene moiety
worked well to give the 3,4’-pyranyl spirooxindole
3aj in high yield (96%) with excellent diastereo- and
enantioselectivitie (>20:1 dr, 98% ee). As a scope
limiting issue, when the substituent R4 or R5 was alkyl,
only trace reaction was observed in spite of extending
reaction time to 48 h, indicating the lower reactivity
of substrates 2f and 2k. We attempted to synthesize
the allyl ketones with a vinyl phenyl substitution and
could only successfully synthesize (3E,5E)-1,6-
diphenylhexa-3,5-dien-1-one 2l with R4 as a vinyl
Table 2. Substrate scope of isatin-derived β,γ-unsaturated
α-keto esters 1b–1n.[a]
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
phenyl group. However, the substrate was unable to
react with 1a. The stereoscopic configuration of this
reaction product 3ai was unambiguously identified on
the basis of single-crystal X-ray diffraction analysis
as (2'R, 3S, 3'S) (Figure 3).[16] And the
stereochemistry of the other products was tentatively
assigned by analogy to 3ai.
Table 3. Substrate scope of allyl ketones 2b–2k.[a]
Figure 3. X-ray structure of 3ai (another two symmetric
molecules and one ethyl acetate molecule are omitted for
clarity).
To demonstrate the potential utility of the
above methodology, a gram-scale reaction of 1f
and 2a was carried out under the standard
conditions. As exemplified in Scheme 2a, the
desired 3,4’-pyranyl spirooxindole 3fa could be
obtained in 93% yield with 18:1 dr and 99% ee,
which indicated this present strategy shows
promising prospects for mass production.
Remarkably, an elegant derivatization of 3fa into
1-benzazepine 5fa was developed because of the
prevalent presence of 1-benzazepine motifs in
various biologically active molecules.[17] As
illustrated in Scheme 2b, the N-unprotected
spirocyclic oxindole 3fa could be easily
transferred to Boc-protected spirocyclic oxindole
4fa in 90% yield. Inspired by previous studies on
the further transformations of spirooxindoles,[6c,18]
the structurally complex enantioenriched 1-
benzazepine derivative 5fa with bridge ring could
be facilely delivered in 98% yield with 18:1 dr
and 97% ee by treatment of isolated 4fa with
conc. HCl in MeOH at 80
℃ (for details, see the
Supporting Information). And then in the
presence of AcOH and 4-bromophenylhydrazine
hydrochloride under reflux reactions, 5fa could be
conveniently transformed into 6fa in moderate
yield (Scheme 2c).
In addition, to further validate the synthetic
utility of this protocol, the 3,4’-pyranyl
spirooxindole 3aa was reduced to corresponding
product 6aa by treating with NaBH4 in MeOH at
[a] Reaction conditions: 1a (0.10 mmol), 2 (0.12 mmol), and
catalyst C4 (5 mol %) in CH2Cl2 (1.0 mL) were stirred at
0 ℃ for 15 min. The dr and ee values were determined by
1H NMR and HPLC anslysis, respectively.
[b] Reaction performed for 48 h.
[c] No reaction occurred.
0
℃
. Without further purification, the 6aa reacted
with p-toluenesulfonic acid (TsOH·H2O) in
toluene at 80 , and the 6:1 E/Z geometric isomer
℃
7aa was obtained in 64% yield for the two steps
without sacrifice of the enantioselectivity
(Scheme 2d). Unfortunately, the expected
transesterification product 7aa’ was not observed
(for details, see the Supporting Information).
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
In conclusion, we have successfully developed a
highly efficient method to synthesize chiral 3,4’-
pyranyl spirooxindoles via remote cascade
asymmetric
inverse-electron-demand
oxa-
Diels−Alder reactions of allyl ketones with isatin-
derived β,γ-unsaturated α-keto esters. By using
bifunctional squaramide catalyst,
a
series of
structurally diverse 3,4’-pyranyl spirooxindoles could
be obtained in high yields (up to >99%) with
excellent stereoselectivities (up to >20:1 dr, 99% ee).
In addition, the potential utility of this methodology
has been demonstrated by gram-scale synthesis and
further transformations. Remarkably, the bioactive 1-
benzazepine motif has been facilely construted by
derivatization reaction.
Experimental Section
General Methods
Commercially available compounds were used without
further purification. Solvents were dried according to
standard procedures. Column chromatography was
performed with silica gel (200-300 mesh). Melting points
were determined with an XT-4 melting-point apparatus and
are uncorrected. 1H NMR spectra were measured with
Bruker Ascend 400 MHz spectrometer in CDCl3, chemical
Scheme 2 Further investigation of the potential utility
of the reaction.
shifts were reported in
δ (ppm) units relative to
tetramethylsilane (TMS) as the internal standard. 13C NMR
spectra were measured at 100 MHz (Bruker Ascend 400
MHz spectrometer), chemical shifts were reported in ppm
relative to TMS with the solvent resonance as internal
standard (CDCl3 at 77.00 ppm). 19F NMR spectra were
measured at 377 MHz (Bruker Ascend 400 MHz
spectrometer). Proton coupling patterns are described as
broad (br) singlet (s), doublet (d), triplet (t), quartet (q) and
multiplet (m). High resolution mass spectra were measured
with an Agilent 6520 Accurate-Mass-Q-TOF MS system
equipped with an electrospray ionization (ESI) source.
Enantiomeric excesses were determined by chiral HPLC
analysis using an Agilent 1200 LC instrument with a
Daicel Chiralpak IA, IC or AD-H column.
Finally, on the basis of the absolute configuration
of the major isomer 3aa and the literature reports,[5a,19]
a plausible transition-state model was tentatively
proposed to account for the stereoselectivity. As
depicted in Scheme 3, the substrates are
synergistically activated by the squaramide C4
through the deprotonation of allyl ketone 2a to form
dienolate by the tertiary amine moiety and the
activation of isatin-derived β,γ-unsaturated α-keto
esters 1a by double hydrogen bonds from the amide
N−H. And immediately, the generated dienolate
interacts in situ with the oriented oxindole keto ester,
which undergoes the IED oxa-Diels−Alder sequence
to generate the product 3aa.
The isatin-derived β,γ-unsaturated α-keto esters 1a−1n
were prepared according to the reported literature
procedures.[5] The allyl ketones 2a−2h, 2j and 2k were
prepared
according
to
the
reported
literature
procedures.[15,20]
Synthesis of allyl ketone 2i
To a solution of 1-(4-bromophenyl)ethan-1-one S1 (989.9
mg, 5.0 mmol, 1.0 equiv.) and phenyl acetylene S2 (510.7
mg, 5.0 mmol, 1.0 equiv.) in DMSO (12.5 mL) was added
KOH (303.1 mg, 5.5 mmol, 1.1 equiv.). The resulting
solution was stirred at 100 °C for 1 h. The reaction mixture
was cooled to room temperature, and the reaction was
diluted with H2O (12.5 mL), neutralized with saturated
aqueous NH4Cl and extracted with ethyl acetate (4×12.5
Scheme 3. Proposed transition state for the reaction.
Conclusion
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
mL). The organic extract was washed with H2O (3×10 mL), evaporated under reduced pressure and directly purified by
brine (10 mL) and dried with anhydrous NaSO4. After flash column chromatography on silica gel (petroleum
removal of ethyl acetate, the product was purified by flash ether/ethyl acetate = 4:1) to afford the pure product 6fa as a
chromatography (petroleum ether/ethyl acetate, v:v = 30:1) light yellow solid.
to afford 2i as a white solid (783.1 mg, 52% yield).
Synthesis of compound 8aa
General procedure for the enantioselective synthesis of
compounds 3
A glass vial equipped with a magnetic stirring bar was
charged with 3aa (55.8 mg, 0.10 mmol, 1.0 equiv.) in
Isatin-derived β,γ-unsaturated α-keto esters 1 (0.10 mmol), methanol (1.0 mL) at 0 ℃. Then NaBH4 (7.6 mg, 0.20
allyl ketones 2 (0.12 mmol), and C4 (2.8 mg, 0.005 mmol) mmol, 2.0 equiv.) was added at the same temperature for
were dissolved in CH2Cl2 (1.0 mL), and the mixture was 10 minutes. After full conversion of the first step,
stirred at 0 ℃ for 15 minutes. After completion of the extraction, dry, concentration was followed, TsOH·H2O
reaction, the reaction mixture was concentrated and directly (19.0 mg, 0.10 mmol, 1.0 equiv.) and toluene (1.0 mL)
purified by flash column chromatography on silica gel were added into crude product 7aa. And then stirred at
(petroleum ether/ethyl acetate = 5:1 to 3:1) to afford the 80 ℃for a further 1 h, after the reaction was completed, the
pure products 3 as solid.
reaction mixture was evaporated under reduced pressure
and directly purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 6:1 to 4:1) to
afford the 6:1 E/Z geometric isomers 8aa as a white solid.
Synthesis of compound 3fa on a preparative scale
Isatin-derived β,γ-unsaturated α-keto ester 1f (98.1 mg, 0.4
mmol, 1.0 equiv.), allyl ketone 2a (106.7 mg, 0.48 mmol,
1.2 equiv.), and C4 (11.2 mg, 0.02 mmol) were dissolved
in CH2Cl2 (4.0 mL), and the mixture was stirred at 0 ℃ for
45 minutes. After completion of the reaction, the reaction
mixture was concentrated and directly purified by flash
column chromatography on silica gel (petroleum
ether/ethyl acetate = 4:1 to 2:1) to afford the pure product
3fa as a white solid.
Acknowledgements
The authors are grateful for financial support from the National
Natural Science Foundation of China (grant number 21272024)
and the Graduate Technology Innovation Project of Beijing
Institute of Technology (2019CX20043). We also thank Analysis
& Testing Center of Beijing Institute of Technology for the
measurement of NMR, mass spectrometry, and X-ray diffraction
analysis
Synthesis of compound 4fa
References
A mixture of spirooxindole 3fa (140.9 mg, 0.3 mmol, 1.0
equiv.) and DMAP (3.7 mg, 0.03 mmol, 0.1 equiv.) in
DCM (2.0 mL) was cooled in an ice-bath with stirring and
a solution of (Boc)2O (78.6 mg, 0.36 mmol, 1.2 equiv.) in
DCM (0.5 mL) was added slowly. The solution was stirred
another 2 h at room temperature. The reaction was
evaporated under reduced pressure and directly purified by
flash column chromatography on silica gel (petroleum
ether/ethyl acetate = 5:1 to 3:1) to afford the pure product
4fa as a light yellow solid.
[1] For selected reviews, see: a) B. M. Trost, M. K.
Brennan, Synthesis, 2009, 2009, 3003; b) M. M. M.
Santos, Tetrahedron 2014, 70, 9735; c) B. Liu, D.-Q.
Yu, H.-M. Liu, Eur. J. Med. Chem. 2015, 97, 673; d) T.
L. Pavlovska, R. G. Redkin, V. V. Lipson, D. V.
Atamanuk, Mol Diver. 2016, 20, 299; e) N. Ye, H.
Chen, E. A. Wold, P.-Y. Shi, J. Zhou, ACS Infect. Dis.
2016, 2, 382.
[2] For selected reviews, see: a) J.-B. Xu, J.-M. Yue, Org.
Chem. Front. 2014, 1, 1225; For selected examples,
see: b) P. Eastwood, J. González, E. Gómez, F. Caturla,
N. Aguilar, M. Mir, J. Aiguadé, V. Matassa, C. Balagué,
A. Orellana, M. Domínguez, Bioorg. Med. Chem. Lett.
2011, 21, 6253; c) S. R. Mandha, S. Siliveri, M. Alla, V.
R. Bommena, M. R. Bommineni, S. Balasubramanian,
Bioorg. Med. Chem. Lett. 2012, 22, 5272; d) S.-S. Ma,
W.-L. Mei, Z.-K. Guo, S.-B. Liu, Y.-X. Zhao, D.-L.
Yang, Y.-B. Zeng, B. Jiang, H.-F. Dai, Org. Lett. 2013,
15, 1492.
Synthesis of compound 5fa
A glass vial equipped with a magnetic stirring bar was
charged with 4fa (56.8 mg, 0.10 mmol) in a mixture
solvent (1.5 mL, v/v, MeOH: con. HCl = 4:1), and refluxed
at 80 ℃ for 1 hour. After the reaction was completed, the
reaction mixture was evaporated under reduced pressure
and directly purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1 to 1:1) to
afford the pure product 5fa as a light yellow solid.
[3] For selected reviews, see: a) D. Cheng, Y. Ishihara, B.
Tan, C. F. Barbas III, ACS Catal. 2014, 4, 743; b) G.-J.
Mei, F. Shi, Chem. Commun. 2018, 54, 6607; For
selected examples, see: c) B. Liang, S. Kalidindi, J. A.
Porco, C. R. J. Stephenson, Org. Lett. 2010, 12, 572; d)
Y.-B. Shen, S.-S. Li, X.-C. Liu, L.-P. Yu, Q. Liu, J.
Xiao, Adv. Synth. Catal. 2019, 361, 1453.
Synthesis of compound 6fa
A glass vial equipped with a magnetic stirring bar was
charged with 5fa (45.3 mg, 0.10 mmol) and 4-
bromophenylhydrazine hydrochloride in ethanol (1.0 mL),
and two drops of acetic acid was added. The reaction
mixture was boiled under reflux for 2 hours. After the
reaction was completed, the reaction mixture was
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
[4] For selected examples, see: a) W.-B. Chen, Z.-J. Wu,
Q.-L. Pei, L.-F. Cun, X.-M. Zhang, W.-C. Yuan, Org.
Lett. 2010, 12, 3132; b) X. Jiang, Y. Sun, J. Yao, Y.
Cao, M. Kai, N. He, X. Zhang, Y. Wang, R. Wang,
Adv. Synth. Catal. 2012, 354, 917; c) F.-F. Pan, W.
Yu, Z.-H. Qi, C.-H. Qiao, X.-W. Wang, Synthesis
2014, 46, 1143; d) J. Peng, G.-Y. Ran, W. Du, Y.-C.
Chen, Org. Lett. 2015, 17, 4490; e) P. Kumari, S.
Nandi, G. Kumar, N. H. Khan, R. I. Kureshy, S. H. R.
Abdi, E. Suresh, H. C. Bajaj, RSC Adv. 2016, 6,
52384; f) L.-Y. Cui, Y.-M. Wang, Z.-H. Zhou, RSC
Adv. 2016, 6, 64474; g) J. Xie, X.-Y. Xing, F. Sha,
Z.-Y. Wu, X.-Y. Wu, Org. Biomol. Chem. 2016, 14,
8346.
Chem. Int. Ed. 2013, 52, 11088; d) Q.-J. Liu, L. Wang,
Q.-K. Kang, X. P. Zhang, Y. Tang, Angew. Chem. Int.
Ed. 2016, 55, 9220.
[12] For selected examples, see: a) K. Juhl, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2003, 42, 1498; b) T.
Akiyama, H. Morita, K. Fuchibe, J. Am. Chem. Soc.
2006, 128, 13070; c) J. Shen, D. Liu, Q. An, Y. Liu, W.
Zhang, Adv. Synth. Catal. 2012, 354, 3311; d) H.
Huang, S. Konda, J. C.-G. Zhao, Angew. Chem. Int. Ed.
2016, 55, 2213.
[13] For selected examples, see: a) Z. Mao, W. Li, Y. Shi,
H. Mao, A. Lin, C. Zhu, Y. Cheng, Chem. Eur. J. 2013,
19, 9754; b) Y.-H. Zhou, L.-L. Lin, C.-K. Yin, Z.-M.
Wang, X.-H. Liu, X.-M. Feng, Chem. Commun. 2015,
51, 11689; c) L. Wei, C.-J. Wang, Chem. Commun.
2015, 51, 15374.
[5] a) N. Kumarswamyreddy, V. Kesavan, Org. Lett. 2016,
18, 1354; b) S. Muthusamy, M. Prakash, C.
Ramakrishnan, M. M. Gromiha, V. Kesavan,
ChemCatChem 2016, 8, 1708; c) V. P. R. Gajulapalli, K.
Lokesh, M. Vishwanath, V. Kesavan, RSC Adv. 2016, 6,
12180; d) S.-J. Yin, S.-Y. Zhang, J.-Q. Zhang, B.-B.
Sun, W.-T. Fan, B. Wu, X.-W. Wang, RSC Adv. 2016, 6,
84248.
[14] a) J. Trenner, C. Depken, T. Weber, A. Breder, Angew.
Chem., Int. Ed. 2013, 52, 8952; b) B. Zhu, W. Zhang, R.
Lee, Z. Han, W. Yang, D. Tan, K.-W. Huang, Z. Jiang,
Angew. Chem., Int. Ed. 2013, 52, 6666; c) Y. Gu, Y.
Wang, T.-Y. Yu, Y.-M. Liang, P.-F. Xu, Angew. Chem.,
Int. Ed. 2014, 53, 14128; d) B. Qiao, Y.-J. Huang, J.
Nie, J.-A. Ma, Org. Lett. 2015, 17, 4608; e) Z. Jing, X.
Bai, W. Chen, G. Zhang, B. Zhu, Z. Jiang, Org. Lett.
2016, 18, 260; f) X. Bai, G. Zeng, T. Shao, Z. Jiang,
Angew. Chem., Int. Ed. 2017, 56, 3684; g) I. Iriarte, O.
Olaizola, S. Vera, I. Gamboa, M. Oiarbide, C. Palomo,
Angew. Chem., Int. Ed. 2017, 56, 8860.
[6] a) S. Zhao, J.-B. Lin, Y.-Y. Zhao, Y.-M. Liang, P.-F.
Xu, Org. Lett. 2014, 16, 1802; b) X.-L. He, H.-R. Zhao,
C.-Q. Duan, W. Du, Y.-C. Chen, Org. Lett. 2018, 20,
804; c) L. Qiao, Z.-W. Duan, X.-N. Wu, D.-H. Li, Q.-Q.
Gu, Y.-K. Liu, Org. Lett. 2018, 20, 1630.
[7] For selected reviews, see a) H. Pellissier, Tetrahedron
2009, 65, 2839; b) J.-L. Li, T.-Y. Liu, Y.-C. Chen, Acc.
Chem. Res. 2012, 45, 1491; c) M.-S. Xie, L.-L. Lin, X.-
M. Feng, Chem. Rec. 2017, 17, 1184.
[15] X.-L. Li, X.-W. Kong, S. Yang, M. Meng, X.-Y. Zhan,
M. Zeng, X.-Q. Fang, Org. Lett. 2019, 21, 1979.
[16] CCDC 1971185 (for 3ai) contains the supplementary
[8] For selected examples, see: a) H. Lv, X.-Y. Chen, L.-H.
Sun, S. Ye, J. Org. Chem. 2010, 75, 6973; b) X.-Y. Hao,
X.-H. Liu, W. Li, F. Tan, Y.-Y. Chu, X.- H. Zhao, L.-L.
Lin, X.-M. Feng, Org. Lett. 2014, 16, 134; c) X.-Y. Hao,
L.-L. Lin, F. Tan, C.-K. Yin, X.-H. Liu, X.-M. Feng,
ACS Catal. 2015, 5, 6052; d) F. Wang, Z. Li, J. Wang,
X. Li, J.-P. Cheng, J. Org. Chem. 2015, 80, 5279.
crystallographic data for this paper. These data can be
obtained
free
of
charge
via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
[17] For a review see: a) R. L. Webb, D. Miller, V. Traina,
H. J. Gomez, Cardiovascular Drug Rev. 1990, 8, 89;
For selected examples, see: b) P. D. Leeson, L. L.
Iversen, J. Med. Chem. 1994, 37, 4053; c) J. C. Corbel,
P. Uriac, J. Huet, C. A. E. Martin, C. Advenier, Eur. J.
Med. Chem. 1995, 30, 3; d) K. Kondo, H. Ogawa, H.
Yamashita, H. Miyamoto, M. Tanaka, K. Nakaya, K.
Kitano, Y. Yamamura, S. Nakamura, T. Onogawa, T.
Mori, M. Tominaga, Biomed. Chem. Lett. 1999, 7, 1743;
e) L. M. Fleeman, P. J. Irwin, P. A. Phillips, J. West,
Aust Vet. J. 2000, 78, 825; f) X. Wang, V. Gattone II, P.
C. Harris, V. E. Torres, J. Am. Soc. Nephrol. 2005, 16,
846.
[9] For selected examples, see: a) Ł. Albrecht, G.
Dickmeiss, C. F. Weise, C. Rodríguez-Escrich, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2012, 51, 13109; b)
C. F. Weise, V. H. Lauridsen, R. S. Rambo, E. H.
Iversen, M.-L. Olsen, K. A. Jørgensen, J. Org. Chem.
2014, 79, 3537; c) A. Skrzyńska, A. Albrecht, Ł.
Albrecht, Adv. Synth. Catal. 2016, 358, 2838; d) S.
Wang, C. Rodriguez-Escrich, M. A. Pericàs, Org. Lett.
2016, 18, 556.
[10] For selected examples, see: a) B. Wang, X.-M. Feng,
Y.-Z. Huang, H. Liu, X. Cui, Y.-Z. Jiang, J. Org. Chem.
2002, 67, 2175; b) Q. Fan, L.-L. Lin, J. Liu, Y.-Z.
Huang, X.-M. Feng, G.-L. Zhang, Org. Lett. 2004, 6,
2185; c) L. Yang, W. Huang, X.-H. He, M.-C. Yang, X.
Li, G. He, C. Peng, B. Han, Adv. Synth. Catal. 2016,
358, 2970.
[18] a) J.-W. Ren, L. Zheng, Z.-P. Ye, Z.-X. Deng, Z.-Z.
Xie, J.-A. Xiao, F.-W. Zhu, H.-Y. Xiang, X.-Q. Chen,
H. Yang, Org. Lett. 2019, 21, 2166; b) Z. Jia, X. Hu, Y.
Zhao, F. G. Qiu, A. S. C. Chan, J. Zhao, Org. Lett. 2019,
21, 9584.
[11] For selected examples, see: a) H. Liu, G. Dagousset, G.
Masson, P. Retailleau, J. Zhu, J. Am. Chem. Soc. 2009,
131, 4598; b) G. Dagousset, J. Zhu, G. Masson, J. Am.
Chem. Soc. 2011, 133, 14804; c) L. He, G. Laurent, P.
Retailleau, B. Folléas, J.-L. Brayer, G. Masson, Angew.
[19] a) Y. Lin, B.-L. Zhao, D.-M., J. Org. Chem. 2018, 83,
7741; b) P. S. Akula, B. C. Hong, G. H. Lee, Org. Lett.
2018, 20, 7835.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
[20] a) B. A. Trofimov, E. Y. Schmidt, N. V. Zorina, E. V.
Ivanova, Igor' A. Ushakov, J. Org. Chem. 2012, 77,
6880; b) S. Undeela, J.-P. Ramchandra, R.-S. Menon,
Tetrahedron Lett. 2014, 55, 5667; c) F. Pünner, Y.
Sohtome, M. Sodeoka, Chem. Comm. 2016, 52, 14093.
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001242
Advanced Synthesis & Catalysis
FULL PAPER
Organocatalytic Remote Asymmetric Inverse-
Electron-Demand Oxa-Diels−Alder Reaction of
Allyl Ketones with Isatin-Derived Unsaturated
Keto Esters
Adv. Synth. Catal. 2020, 362, Page – Page
Ye Lin, Xi-Qiang Hou, Bing-Yu Li and Da-Ming
Du*
9
This article is protected by copyright. All rights reserved.