Diastereoselective [3 + 1] Cyclization Reaction of Oxindolyl Azaoxyallyl Cations with Sulfur Ylides: Assembly of 3,3′-Spiro[β-lactam]-oxindoles

Article abstract of DOI:10.1021/acs.orglett.1c00130

Oxindoles and β-lactams are attractive structural motifs because of their unique biological importance. However, the fusion of the two moieties featuring 3,3′-spirocyclic scaffolds is a challenging task in organic synthesis. Herein we designed a novel type of oxindole-based azaoxyallyl cation synthons, which could readily participate in the [3 + 1] cyclization with sulfur ylides. With this protocol, a collection of 3,3-spiro[β-lactam]-oxindoles were facilely produced in up to 94% yield with perfect diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.1c00130

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Letter
Diastereoselective [3 + 1] Cyclization Reaction of Oxindolyl
Azaoxyallyl Cations with Sulfur Ylides: Assembly of
3,3′-Spiro[β-lactam]-oxindoles
Hai-Jun Leng, Qing-Zhu Li,* Peng Xiang, Ting Qi, Qing-Song Dai, Zhi-Qiang Jia, Chuan Gou,
Xiang Zhang, and Jun-Long Li*
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ABSTRACT: Oxindoles and β-lactams are attractive structural motifs because of their unique biological importance. However, the
fusion of the two moieties featuring 3,3′-spirocyclic scaffolds is a challenging task in organic synthesis. Herein we designed a novel
type of oxindole-based azaoxyallyl cation synthons, which could readily participate in the [3 + 1] cyclization with sulfur ylides. With
this protocol, a collection of 3,3-spiro[β-lactam]-oxindoles were facilely produced in up to 94% yield with perfect diastereoselectivity.
itrogen-containing heterocyclic frameworks are widely
Ndistributed in many bioactive natural products and
medicinally relevant molecules.1 Among them, β-lactams,
representing a unique type of four-membered azacycles, are
well known for their significant antibiotic bioactivities.2 In
addition, oxindole-based natural alkaloids and pharmaceutical
molecules have also exhibited a broad range of biological
activities, including antitumor, anti-HIV, antimicrobial, and
antimalarial activities.3,4 According to the theory of combina-
tion principles in medicinal chemistry,5 merging β-lactam and
oxindole moieties into a rigid spirocyclic scaffold might provide
a great opportunity for discovering valuable lead compounds.
For example, molecules bearing a 3,2′-spiro[β-lactam]-
oxindole skeleton could act as promising antipoliovirus agents
and human rhinovirus 3C-proteinase inhibitors.6 Therefore,
the exploration of diverse spiro[β-lactam]-oxindoles for drug
discovery could be an emerging dynamic research field (Figure
1).
Figure 1. Motivation and state-of-the-art for constructing spiro[β-
lactam]-oxindole scaffolds.
In fact, the development of efficient synthetic strategies to
construct spiro[β-lactam]-oxindoles has already attracted
considerable attention from the synthesis community. A
number of methods have been established to synthesize 3,2′-
spiro[β-lactam]-oxindole skeletons through [2 + 2] annula-
Received: January 13, 2021
Published: February 1, 2021
tions, which are typically based on the isatin-derived ketimines
as key building blocks.7 However, a similar 3,3′-spiro[β-
lactam]-oxindole scaffold, featuring the spiro-center at C3′
position, has rarely been investigated, probably because of the
synthetic challenge to utilize the existing substrates to prepare
this unique skeleton. Consequently, it is highly desirable to
https://dx.doi.org/10.1021/acs.orglett.1c00130
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1451−1456
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a
design a novel and suitable building block that could refresh
the retrosynthetic planning and streamline the whole reaction
process.
Table 1. Optimization Studies
Azaoxyallyl cations, generated from α-halo hydroxamates,
have emerged as a highly reactive three-atomic synthon for
preparing structurally diverse lactam heterocycles.8 In 2011,
Jeffrey and coworkers reported the first synthetic application of
azaoxyallyl cations in [4 + 3] cycloadditions by using furan or
cyclopentadiene, and they also provided experimental evidence
to demonstrate the existence of this transient intermediate.9
Since then, the chemistry of azaoxyallyl cations has been
extensively explored by organic chemists, and a variety of [3 +
2]10 and [3 + 3]11 cyclizations have been continuously
developed during the past decade (Scheme 1a). Recently, the
b
c
entry
solvent
base
yield (%)
dr
1
2
3
4
5
6
7
8
HFIP
toluene
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
NaOH
K2HPO4
Et3N
<5
<5
<5
<5
<5
58
<5
<5
7
15
15
<5
<5
<5
<5
85
80
54
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
>20:1
Scheme 1. Design of the Oxindole-based Azaoxyallyl
Cations
9
10
11
12
13
14
15
16
17
18
>20:1
>20:1
iPr2NEt
DMAP
DABCO
TMG
DBU
d
Cs2CO3
Cs2CO3
Cs2CO3
>20:1
>20:1
>20:1
e
f
a
Unless otherwise noted, reactions were performed with oxindoles 1a
(0.10 mmol), sulfonium salts 2a (0.05 mmol), and base (0.20 mmol)
b
in 1.0 mL of solvent at room temperature for 15 min. Isolated yield.
c
d
e
1
Determined by crude H NMR analysis. In 0.5 mL of CH2Cl2. In
f
0.25 mL of CH2Cl2. At 0 °C. HFIP: hexafluoroisopropanol; DMAP:
4-dimethylaminopyridine; TMG: tetramethylguanidine; DBU: 1,8-
diazabicyclo[5.4.0]undec-7-ene.
Chen and Liu group reported an elegant [3 + 1] annulation by
using Jeffrey’s azaoxyallyl cations in the presence of sulfur
ylides, and a collection of lactams were obtained in moderate
to good yields.10e Despite these advancements, previous
reports mostly relied on the use of simple α-halo hydroxamates
as the key azaoxyallyl cation precursor. We envisioned that the
design of a novel azaoxyallyl cation based on an oxindole
skeleton might be quite interesting because the high reactivity
of the azaoxylallyl cation intermediate could allow for rapid
access to structurally challenging molecules, such as 3,3′-
spiro[β-lactam]-oxindoles. On the basis of these considerations
and our continuous interest in assembling biologically relevant
heterocycles,12 we herein report a highly diastereoselective [3
+ 1] annulation of the newly designed oxindolyl azaoxyallyl
cations with sulfur ylides. The present reaction could reach
completion within a very short period of time, which further
demonstrates the high reactivity of this new synthon. This
protocol could afford a range of functionalized 3,3′-spiro[β-
lactam]-oxindoles (Scheme 1b).
First, we prepared the designed oxindolyl azaoxyallyl cation
precursors 1 in an efficient manner. (For details, see the
Supporting Information.) Then, the model reaction of 1a and
sulfonium salt 2a was investigated under alkaline conditions at
room temperature. As illustrated in Table 1, hexafluoroisopro-
panol could not promote this reaction, despite the fact that it
was frequently utilized as a privileged solvent because of its
ability to stabilize the highly reactive azaoxyallyl cations (entry
1).8−10 A poor conversion rate was still observed by using
K2CO3 as the base in various solvents (entries 2−5). To our
delight, the target [3 + 1] annulation could be triggered with
Cs2CO3, which diastereoselectively offered the desired product
3a in 58% isolated yield within a short time (entry 6).
Encouraged by this result, we investigated a series of inorganic
and organic bases, but no better results were obtained (entries
7−15). Fortunately, we found that the isolated yield could be
improved to 85% by using a slightly higher concentration
(entry 16). However, further increasing the concentration to
0.2 M afforded a lower yield (entry 17). Lowering the reaction
temperature to 0 °C could not improve the results (entry 18).
Next, we evaluated the generality and limitation of this [3 +
1] cyclization under the optimized conditions by testing
various substituted α-chloro hydroxamates 1 and sulfonium
salts 2. The results are summarized in Scheme 2. Sulfonium
salts 2 bearing either electron-rich or electron-deficient
substituents at the para or meta positions were well tolerated
in this reaction system, affording the 3,3′-spiro[β-lactam]-
oxindole derivatives 3a−3k in good to excellent yields.
However, a lower yield was obtained by testing the ortho-
fluoro-substutited sulfonium salt (3l). The dichloro-substituted
2 could also be well compatible and gave the product 3m in
70% yield. Moreover, the 2-naphthyl-substituted β-lactam 3n
was obtained in 75% yield. The [3 + 1] cyclization proceeded
smoothly with sulfonium salts bearing a heteroarene, such as
furan or thiophene, which delivered the corresponding
products 3o and 3p in satisfying yields. Besides ketonic
sulfonium salts, 2 incorporating an ester functionality could
also be tolerated, and 3q was produced in an acceptable yield.
Furthermore, the hydroxamate 1 featuring a methyl substituent
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Letter
a b
,
Subsequently, we performed several experiments to
demonstrate the potential utility of this synthetic method.
First, the [3 + 1] annulation of azaoxyallyl cation precursor 1a
and sulfonium salt 2a was conducted on a 1.5 mmol scale,
which gave the desired 3a in 70% yield (Scheme 3a). The
Scheme 2. Substrate Scope of the [3 + 1] Annulation
Scheme 3. Further Synthetic Investigations
asymmetric [3 + 1] annulation could also be achieved by using
a champhor-derived chiral sulfonium salt 2r, delivering 3a in
40% yield with 64% enantioselectivity (Scheme 3b). Then, we
explored the synthetic transformations to investigate the
versatility of this β-lactam-incorporated spirooxindole 3a. As
shown in Scheme 3b, treating 3a with Pd/C catalyst under a
H2 atmosphere led to the cleavage of the N−O bond as well as
the reduction of the ketone moiety, delivering the benzyl-
substituted β-lactam product 4 in satisfying yield. The
chlorinated compound 5 could also be easily accessed in
65% overall yield through an efficient reduction/chlorination
sequence (Scheme 3c).
The mechanism of this [3 + 1] annulation was speculated, as
shown in Scheme 4. Initially, the highly reactive azaoxyallyl
cation intermediate and sulfur yield species were both
generated under alkaline conditions. Next, the nucleophilic
attack of sulfur ylide to azaoxyallyl cation (the delocalization of
positive charge via resonance through the aromatic ring
probably contributes to the stabilization of the azaoxyallyl
cation, TS1) provided a zwitterionic intermediate TS2. Finally,
a
Unless otherwise noted, reactions were performed with 0.20 mmol of
1, 0.10 mmol of 2, and 0.20 mmol of Cs2CO3 in 1.0 mL of CH2Cl2 at
b
rt for 15 min. Isolated yield. dr was determined to be >20:1 in all
c
cases by crude 1H NMR analysis. Structure of 3a was determined by
Scheme 4. Proposed Mechanism of the [3 + 1] Annulation
X-ray diffraction analysis.
at the five-position on the oxindole skeleton was found to be
highly reactive in the target reaction, which delivered 3r in
excellent yield. Nevertheless, the use of 6-chloro-substituted 1
resulted in lower reaction efficiency (3s). N-allyl- and N-ethyl-
protected 1 could also well participate in this reaction and
afforded the spirocyclic products 3t and 3u in excellent yields.
Interestingly, this annulation could also proceed efficiently
when the NH-free oxindolyl azaoxyallyl cation precursors were
utilized (3v).
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an intramolecular cyclization took place to release the dimethyl
sulfide and delivered the spiro-β-lactam 3a.
of Antibiotics, School of Pharmacy, Chengdu University,
Chengdu 610052, China
In conclusion, we have developed a novel azaoxyallyl cation
precursor, which involved a biologically interesting spiroox-
indole motif. Such building blocks could be easily prepared and
have been successfully applied in the [3 + 1] annulation with
sulfur ylides. The 3,3′-spiro[β-lactam]-oxindole skeleton,
which was previously difficult to access, could be easily
constructed by using this protocol. A variety of novel
spirooxindoles with diverse functional groups were obtained
within a short period of time under mild conditions. The
potential utility of this method was further demonstrated by
synthetic transformations. A stepwise bond-formation mecha-
nism was proposed based on previous ylide [3 + 1] annulation
processes. Further applications of these new azaoxyallyl cation
synthons and the biological evaluations of the corresponding
spirooxindoles are currently underway in our laboratory.
Ting Qi − Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province, Sichuan Industrial Institute
of Antibiotics, School of Pharmacy, Chengdu University,
Chengdu 610052, China
Qing-Song Dai − Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province, Sichuan Industrial Institute
of Antibiotics, School of Pharmacy, Chengdu University,
Chengdu 610052, China
Zhi-Qiang Jia − Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province, Sichuan Industrial Institute
of Antibiotics, School of Pharmacy, Chengdu University,
Chengdu 610052, China
Chuan Gou − Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province, Sichuan Industrial Institute
of Antibiotics, School of Pharmacy, Chengdu University,
Chengdu 610052, China
Xiang Zhang − Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province, Sichuan Industrial Institute
of Antibiotics, School of Pharmacy, Chengdu University,
Chengdu 610052, China
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00130.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00130
Complete experimental procedures, characterization of
new products, NMR spectra, HRMS data, and X-ray
crystallographic data for 3a (PDF)
Notes
FAIR data, including the primary NMR FID files, for
compounds 1a−1f, 3a−3v, 4, 5, S3, and S4 (ZIP)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Accession Codes
■
Financial support from the National Natural Science
Foundation of China (nos. 21871031, 21702021, and
22071011), the “Thousand Talents Program” of Sichuan
Province, the “Chengdu Talents Program”, and the scientific
research fund of Chengdu University is gratefully acknowl-
edged.
CCDC 2041237 contains the supplementary 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
REFERENCES
AUTHOR INFORMATION
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Corresponding Authors
Qing-Zhu Li − Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province, Sichuan Industrial Institute
of Antibiotics, School of Pharmacy, Chengdu University,
Chengdu 610052, China; Email: liqz_cdu@hotmail.com
Jun-Long Li − Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province, Sichuan Industrial Institute
of Antibiotics, School of Pharmacy, Chengdu University,
Chengdu 610052, China; State Key Laboratory of
Southwestern Chinese Medicine Resources, School of
Pharmacy, Chengdu University of Traditional Chinese
Medicine, Chengdu 611137, China; orcid.org/0000-
0002-4700-0142; Email: lijunlong709@hotmail.com
Authors
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Peng Xiang − Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province, Sichuan Industrial Institute
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