Asymmetric Construction of Bispiro-Cyclopropane-Pyrazolones via a [2+1] Cyclization Reaction by Dipeptide-Based Phosphonium Salt Catalysis

Article abstract of DOI:10.1002/adsc.202000073

We reported herein an efficient alternative for asymmetric synthesis of structurally complicated chiral bispiro-cyclopropane-pyrazolones via dipeptide-based phosphonium salt catalyzed [2+1] cyclization of 2,3-dioxopyrrolidines and halogenated pyrazolones. With this catalytic asymmetric protocol, a broad range of bispiro heterocyclic compounds bearing a pyrazolone unit were prepared in high yields with excellent diastereo- and enatioselectivities. Of note, this transformation proceeds in a really short time under mild reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202000073

Title: Asymmetric Construction of Bispiro-Cyclopropane-Pyrazolones
via a [2 + 1] Cyclization Reaction by Dipeptide-Based
Phosphonium Salt Catalysis
Authors: Dongming Lu, Xin Liu, Jia-Hong Wu, Song Zhang, Jian-Ping
Tan, xiaojun yu, and Tianli Wang
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
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000073
Link to VoR: http://dx.doi.org/10.1002/adsc.202000073

10.1002/adsc.202000073
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric Construction of Bispiro-Cyclopropane-Pyrazolones
via a [2 + 1] Cyclization Reaction by Dipeptide-Based
Phosphonium Salt Catalysis
Dongming Lu,a Xin Liu,a Jia-Hong Wu,a Song Zhang,a Jian-Ping Tan,a Xiaojun Yu,a,b
and Tianli Wanga,*
a
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, People’s Republic of China
E-mail: wangtl@scu.edu.cn
b
Department of Chemistry, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, People’s
Republic of China
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/ ((Please delete if not
appropriate))
Abstract. We reported herein an efficient alternative for
asymmetric synthesis of structurally complicated chiral
bispiro-cyclopropane-pyrazolones via dipeptide-based
phosphonium salt catalyzed [2 + 1] cyclization of 2,3-
dioxopyrrolidines and halogenated pyrazolones. With this
catalytic asymmetric protocol, a broad range of bispiro
heterocyclic compounds bearing a pyrazolone unit were
prepared in high yields with excellent diastereo- and
enatioselectivities. Of note, this transformation proceeds in
a really short time under mild reaction conditions.
Keywords: dipeptide-based phosphonium salts; [2+1]
cyclization; bispiro-cyclopropane-pyrazolones; asymmetric
synthesis; hydrogen-bonding interaction
Figure 1. Selected bioactive molecules containing (spiro-)
pyrazolone core.
Asymmetric organocatalysis has been a frontier in
the realm of asymmetric catalysis, which shows
powerful capability in building a range of chiral
molecules. Among the manifold organogatalysts,
chiral phase-transfer catalyst (PTC) is one type of
fundamental organocatalysts.[1] Over the past decades,
quaternary ammonium salts, being regarded as
privileged components in PTC, have been widely
employed in asymmetric synthesis. By contrast, PTCs
involving phosphonium salts just began to flourish
until very recently.[2] Outstanding contributions in this
field have been made by the research groups of Ooi[3]
and Marouka.[4] Later, Ma and co-workers disclosed a
binol-derived P-spiro-phosphonium salt and realized
its application in asymmetric amination of
benzofuranones[5]. Recently, Zhao[6] and Lu[7]
pioneered the development of bifunctional
phosphonium catalysts derived from natural amino
acids, and demonstrated their effectiveness in many
organic transformations. Quite recently, our group
developed an novel pattern of dipeptide-based
phosphonium salt catalysts and fulfilled its utilization
in the asymmetric synthesis of challenging tetra-
Substituted aziridines[8] and other biologically
momentous hetercyclic molecules.[9,10] Of note, such
dipeptide-based phosphonium catalyst possesses
remarkably high tunability, and further, this catalyst
with an ion-pairing moiety and peptide backbone that
captures essential features of enzymatic active sites
with hydrogen-donating characteristics becomes a
multifunctional phase-transfer catalyst, which can be
advantageous for asymmetric induction.[11] However,
its applications in asymmetric synthesis are still in its
infancy.
On the other hand, pyrazolone unit is widespread in
both natural products and pharmaceutical targets
(Figure 1).[12] Particularly, structurally spiro
Scheme 1. Asymmetric synthesis of bispiro-cyclopropane-
pyrazolones via [2 + 1] reaction by dipeptide-based
phosphonium salt catalysis.
1
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10.1002/adsc.202000073
Advanced Synthesis & Catalysis
pyrazolone frameworks are an interesting and selectivities of this transformations, may due to the
important subclass of bioactive agents, and these ring strongly steric hindrance of final products. In
systems are always displayed in numerous drug leads continuation of our major interest in bifunctional
and pharmaceuticals.[13] In this context, catalytic organocatalysis involving phosphonium salt catalysts,
asymmetric construction of chiral spiro-pyrazolones we questioned whether our dipiptide-based
has stimulated considerable interest among synthetic phosphonium salt catalysis can be an efficient
chemists, and a number of methods have been alternative for achieving high stereoinduction, and
developed for preparing such scalffords.[14] It should thus prepare structurally rigid and optically pure
be noted that the catalytic asymmetric construction of bispiro-cyclopropane-pyrazolone molecules (Scheme
structurally rigid bispiro-cyclopropane-pyrazolone 1). Herein, we describe a highly stereoselective [2 + 1]
molecules is still rare. To the best of our knowledge, cyclization reaction between 2,3-dioxopyrrolidines
only one example related to this issue has been and halogenated pyrazolones under dipeptide-based
reported so far. In 2015, Du and co-workers phosphonium salt catalytic conditions, providing an
disclosed a cascade reaction of arylidenepyrazolones efficient and complementary way to bispiro-
and 3-chlorooxindoles to provide such compounds in cyclopropane-pyrazolone derivatives.
Initially,
the
cyclization
between
2,3-
moderate stereoselectivities (2.4:16.7:1 d.r. and
4074% ee).[15] From our review, the main challenge,
lying on controlling the enantio- and diastereo-
dioxopyrrolidine 1a and 4-bromo-pyrazolone 2a1 was
chosen as a model reaction for optimizing reaction
conditions. The reaction was performed with different
bifunctional phosphonium salt catalysts in the
presence of K2CO3 in toluene at room temperature.
Pleasingly, the model reaction proceeded swiftly
while dipeptide-based phosphonium salts were
employed as catalysts (entries 18).[16a] Both L- and
D-valine-based dipeptide-phosphonium iodides could
promote this reaction, affording the cycloadduct in
good yield but with poor enantioselectivities (entries
12). By contrast, the dipeptide-phosphonium
bromides were found to be slighly more favorable in
asymmetric induction (entries 34). Accordingly,
several dipeptide-based phosphonium bromides were
prepared and evaluated (entries 58), and the L-Val-
L-OTBDPS-Thr-derived phosphonium salt P8 was
found to be the best catalyst, furnishing the desired
product in moderate enantioselectivity (entry 8). With
a promising ee value in hand, a series of bases were
tested (entries 810),[16b] and the relatively weak base
of (NH4)2CO3 proved to be a suitable choice with
affording the adduct in excellent yield and good
enantioselectivity (entry 12). The solvent screening
was explored, and none of the solvents were shown to
be superior to toluene.[16c] Subsequently, it was found
that decreasing reaction temperature led to a better
diastereoselectivity and enantioselectivity without
sacrificing the isolated yield (entry 13). Moreover, the
desired product 3a2 could be isolated in 95% yield
with >20:1 d.r. and 95% ee when pyrazolone 2a2 was
used instead of 2a1 (entry 14).
Table 1. Optimization of reaction conditions.[a]
3, yield
(%)[b]
ee
(%)
3
entry
cat.
solvent
base
d.r.
1
2
P1
P2
P3
P4
P5
P6
P7
P8
P8
P8
P8
P8
P8
P8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
K2CO3
K2CO3
3a1, 75
3a1, 83
1:1
1:1
6
3
K2CO3
3a1, 82
3a1, 88
3a1, 89
3a1, 86
3a1, 78
3a1, 93
3a1, 91
3a1, 87
3a1, 94
3a1, 96
3a1, 95
3a2, 95
16
34
38
34
39
46
59
43
13
73
94
95
1:1
4
K2CO3
1.3:1
1.3:1
1.3:1
1.3:1
1.3:1
1.3:1
1.3:1
1.3:1
1:1.6
4.5:1
>20:1
5
K2CO3
6
K2CO3
7
K2CO3
8
K2CO3
9
Cs2CO3
K3PO4
10
11
12
13[c]
14[c]
PhONa
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
With the optimized conditions identified, the
generality protocol for different 2,3-dioxopyrrolidines
[a]
All reactions were performed with 1a (0.1 mmol), was investigated. Generally, a diverse array of 2,3-
2a1/2a2 (0.12 mmol), and catalyst (10 mol%) in solvent
dioxopyrrolidine derivatives bearing different
aromatic substituents were found to be well tolerated
under the standard reaction conditions (3ar). 2,3-
dioxopyrrolidines bearing either electron-neutral, -
withdrawing or -donating groups in the ortho-, meta-,
1
for 0.5 h. The d.r. values were determined by H NMR
analysis and ee values were determined by HPLC
analysis.
[b] Isolated yield.
[c] The reaction was performed at -20 oC.
2
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10.1002/adsc.202000073
Advanced Synthesis & Catalysis
Table 2. Scope of 2,3-dioxopyrrolidines 1.[a,b]
also well tolerated in this catalytic process and
provided the corresponding product in good yield and
stereoselectivities. Surprisingly, both naphthyl and
thienyl substituted dioxopyrrolidines were also
compatible with the reaction conditions for giving the
desired product in quantitive yields with excellent d.r.
and ee values (3su). Moreover, the N-tert-butyl
substituted dioxopyrrolidine was also tolerated,
affording the desired product 3v in 96% yield
with >20:1 d.r. and 94% ee.
Encouraged by these results, we turned our
attention to the scope of halogenated pyrazolones.
The results were outlined in Table 3. Varies
pyrazolones bearing linear aliphatic chains were
found to be suitable, irrelevant with the length of
these chains, producing the desired cycloadducts (4a–
c) in high yields with excellent stereoselectivities.
Table 3. Scope of halogenated pyrazolones 2.[a,b]
[a]
All reactions were performed with 1 (0.1 mmol), 2a2
/2a2' (0.12 mmol), catalyst P8 (10 mol%) and (NH4)2CO3
(0.2 mmol) in 0.5 mL toluene at -20 oC for 0.5 h. The d.r.
values were determined by 1H NMR analysis and ee
values were determined by HPLC analysis.
[b] Isolated yield.
[c]
[a]
2' was used.
All reactions were performed with 1a (0.1 mmol), 2
(0.12 mmol), catalyst P8 (10 mol%) and (NH4)2CO3 (0.2
o
or para-position of the phenyl ring could deliver the
corresponding products in high yields (8998%) with
excellent stereoselectivities (all >20:1 d.r. and
9096% ee). Of note, chlorogenated pyrazolones was
mmol) in 0.5 mL toluene at -20 C for 0.5 h. The d.r.
values were determined by 1H NMR analysis and ee
values were determined by HPLC analysis.
[b] Isolated yield.
3
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10.1002/adsc.202000073
Advanced Synthesis & Catalysis
Table 4. Preliminary investigation of the reaction
Both acyclic and cyclic branched aliphatic
pyrazolones were also suitable reactants and resulted
in corresponding adducts with satisfying yields and
stereoselectivities (4df). The pyrazolone substrates
bearing different benzyl substituents, regardless of
their steric hindrance or electron properties, could be
readily transformed into the expected adducts in
parallel yields with no loss of diastereoselectivities
and enantioselectivities (4gl). To illustrate the
robustness and utility of this catalytic protocol, the
scaled-up reaction was conducted and corresponding
adduct 3n was obtained in satisfying yield with >20:1
d.r. and 95% ee (Scheme 2a). Besides, the optically
active products were readily converted into other
bioactive compounds (5 and 6) in high yields
(Scheme 2b). The relative and absolute configuration
of the above [2 + 1] annulation products were
assigned on the basis of X-ray crystallographic
mechanism and proposed transition state models.[a,b]
entry
solvent
toluene
toluene
toluene
MeOH
cat.
P8
t (h)
0.5
0.5
0.5
1
yield (%)[b]
ee (%)
95
1
2
3
4
96
94
93
23
18
P8-1
P8-2
P8
23
0
[a] All reactions were performed with 1a (0.1 mmol), 2a2
(0.12 mmol), catalyst (10 mol%) and (NH4)2CO3 (0.2
o
mmol) in 0.5 mL solvent at -20 C for 0.5 h. The d.r.
values were determined by 1H NMR analysis and ee
values were determined by HPLC analysis.
[b] Isolated yield.
analysis of derivative compound
6
(CCDC
1951824).[17]
observations and our previous studies, the plausible
transition state models were presented (TS-1 and TS-
2) in Table 4.
In conclusion, we have disclosed a highly efficient
and stereoselective [2 + 1] annulation reaction
between 2,3-dioxopyrrolidines and halogenated
pyrazolones under dipeptide-based phosphonium salt
catalytic conditions. This method represented an
efficient and complementary approach for the
construction of optically active bispiro-cyclopropane-
pyrazolone derivatives in high yields with excellent
diastereo- and enantioselectivities. Of note, these
results indicated that such type of highly tunable
Scheme 2. Scale-up synthesis and transformation of chiral
dipeptided phosphonium salt catalysis was
a
product.
practicable approach for constructing structurally
complex chiral molecules, and further investigation is
ongoing in our laboratory.
To gain some insights into the dual activation of
this dipeptide-based catalytic system, the control
experiments were performed (Table 4). The
methylated catalysts P8-1 and P8-2 were further
prepared and applied to the model [2 + 1] cyclization,
Experimental Section General
respectively.
It
was
found
that
their
Procedure for [2+1] Annulation
enantioselectivities decreased sharply (entries 13).
Notably, when methanol was used as solvent, racemic
product was obtained (entry 4). These preliminary
results clearly verified the significance of the H-
bonding as well as ion-pair interactions in such
catalytic system. Based on these experimental
To a flame-dried round bottle flask with a magnetic
stirring bar were added the 2,3-dioxopyrrolidines 1
(0.1 mmol), halogenated pyrazolones 2 (0.12 mmol),
phosphonium salt P8 (0.005 mmol) and (NH4)2CO3
(0.4 mmol), followed by the addition of toluene (0.5
4
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10.1002/adsc.202000073
Advanced Synthesis & Catalysis
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0.5 h. The solvent was then removed under reduced
pressure, and the residue was purified by column
chromatography on silica gel (petroleum ether/ethyl
acetate = 10:1 to 3:1) to afford 3/4 as a white solid.
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Acknowledgements
We acknowledge financial support from the National
Key R&D Program of China (2018YFA0903500), the
National Natural Science Foundation of China
(21971165, 21921002), the “1000-Youth Talents
Program” (YJ201702) and the Fundamental Research
Funds for the Central Universities. We also
acknowledge the comprehensive training platform of
the Specialized Laboratory in the College of
Chemistry at Sichuan University and the Analytical &
Testing Center of Sichuan University for compound
testing.
[5] C.-L. Zhu, F.-G. Zhang, W. Meng, J. Nie, D. Cahard,
J.-A. Ma, Angew. Chem. Int. Ed. 2011, 50, 5869–5872;
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[6] For recent review on phosphonium salt catalyzed
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Zhao, Chin. J. Chem. 2019, 37, 1111–1119; For
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Cao, Z. Chai, J. Zhang, Z. Ye, H. Xiao, H. Wang, J.
Chen, X. Wu, G. Zhao, Chem. Commun. 2013, 49,
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Advanced Synthesis & Catalysis
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DOI:10.1002/adsc.202000001.
[16] a) See the Table S1 in Supporting Information for
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crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
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10.1002/adsc.202000073
Advanced Synthesis & Catalysis
COMMUNICATION
Asymmetric Construction of Bispiro-
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Adv. Synth. Catal. Year, Volume, Page – Page
D. Lu, X. Liu, J.-H. Wu, S. Zhang, J.-P. Tan, X. Yu
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