Squaramide-catalysed asymmetric Michael addition/cyclization cascade reaction of 4-arylmethylidene-2,3-dioxopyrrolidines with 2-isothiocyanato-1-indanones

Article abstract of DOI:10.1039/d1ob01223a

A highly efficient cinchona alkaloid-derived squaramide catalysed asymmetric Michael/cyclization cascade reaction of 4-arylmethylidene-2,3-dioxopyrrolidines with 2-isothiocyanato-1-indanones was successfully developed. This protocol provides an efficient

Full text of DOI:10.1039/d1ob01223a

Organic &
Biomolecular Chemistry
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Squaramide-catalysed asymmetric Michael
addition/cyclization cascade reaction of
-arylmethylidene-2,3-dioxopyrrolidines with
-isothiocyanato-1-indanones†
Cite this: Org. Biomol. Chem., 2021,
9, 7181
1
4
2
a
a
b
a
Xi-Qiang Hou,‡ Jiang-Bo Wen,‡ Li Yan and Da-Ming Du
*
A highly efficient cinchona alkaloid-derived squaramide catalysed asymmetric Michael/cyclization
cascade reaction of 4-arylmethylidene-2,3-dioxopyrrolidines with 2-isothiocyanato-1-indanones was
successfully developed. This protocol provides an efficient and mild access to indanone-derived spiropyr-
rolidone scaffolds containing three contiguous stereocenters with two spiroquaternary stereocenters in
excellent yields (up to 99%) with high enantio- and diastereoselectivities (up to 99% ee and up to >20 : 1
dr). This method provides an economical and practical approach for the asymmetric synthesis of medicin-
ally relevant molecules.
Received 24th June 2021,
Accepted 2nd August 2021
DOI: 10.1039/d1ob01223a
rsc.li/obc
In the past decades, a huge number of assembled pharma-
ceutically relevant spiropyrrolidine frameworks have been
Introduction
The wide occurrence of spirocyclic scaffolds in bioactive reported, and these derivatives are basically able to show inter-
natural products and pharmaceuticals impels the quest to esting biological activities. Furthermore, the synthesis and
develop a series of synthons or new methodologies to con- preparation of such spiropyrrolidine derivatives with the spiro-
1
struct the spirocyclic compounds. The densely functionalized pyrrolidine skeleton occupying the central structure provide
chiral spiropyrrolidine scaffolds, especially found in natural the possibility of the development of new drugs. Nevertheless,
compounds and medicinal products as a privileged structure to the best of our knowledge, most reports on constructing
4
(
Fig. 1A–E) have widely attracted the attention of chemists and spiropyrrolidine derivatives are basically based on indole and
2
5
pharmacologists. For example, spirotryprostatin A exists in a 3-unsaturated substituted isatin derivatives as starting sub-
subclass of spirooxindole alkaloids and it has potential value strates (Scheme 1a). Although the asymmetric Michael
against cancer. On the other hand, it has also been illustrated addition/cyclization of activated isothiocyanates with
that the structure of the pyrrolidine compound derived from α,β-unsaturated ketone derivatives was well-developed in the
indanone (Fig. 1F) is a privileged pharmacophore in various past decade, with our continuing interest in organocatalyzed
therapeutic chemicals. Owing to the structural importance of cycloaddition reactions and based on the previous work
6
3
7
these two scaffolds mentioned above, the synthesis of a class (Scheme 1b), herein we desired to provide another novel strat-
of indanone-derived spiropyrrolidone compounds is obviously
of very important potential medicinal significance. However, it
is surprising that the enantioselective synthesis of such
scaffolds has not been reported thus far.
a
School of Chemistry and Chemical Engineering Beijing Institute of Technology, 5
South Zhongguancun Street, Beijing 100081, P. R. China. E-mail: dudm@bit.edu.cn;
http://cce.bit.edu.cn/
b
Analytical and Testing Center, Beijing Institute of Technology, Liangxiang Campus,
Liangxiang East Road, Beijing 102488, People’s Republic of China
1
13
†
Electronic supplementary information (ESI) available: Copies of H and
C
NMR spectra of new compounds, and HPLC chromatograms. CCDC 2081838.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1ob01223a
‡
These two authors contributed equally.
Fig. 1 Some pharmaceutical scaffold motifs and our product.
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Table 1 Screening of the organocatalysts and optimization of the reac-
a
tion conditions
b
c
d
Entry
Solvent
Catalyst
Yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
C1
C2
C3
C4
C5
C6
C7
C8
97
61
72
63
97
99
71
92
87
69
71
22
74
84
78
83
50
72
94
98
91
88
99
82
>99
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
−84
−82
−80
−76
85
84
80
92
C9
−78
−80
−43
−83
−79
51
0
−71
0
64
93
84
84
65
85
43
88
10
11
12
13
14
15
16
17
18
19
C10
C11
C12
C13
C14
C15
C16
C17
C8
C8
C8
C8
C8
Scheme 1 Asymmetric synthesis of spiropyrrolidone derivatives.
CN
egy to enantioselectively construct a series of indanone-derived
spiropyrrolidone compounds via the Michael addition/cycliza- 20
AcOEt
DCE
CHCl
Toluene
AcOEt
AcOEt
AcOEt
21
22
23
3
tion cascade reaction of 2-isothiocyanato-1-indanones with
-arylmethylidene-2,3-dioxopyrrolidines (Scheme 1c). Notably,
4
e
f
C8
C8
C8
this protocol provides direct access to indanone-derived spiro- 24
pyrrolidone compounds, which are difficult to access using
g
25
other methods.
a
Unless otherwise noted, the reactions were carried out with 1a
(
0.1 mmol), 2a (0.12 mmol), and catalyst (5 mol%) in 2.0 mL of solvent
b
at room temperature (25 °C) for 15 h. Isolated yield after purification
c
1
by column chromatography. Determined by HNMR analysis.
d
f
e
Determined by HPLC analysis. The reaction was performed at 0 °C.
Results and discussion
g
The reaction was performed at −30 °C. The reaction was performed
at 50 °C.
To test the feasibility of our reaction, we set out to evaluate the
reaction conditions using 4-benzylidene-2,3-dioxopyrrolidine
1
a and 2-isothiocyanato-1-indanone 2a as model substrates.
We found that the reaction could smoothly proceed under the (Table 1, entries 9 and 10). Under the same experimental con-
basic conditions, so various cinchona-derived organocatalysts ditions, the catalytic effects of catalyst C11 and the catalysts
(
Fig. 1) were screened in this reaction (Table 1, entries 1–13). derived from thiourea C12 and C13 were not satisfactory
Firstly, in the presence of squaramide C1, the desired [3 + 2] (Table 1, entries 11–13). The cinchonidine-derived catalyst C14
annulation occurred to yield ent-3aa in 97% yield with 84% ee was also tested, and it had a lower enantioselectivity (Table 1,
and >20 : 1 dr (Table 1, entry 1). Then several widely used entry 14). Meanwhile, some other catalysts were also employed
quinine-derived squaramide catalysts C2–C4 were tested (Table 1, entries 15–17), such as the different hydrogen-bond
(
Table 1, entries 2–4), and we were delighted to find that C1 donor catalyst C15, the cyclohexanediamine-derived squara-
worked well for the annulation reaction. Next, we attempted to mide catalyst C16 and catalyst C17, but they all did not work
improve the results by changing the pseudo-enantiomer of the well. It is obvious that the cinchona squaramide catalysts used
organocatalysts, and a few quinidine-derived catalysts C5–C8 in this study have advantages compared with other organo-
were used. In the view of the experimental results, we can see catalysts described in the manuscript (Fig. 2).
that the quinidine-derived catalyst had a better effect than the
After a preliminary screening of the catalysts, a study of the
series of quinine-derived catalysts, and the enantiomer 3aa solvent effect using C8 as the best organocatalyst was carried
was obtained (Table 1, entries 5–8). Among them, the mono- out. Compared with the other solvents, AcOEt exhibited excel-
nitro substituted hydroquinidine-derived squaramide catalyst lent reactivity (94% yield) with excellent enantio- and
C8 performed most prominently and afforded 3aa in 92% yield diastereoselectivity (93% ee and >20 : 1 dr). We also investi-
with 92% ee and >20 : 1 dr (Table 1, entry 8). Afterwards, we gated the reaction temperature and the concentration of the
also screened the catalysts derived from cinchonidine, and substrates; neither lowering nor increasing the temperature
found that it did not greatly improve the effect of the reaction was helpful in the improvement of the effect (Table 1, entries
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Fig. 2 The screened organocatalysts for the reaction.
2
3–25). The solubility of squaramide-derived catalysts in
organic solvents is actually not very good, especially the nitro-
substituted quinidine-derived catalyst C8. We performed this
reaction at 50 °C to increase the solubility of the catalyst by
increasing the temperature, and it maybe promoted the ee
value. Since the temperature increase inevitably promotes the
occurrence of background reaction and poor chiral control, the
ee value decreases. When the temperature is lowered, the solu-
bility of the catalyst and substrates may be affected, thereby
destroying the best catalytic effect, and the ee value decreases.
At the same time, lowering the temperature will also affect the
catalytic effect of the catalyst; the catalytic reaction is actually a Scheme 2 Substrate scope for the asymmetric addition reaction.
competitive process between the background reaction and Reactions were carried out by using 1 (0.1 mmol), 2 (0.12 mmol), and
catalyst C8 (5 mol%) in 2.0 mL of AcOEt at room temperature for 15 h.
The dr value was determined by H NMR and the ee value was deter-
mined by HPLC analysis.
catalytic reaction, and room temperature gave the best result
for this reaction. From the above conditions evaluated, the
1
optimized reaction conditions were as follows: 4-arylmethyl-
idene-2,3-dioxopyrrolidine 1a and 2-isothiocyanato-1-inda-
nones 2a at a molar ratio of 1 : 1.2 in 2 mL of AcOEt with
5
mol% catalyst C8 at room temperature for 15 h.
After the optimal conditions were obtained, the applica- decreased in enantioselectivities (Scheme 2, 3fa, 3ia). In par-
bility of different substrates to this Michael addition/cycliza- ticular, for the nitro substituent group at the 3-position
tion cascade reaction was investigated. As summarized in (Scheme 2, 3ga), the yield and enantioselectivity decreased dra-
Scheme 2, a wide range of different substrates of 2,3-dioxopyr- matically (60% yield, 77% ee). Subsequently, we tested the
rolidines 1 were tolerated under the optimized conditions. It 4-position substituted group (Scheme 2, 3ka–oa) and it showed
was found that electron-donating or halogen substituents at high yields and enantioselectivities (up to >99% yield and up
the 2-position on the benzene ring (Scheme 2, 3ba–ea) pro- to 91% ee). To further estimate the efficiency of the method-
vided good yields (up to 87%) with excellent enantio- and ology, the 2,3-dioxopyrrolidines derived from thiophene and
diastereoselectivities (up to 94% ee and >20 : 1 dr). naphthaldehyde were also employed (Scheme 2, 3pa–ra), and
Subsequently, we exploited 2,3-dioxopyrrolidine substrates the thiophene-derived product had good yield and excellent
with substituents with different electronic effects at the 3-posi- enantioselectivity (71% yield and >99% ee). The 2-naphthyl
tion of the benzene ring (Scheme 2, 3fa–ja). We can see in substituted product showed more satisfactory results (92%
Scheme 2 that the electron-donating group maintained the yield and 94% ee) than the 1-naphthyl substituted product
target products with excellent yields and enantioselectivities (60% yield and 75% ee), probably due to the steric hindrance.
(
3ha and 3ja), but the halogen group substituted 2,3-dioxopyr- We once tried alkyl aldehydes such as butyraldehyde and pro-
rolidine compounds decreased a lot in yields and slightly pionaldehyde to construct some 4-alkylidene-2,3-dioxopyrroli-
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dines, but failed in synthesizing the corresponding 4-alkyli-
dene-2,3-dioxopyrrolidines.
After investigating the substrate scope of 2,3-dioxopyrroli-
dines, we explored further the scope of 2-isothiocyanato-1-
indanones. 2-Isothiocyanato-1-indanones with electron-donat-
ing and withdrawing groups (3ab–ad) at the 5 or 6-position all
showed excellent results (up to 94% yield and up to 93% ee).
The other 2-isothiocyanato-1-indanones showed poor
efficiency except for two of them which cannot be separated by
HPLC.
The absolute configuration of the target product 3ja was
8
identified by single crystal X–ray diffraction analysis. The
absolute configuration of 3ja was determined to be (2R,3′R,4′S)
(Fig. 3). The absolute configurations of the other products
were assigned by analogy.
Afterwards, we also attempted to conduct some derivatiza-
tion studies to illustrate the synthetic potential of the cascade
reaction. As shown in Scheme 3, the corresponding chiral
product 3qa could easily react with MeI in the presence of
K CO , and the methylation product 4 could be obtained in
high yield with enantioselectivity maintained. Simultaneously,
the transformation of the thiolactam moiety to lactam was
also attempted. 3qa reacted with aqueous hydrogen peroxide
2
3
Scheme 4 Proposed mechanism for the reaction.
initial Michael reaction step. Simultaneously, the catalyst acti-
vates 2,3-dioxopyrrolidines 1 by hydrogen bonds and the enol
ion attacks the double bond of 1a from the Si face via inter-
mediate A. Afterwards, the newly generated anion on the
α-carbon center of 1a attacks the carbon atom of the isothio-
cyanato moiety in the intramolecular cyclization reaction
through the intermediate B. The final adduct 3aa is obtained
via protonation through intermediate C, and the catalyst C8 is
removed to enter the next cycle.
2 2
and formic acid in CH Cl , and the target product 5 was
obtained in high yield with a small decrease in enantio-
selectivity. Meanwhile, the optically pure product 3la (>99%
ee) could be obtained via recrystallization from its 89% ee
product, and this may be useful for further modifications to
synthesize pharmaceutical or biologically active compounds.
On the basis of the experimental results and the absolute
configuration of 3ja, we speculated a plausible mechanism
(Scheme 4). The squaramide C8 promotes the cycloaddition
reaction to generate 3aa in a dual activation model. The 2-iso-
thiocyanato-1-indanone is enolized via quinidine amine in the
Conclusions
In summary, we have developed a highly enantioselective
Michael addition/cyclization cascade reaction of 4-arylmethyl-
idene-2,3-dioxopyrrolidines with 2-isothiocyanato-1-indanones
under the catalysis of a chiral squaramide catalyst derived
from quinidine. The desired indanone-derived spiropyrroli-
done products bearing three adjacent stereocenters were
obtained in good to excellent yields (up to 99%) with excellent
stereoselectivities (up to >20 : 1 dr and >99% ee). Furthermore,
this cascade reaction may provide a convenient method for the
synthesis of other potentially bioactive spiropyrrolidone
derivatives.
Fig. 3 X-ray crystal structure of 3ja.
Experimental
General methods
All solvents and chemicals commercially available were used
without further purification. Column chromatography was per-
formed with silica gel (200–300 mesh) using mixtures of pet-
roleum ether and ethyl acetate. Melting points were deter-
Scheme 3 Further investigation of the potential utility of the reaction.
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silane and referenced to the solvent peak (CDCl , δ(C) =
7
patterns are described as singlet (s), doublet (d), triplet (t),
quartet (q), and multiplet (m). High-resolution mass spectra
were obtained with an Agilent 6520 Accurate-Mass-Q-TOF MS
system equipped with an electrospray ionization (ESI) source.
The enantiomeric excesses were determined by chiral HPLC
3
6
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General procedure for the asymmetric Michael addition/
cyclization reaction for the synthesis of compounds 3
To a dried small bottle were added 2,3-dioxopyrrolidines 1
(0.1 mmol), 2-isothiocyanato-1-indanone 2 (0.12 mmol), and
squaramide catalyst C8 (5 mol%) in 2.0 mL of AcOEt at room
temperature. The reaction mixture was stirred for 15 h and the
progress of the reaction was monitored by TLC analysis (pet-
roleum ether/ethyl acetate = 1 : 1). After the completion of the
reaction, the crude product mixture was purified by flash
column chromatography on silica (petroleum ether/ethyl
acetate = 5 : 1–3 : 1) to afford the pure product 3. The racemic
standard of 3 was prepared using an achiral catalyst.
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Conflicts of interest
(
There are no conflicts of interest to declare.
4
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2
1272024) and the Graduate Technology Innovation Project of
Beijing Institute of Technology (2019CX20043). We also thank
the Analysis & Testing Center of Beijing Institute of Technology
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Notes and references
1
For selected reviews and examples, see: (a) R. Rios, Chem. 7 B.-L. Zhao and D.-M. Du, Org. Lett., 2018, 20, 3797–3800.
Soc. Rev., 2012, 41, 1060–1074; (b) L. K. Smithand and 8 CCDC 2081838† (for 3ja) contains the supplementary crys-
I. R. Baxendale, Org. Biomol. Chem., 2015, 13, 9907–9933; tallographic data for this paper.
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