Enantioselective Construction of Spirooxindole-Fused Cyclopenta[c]chromen-4-ones Bearing Five Contiguous Stereocenters via a Stepwise (3+2) Cycloaddition

Article abstract of DOI:10.1002/adsc.201901655

The bifunctional quinine-catalyzed stepwise (3+2) cycloaddition for the enantioselective construction of spirooxindole-fused cyclopenta[c]chromen-4-ones is developed. The reactions of 3-homoacylcoumarins and alkylidene oxindole electrophiles generate aforementioned spirooxindole-chromenone adducts bearing five contiguous stereocenters, of which one is the spiro all-carbon quaternary stereocenter in high yields (up to 99%) with excellent stereoselectivities (up to >20:1 dr and 99% ee). This methodology was investigated for three different alkylidene oxindole electrophiles and could also be practically demonstrated on a gram scale. Mechanistic investigations revealed that the (3+2) cycloaddition for the enantioselective synthesis of spirooxindole-fused cyclopenta[c]chromen-4-ones is proceeding via a stepwise reaction pathway. (Figure presented.).

Full text of DOI:10.1002/adsc.201901655

Title: Enantioselective Construction of Spirooxindole-Fused
Cyclopenta[c]chromen-4-ones Bearing Five Contiguous
Stereocenters via a Stepwise (3+2) Cycloaddition
Authors: Sandip Sambhaji Vagh, Praneeth Karanam, Cheng-Chieh
Liao, Ting-Han Lin, Yan-Cheng Liou, Athukuri Edukondalu, Yi-
Ru Chen, and Wenwei Lin
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901655
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Construction of Spirooxindole-Fused
Cyclopenta[c]chromen-4-ones Bearing Five Contiguous
Stereocenters via a Stepwise (3+2) Cycloaddition
Sandip Sambhaji Vagh,a,† Praneeth Karanam,a,† Cheng-Chieh Liao,a Ting-Han Lin,a
Yan-Cheng Liou,a Athukuri Edukondalu,a Yi-Ru Chena and Wenwei Lina,*
a
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei 11677, Taiwan,
R.O.C. Fax: (+886) 2-2932-4249; Email: wenweilin@ntnu.edu.tw
†
These authors contributed equally.
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))
hand, coumarin derivatives such as cyclopentane-
(3+2) cycloaddition for the enantioselective construction of fused coumarins are considered as important motifs
Abstract. The bifunctional quinine-catalyzed stepwise
spirooxindole-fused
cyclopenta[c]chromen-4-ones
is
in medicinal chemistry and feature in many alkaloids
and sesquiterpenes.[6] The fusion of spirooxindole and
coumarin would give rise to new templates which
may hold potential for drug discovery based on the
individual medicinal strength of spirooxindole- and
coumarin-based drugs.
Our group has long been working toward the
development of novel organocatalytic reactions in
generating complex molecular architectures.[7] In
2018, we reported a quinine-derived bifunctional
thiourea-catalyzed concerted (3+2) cycloaddition
reaction for the highly stereoselective synthesis of
developed. The reactions of 3-homoacylcoumarins and
alkylidene oxindole electrophiles generate aforementioned
spirooxindole-chromenone adducts bearing five contiguous
stereocenters, of which one is the spiro all-carbon
quaternary stereocenter in high yields (up to 99%) with
excellent stereoselectivities (up to >20:1 dr and 99% ee).
This methodology was investigated for three different
alkylidene oxindole electrophiles and could also be
practically demonstrated on a gram scale. Mechanistic
investigations revealed that the (3+2) cycloaddition for the
enantioselective
cyclopenta[c]chromen-4-ones is proceeding via a stepwise
reaction pathway.
synthesis
of
spirooxindole-fused
five
membered
coumarin/indanedione-fused
spirocyclopentanes
bearing
four
contiguous
stereocenters.[8] Inspired from our previous work, we
were keen on developing a (3+2) cycloaddition
reaction for spirooxindole scaffolds, utilizing 3-
Keywords: spiro compounds; cyclopenta[c]chromen-4-
ones; stepwise (3+2) cycloaddition; organic catalysis; 3-
homoacylcoumarins
homoacylcoumarin
and
alkylidene
oxindole
electrophiles. The supposed cycloaddition reaction
would lead to less explored hybrid scaffolds that
comprise both the privileged moieties and also bear
five contiguous stereocenters, including a quaternary
spiro-stereocenter. In this context, we report a
bifunctional quinine derivative-catalyzed, highly
enantioselective (3+2) cycloaddition reaction for the
The spirooxindole skeleton has immense importance
in modern organic chemistry because of its
prevalence in both natural products and biologically
active
molecules.[1]
Consequently,
intensive
investigation regarding their synthesis has been going
on recently.[2] Although various elegant methods have
been documented for the synthesis of these privileged
motifs,[3] contrastingly, the methods to access
spirooxindole scaffolds bearing an all-carbon
quaternary spiro-stereocenter on the cyclopentane
ring are underdeveloped.[4] The key challenge en
route to chiral spirooxindole is formation of multiple
stereocenters with a quaternary spiro-stereocenter in
highly enantioselective manner. More importantly,
enantioselective methods for the generation of
spirocyclopentane oxindoles which forms the core of
many potent drugs are very scarce.[5] On the other
generation
of
complex
spirooxindole-fused
cyclopenta[c]chromen-4-ones in high yields and
excellent enantioselectivities.
1
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
indicated time after which no considerable improvement in
[c]
the yield of 3aa was observed.
Yield of the 3aa was
1
determined by H NMR analysis of the crude reaction
mixture using 1,3-dinitrobenzene as an internal standard. [d]
Enantiomeric excess was determined by HPLC analysis on
[e]
a chiral stationary phase.
Enantiomer of 3aa was
[f]
[g]
obtained. Catalyst IV (10 mol%) was used.
IV (5 mol%) was used.
Catalyst
Initially, the (3+2) cycloaddition reaction between
3-homoacylcoumarin (1a) and N-Boc protected
methyleneindolinone (2a) was carried out with 20
mol% of 1,4-diazabicyclo[2.2.2]octane (DABCO) in
CH2Cl2 at 30 °C. We were pleased to notice the
formation of spiroxindole 3aa in 99% yield after 12 h
(entry 1, Table 1). Encouraged by this result, we next
examined a series of bifunctional hydrogen-bonding
catalysts (entries 2-5). Among them (Figure 1),
catalyst IV was found to be better interms of both
yield and enantioselectivity (93% yield and 98% ee,
entry 5). To test the influence of hydrogen-bonding
activation, several other squaramide derivatives
(entries 6-8) were screened (see Supporting
Information for detailed optimization). Although all
of them are found to effectively catalyze the (3+2)
cycloaddition reaction, catalyst IV was still found to
be superior. Interestingly, the pseudo enantiomeric
catalyst VI also showed very good catalytic activity
to afford the enantiomer of the product 3aa in good
yield and high enantioselectivity (83% yield and 95%
ee, entry 7). Having found the choice of catalyst,
solvent screening was carried out (entries 9-13).
While the solvents such as CHCl3, CH3CN, THF and
EtOAc, provided comparable results, EtOH as
solvent, afforded the product in relatively poor yield
and ee, presumably due to the disruption of
hydrogen-bonding between the catalyst and the
substrates by the solvent. It is worthy to note that in
all cases, the diastereoselectivity was found to be
excellent (>20:1). Decreasing the catalyst loading
also resulted in similiar yields and ee values, albeit
after longer reaction times (entries 14 and 15). Thus,
the optimal conditions for 3aa were established with
5 mol% of catalyst IV and CH2Cl2 as the solvent at
30 °C (entry 15).
Figure 1. Chiral Catalysts Screened for the Reaction.
Table 1. Optimization of Reaction Conditions.[a]
entry catalyst
solvent
t
3aa
ee
(h)[b] (%)[c] (%)[d]
1
2
3
4
5
6
7
8
DABCO
I
II
III
IV
V
VI
VII
IV
IV
IV
IV
IV
IV
IV
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CH3CN
THF
12
12
2
2
2
2
2
2
2
2
3
2
5
6
12
99
59
89
86
93
87
83
78
92
73
92
93
67
93
93
rac
20
73[e]
96
98
94
95[e]
91[e]
97
9
10
11
12
13
14[f]
15[g]
95
97
97
82
98
98
EtOAc
EtOH
CH2Cl2
CH2Cl2
[a] Unless otherwise specified, all the reactions were carried
out using 1a (0.1 mmol), 2a (1.1 equiv) and catalyst (20
[b]
mol%) in the given solvent (0.5 mL) at 30 °C.
The
Table 2. Substrate Scope of (3+2) Cycloaddition Reaction.[a,b,c]
2
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
[a]
Unless otherwise specified, all the reactions were carried out using 1 (0.3 mmol), 2
(1.1 equiv) and catalyst IV (5 mol%) in CH2Cl2 (1.5 mL) at 30 °C. [b] Isolated yield. [c]
Enantiomeric excess was determined by HPLC analysis on a chiral stationary phase.
[d]
[e]
Reaction was performed on a gram scale of 1a (4 mmol, 1.05 g). Catalyst IV (30
mol%) was used. [f] Diastereomeric ratio was 6:1. [g] Diastereomeric ratio was 10:1.
Having the optimized conditions in hand, we set
of the reaction, substrates with other N-protecting
groups, such as methyl, benzyl and acetyl groups,
were also investigated. All the substrates were
tolerated well in the reaction to afford the
corresponding products 3ai-3ak, albeit requiring
much longer reaction times. These substrates were
furnished with lower yields and diastereoselectivities
when compared to those of the substrates bearing a
N-Boc substitution. It is worth noting that the reaction
for 3aa could be performed on a gram scale with
similar efficiency.
out to investigate the substrate scope of the (3+2)
cycloaddition reaction with respect to both the
substrates (Table 2). Initially, the scope of 3-
homoacylcoumarin 1 bearing various R1 and R2
groups were tested. In general, all the tested
substrates 1 reacted smoothly with 2a to give the
products 3aa-3ha in high yields and excellent
enantioselectivites, regardless of their electronic
nature. Notably, the substrate 1d bearing a R1 = Me
substitution, afforded 3da in relatively lower yield,
although excellent enantioselectivity was maintained.
Additionally, the substrate 1h with R2 = 5-OH
substitution on the coumarin ring required higher
loading of the catalyst (30 mol%) to result
corresponding product 3ha. This further demonstrates
that the hydrogen-bonding between the substrate and
the catalyst has great influence on the reaction. Next,
various alkylidene oxindole esters 2 bearing different
R3 and R4 groups were tested for the reaction with 1a.
Substrates bearing Me and t-Bu esters, such as 2b and
2c, also afforded corresponding products 3ab and 3ac
with excellent enantioselectivities. Furthermore, the
effect of various R4 substituents on the aromatic ring
of oxindole esters was also investigated. It was
delightful to observe the formation of corresponding
products 3ad-3ag in excellent yields and
enantioselectivities, regardless of the nature and
position of the substitution. The substrate with a
strong electron-withdrawing group, such as 2h (R4 =
5-NO2), also furnished the desired product 3ah in
75% yield and 94% ee, albeit with moderate
diastereomeric ratio (6:1). Finally, for the generality
After successful application of alkylidene oxindole
esters 2 in (3+2) cycloaddition reaction, we wish to
explore the utility of alkylidene oxindoles bearing a
ketone group. Accordingly, the substrate 4a was
examined with 1a under the optimized conditions
(see
Supporting
Information
for
detailed
optimization). Although the same catalytic system
(catalyst IV) was effective in delivering 5aa bearing
five contiguous stereocenters, the catalyst loading had
to be doubled in CH2Cl2 (0.1 M) to obtain the optimal
results as shown in Scheme 1.
Scheme 1. Optimal Conditions for 5aa.
3
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
Examination of the substrate scope with respect to
Next, several control experiments have been
performed to investigate the mechanism. The reaction
of the alkylidene oxindole ester 2a and the catalyst
IV has been examined in CH2Cl2 at 30 °C for 12 h.
E/Z-isomerization was observed by the analysis of 1H
NMR spectrum, and the ratio of E/Z-isomers of
alkylidene oxindole ester 2a was 90:10. Furthermore,
subsequent addition of 3-homoacylcoumarin (1a) to
the reaction mixture furnished the desired product
3aa in 90% yield and lower enantioselectivity (85%
ee) after 15 h. Interestingly, the reaction of the
alkylidene oxindole ketone 4a with the catalyst IV
shows no E/Z-isomerization in CH2Cl2 after 12 h, and
further treatment with 3-homoacylcoumarin 1a
afforded the desired product 5aa in 75% yield and
97% ee which is almost similar ee as standard
condition (Scheme 2). It could be understood that the
reaction of E-isomer of 2a/4a with 1a provides the
desired products 3aa and 5aa with high ee values, but
the enantioselectivity of the product 3aa has been
diminished by the formation of Z-isomer of 2a.
both the substrates 1 and 4 revealed slightly lower
yields for most of the products 5, when compared to
the adducts 3 formed from 1 and 2, albeit with
excellent ee values (Table 3). Again, the substrate 1d
showed less reactivity towards 4a to afford adduct
5da in poor yield, along with formation of a
diastereomer 5da' in 2:1 ratio. It is worth noting that
ee was still excellent and the diastereomer 5da' was
easily separated by using flash chromatography and
subsequently confirmed by X-ray analysis.[9] The less
reactive substrate 1h bearing a R2 = 5-OH group was
found to be unreactive after 48 h, even usage of
higher loading of the catalyst (30 mol%). The low
reactivity of the alkylidene oxindole ketone 4a
compared to the alkylidene oxindole ester 2a could
be the reason. Furthermore, substrates bearing
different R5 and R6 groups on 4 also afforded the
desired products 5ab-5af in good yields and excellent
enantioselectivities under the optimized conditions.
The alkylidene oxindole substrate bearing
a
heteroaryl substitution such as 4e (2-furyl) also
afforded the corresponding product 5ae in good yield
and excellent stereoselectivities (80% yield, >20:1 dr
and 98% ee). In addition, the preparative utility of
this (3+2) cycloaddition reaction, was also
demonstrated by performing a gram scale reaction for
5aa under the same conditions.
Table 3. Substrate Scope of 5.[a,b,c]
Scheme 2. Isomerization of 2a/4a with Catalyst IV.
Generally, the (3+2) cycloaddition could proceed
either via a concerted pathway or a stepwise double
Michael cascade pathway. Based on the absolute
configurations of products 3aa/5aa, we have
constructed possible reaction models in the concerted
reaction pathway for formation of 3aa/5aa from E-
isomer of 2a/4a and 1a in presence of the catalyst.
But we could not find the exact configurations of
3aa/5aa from that of the possible proposed concerted
product. Instead, the epimer of the desired product
(epi-3aa/5aa) should observed in the concerted
pathway (Scheme 3). Notably, even the exact
configuration of proposed concerted product provided
from the Z-isomer of 2a/4a with 1a is contradictory
to the results in control experiments (Scheme 2).
Therefore, one of the possibilities of formation of the
aforementioned products from E-isomer in (3+2)
cycloaddition via a concerted pathway is ruled out.
Next, we have considered (3+2) cycloaddition
reaction through a stepwise double Michael cascade
reaction pathway to lead the desired products from
the E-isomer of 2a/4a and 1a.
[a] Unless otherwise specified, all the reactions were carried
out using 1 (0.2 mmol), 4 (1.1 equiv) and catalyst IV (10
[b]
[c]
mol%) in CH2Cl2 (2 mL) at 30 °C.
Isolated yield.
Enantiomeric excess was determined by HPLC analysis on
[d]
a chiral stationary phase. Reaction was performed on a
Based on all these results and the absolute
configurations of products, a plausible reaction
mechanism is presented in Scheme 3. Initially, chiral
catalyst IV activates the 3-homoacylcoumarin 1a by
deprotonation to provide a conjugate acid-base pair
with H-bonding interactions. The first Michael
[e]
gram scale of 1a (3.8 mmol, 1.0 g).
performed on 0.4 mmol scale.
Reaction was
[f]
Diastereomeric ratio of
5da and 5da' was 2:1. [g] Catalyst IV (30 mol%) was used.
n.r. = No reaction with the recovery of 1h and 4a.
4
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
addition from the Re face attack of 1a to the Re face
of the alkylidene oxindole ester 2a or ketone 4a
provides the Michael adduct A. The squramide NH
group of IV forms the hydrogen bonding with the
carbonyl group of Michael adduct A. The H-bonding
interactions along with the steric hindrance would
lead to the favorable confirmer of the Michael adduct
A to provide 3aa/5aa with observed configurations.
Subsequently, second Michael addition of oxindole
with its Re face to the Si face of coumarin to afford
3aa/5aa in good yields with high enantioselectivities.
Scheme 3. Plausible Mechanism for 3aa and 5aa.
mol%) in CH3CN (0.2 M) as solvent at 30 °C in 9 h
(Scheme 4).
Again, substrates 1 and 6 possessing different
substitutions were examined for their applicability. In
general, all reactions resulted in good to excellent
yields and good enantioselctivites irrespective of
nature of the substrates and position of the
substitution (Table 4). Substrates bearing different R1
and R2 groups on 1 reacted well with 6a to provide
the corresponding products 7aa-7ka in 63-99% yields
and 73-90% ee values. The substrate 1h (R2 = 5-OH)
also well tolerated with 6a to furnish the
corresponding product 7ha in 63% yield and 90% ee.
Notably, the benzylidene oxindole 6f bearing an
ortho-OH substituent was found to be unreactive.
Delightfully, the substrate bearing the naphthyl (6g)
group also furnished the corresponding product 7ag
in good yield and selectivity, albeit requiring longer
reaction time. In addition, the substrate 6h bearing a
furyl group was tolerated to afford the desired
product 7ah in relatively lower yield and
Scheme 4. Optimal Conditions for 7aa.
Having successfully extended the scope of
alkylidene oxindole electrophiles, we further tested
the applicability of benzylidene oxindoles in the
(3+2) cycloaddition reaction. Accordingly, E-
benzylidene oxindole 6a was tested for the reaction
with 1a. However, our previous choice of the catalyst
IV was not efficient. Therefore, further detailed
optimization studies had to be carried out (see
Supporting Information). Subsequently, the optimal
yield of the adduct 7aa (99% yield, >20:1 dr, 90% ee)
was obtained when 1a and 6a (1.2 equiv) were
reacted in the presence of the catalyst VIII (20
5
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
enantioselectivity. Furthermore,
a
gram scale
The removal of Boc group from 3aa, 5ea and 7ea
was conducted smoothly by treatment with TFA in
CH2Cl2 at 30 °C to result the corresponding products
8aa, 9ea and 10ea in high yields without erosion of
enantioselectivity (Scheme 6). The absolute
configurations of products 3, 5 and 7 were established
by single crystal X-ray diffraction analysis of the
corresponding Boc-deprotected compounds 8-10.[9]
preparation of 7aa was found to be equally efficient.
Table 4. Substrate Scope of 7.[a,b,c]
Scheme 6. Deprotection of Compounds 3aa/5ea/7ea.
In conclusion, we have developed a bifunctional
quinine
derivative-catalyzed
stepwise
(3+2)
cycloaddition reaction for the generation of complex
spirooxindole adducts in high yields (up to 99%),
good to excellent diastereoselectivities (up to >20:1
dr) and excellent enantioselectivities (up to 99% ee).
Apart from bearing five contiguous stereocenters,
including a spiro all-carbon quaternary stereocenter,
the products also incorporate a biologically active
[a] Unless otherwise specified, all the reactions were carried
out using 1 (0.2 mmol), 6 (1.2 equiv), catalyst VIII (20
[b]
[c]
mol%) in CH3CN (1 mL) at 30 °C.
Isolated yield.
spirooxindole
moiety
as
well
as
a
Enantiomeric excess was determined by HPLC analysis on
cyclopenta[c]chromen-4-one core which are core
structures of many natural products. Different
Michael acceptors such as alkylidene oxindole esters,
ketones and benzylidene oxindoles were investigated
for the substrate scope of this stepwise (3+2)
cycloaddition reaction. In addition, the reaction could
be performed on a gram scale with similar efficacy.
The mechanistic investigations proved that this is a
[d]
a chiral stationary phase. Reaction was performed on a
gram scale of 1a (3.8 mmol, 1.0 g). n.r. = No reaction with
the recovery of 1a and 6f.
To investigate the differentiation between
enantioselectivities of desired products from
alkylidene oxindole carbonyl derivatives 2/4 and
benzylidene oxindole derivatives 6, we have
performed crucial control experiments. The reaction
of benzylidene oxindole (6a) and catalyst VIII in
CH3CN provided the ratio of E/Z-isomers of 6a in
80:20 within 9 h. Furthermore, addition of 3-
homoacylcoumarin (1a) to the reaction mixture
furnished the desired product 7aa with 73% ee which
is lower than that obtained in the standard condition
(Scheme 5). It was found that the predominating
factor for the diminished enantiomeric ratios of the
final products 7 in comparison with 3 and 5, is the
isomerization ability of their benzylidene oxindole
derivatives 6. In the presence of chiral catalyst,
isomerization of alkylidene oxindole ester 2 and
ketone 4 derivatives to their Z-isomers are much
slower than the benzylidene oxindole derivatives 6.
(3+2) cycloaddition reaction via
a
stepwise
Michael/Michael cascade pathway instead of
concerted pathway. We have found that 3-
homoacylcoumarin as 1,3-dipole precursor proceeds
the stepwise (3+2) cycloaddition reaction with
unsymmetrical alkylidene oxindole electrophiles
whereas a concerted (3+2) cycloaddition has been
reported with symmetric indandione alkylidenes.[8]
Further studies regarding the application of 3-
homoacylcoumarin in other organocatalytic reactions
are underway in our laboratory.
Experimental Section
Typical procedure for the synthesis of spirooxindole-
fused cyclopenta[c]chromen-4-ones 3: A capped glass
vial equipped with a magnetic stir bar was charged with 1
(0.3 mmol), 2 (1.1 equiv), catalyst IV (9.4 mg, 5 mol%)
and CH2Cl2 (1.5 mL) and stirred at 30 °C. The progress of
1
the reaction was monitored by TLC and H NMR data
analysis. After the completion of reaction, 1N HCl (5 mL)
was added and extracted with CH2Cl2 (2x3 mL). The
combined organic extracts were dried over anhydrous
Na2SO4 and concentrated in vacuo and the crude residue
was subjected to flash column chromatography over silica
gel (hexanes/EtOAc) to afford pure spirooxindole-fused
cyclopenta[c]chromen-4-ones 3.
Scheme 5. Isomerization of 6a with Catalyst VIII.
6
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
Typical procedure for the synthesis of spirooxindole-
fused cyclopenta[c]chromen-4-ones 5: A capped glass
vial equipped with a magnetic stir bar was charged with 1
(0.2 mmol), 4 (1.1 equiv), catalyst IV (12.6 mg, 10 mol%)
and CH2Cl2 (2.0 mL) and stirred at 30 °C. The progress of
[3] a) Y.-C. Zhang, F. Jiang, F. Shi, DOI:
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Yuan, Adv. Synth. Catal. 2015, 357, 3007-3031; g) D.
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1
the reaction was monitored by TLC and H NMR data
analysis. After the completion of reaction, the reaction
mixture was concentrated in vacuo and the crude residue
was subjected to flash column chromatography over silica
gel (hexanes/EtOAc) to obtain pure spirooxindole-fused
cyclopenta[c]chromen-4-ones 5.
Typical procedure for the synthesis of spirooxindole-
fused cyclopenta[c]chromen-4-ones 7: A capped glass
vial equipped with a magnetic stir bar was charged with 1
(0.2 mmol), 6 (1.2 equiv), catalyst VIII (13.1 mg, 20
mol%) and CH3CN (1.0 mL) and stirred at 30 °C. The
1
progress of the reaction was monitored by TLC and H
NMR data analysis. After the completion of reaction, the
reaction mixture was concentrated in vacuo and the crude
residue was subjected to flash column chromatography
over silica gel (hexanes/EtOAc) to obtain pure
spirooxindole-fused cyclopenta[c]chromen-4-ones 7.
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Acknowledgements
The authors thank the Ministry of Science and Technology of the
Republic of China (MOST 107-2628-M-003-001-MY3) for
financial support.
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
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[9] See Supporting Information for crystal data of
compounds 5ac (CCDC 1962249), 8aa (CCDC
1948942), 9ea (CCDC 1911409), 10ea (CCDC
1893243) and 5da' (CCDC 1959572). It is worth
noting that the stereo-configuration of 5da'is different
from that of the proposed concerted product epi-5da.
8
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10.1002/adsc.201901655
Advanced Synthesis & Catalysis
COMMUNICATION
Enantioselective Construction of Spirooxindole-
Fused Cyclopenta[c]chromen-4-ones Bearing Five
Contiguous Stereocenters via a Stepwise (3+2)
Cycloaddition
Adv. Synth. Catal. Year, Volume, Page – Page
Sandip Sambhaji Vagh,† Praneeth Karanam,†
Cheng-Chieh Liao, Ting-Han Lin, Yan-Cheng
Liou, Athukuri Edukondalu, Yi-Ru Chen and
Wenwei Lin*
9
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