Catalytic asymmetric hetero-Diels-Alder reactions of enones with isatins to access functionalized spirooxindole tetrahydropyrans: Scope, derivatization, and discovery of bioactives

Article abstract of DOI:10.1039/c5ob02393a

The development of concise methods for the synthesis of functionalized small molecules is important in the search for new bioactive molecules. To contribute to this, we have developed oxa-hetero-Diels-Alder reactions of enones with isatins catalyzed by amine-based catalyst systems. Various spirooxindole tetrahydropyranones were synthesized either in enantiomerically enriched forms or as racemic forms depending on the catalyst system. The reaction products were further transformed at the ketone carbonyl group and the indole nitrogen. Using these reactions, functionalized spirooxindole tetrahydropyran derivatives with functional groups in four directions in a three-dimensional space were concisely obtained. From these synthesized compounds, an inhibitor of human ion channel Nav1.7 with μM-level activity was identified, indicating that the developed reaction methods are useful for providing molecules for the discovery of new biofunctional molecules.

Full text of DOI:10.1039/c5ob02393a

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Catalytic Asymmetric Hetero-Diels-Alder Reactions of Enones with Isatins to Access
Functionalized Spirooxindole Tetrahydropyrans: Scope, Derivatization, and Discovery of
Bioactives
Hai-Lei Cui, Pandurang V. Chouthaiwale, Feng Yin, and Fujie Tanaka*a
Abstract: The development of concise methods for the synthesis of functionalized small
molecules is important in the search of new bioactive molecules. To contribute to this, we have
developed oxa-hetero-Diels-Alder reactions of enones with isatins catalyzed by amine-based
catalyst systems. Various spirooxindole tetrahydropyranones were synthesized either in
enantiomerically enriched forms or as racemic forms depending on the catalyst system. The
reaction products were further transformed at the ketone carbonyl group and the indole nitrogen.
Using these reactions, functionalized spirooxindole tetrahydropyran derivatives with functional
groups in four directions in three-dimensional space were concisely obtained. From these
synthesized compounds, an inhibitor of human ion channel Nav1.7 with µM-level activity was
identified, indicating that the developed reaction methods are useful for providing molecules for
the discovery of new biofunctional molecules.
Introduction
The development of concise methods for the synthesis of series of functionalized small
molecules is important in the search of new bioactive molecules.1 The desired reaction methods
for these purposes should accept a wide range of reactants to generate various product
compounds, yet should provide the desired products with high selectivities. Optimally, these
reactions should be performed under safe, mild conditions. To address these points, we have
recently developed hetero-Diels-Alder (hDA) reactions of enones with isatins catalyzed by
amine-based catalyst systems that provide spirooxindole tetrahydropyranones under mild
conditions (Scheme 1); the initial results have been reported as a communication.2 We have also
reported mechanistic investigation of the reactions catalyzed by the amine-based three-
component catalyst systems.3 Here we report expansion of the scope of the hDA reactions,
derivatization of the hDA reaction products, and the use of the molecules synthesized by the hDA
reaction methods for identification of biofunctional molecules.
R1
O
O
O
O
catalyst
further
R2
+
O
transformation
positions
R2
O
N
H
R1
N
H
R1
H
N
cat
O
O
NH
R2
Scheme 1. The hetero-Diels Alder reactions catalyzed by amine-based catalysts.
Results and Discussion
1. Hetero-Diels-Alder reactions of enones with isatins
Spirooxindole cores are present in many bioactive molecules.4 Although a number of
spirooxindole cores have been synthesized,2-7 efficient methods for the synthesis of
tetrahydropyran-derived spirooxindoles had not been reported until our recent communication.2
1

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We reasoned that the spirooxindole tetrahydropyran core would be a useful molecular scaffold if
these compounds could be easily synthesized. We designed and optimized hDA reactions of
enones with isatins catalyzed by amine-based catalysts to concisely access to spirooxindole
tetrahydropyranones (Scheme 1).2,3 This method should allow concise access to various hDA
products when substituted enones and isatins are used as reactants. In addition, in our design, the
hDA reactions can be performed without the need of protection of the isatin nitrogen2 and the
hDA reaction products can be used for further functionalization at the ketone carbonyl group and
the indole nitrogen (Scheme 1). With substitutions on enones and isatins and with the
derivatization at the ketone and the isatin nitrogen, functional groups will point in four directions
from the spirooxindole tetrahydropyran core; this structural feature may be useful for the search
of biofunctional molecules.
Enamine activation of enones in situ has been demonstrated in many reactions including
cycloadditions to form all-carbon 6-membered products and nitrogen-containing 6-membered
products.8,9,10 However, formation of tetrahydropyranones via the reactions of in situ-formed
enamines were less explored until our communication.2,11 We performed the search for suitable
amine-based catalysts by evaluation of amine-acid and amine-acid-additive combinations in the
reaction of enone 1a and isatin 2a to give hDA reaction product 3aa in high yield with high
diastereo- and enantioselectivities.2 The catalyst system composed of amine A, acid B, thiourea C
was identified as the best among those tested (Scheme 2). Selected results of the screening from
our previous report2,3 are shown in Table 1. The enantioselectivity of 3aa was higher in the
reaction using the three-component catalyst system composed of A, B, and C than in the
reactions using only A and B or only A and C (entries 1, 2, and 5 versus entries 3 and 4). The
reaction catalyzed by only amine A and acid B without thiourea C was slower than the reaction
catalyzed by the combination of A, B, and C (entry 3). In addition, reaction in the presence of B
and C without amine A did not afford 3aa. Thus, the three components, amine A, acid B, and
thiourea C, are needed to obtain the hDA reaction product in high conversion or yield with high
diastereo- and enantioselectivity.2,3 When the loadings of acid B and thiourea C were increased,
the reaction with a reduced loading of amine A also afforded product 3aa with high diastereo-
and enantioselectivities (entry 6). Effects of loadings of the catalyst components are discussed in
our report on the mechanism of the reaction.3 The diastereomers of 3aa were able to be obtained
as single diastereomer by silica gel column purification, and the enantiomeric purity of the major
enantiomer was able to be increased by crystallization.2,3 The major stereoisomer of the product
obtained by the reaction catalyzed by amine A, acid B, thiourea C was determined to be
(2’S,6’R)-3aa by the X-ray crystal structural analysis of the p-toluenesulfonohydrazide
derivative.2
Using the catalyst system composed of amine A, acid B, and thiourea C, various hDA
products 3 were obtained under mild conditions (Charts 1 and 2).2,3 Reactions of substituted
isatins and functionalized α,β-unsaturated ketones (such as phthalimide-, siloxy-, and halide-
bearing enones) also afforded the corresponding hDA reaction products.
2

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O
6'
O
O
catalyst
system
O
2'
+
O
rt
N
H
O
N
1a
catalyst system
2a
(2'S,6'R)-3aa
H
CF3
CF3
OtBu
N
NH2
S
COOH
CF3
N
H
N
H
CF3
NHBoc
A (0.2 equiv) B (0.4 equiv)
N
C (0.2 equiv)
Scheme 2. Catalyst system identified for the diastereo- and enantioselective hDA reaction.
Table 1. Catalyst Systems for the Synthesis of 3aa.a
entry Amine
(equiv)
acid (equiv) + additive time (h)
(equiv)
<conversion>
yield (%)b
or drc
ee (%)d
1
A (0.2)
A (0.1)
A (0.2)
A (0.2)
A (0.2)
A (0.1)
B (0.4) + C (0.2)
B (0.2) + C (0.1)
B (0.4)
18
48
48
48
18
48
<100>
<59>
<77>
<100>
67
18:1
93
94
87
62
93
94
2e
8.0:1
11:1
1.0:1
18:1
15:1
3
4f
5g
6h
C (0.6)
B (0.4) + C (0.2)
B (0.8) + C (0.4)
93
a Reaction was performed using enone 1a (0.5 mmol) and isatin 2a (0.1 mmol) in the presence of
amine (0.02 mmol) and acid (0.04 mmol) with or without additive C (0.02 mmol) in toluene (0.2
b
1
mL) at 24 °C except as indicated. Yield was isolated yield; conversion was determined by H
c
1
d
NMR based on the ratio of 3aa to 2a. Determined by H NMR. The major diastereomer of
3aa; determined by HPLC. Amine A (0.01 mmol), acid B (0.02 mmol), and thiourea C (0.01
e
f
g
mmol) were used. Thiourea C (0.06 mmol) were used. Reaction was performed using enone
(1.0 mmol) and isatin (0.2 mmol) in the presence of amine (0.04 mmol), acid (0.08 mmol), and
thiourea (0.04 mmol) in toluene (0.4 mL). h Reaction was performed using enone (0.5 mmol) and
isatin (0.1 mmol) in the presence of amine (0.01 mmol), acid (0.08 mmol), and thiourea (0.04
mmol) in toluene (0.2 mL).
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O
O
O
Cl
Br
O
O
O
O
O
O
N
H
N
H
N
H
3aa
18 h, 67% (dr 18:1, 93% ee)
3ab
38 h, 90%c
3ac
42 h, 92%c
48 h, 93% (dr 15:1, 94% ee)b (dr >20:1, 81% ee) (dr >20:1, 82% ee)
(after crystallization >99.6% ee)
O
O
O
O
O
O
Me
Br
O
O
O
N
H
N
H
N
H
Cl
3ad
48 h, 82%
(dr >20:1, 93% ee)
3ae
20 h, 79%
(dr 11:1, 86% ee)
3af
48 h, 88%
(dr 14:1, 90% ee)
Chart 1. The hDA reaction products obtained from various isatins.a
a
Reaction conditions: enone (1.0 mmol) and isatin (0.2 mmol) in the presence of amine A (0.04
mmol), acid B (0.08 mmol), and thiourea C (0.04 mmol) in toluene (0.4 mL) at 24 °C. b Reaction
in the presence of A (0.01 mmol), B (0.08 mmol), and thiourea C (0.04 mmol); taken from Table
c
1, entry 6. Reaction in the presence of A (0.02 mmol), B (0.04 mmol), and thiourea C (0.02
mmol).
Ph
O
O
O
O
O
O
O
O
O
N
H
N
H
N
H
3ba
3ca
3da
21 h, 71%
48 h, 68%
52 h, 77%
(dr 18:1, 91% ee)
(dr 6.1:1, 93% ee)
(dr 14:1, 91% ee)
O
N
O
O
O
O
O
O
O
O
O
N
H
3fa
N
H
O
N
3ea
20 h, 87%
29 h, 61%
H
3ga
7 days, 86%b
(dr 12:1, 92% ee)
(dr 8.0:1, 93% ee)
TBSO
Cl
(dr >20:1, 93% ee)
O
O
O
O
O
O
N
H
N
H
3ha
3ia
46 h, 87%
16 h, 85%
(dr 11:1, 92% ee)
(dr 6.6:1, 93% ee)
Chart 2. The hDA reaction products obtained from various enones.a
a
Reaction conditions: enone (1.0 mmol) and isatin (0.2 mmol) in the presence of amine A (0.04
mmol), acid B (0.08 mmol), and thiourea C (0.04 mmol) in toluene (0.4 mL) at 24 °C. b Reaction
in the presence of A (0.02 mmol), acid B (0.08 mmol), and thiourea C (0.04 mmol) in toluene
(0.6 mL)-CH2Cl2 (0.4 mL).
4

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The opposite enantiomer of the product obtained by the reaction catalyzed by A, B, and C
was synthesized using amine (R,R)-D with acid B or E as the catalyst (Scheme 3, Table 2). The
reaction using amine (R,R)-D and acid E as the catalyst gave (2’R,6’S)-3aa as the major
stereoisomer, and the reaction using amine (S,S)-D and acid E as the catalyst gave (2’S,6’R)-3aa
as the major stereoisomer. That is, the product stereochemistry relied on the configuration of
amine D. Addition of thiourea C to the reaction catalyzed by amine D and acid E enhanced the
reaction rate but did not improve the enantioselectivity.
O
6'
O
O
catalyst
system
O
2'
+
O
rt
N
H
O
N
1a
2a
(2'R,6'S)-3aa
H
catalyst system
NH2
catalyst system
NH2
OtBu
COOH
COOH
or
NHBoc
NHBoc
NH2
NH2
(R,R)-D (0.2 equiv) B (0.4 equiv)
(R,R)-D (0.2 equiv)
E (0.4 equiv)
Scheme 3. Catalyst systems for the synthesis of opposite enantiomer of the hDA product
obtained using catalyst system composed of amine A, acid B, and thiourea C.
Table 2. Catalyst Systems for the Synthesis of 3aa.a
entry
amine
acid + additive
time (h)
yield
or drc
ee (%)d
<conversion> (%)b
1
(R,R)-D
(R,R)-D
(R,R)-D
(R,R)-D
(S,S)-D
(S,S)-D
B
17
20
5.5
17
17
7
<100>
<100>
<100>
66
17:1
-79e
-85e
-75e
-85e
90
2
E
8.0:1
8.7:1
>20:1
>20:1
14:1
3f
4g
5g
6
E + C
E
E
E
56
83
86
a Reaction was performed using enone 1a (0.5 mmol) and isatin 2a (0.1 mmol) in the presence of
amine (0.02 mmol) and acid (0.04 mmol) with or without additive C (0.02 mmol) in toluene (0.2
b
1
mL) at 24 °C except as indicated. Yield was isolated yield; conversion was determined by H
c
1
d
NMR based on the ratio of 3aa to 2a. Determined by H NMR. The major diastereomer of
e
f
3aa; determined by HPLC. Minus value indicates that the major isomer was (2’R,6’S)-3aa.
Thiourea C (0.2 mmol) was used. g Toluene (1.0 mL) was used.
Whereas various highly enantiomerically enriched hDA reaction products were
synthesized using the catalyst system composed of amine A, acid B, and thiourea C, this catalyst
system was not suitable for the reactions of 4-arylbut-3-ene-2-ones to afford hDA reaction
products. The catalyst system composed of A, B, and C afforded the corresponding aldol as the
major product compared to the hDA product. For the reaction of 4-phenylbut-3-ene-2-one,
catalyst system composed of amine D and acid B gave hDA reaction product 3ja (Scheme 4).
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The diastereo- and enantioselectivities of the hDA reactions to give 3ja depended on reaction
time: The initially formed major diastereomer of 3ja was gradually reduced, and this became the
minor diastereomer after 6 days. The ee value of the initially formed major diastereomer was
reduced with the dr changes as we reported in our mechanistic investigation paper.3 After
isolation of product 3ja, no changes in dr and ee values were observed. With the use of the
catalyst system composed of amine D and acid B for appropriate reaction time, enantiomerically
enriched hDA reaction products from 4-arylbut-3-ene-2-ones were obtained as shown in Chart 3.
Ph
O
O
O
catalyst
system
O
+
O
rt
Ph
N
H
O
N
H
2a
3ja
catalyst system
NH2
OtBu
COOH
NHBoc
NH2
(S,S)-D (0.2 equiv) B (0.4 equiv)
Scheme 4. Catalyst system for the hDA reaction of 4-arylbut-3-ene-2-ones.
NC
MeO
Ph
O
O
O
O
O
O
O
N
O
O
H
N
H
N
H
3ja
17 h, 62%
(dr 2.4:1, 77% ee)
3la
16 h, 62%
(dr 1.7:1, 41% ee)
3ka
16 h, 51%
(dr 3.7:1, 81% ee)
Chart 3. The hDA reaction products obtained from aryl enones.
Conditions for the synthesis of racemic products were also identified. For racemic
synthesis, the cis/(±)-trans-mixture-1,2-diaminocyclohexane-(±)-N-Boc-proline system (catalyst
system rac-I) was found to be efficient to afford the hDA reaction products in good yields with
high diastereoselectivities (Scheme 5). Major diastereomers obtained by the methods shown in
Scheme 5 were the same as the major diastereomers obtained using catalyst system composed of
A, B, and C shown in Scheme 2. Note that when cis/(±)-trans-mixture-1,2-diaminocyclohexane-
acetic acid system was used as catalyst, the dr value of the hDA reaction product was moderate
(data not shown). Racemic hDA products with no or very low diastereoselectivities were also
obtained using benzylamine and N-protected amino acid as catalyst.3 For initial stages of
biofunctional assays, racemic compounds may be used for identification of active molecules,
avoiding doubled numbers of samples for testing each enantiomer of a compound. The
compounds shown in Charts 1-3 were synthesized using catalyst system rac-I to provide the
racemic versions. Products shown in Chart 4 were also obtained in reactions using the racemic
catalyst system.
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O
6'
catalyst
system
rac-I
O
O
O
2'
+
O
rt
N
H
O
N
H
1a
2a
(±)-rel-(2'S,6'R)-3aa
catalyst system rac-I
NH2
COOH
N
NH2
Boc
cis/(±)-trans-mixture racemic
(0.2 equiv) (0.4 equiv)
Scheme 5. Catalyst system for the synthesis of (±)-hDA products.
Cl
O
O
Br
Br
O
O
O
O
N
H
N
H
3ic
catalyst system rac-I
22 h, 91% (dr >20:1)
3fc
catalyst system rac-I
24 h, 78% (dr >20:1)
Ph
O
O
Br
Br
O
O
O
O
N
H
N
H
3jc
catalyst system rac-I
9 h, 38% (dr >20:1)
3mc
catalyst system rac-I
95 h, 36% (dr >8:1)
Chart 4. Racemic hDA reaction products synthesized using the racemic catalyst system.
Using these methods, hDA products were obtained as the major products under the
appropriate conditions; however, small amount of aldol product was co-existed during the
reaction.2,3,12 Thus, aldols 4 and 4c were also obtained (Chart 5). The aldol products should also
be candidates of biofunctional molecules.
Br
HO
HO
O
O
O
O
N
H
N
H
4
4c
Chart 5. Aldol products obtained.
2. Transformations of the hetero Diels-Alder reaction products
As described in our design, transformations of the obtained hDA products can further
provide various functionalized molecules useful in searches for biofunctional molecules. To
demonstrate the use of the hDA products for further transformations, several transformations at
the ketone and the indole nitrogen were examined.
For transformation reactions at the ketone carbonyl group, for example, reduction,
reductive ammination, allylation, and oxime formation were performed and products 5-10 were
readily obtained (Scheme 6). When enantiomerically enriched hDA product 3aa was used for the
reactions, the transformed products retained the enantiopurity of the hDA product.
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For reactions at the indole nitrogen, methylation, benzylation, alkylation through Michael
additions, and tosylation were performed and products 11-16 were obtained (Scheme 7). The
indole nitrogen-modified products were also used for reactions at the ketone carbonyl group to
synthesize 17-19 (Scheme 8). The compound variations were concisely increased from the hDA
products.
O
OH
NaBH4
O
O
MeOH, 0 °C, 1 h
O
O
N
N
H
H
72% (92% ee)
5
3aa (93% ee)
PhCH2NH2
NaBH(OAc)3
H
N
Ph
O
CH2Cl2
rt, 23 h
O
N
H
70% (92% ee)
6
OH
Br
In
O
O
O
DMF-H2O, rt, 2 h
O
O
N
N
H
H
80% (98% ee)
7
3aa (99% ee)
N
H
O
N
O
O
NaBH(OAc)3
O
O
N
8
76%
CH2Cl2, rt, 36 h
N
H
3aa (racemic)
H
NOH
NH2OH·HCl, K2CO3
CH2Cl2, rt, 2 h
O
O
O
O
N
H
9
58%
N
O
Ph
PhCH2ONH2
MeOH, reflux, 2 h
O
N
H
10
95%
O
N
O
Ph
PhCH2ONH2
O
MeOH, rt, 48 h
O
O
N
N
H
H
(2'S,6'R)-3aa (>99.5% ee)
(2'S,6'R)-10
95% (>99.5% ee)
Scheme 6. Transformations of the hDA products at the ketone carbonyl group.
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O
O
O
O
MeI, K2CO3
O
O
N
DMSO, rt, 4 h
N
H
Me
11 77%
3aa (racemic)
O
PhCH2Cl, K2CO3
DMF, rt, 16 h
O
O
N
Ph
O
12 70%
O
O
Br
Br
Br
O
MeI, K2CO3
O
O
DMSO, rt, 4 h
N
H
N
Me
13 77%
3ac (racemic)
O
O
O
O
Ph3P
CH2Cl2
rt, 4 h
N
O
14 98%
O
O
Br
O
DBU
O
CH2Cl2
rt, 22 h
N
O
15 58%
O
Br
O
TsCl, Et3N
O
CH2Cl2
rt, 41 h
N
Ts
16 22%
Scheme 7. Transformations of the hDA products at the indole nitrogen.
H
N
O
PhCH2NH2
NaBH(OAc)3
Ph
O
O
O
O
CH2Cl2
rt, 24 h
N
N
R
R
11: R = Me
12: R = CH2Ph
17: R = Me
18: R = CH2Ph 54%
74%
H
N
O
PhCH2NH2
NaBH(OAc)3
Br
Br
Ph
O
O
O
N
O
CH2Cl2
rt, 24 h
N
Me
Me
19 70%
13
Scheme 8. Transformations of the indole nitrogen-modified hDA products.
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3. Identification of biofunctional molecules from the hetero Diels-Alder reaction products
and their derivatives
To demonstrate the usefulness of the hDA reaction methods and of the molecules
obtained by the methods, nineteen (19) of the synthesized compounds were evaluated in an open
innovation drug discovery system.13 The 19 compounds were 3aa, 3ab, 3ac, 3ad, 3ae, 3af, 3ga,
3ja, 3fc, 3jc, 5, 6, 7, 9, 11, 13, 14, 15, and 16. As described above, use of racemic versions of
compounds minimizes the number of samples evaluated. Interesting compounds identified in
assays of racemic compounds may be tested later by using each eanantiomer separately for
further investigation. Thus, for these initial evaluations, we used racemic compounds.
In the screens, compound 6 was identified as an inhibitor (antagonist) of human ion
channel Nav1.7; the IC50 was determined to be 1.0 µM. The human Nav1.7 has recently proposed
as a target for pain reduction.14 None of other 18 compounds tested inhibited the human Nav1.7
activity (<50% inhibition at compound concentration 3 µM). As this initial phase of synthesis and
screening resulted in an inhibitor with activity at the 1 µM-level, further analyses of compounds
accessed using our developed hDA reaction methods should lead to discovery of functional
molecules. As the spirooxindole tetrahydropyranone core synthesized by our hDA reaction
methods can easily have functionalized substituents that point in four directions in the three-
dimensional space, our methods may be useful for further structure-activity relationship analyses
and for the discovery of other biofunctional molecules.
Conclusions
We have developed the hDA reactions of enones with isatins catalyzed by amine-based
catalyst systems and have expanded the scope of the hDA reactions. With the developed catalyst
systems, various spirooxindole tetrahydropyranones were synthesized either in enantiomerically
enriched forms or in racemic forms. Further, we have demonstrated that the hDA reaction
products can be transformed at the ketone carbonyl group and the indole nitrogen. Using these
reactions, various functionalized spirooxindole tetrahydropyran derivatives were concisely
obtained. From the synthesized compounds, an inhibitor of ion channel Nav1.7 with the IC50 of
1.0 µM was identified. Our developed hDA reaction methods and further transformations of the
hDA products will provide molecules useful for discoveries of biofunctional molecules. We are
continuing the search of functional molecules from the pool of the compounds synthesized using
our hDA reaction methods. The results will be reported in due course.
Acknowledgements
We thank Dr. Michael Chandro Roy, Research Support Division, Okinawa Institute of
Science and Technology Graduate University for mass analyses, Lilly Open Innovation Drug
Discovery for biological screening assays of compounds, and Mr. Jyunsuke Machida for
technical assistance. This study was supported by the Okinawa Institute of Science and
Technology Graduate University, by a Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysts” from the MEXT (Japan), and in part
by an Okinawa Intellectual Cluster Program (Okinawa, Japan).
Footnotes (First page)
a
Chemistry and Chemical Bioengineeing Unit, Okinawa Institute of Science and Technology
Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan.
E-mail: ftanaka@oist.jp
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DOI: 10.1039/C5OB02393A
† Electronic Supplementary Information (ESI) available: Synthesis and characterization of
compounds.
Notes and references
For H.-L. Cui, present address: Chongqing University of Arts and Sciences, 319 Honghe Ave.,
Yongchuan, Chongqing 402160 (P. R. China).
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