Simple amino silyl ether organocatalyst for asymmetric hetero Diels–Alder reaction of isatins with enones

Article abstract of DOI:10.1002/chir.23319

New two catalysts component system comprising of a primary β-amino silyl ethers as an organocatalyst and N-protected amino acids as a co-catalyst put together worked as an efficient organocatalyst system in the hetero Diels–Alder reaction of isatins with enones affording the chiral spirooxindole-tetrahydropyranones in good chemical yields and stereoselectivities (up to 94%, up to dr 78:22., up to 85% ee).

Full text of DOI:10.1002/chir.23319

Received: 3 March 2021
DOI: 10.1002/chir.23319
Revised: 19 April 2021
Accepted: 28 April 2021
R E S E A R C H A R T I C L E
Simple amino silyl ether organocatalyst for asymmetric
hetero Diels–Alder reaction of isatins with enones
Perumalsamy Parasuraman1 | Divakar Ganesan1 | Zubeda Begum1
Chigusa Seki1 | Yuko Okuyama2 | Eunsang Kwon3 | Koji Uwai1
|
|
Michio Tokiwa4 | Suguru Tokiwa4 | Mitsuhiro Takeshita4 | Hiroto Nakano1
1Graduate School of Engineering,
Abstract
Muroran Institute of Technology,
Muroran, Japan
New two catalysts component system comprising of a primary β-amino silyl
ethers as an organocatalyst and N-protected amino acids as a co-catalyst
put together worked as an efficient organocatalyst system in the hetero
Diels–Alder reaction of isatins with enones affording the chiral spirooxindole-
tetrahydropyranones in good chemical yields and stereoselectivities (up to
94%, up to dr 78:22., up to 85% ee).
2Department of Pharmaceutical Sciences,
Tohoku Medical and Pharmaceutical
University, Sendai, Japan
3Research and Analytical Center for Giant
Molecules, Graduate School of Sciences,
Tohoku University, Sendai, Japan
4Tokiwakai Group, Iwaki, Japan
K E Y W O R D S
Correspondence
hetero Diels–Alder reaction, organocatalysis, spirooxindole, β-amino alcohol, β-amino silyl
ether
Hiroto Nakano, Graduate School of
Engineering, Muroran Institute of
Technology, 27-1 Mizumoto, Muroran
050-8585, Japan.
Email: catanaka@mmm.muroran-it.ac.jp
1 | INTRODUCTION
Recently, asymmetric cooperative catalysis has
attracted immense interest, in which two catalysts work
Spirooxindole skeleton A is found in many biologically
active natural compounds1–7and drugs8–10 such as
anti-malarial,11–13 anti-cancer,14,15 anti-viral,16 anti-
tuberculosis,17 and anti-proliferative18 (Scheme 1). There-
fore, it is important to establish an effective asymmetric
synthetic methodology for the synthesis of chiral
spirooxindoles A. In the past decade, the study of
organocatalysis has immensely attracted wide range of
researchers in creating and exploring new chiral com-
pounds as organocatalysts in synthetic organic
chemistry,19,20 due to their ease of handling, inert to
atmosphere, low toxic nature. Organocatalyzed asymmet-
ric hetero Diels–Alder (hDA) reaction has been found to
be an efficient synthetic protocol for the synthesis of
various pharmaceutically and biologically active chiral
compounds.21,22 However, enantioselective hDA reaction,
for the synthesis of chiral spirooxindoles still remains a
challenging task in the field of synthetic organic chemis-
try in terms of drug discovery.
simultaneously to form products which cannot be accom-
plished by the use of a single catalyst alone.23–28 Most
recently, we have also reported a simple two catalysts
component system consisting of a primary β-amino alco-
hol B as a catalyst and N-protected amino acid C as a co-
catalyst for this asymmetric hDA reaction.29 This dual
component system showed efficient catalytic activity
affording the chiral spirooxindole-tetrahydropyranone Z,
which acts as a synthetic precursor for many biologically
active compounds. Based on these backgrounds, we have
designed a new, simple two catalysts component system,
using simple amino silyl ether D as an organocatalyst and
amino acid C as a co-catalyst for this reaction (Scheme 1).
As of catalyst D, it can be prepared easily from the
commercially available amino acids in few steps and also
D contains a primary amino group as a covalent site and
both a silyl ether group and an alkyl or an aryl group at
α- and/or β-positions as steric influence sites in the single
molecule (Scheme 1).
Chirality. 2021;1–11.
wileyonlinelibrary.com/journal/chir
© 2021 Wiley Periodicals LLC.
1

2
PARASURAMAN ET AL.
SCHEME 1 Concept of organocatalyst
Furthermore, simple amino acids as co-catalysts C also
can be easily prepared from the corresponding amino
acids. Herein, we describe the utility of the two catalysts
component system using primary β-amino silyl ethers
D having only one chiral carbon center on the molecule as
a catalyst and simple N-protected amino acids E as a
co-catalyst in the hDA reaction of X with Y to afford
chiral Z in good chemical yields (up to 94%) with satisfac-
tory stereoselectivities (up to dr 78:22, up to 85% ee).
were recorded with a micro-melting point apparatus.
Infrared (IR) spectra were recorded with a JASCO-4100
Fourier transform infrared spectrophotometer. 1H and
13C nuclear magnetic resonance (NMR) spectroscopic
data were recorded using a JEOL JNM-ECA500 instru-
ment with tetramethylsilane as the internal standard.
High-performance liquid chromatography (HPLC) data
were collected using the TOSOH instrument equipped
with (UV-8020, DP-8020, and SD-8022) detectors
using CHIRALPAK IB column. Optical rotations were
recorded using a JASCO DIP-360 digital polarimeter.
High-resolution mass spectrometry (HRMS) data were
collected by electron impact (EI) modes using Hitachi
RMG-GMG and JEOL JNX-DX303 sector instruments.
2 | MATERIALS AND METHODS
2.1 | General information
All reagents and dry solvents were purchased from com-
mercial vendors and used directly without further
purification. All reactions were placed in dried sample
vials inserted with magnetic beads. Thin-layer chroma-
tography (TLC) was performed on Merck silica gel
60 F254 plates and the analytes were identified under UV
light. Flash column chromatography was performed
using silica gel pore size 60N (40–100 μm). Melting points
2.2 | General procedure for the
asymmetric hetero Diels–Alder reaction
To
a solution of the corresponding isatins 4a–f
(0.2 mmol, 1 eq) and enones 5a–e (0.8 mmol, 4 eq) in
anhydrous toluene (0.3 ml) were added catalysts 2a–o
(0.04 mmol, 20 mol %) and co-catalysts 3a–s (0.08 mmol,

PARASURAMAN ET AL.
3
40 mol %) at room temperature and the mixture was
stirred at that temperature for 48 h. After the completion
of reaction, the mixture was purified by flash column
chromatography (SiO2, hexane: ethyl acetate = 7:3) to
afford the corresponding major hDA adducts 6a–i. The
diastereoselectivity (dr) of the obtained hDA adducts
782, 700. 1H NMR (500 MHz, CDCl3) δ 7.27–7.30 (m,
2H), 7.19–7.22 (m, 3H), 3.67 (q, J = 4.6 Hz, 1H), 3.56 (dd,
J = 10.0, 6.0 Hz, 1H), 3.31 (s, 2H), 3.12–3.18 (m, 1H), 2.83
(q, J = 6.7 Hz, 1H), 2.66 (dd, J = 13.5, 7.7 Hz, 1H), 1.04–
1.06 (m, 21H). 13C NMR (125 MHz, CDCl3) δ 138.26,
129.38, 128.68, 126.66, 77.39, 77.15, 76.89, 66.24, 54.89,
38.94, 18.06, 11.96. MS (FAB): m/z: 307 [M]+, HRMS
(FAB): calcd. for C18H33N1O1Si1 m/z 307.55; found:
307.64.
1
were determined by the crude reaction mixture by H
NMR. The enantiomeric excess (ee) of 6a–i were
determined by HPLC (CHIRALPAK IB, hexane:
iPrOH = 90:10 or 95:5, 0.6 ml,1.0 ml/min, λ = 245 nm).
2.6 | (S)-1-([1,1,1,1,3,3,3-heptamethyl-
2-{trimethylsilyl}-1-trisilan-2-yl]oxy)
3-phenylpropane-2-amine- propane-
2-amine (2o)
2.3 | General procedure for the synthesis
of catalysts 2a–o
To a solution of the corresponding amino alcohol 1a–o
(6.79 mmol, 1 eq) in dry CH2Cl2, cooled at 0 C or ꢀ30 C
were added corresponding trialkyl silyl chloride or
trifluoromethane sulfonate (1.2 eq) and triethylamine
(1.2 eq) for 10 min under argon atmosphere. The solution
was stirred for 24 h at room temperature. After the
completion of reaction, the reaction mixture was diluted
with water and extracted with dichloromethane. Organic
layer was separated and dried with sodium sulfate.
Solvent was evaporated under reduced pressure, the
obtained crude mixture was purified by flash column
chromatography (SiO2, hexane: ethyl acetate = 7:3 and
MeOH:CH2Cl2 = 9:1) to give the corresponding amino
silyl ether catalysts 2a–o.
Colorless liquid. 88% yield. [α]D24 = ꢀ17.24 (c = 0.58,
CH2Cl2). IR (neat) cmꢀ1: 2947, 2892, 1558, 1540, 1070,
769, 699. 1H NMR (500 MHz, CDCl3) δ 7.27–7.29 (m,
2H), 7.17–7.20 (m, 3H), 3.37 (q, J = 4.6 Hz, 1H), 3.31 (dd,
J = 9.5, 6.6 Hz, 1H), 2.99–3.04 (m, 1H), 2.72 (q,
J = 6.3 Hz, 1H), 2.54 (q, J = 6.9 Hz, 1H), 1.45 (d,
J = 22.3 Hz, 2H), 0.17 (s, 27H). 13C NMR (125 MHz,
CDCl3) δ 139.16, 129.38, 128.53, 126.31, 77.39, 77.15,
76.89, 71.98, 54.82, 40.47, 0.39. MS (FAB): m/z: 397 [M]+,
HRMS (FAB): calcd. for C18H39N1O1Si4 m/z 397.86;
found: 397.91.
3 | RESULTS AND DISCUSSION
2.4 | (S)-1-phenyl-3-([triethylsilyl]oxy)
propane-2-amine (2l)
3.1 | Preparation of catalysts and co-
catalysts
Light yellow oil. 89% yield. [α]D24 = +6.24 (c = 0.48,
CH2Cl2). IR (neat) cmꢀ1: 3027, 2875, 1602, 1495, 1097,
794, 699.1H NMR (500 MHz, CDCl3) δ 7.25–7.30 (m, 2H),
7.20 (td, J = 5.0, 2.1 Hz, 3H), 4.11 (s, 2H), 3.62 (q,
J = 4.6 Hz, 1H), 3.49 (dd, J = 9.7, 6.3 Hz, 1H), 3.21 (qd,
J = 6.8, 4.3 Hz, 1H), 2.81 (dq, J = 46.5, 6.9 Hz, 2H),
0.92–0.99 (m, 9H), 0.56–0.63 (m, 6H). 13C NMR
(125 MHz, CDCl3) δ 138.31, 129.37, 128.61, 126.56, 77.41,
77.17, 76.91, 65.35, 54.62, 38.90, 6.90, 4.42. MS (FAB):
m/z: 265 [M]+, HRMS (FAB): calcd. for C15H27N1O1Si1
m/z 265.47; found: 265.69.
The desired amino silyl ethers 2a–n30,31 having several
trialkylsilyl groups on oxygen atom at α-position
were easily prepared by the reactions of the
corresponding β-amino alcohols 1a–n with XOTf (X:
TMS [trimethylsilyl]),30 XCl (X: TES [triethylsilyl]),31
XOTf (X: TIPS [triisopropylsilyl]),31 and XCl (X:
TBDMS [tert-butyldimethylsilyl]),31 respectively, in
moderate to good yields (46%–90%)(Scheme 2).
Furthermore, the bulkiest β-amino silyl ether catalyst
2o having a super silyl TTMSS (tris[trimethylsilyl]
silyl)31 group on oxygen atom was also easily prepared
from the reaction of the corresponding amino alcohol
with TTMSSCl in good yield (88%). Furthermore,
several N-Cbz32 and N-Boc-amino acids 3a–s as co-
catalysts were also easily derived from the
corresponding commercially available nonprotected
acyclic and sterically bulky cyclic amino acids, respec-
tively (Scheme 2).
2.5 | (S)-1-phenyl-3-([triisopropylsilyl]
oxy)propane-2-amine (2m)
Light yellow oil. 90% yield. [α]D24 = +1.81 (c = 0.55,
CH2Cl2). IR (neat) cmꢀ1: 2941, 2864, 1558, 1105,

4
PARASURAMAN ET AL.
SCHEME 2 Synthesis of catalysts 2a–o and co-catalysts 3a–s

PARASURAMAN ET AL.
5
3.2 | Optimization of catalysts
(Entries 1–6). Among these catalysts 2a–f, the use of cata-
lysts 2e–f with bulkier Bn or Ph groups at β-position on
the molecules showed better catalytic activity than others
(Entries 5 and 6). Particularly, the catalyst 2e showed
best catalytic activity to afford chiral adduct 6a in good
chemical yield (74%) and enantioselectivity (81% ee) with
moderate diastereoselectivity (67:33, Entry 5). When only
catalyst 2e, without a co-catalyst was used in this reaction
satisfactory result was not obtained (Entry 7). On the
other hand, the reactions using catalysts 2g–k with
tertiary OTMS groups hardly proceeded and
enantioselectivity was considerably decreased (Entries
8–12). Next, based on these results, the reaction using
catalysts 2l–o having different bulkier silyl groups on
oxygen atom and co-catalyst 3a were carried out under
same reaction condition (Entries 13–16). However, these
catalysts 2l–o did not show better catalytic activity than
First, we examined the hDA reaction of isatin 4a as a
dienophile with heptene-2-one 5a as a diene using
β-amino silyl ether organocatalysts 2a–f with primary
trimethylsiloxy (OTMS) group or 2g–o with tertiary
OTMS groups (20 mol %) and the simplest N-Boc-amino
acid 3a as a co-catalyst (40 mol %) at room temperature
for 48 h (Table 1). Two equivalents of co-catalyst against
catalyst was used for a reason that, co-catalyst may work
in both way, in the acceleration of the formation of diene
and also in the activation of isatin. Amino silyl ethers
2a–f showed catalytic activities in this reaction and the
corresponding chiral hDA adduct [20S,60R]-6a was
obtained in good enantioselectivities (72%–85% ee) and
moderate diastereoselectivities (53:47–67:33) with chemi-
cal yields in the range of extremely low to good (2%–77%)
TABLE 1 Asymmetric hetero
Diels–Alder reaction of 4a with 5a using
catalysts 2a–o and co-catalyst 3a
Entry
1
Cat 2a–o (mol %)
Co-cat 3a mol %
Yield (%)a
drb
eec (%)
72
2a (20)
2b (20)
2c (20)
2d (20)
2e (20)
2f (20)
2e (20)
2g (20)
2h (20)
2i (20)
2j (20)
2k (20)
2l (20)
2m (20)
2n (20)
2o (20)
40
40
40
40
40
40
—
40
40
40
40
40
40
40
40
40
11
9
54:46
64:36
67:33
63:37
67:33
53:47
56:44
65:35
—
2
79
3
44
85
4
2
76
5
74
81
6
77
72
7
31
59
8
2
40
9
trace
trace
trace
9
—
10
11
12
13
14
15
16
—
—
—
—
74:26
61:39
69:31
66:34
51:49
14
64
75
46
15
65
18
84
51
aIsolated yields.
bDr was determined by 1H nuclear magnetic resonance (NMR).
cEe were determined by high-performance liquid chromatography (HPLC) using a Daicel CHIRALPAK IB
column.

6
PARASURAMAN ET AL.
2e. From these results, it was revealed that the best cata-
lyst was β-amino silyl ether 2e with primary OTMS group
in this reaction. This catalysts component system also
slightly afforded an aldol product 7 as by product in low
chemical yield (10%) and enantioselectivity (9% ee).
3.3 | Optimization of co-catalysts
We next examined this reaction using the combinations
of superior catalyst 2e (20 mol %) with several acids 3b–s
as co-catalysts (40 mol %) at room temperature for 48 h
TABLE 2 Asymmetric hetero Diels–Alder reaction of 4a with 5a using catalyst 2e and co-catalyst 3b–s
Entry
1
Enone 5a eq
Cat 2e mol %
Co-cat 3b–s (mol %)
3b (40)
3c (40)
3d (40)
3e (40)
3f (40)
Yield (%)a
69
drb
eec (%)
82
79
79
80
78
78
80
81
80
80
—
80
81
82
81
80
78
78
84
76
80
79
82
82
83
81
79
78
76
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
1
2
3
5
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
10
10
10
20
20
20
20
65:35
69:31
68:32
69:21
70:30
65:35
68:32
65:35
67:33
65:35
—
2
85
3
76
4
94
5
85
6
3g (40)
3h (40)
3i (40)
91
7
90
8
53
9
3j (40)
80
10
11
12
13
14
15
16
17
18
19c
20d
21
22
23
24
25
26
27
28
29
3k (40)
3l (40)
82
trace
79
3m (40)
3n (40)
3o (40)
3p (40)
3q (40)
3r (40)
3s (40)
3o (40)
3o (40)
3o (20)
3o (10)
3o (10)
3o (20)
3o (5)
76:24
68:22
77:23
67:33
77:23
68:32
57:43
82:18
77:23
75:25
72:28
71:29
69:31
72:28
70:30
78:22
78:22
76:24
78
85
79
76
87
75
35
79
85
82
30
50
17
3o (40)
3o (40)
3o (40)
3o (40)
48
78
84
92
aIsolated yields.
bDr was determined by 1H nuclear magnetic resonance (NMR).
cReaction was carried out at 0ꢁC.
dReaction was carried out at 40ꢁC.
eEe were determined by high-performance liquid chromatography (HPLC) using a Daicel CHIRALPAK IB column.

PARASURAMAN ET AL.
7
(Table 2). First, the reactions using N-Cbz-amino acids 3b
and also common aromatic and aliphatic acids 3c–l as
co-catalysts were carried out respectively (Entries 1–11).
Almost all co-catalysts 3b–k assisted the progress of the
reaction, affording chiral 6a with moderate to good
chemical yields and stereoselectivities. However, only
bulkier aromatic acid 3i afforded 6a in moderate chemi-
cal yields, although no change in the stereoselectivities
was observed (Entry 8). Furthermore, the strongest tri-
fluoro acetic acid 3l as a co-catalyst did not work in this
reaction condition (Entry 11). Next, the reactions using
chiral N-Boc-amino acids 3m,n as co-catalysts were
examined and these 3m,n also showed good co-catalytic
activities (Entries 12 and 13). Moreover, the combina-
tions of catalyst 2e with bulkier chiral cyclic amino acids,
N-Boc-, N-Cbz-prolines 3o–r, and N-Boc-piperidine 3s,
were also examined in this reaction condition (Entries
14–18), respectively. The use of chiral co-catalysts 3o–s
having bulkier cyclic structure and specific steric
configuration might be effective for increasing the
stereoserectivities in this reaction to afford chiral 6a. As a
result, 3o–s showed good catalytic activities affording 6a,
but chemical yields and stereoselectivities were almost
the same as the results of general acyclic amino acids
3a,b,m,n and common organic acids 3c–k. In 3o–s,
N-Boc-L-proline 3o showed best co-catalytic activity
and afforded 6a in good chemical yield (85%)
and stereoselectivities (dr 77:23, 82% ee) (Entry 14). How-
ever, this combination of 2e with 3o at 0ꢁC brought about
a large decrease in chemical yield up to 35%, although
good stereoselectivity (dr 82:18, 84% ee) was maintained
(Entry 19). On the other hand, the reaction at 40ꢁC
afforded 6a with good chemical yield and stereo-
selectivity (Entry 20). From these results, it was revealed
that the combination of 2e with 3o was the best one in
this reaction.
Next, we examined the molar ratio of catalyst 2e and
co-catalyst 3o, in this reaction of 4a (1 equiv.) with 5a
(4 equiv.) at room temperature (Entries 21–25). Satisfac-
tory enantioselectivities and diastereoselectivities were
observed under all of the molar ratios of 2e and 3o. How-
ever, chemical yields were comparatively lowered, when
the reaction was carried out with 10 mol % of catalyst 2e
and 5%–20% of co-catalyst 3o (Entries 23–25). On the
other hand, the use of the equivalent ratio of catalyst
(20 mol %) and co-catalyst (10 mol % or 20 mol %) were
relatively effective (Entries 21 and 22). Furthermore, the
ratio of substrates 4a and 5a were examined in the
presence of optimized catalyst 2e (20 mol %) and co-
catalyst 3o (40 mol %) system under the same reaction
condition (Entries 26–29). Good chemical yields
and stereoselectivities were observed except, when
1 equivalent of 5a to 2e was used, which brought about
the decrease in chemical yield (48%, Entry 26).
We also examined the effects of various solvents to
this reaction using the optimized catalysts combination
of 2e (20 mol %) and 3o (40 mol %) at room tempera-
ture (Table 3). As
a
result, aromatic solvents
performed better giving satisfactory chemical yields and
stereoselectivities (Entries 1–3). Particularly, toluene
was found to be effective in this reaction (Entry 1)
affording high enantioselectivity (Entry 1). From these
results, it was revealed that the catalysts combination of
2e (20 mol %) as a catalyst and chiral N-Boc-L-proline
3o as a co-catalyst (40 mol %), toluene as a solvent, at
room temperature and 48 h reaction time was the best
reaction condition for this reaction. Furthermore, in
order to demonstrate the practical utility of the catalysts
combination of 2e and 3o, the reaction of 4a with 5a
was conducted on gram scale (4a: 1 g) using the
above optimized reaction conditions, the corresponding
product 6a was obtained in good chemical yield (88%),
diastereoselectivity (dr 78:22), and enantioselectivity
(79% ee). This result indicated that the catalysts
TABLE 3 Solvent screening for optimized reaction condition
Entry
Solvent
Toluene
Benzene
Xylene
Cyclohexane
Hexane
Et2O
Yield (%)a
drb
eec (%)
82
1
85
92
92
86
75
62
82
35
82
86
74
30
25
82
77:23
77:23
77:23
51:49
67:33
67:33
55:46
70:30
61:39
61:39
65:35
53:47
79:21
63:37
2
77
3
79
4
74
5
64
6
75
7
iPr2O
71
8
THF
74
9
CH2Cl2
CHCl3
78
10
11
12
13
14
80
C2H4Cl2
CH3CN
MeOH
Neat
80
79
67
73
aIsolated yields.
bDr was determined by 1H nuclear magnetic resonance (NMR).
cEe value were determined by high-performance liquid chromatography
(HPLC) using a Daicel CHIRALPAK IB column.

8
PARASURAMAN ET AL.
component system of 2e and 3o can also be effective on
practical scale.
[20S,60R]-6a in low chemical yield and stereoselectivities
(31%, dr 56:44, 59% ee) (Entry 7, Table 1). On the other
hand, the same reaction in the presence of 2e using 3o
afforded chiral hDA adduct 6a in good results (85%, dr
77:23, 82% ee) (Entry 14, Table 2). Furthermore, in the
absence of co-catalyst 3o, the formation of diene interme-
diate I was not observed in the reaction of catalyst 2e
with enone 5a, although the formation of I was observed
using 3o. These results may indicate that co-catalyst
works as an acid for accelerating the formation of diene
intermediate. Based on these experiment results and the
high enantiopurity of the obtained hDA adduct [20S,60R]-
6a (82% ee, Table 3), the model of the enantioselective
reaction course was proposed as shown in Scheme 4.
First, the reactions of catalyst 2e with enone 5a in the
presence of co-catalyst 3o as an acid forms the diene
intermediate I-1 that has less steric interaction between
amino silyl ether part and substituted diene part than
that of intermediate I-2. Furthermore, isatin 4a is acti-
vated by the hydrogen bonding interaction with N-Boc-L-
proline co-catalyst 3o. Then, the reaction might proceed
through TS-1 to afford chiral 6a that has a less steric
interaction between I-1 and dienophile 4a than those of
TS-2–TS-4 to afford 6a0–6a000 that have more steric inter-
action between I-1 and 4a. Thus, the diene I-1 might
3.4 | Substrate scope for the asymmetric
hDA reaction
We examined the generality of the developed superior
two catalysts component system of 2e and 3o in the reac-
tions of different isatins 4a–f with enones 5a–e
(Scheme 3). This component system also showed good
catalytic activity in the reactions and afforded the
corresponding chiral spirooxindole-tetrahydropyranones
6a–i in moderate to good chemical yields and
stereoselectivities as shown in Scheme 3. However, the
reactions of 4a with enones 5e with bulky phenyl group
hardly proceeded in this reaction condition to afford the
corresponding adduct 6j, respectively.
3.5 | Plausible reaction mechanism
The hDA reaction of isatin 4a with enone 5a in the
presence of catalyst 2e without the superior co-catalyst
3o afforded the corresponding chiral hDA adduct
SCHEME 3 Substrate scope for the asymmetric hetero Diels–Alder (hDA) reaction

PARASURAMAN ET AL.
9
SCHEME 4 Plausible reaction mechanism for the asymmetric hDA reaction

10
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attack stereoselectively from less sterically hindered site
towards the incoming activated isatin dienophile 4a to
afford [20S,60R]-6a with good optically purity (82% ee). In
this reaction, aldol product 7 was formed as a by product.
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obtained aldol product 7 and Michael adduct 6a were
quite low (7: 10%, 9% ee, 6a: 7%, dr 77:23, 77% ee). Based
on these results, it may be assumed that the reaction of
2e with 3o proceeds via hDA reaction pathway.
4 | CONCLUSION
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We have developed a simple two catalysts component
system consisting of a primary β-amino silyl ether 2e as a
catalyst and N-Boc-L-proline 3o as a co-catalyst for the
asymmetric hDA reaction of isatins with enones for
the first time. This dual component system showed
efficient catalytic activity to afford the chiral
spirooxindole-tetrahydropyranones 6a–i in good chemi-
cal yields (up to 94%) and with enough stereoselectivities
(up to dr 78: 22, up to 85% ee), which are expected to act
as efficient synthetic intermediates for the synthesis of
biologically active compound and also in drug discovery.
The modification of the combination of β-amino silyl
ether and detailed mechanistic study of this reaction
using our catalysts system are in progress.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
available in the supporting information of this article.
ORCID
Hiroto Nakano https://orcid.org/0000-0002-2557-7207
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
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How to cite this article: Parasuraman P,
Ganesan D, Begum Z, et al. Simple amino silyl
ether organocatalyst for asymmetric hetero Diels–
Alder reaction of isatins with enones. Chirality.
2021;1–11. https://doi.org/10.1002/chir.23319