Highly enantioselective Michael/cyclization tandem reaction between dimedone and isatylidene malononitriles

Article abstract of DOI:10.1016/j.tet.2018.10.029

A highly enantioselective Michael/cyclization tandem reaction between dimedone and isatylidene malononitriles has been developed. With 5 mol% of bifunctional organocatalyst C15, chiral spiro[2-amino-4H-pyran-oxindole] derivatives were obtained in excellent yields (97–99%) with excellent enantioselectivities (up to > 99% ee).

Full text of DOI:10.1016/j.tet.2018.10.029

Accepted Manuscript
Highly enantioselective Michael/cyclization tandem reaction between dimedone and
isatylidene malononitriles
Jia-Long Hu, Feng Sha, Qiong Li, Xin-Yan Wu
PII:
S0040-4020(18)31235-3
https://doi.org/10.1016/j.tet.2018.10.029
TET 29862
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 August 2018
Revised Date: 11 October 2018
Accepted Date: 15 October 2018
Please cite this article as: Hu J-L, Sha F, Li Q, Wu X-Y, Highly enantioselective Michael/cyclization
tandem reaction between dimedone and isatylidene malononitriles, Tetrahedron (2018), doi: https://
doi.org/10.1016/j.tet.2018.10.029.
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Highly enantioselective Michael/cyclization
tandem reaction between dimedone and
isatylidene malononitriles
Leave this area blank for abstract info.
Jia-Long Hu, Feng Sha, Qiong Li, and Xin-Yan Wu*
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular
Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China

1
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Tetrahedron
journal homepage: www.elsevier.com
Highly enantioselective Michael/cyclization tandem reaction between dimedone and
isatylidene malononitriles
Jia-Long Hu, Feng Sha, Qiong Li, and Xin-Yan Wu
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and
Technology, Shanghai 200237, P. R. China
ARTICLE INFO
ABSTRACT
A
highly enantioselective Michael/cyclization tandem reaction between dimedone and
Article history:
Received
Received in revised form
Accepted
isatylidene malononitriles has been developed. With 5 mol% of bifunctional organocatalyst C15,
chiral spiro[2-amino-4H-pyran-oxindole] derivatives were obtained in excellent yields (97-99%)
with excellent enantioselectivities (up to > 99% ee).
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
asymmetric catalysis
organocatalysis
4H-pyran
spirooxindole
tandem reaction
1. Introduction
Dimedone is a cyclic 1,3-dicarbonyl compound with an
outstanding reactivity, which can be used as a 1O,3C-bis-
nucleophile.7 Among the asymmetric synthetic protocols
developed for 2-amino-4H-pyran scaffolds with dimedone, the
enantioselectivity had hardly exceeded 77% ee.5a,8 Furthermore,
the enantioselective tandem reaction with dimedone to construct
chiral spiro[2-amino-4H-pyran-oxindoles] has been barely
documented. A rare example is the three-component tandem
reaction among dimedone, isatins and malononitrile, catalyzed by
cupreine, affording spiro[2-amino-4H-pyran-oxindoles] with
only 7% ee, however.5a With continuing interest in the
asymmetric synthesis of chiral spirooxindoles,5d,5e,9 herein we
The chiral spirooxindole scaffold is widely found in natural
products and bioactive compounds.1 In the past decade, great
efforts have been made towards the asymmetric synthesis of
chiral spirooxindoles owing to their excellent biological
activities.1c,1f,2 Both asymmetric cycloadditions and formal
cycloaddition reactions (i.e. actual tandem reactions for the latter)
with 3-alkenyl-2-oxindoles are common strategies to produce
chiral spirooxindoles. These strategies have received much
attention because of their high efficiency and the atom-
economy.2d,2g,3 4H-Pyrans are important heterocycles with a
variety of bioactivities including anti-tumor, antimicrobial and
kinase inhibitory activities.4 However, the asymmetric
construction of chiral spirooxindoles incorporating a 4H-pyran
motif has been barely descried. Traditionally isatylidene
malononitriles derived from isatins have been applied as 1,3-bis-
electrophiles in the enantioselective formal [3+3] cycloaddition
reaction to construct chiral spirooxidoles incorporating a 2-
amino-4H-pyran scaffold. Over the past few years, several
efficient strategies have been developed for this enantioselective
process.5 In the previous reports, the 1,3-bis-nucleophiles used
include dicarbonyl compounds5a,5b, phenols5b, β-hydroxyl-α,β-
unsaturated carbonyl compounds5b,5c, pyrazolones5d and α-cyano
ketones5e. The introduction of an amino group to the 4H-pyrans
motif has been proven to be useful for some synthetic
transformations.5b,5d,6
report
a highly enantioselective tandem reaction between
dimedone and isatylidene malononitriles.
2. Results and discussion
Initially, the Michael/cyclization tandem reaction between
dimedone (1) and N-benzyl isatylidene malononitrile (2a) was
selected as a model reaction to screen the chiral organocatalysts
(Fig. 1). The reactions were performed with 5 mol% of chiral
organocatalysts in dichloromethane at -20 oC (Table 1). All chiral
oraganocatalysts screened could promote the tandem reaction
efficiently, providing 99% chemical yield with different
enantioselectivities. Cinchona alkaloid-derived bifunctional
organocatalysts C3-C7 with sulfamide, thiourea or squaramide as
H-bonding donator provided better enantioselectivities than
———
Corresponding author. E-mail addresses: xinyanwu@ecust.edu.cn (X.-Y. Wu).

2
Tetrahedron
quinine (C1) and cinchonideine (C2) (entries 3-7 vs entries 1
ACCEPTED MANUSCRIPT
and 2). Among them, thiourea C5 resulted in the best
enantioselectivity (72% ee, entry 5). In the presence of
(DHQD)2PYR (C8), only 10% ee was obtained (entry 8). These
results indicated that the hydrogen-bonding effect of the
organocatalysts played an important role in controlling the
stereoselectivity. To improve the enantioselectivity of the model
reaction, tertiary amine organocatalysts based on chiral 1,2-
diaminocyclohexane or 1,2-diphenylethanediamine backbone
were investigated (entries 9-16). To our delight, the squaramide
C15 could achieve chiral spirooxindole 3a in 76% ee (entry 15).
Based on the above results, chiral squaramide C15 was selected
as catalyst for further studies.
Table 1 Screening of the chiral organocatalysts for the
tandem reactiona
Entry
1
Catalyst
C1
Time (min)
10
Yield (%)b
99
Ee (%)c
-4
2
C2
10
99
0
3
C3
20
99
40
42
72
30
66
10
26
54
64
6
Next, the effect of solvents was investigated (Table 2). In
toluene, halogenated solvents and ethers, the tandem reactions
achieved excellent yields but with only 52%-76% ee (entries 1-
6). Chloroform and 1,2-dichloroethane were examined because
the highest enantioselectivity (76% ee) was obtained in
dichloromethane (entries 2-4). The reaction was completed in
ether in 48 hours, probably due to the poor solubility of
dimedone in ether (entry 5). In the polar aprotic solvents used
such as ethyl acetate, acetonitrile, and DMF, the
enantioselectivity of the tandem reaction was poor (entries 7-9).
In a protic polar solvent, ethanol, the catalytic reaction took 18
hours, and the enantioselectivity was poor (entry 10). This is
probably due to the presence of hydroxyl group-containing
solvent that compromises the hydrogen-bonding effect of the
chiral organocatalyst. As a result, dichloromethane was selected
as the solvent for further reaction optimization.
4
C4
20
99
5
C5
20
99
6
C6
30
99
7
C7
45
99
8
C8
30
99
9
C9
50
99
10
11
12
13
14
15
16
C10
C11
C12
C13
C14
C15
C16
50
99
20
99
40
99
100
120
30
99
22
66
76
52
99
99
To further enhance the enantioselectivity of the tandem
reaction, other reaction conditions including the reaction
temperature, the ratio of dimedone to substrate 2a, the substrate
concentration, the catalyst loading and additives were
investigated (Table 3). The results indicated that a lower reaction
100
99
a All reactions were performed with dimedone (0.12 mmol), substrate 2a
(0.10 mmol) and chiral organocatalyst (5 mol%) in CH2Cl2 (1 mL) at -20 °C.
b Isolated yields.
c Determined by HPLC analysis.
Table 2 The effect of solvent on the Michael/cyclization
tandem reactiona
Entry
Solvent
Toluene
CH2Cl2
CHCl3
ClCH2CH2Cl
Et2O
Time
3 h
Yield (%)b
Ee (%)c
68
76
76
68
58
52
28
4
1
99
99
99
99
99
99
99
92
99
99
2
30 min
20 min
2 h
3
4
5
48 h
6
THF
50 min
35 min
35 min
20 min
18 h
7
EtOAc
CH3CN
DMF
8
9
0
10
EtOH
6
a All reactions were performed with dimedone (0.12 mmol), substrate 2a (0.10
mmol) and organocatalyst C15 (5 mol%) in solvent (1 mL) at -20 °C.
b Isolated yields.
Fig. 1 Structures of the chiral organocatalysts screened.

3
c Determined by HPLC analysis.
b Isolated yields.
ACCEPTED MANUSCRIPT
c Determined by chiral HPLC analysis.
d In 2 mL CH2Cl2.
temperature could lead to a slightly higher enantioselectivity but
with a longer reaction time, and a temperature of -20 oC gave the
best result (entries 1-4). The ratio of substrates affected the
enantioselectivity rather than yields (69%-76% ee, entries 5-8
and 2). When the substrate concentration was increased to 0.2 M,
the spirooxindole 3a was obtained in 72% ee (entry 10). The
enantioselectivity of the tandem reaction was reduced to 74% ee
when 2 mol% chiral organocatalyst C15 was used (entry 11 vs
entry 2). Then, we chose molecular sieves as an additive to
improve the enantioselectivity (entries 12-17). The results
showed that adding 4Å molecular sieves to the reaction system
could improve the enantioselectivity. The improvement of
enantioselectivity was related to the quantity of molecular sieves
added and their pore size. Adding 50 mg of 4Å molecular sieves
to a 0.1 mmol reaction system increased the enantioselectivity to
83% ee (entry 14). However, the addition of 3Å molecular sieves
or 5Å molecular sieves did not improve the reaction (entries 16
and 17 vs entry 14). In order to understand the role of molecular
sieves in the catalytic reaction, we added 1 equivanlent amount
e In 0.5 mL CH2Cl2.
f With 2 mol% of catalyst C15.
of deionized water to the reaction system. The enantioselectivity
was reduced when compared with that in the absence of
deionized water, and the yield was unchanged (entry 18 vs entry
2 and entry 19 vs entry 14). When 5 equiv. water was added to
the system with 50 mg of 4Å molecular sieves, the chemical
yield and enantioselectivity were decreased obviously (entry 20
vs entries 14 and 19). We postulate that the molecular sieves
functioned mainly by water absorption. Considering these results,
the optimal reaction conditions were determined to be 0.1 M
isatylidene malononitrile in dichloromethane with 1.2 equiv. of
dimedone, 5 mol% of the chiral organocatalyst C15 and 4Å
molecular sieves (50 mg/0.1 mmol isatylidene malononitrile) at -
20 oC.
Under the optimized reaction conditions, the substrate scope
of the tandem reaction was investigated (Table 4). In all cases,
excellent chemical yields were achieved. The results indicated
that the substituents on the nitrogen atom of isatylidene
malononitriles significantly influenced the enantioselectivity
(entries 1-6), and the N-trityl substrate yielded the best result
(98% ee, entry 6). The different N-trityl isatylidene
malononitriles were tolerated to the tandem reaction, providing
97-99% yields with 94-99.7% ee values (entries 6-18). Notably,
4-substituted (such as 4-Cl) isatylidene malononitrile could
undergo the tandem reaction, although a longer reaction time was
required to improve the conversion (entry 7).
Table 3 Further optimization of reaction conditionsa
Entry 1:2a
Temp. Additives
(oC)
Time
Yield
(%)b
Ee
(%)c
1
1.2:1
1.2:1
1.2:1
1.2:1
2:1
0
-
-
-
-
-
-
-
-
-
-
-
20 min
30 min
18 h
99
99
99
99
99
99
99
99
98
99
99
99
99
99
99
99
99
99
99
66
76
76
78
72
74
70
69
76
72
74
78
80
83
78
80
78
74
77
Table 4 Substrate scope of the enantioselective
2
-20
-50
-78
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
Michael/cyclization tandem reactiona
3
4
72 h
5
30 min
30 min
35 min
35 min
40 min
30 min
50 min
6
1:1
7
1:1.2
1:2
Entry
1
R1
R2
Time
40 min
1 h
Yield (%)b
3a, 99
3b, 99
3c, 99
3d, 99
3e, 99
3f, 99
Ee (%)c
83
8
Bn
H
9d
10e
11f
12
13
14
15
16
17
18
19
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
1.2:1
2
Ph
H
58
3
Me
H
40 min
1 h
68
4
H
H
6
4 Å MS (10 mg) 30 min
4 Å MS (25 mg) 40 min
4 Å MS (50 mg) 40 min
4 Å MS (75 mg) 40 min
3 Å MS (50 mg) 40 min
5 Å MS (50 mg) 40 min
5
CHPh2
CPh3
CPh3
CPh3
CPh3
CPh3
CPh3
CPh3
CPh3
CPh3
CPh3
CPh3
H
1 h
79
6
H
30 min
36 h
98
7
4-Cl
5-MeO
5-Me
5-F
5-Cl
5-Br
6-MeO
6-Me
6-F
6-Cl
3g, 99
3h, 99
3i, 99
94
8
20 min
40 min
15 min
35 min
30 min
24 h
99
9
98
10
11
12
13
14
15
16
3j, 98
98
H2O (1.8 ꢀL)
30 min
45 min
3k, 99
3l, 97
98
4 Å MS (50
mg), H2O (1.8
ꢀL)
99.2
99.2
99.6
99.1
99
3m, 99
3n, 99
3o, 99
3p, 99
20
1.2:1
-20
4 Å MS (50
mg), H2O (9.0
ꢀL)
45 min
79
70
2 h
a Unless stated otherwise, the reactions were performed with dimedone (0.12
mmol), substrate 2a (0.10 mmol) and chiral organocatalyst C15 (5 mol%) in
CH2Cl2 (1 mL) at -20 °C.
1 h
1 h

4
Tetrahedron
ACCEPTED MANUSCRIPT
17
18
CPh3
CPh3
6-Br
7-F
1 h
3 h
3q, 99
99.7
3r, 99
99
a All reactions were performed with dimedone (0.12 mmol), 2 (0.10 mmol), 4
Å MS (50 mg) and C15 (5 mol%) in CH2Cl2 (1 mL) at -20 °C.
b Isolated yields.
c Determined by chiral HPLC analysis.
Scheme 2 Gram-scale construction of spiro compound 3f
Moreover, we attempted the one-pot three component reaction
of dimedone, malononitrile and N-trityl isatin under the optimal
conditions. However, the corresponding chiral spiro product 3f
was obtained only in 5% yield with 98% ee for 24 hours. N-trityl
isatin was recovered with 61% yield, and N-trityl isatylidene
malononitrile was obtained in 30% yield (Scheme 1a). To
improve the one-pot reaction, 5 mol% piperidine was added. The
yield of product 3f was increased to 34% with an obvious
decrement of enantioselectivity, and there were 37% N-trityl
protected isatin and 27% N-trityl isatylidene malononitrile
remaining (Scheme 1b). We suspected that piperidine could
promote both the knoevenagel condensation and the subsequent
Michael/cyclization reaction, and our suspect has been proved by
examining the corresponding two-component reaction under the
same reaction condition. Therefore, 10 mol% of chiral catalyst
C15 was used to catalyze the one-pot reaction rather than adding
achiral base. To our delight, the yield of product 3f was increased
to 75% with 95% ee after 48 hours (Scheme 1c). While 15%
yield of N-trityl isatylidene malononitrile was isolated, the
Scheme 3 The transformation of spiro compound 3f
As shown in Scheme 3, the transformation of the amino group
of the spiro 2-amino-4H-pyran was achieved by this reaction.5b,5d
Treatment of chiral product 3f with triethyl orthoformate in the
o
presence of acetic acid at 90 C afforded imine 4 in 90% yield
with 99% ee.
The absolute configuration of spirooxindole 3h was addressed
to be R by X-ray crystallography (Fig. 2, CCDC1856973). The
configurations of the other spiro[2-amino-4H-pyran-oxindole]
derivatives 3 were assigned by analogy.
o
reaction temperature was increased to 0 C in order to improve
the conversion. As predicted, the one-pot three component
reaction was achieved in 96% yield and 95% ee (Scheme 1d).
Fig. 2 X-ray structure of product 3h.
3. Conclusions
Scheme 1 Attempt of one-pot three component reaction
In conclusion,
a
highly enantioselective Michael
addition/cyclization tandem reaction of dimedone to isatylidene
malononitriles was developed. In the presence of 5 mol% chiral
tertiary amine-squaramide organocatalyst C15, N-trityl
multicyclic spirooxindoles were achieved with high yields (97-
99%) with excellent enantioselectivities (94->99% ee). This
methodology represents an efficient approach to the synthesis of
novel chiral spiro[2-amino-4H-pyran-oxindole] compounds.
To demonstrate the synthetic utility of this work, gram-scale
construction of spiro compound 3f was performed under the
optimized reaction conditions. The tandem reaction was achieved
in 99% yield with 98% ee (Scheme 2).
4. Experimental section
4.1. General methods

5
1
Melting points were taken without correction. H NMR and
17.6 Hz, 1H), 2.53 (d, J = 17.6 Hz, 1H), 2.23 (d, J = 16.0 Hz,
ACCEPTED MANUSCRIPT
13C NMR spectra were recorded on Bruker 400 spectrometer. H
1H), 2.15 (d, J = 16.4 Hz, 1H), 1.05 (s, 3H), 1.02 (s, 3H); 13C
NMR (100 MHz, DMSO-d6, ppm): δ 195.3, 176.2, 164.5, 158.9,
143.3, 134.8, 133.3, 129.7, 128.5, 128.1, 126.6, 123.5, 123.1,
117.3, 110.9, 108.6, 57.1, 49.8, 46.6, 32.1, 27.7, 27.0; IR (KBr,
cm-1): ν 3440, 3312, 3157, 2951, 2193, 1717, 1684, 1659, 1627,
1601, 1498, 1473, 1357, 1318, 1293, 1254, 1221, 1164, 1054,
759, 701; HRMS (ESI) calcd for C25H22N3O3 ([M+H] +):
412.1658, found: 412.1661; HPLC analysis (OD-H column, λ =
254 nm, eluent: n-hexane/i-PrOH = 80/20, flow rate: 0.9
mL/min): tR = 20.56 min (minor), 26.92 min (major).
1
NMR spectra were referenced to tetramethylsilane (δ 0.00 ppm)
using CDCl3 or DMSO-d6 as solvent. 13C NMR spectra were
referenced to solvent carbons (δ 77.0 ppm for CDCl3 or δ 39.52
ppm for DMSO-d6). IR spectra were recorded on IR Prestige-21
spectrometer. High resolution mass spectra (HRMS) were
performed on electron spray ionization time-of-flight (EI-TOF)
mass spectrometer and electron spray ionization time-of-flight
(ESI-TOF) mass spectrometer. Optical rotations were measured
with a WZZ-2S polarimeter. Enantiomeric excesses were
determined by chiral HPLC analysis using Waters 510 liquid
chromatograph instrument and Waters 2487 dual absorbance
detector with Daicel Chiralcel OD-H column, Chiralpak AD-H
column and Chiralpak AS-H column. Thin-layer chromatography
(TLC) was performed on 10-40 ꢀm silica gel plates. Column
chromatography was performed on silica gel (300-400 mesh)
eluted with ethyl acetate and CH2Cl2.
4.2.3. (R)-2-amino-1',7,7-trimethyl-2',5-dioxo-
5,6,7,8-tetrahydrospiro[chromene-4,3'-indoline] -3-
carbonitrile (3c)
o
20
White solid, 99% yield, 68% ee, mp 254.5-254.6 C, [α]D
+57.4 (c 0.50, CH2Cl2) ; 1H NMR (400 MHz, DMSO-d6, ppm): δ
7.37 (s, 2H), 7.31 (td, J1 = 1.2 Hz, J2 = 7.6 Hz, 1H), 7.12-7.10 (m,
1H), 7.07-7.02 (m, 2H), 3.19 (s, 3H), 2.63 (d, J = 3.6 Hz, 2H),
2.21 (d, J = 16.0 Hz, 1H), 2.14 (d, J = 15.6 Hz, 1H), 1.09 (s, 3H),
1.05 (s, 3H); 13C NMR (100 MHz, DMSO-d6, ppm): δ 194.9,
176.6, 164.3, 158.9, 143.6, 133.6, 128.4, 122.8, 122.4, 117.2,
110.7, 108.2, 57.0, 49.9, 46.5, 32.0, 27.5, 27.1, 26.4; IR (KBr,
cm-1): ν 3382, 3157, 2958, 2199, 1704, 1665, 1607, 1498, 1465,
1351, 1318, 1215, 1164, 1126, 1087, 1048, 900, 746; HRMS
(ESI) calcd for C20H19NaN3O3 ([M+Na]+): 372.1324, found:
372.1319; HPLC analysis (OD-H column, λ = 254 nm, eluent: n-
hexane/i-PrOH = 70/30, flow rate: 0.9 mL/min): tR = 20.53 min
(major), 40.42 min (minor).
All solvents were purified by conventional methods and
distilled before use. Commercially available reagents and chiral
organocatalysts such as quinine (C1), cinchonidine (C2) and
(DHQD)2PYR (C8) were used without further purification.
Organocatalysts
C3-C7,
C9-C1610 and
isatylidene
malononitriles 2a-2r5d,11 were prepared according to literature
procedures.
4.2. General procedure for the asymmetric tandem reaction and
characterization of the products 3a-3r
4.2.4. (R)-2-amino-7,7-dimethyl-2',5-dioxo-5,6,7,8-
tetrahydrospiro[chromene-4,3'-indo-line] -3-
carbonitrile (3d)1 2
To a solution of isatylidene malononitrile 2 (0.10 mmol, 1.0
eq.), chiral catalyst C15 (5 mol%) and 4Å molecular sieves (50
mg) in 1 mL of dichloromethane was added dimedone (0.12
mmol, 1.2 eq.) at -20 oC, and the resulting mixture was stirred at
this temperature until the starting materials disappeared
(monitored by TLC). The residue was directly purified by flash
column chromatography (4:1-20:1 CH2Cl2/EtOAc) to give the
desired spiro product 3.
o
20
White solid, 99% yield, 6% ee, mp 290.0-290.8 C, [α]D
1
+25.9 (c 0.48, CH2Cl2); H NMR (400 MHz, DMSO-d6, ppm): δ
10.41 (s, 1H), 7.24 (s, 2H), 7.13 (d, J = 6.4 Hz, 1H ), 6.98 (d, J =
6.4 Hz, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H ),
2.56 (s, 2H), 2.17 (d, J = 16.0 Hz, 1H), 2.09 (d, J = 15.6 Hz, 1H),
1.03 (s, 3H), 1.00 (s, 3H); HPLC analysis (OD-H column, λ =
254 nm, eluent: n-hexane/i-PrOH = 70/30, flow rate: 0.9
mL/min): tR = 15.87 min (major), 35.63 min (minor).
4.2.1. (R)-2-amino-1'-benzyl-7,7-dimethyl-2',5-
dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3'-
indoline] -3-carbonitrile (3a)
o
20
4.2.5. (R)-2-amino-1'-benzhydryl-7,7-dimethyl-2',5-
dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3'-
indoline] -3-carbonitrile (3e)
White solid, 99% yield, 83% ee, mp 291.1-291.3 C, [α]D
1
+62.1 (c 0.71, CH2Cl2); H NMR (400 MHz, DMSO-d6, ppm): δ
7.54 (d, J = 6.8 Hz, 2H), 7.40 (s, 2H), 7.38-7.28 (m, 3H), 7.20-
7.13 (m, 2H), 7.01 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H),
4.99 (d, J = 16.4 Hz, 1H), 4.93 (d, J = 16.0 Hz, 1H), 2.68 (d, J =
17.6 Hz, 1H), 2.62 (d, J = 17.2 Hz, 1H), 2.27 (d, J = 15.6 Hz,
1H), 2.17 (d, J = 16.0 Hz, 1H), 1.10 (s, 3H), 1.06 (s, 3H); 13C
NMR (100 MHz, DMSO-d6, ppm): δ 195.1, 176.7, 164.5, 159.0,
142.6, 136.2, 133.6, 128.4, 128.3, 127.2, 127.1, 123.0, 122.6,
117.4, 110.7, 108.9, 57.2, 49.9, 46.6, 43.3, 32.0, 27.6, 27.0; IR
(KBr, cm-1): ν 3389, 3331, 3202, 2958, 2199, 1717, 1679, 1659,
1601, 1479, 1466, 1421, 1344, 1293, 1215, 1170, 1048, 984, 894,
753, 701; HRMS (ESI) calcd for C26H22N3O3 ([M-H]+):
424.1661, found: 424.1646; HPLC analysis (OD-H column, λ =
254 nm, eluent: n-hexane/i-PrOH = 80/20, flow rate: 0.9
mL/min): tR = 23.28 min (minor), 34.44 min (major).
o
20
White solid, 99% yield, 79% ee, mp 277.8-278.8 C, [α]D
+116.6 (c 0.25, CH2Cl2); 1H NMR (400 MHz, DMSO-d6, ppm): δ
7.47 (d, J = 7.2 Hz, 2H), 7.42-7.38 (m, 6H), 7.37-7.34 (m, 4H),
7.15-7.13 (m, 1H), 7.00-6.93 (m, 2H), 6.91 (s, 1H), 6.28 (dd, J1 =
1.6 Hz, J2 = 6.4 Hz, 1H), 2.68 (d, J = 17.6 Hz , 1H), 2.62 (d, J =
18.0 Hz , 1H), 2.27 (d, J = 16.0 Hz , 1H), 2.19 (d, J = 16.4 Hz ,
1H), 1.09 (s, 3H), 1.06 (s, 3H); 13C NMR (100 MHz, DMSO-d6,
ppm): δ 195.1, 176.9, 164.6, 159.0, 142.3, 137.8, 137.7, 133.9,
128.5, 128.4, 128.3, 127.7, 127.6, 127.5, 123.1, 122.3, 117.6,
111.0, 110.7, 58.0, 57.3, 49.9, 46.2, 32.0, 27.6, 27.1; IR (KBr,
cm-1): ν 3370, 3176, 2964, 2186, 1698, 1685, 1659, 1601, 1466,
1415, 1351, 1312, 1228, 1164, 1054, 907, 798, 753, 733, 695;
HRMS (ESI) calcd for C26H28N3O3 ([M+H]+): 502.2137, found:
502.2131; HPLC analysis (OD-H column, λ = 254 nm, eluent: n-
hexane/i-PrOH = 80/20, flow rate: 0.9 mL/min): tR = 10.79 min
(minor), 25.87 min (major).
4.2.2. (R)-2-amino-7,7-dimethyl-2',5-dioxo-1'-
phenyl-5,6,7,8-tetrahydrospiro[chromene-4,3'-
indoline] -3-carbonitrile (3b)
o
20
4.2.6. (R)-2-amino-7,7-dimethyl-2',5-dioxo-1'-
trityl-5,6,7,8-tetrahydrospiro[chromene-4,3'-
indoline] -3-carbonitrile (3f)
White solid, 99% yield, 58% ee, mp 295.9-296.8 C, [α]D
+117.3 (c 0.82, CH2Cl2); 1H NMR (400 MHz, DMSO-d6, ppm): δ
7.61 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.42 (s, 2H),
7.38 (d, J = 7.6 Hz, 2H), 7.18 (q, J1 = 7.6 Hz, J2 = 15.6 Hz, 2H),
7.04 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 2.64 (d, J =
o
20
White solid, 99% yield, 98% ee, mp 268.8-270.6 C, [α]D
-
1
10.6 (c 2.31, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.58
(d, J = 7.6 Hz, 6H), 7.28-7.24 (m, 6H), 7.19 (t, J = 6.8 Hz, 3H),

6
Tetrahedron
6.93-6.91 (m, 1H), 6.86-6.84 (m, 2H), 6.40-6.37 (m, 1H), 4.58
1267, 1215, 1048, 1010, 804, 726, 695; HRMS (ESI) calcd for
ACCEPTED MANUSCRIPT
(s, 2H), 2.44 (d, J = 17.2 Hz, 1H), 2.36 (d, J = 17.6 Hz, 1H), 2.17
(d, J = 15.6 Hz, 1H), 2.10 (d, J = 16.0 Hz, 1H), 1.06 (s, 3H), 1.02
(s, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 194.3, 177.2,
163.6, 158.3, 143.1, 141.7, 133.0, 129.8, 127.4, 127.1, 126.7,
122.5, 122.4, 117.5, 116.0, 111.7, 74.8, 61.9, 50.4, 47.2, 40.8,
32.0, 28.6, 27.4; IR (KBr, cm-1): ν 3376, 3189, 2951, 2193, 1717,
1672, 1595, 1460, 1415, 1351, 1318, 1273, 1215, 1170, 1048,
733, 694; HRMS (ESI) calcd for C38H30N3O3 ([M-H]+):
576.2287, found: 576.2286; HPLC analysis (OD-H column, λ =
254 nm, eluent: n-hexane/i-PrOH = 95/5, flow rate: 0.9 mL/min):
tR = 31.33 min (minor), 39.66 min (major).
C39H33NaN3O3 ([M+Na]+): 614.2420, found: 614.1722; HPLC
analysis (OD-H column, λ = 254 nm, eluent: n-hexane/i-PrOH =
95/5, flow rate: 0.9 mL/min): tR = 26.69 min (minor), 34.66 min
(major).
4.2.10. (R)-2-amino-5'-fluoro-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3j)
o
20
White solid, 98% yield, 98% ee, mp 267.3-267.8 C, [α]D
-
1
13.3 (c 1.48, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.56
(d, J = 8.0 Hz, 6H), 7.27 (t, J = 7.6 Hz, 6H), 7.20 (t, J = 7.2 Hz,
3H), 6.67 (dd, J1 = 2.4 Hz, J2 = 7.2 Hz, 1H), 6.56 (td, J1 = 2.8 Hz,
J2 = 9.2 Hz, 1H), 6.32 (dd, J1 = 4.4 Hz, J2 = 8.8 Hz, 1H), 4.70 (s,
2H), 2.44 (d, J = 17.6 Hz, 1H), 2.37 (d, J = 17.6 Hz, 1H), 2.18 (d,
J = 16.4 Hz, 1H), 2.11 (d, J = 16.4 Hz, 1H), 1.06 (s, 3H), 1.03 (s,
3H); 13C NMR (100 MHz, CDCl3, ppm): δ 194.3, 177.0, 163.9,
160.1, 158.3, 157.7, 141.5, 139.1 (d, JC-F = 1.5 Hz), 134.5 (d, JC-F
= 7.3 Hz), 129.8, 127.5, 126.8, 117.2, 116.7 (d, JC-F = 8.0 Hz),
113.7 (d, JC-F = 22.6 Hz), 111.5, 110.1 (d, JC-F = 24.3 Hz), 74.9,
61.7, 50.4, 47.5, 40.8, 32.1, 28.6, 27.5; IR (KBr, cm-1): ν 3453,
3356, 2951, 2193, 1717, 1679, 1595, 1479, 1447, 1351, 1324,
1273, 1221, 1157, 1048, 1016, 958, 900, 811, 746, 733, 701;
HRMS (ESI) calcd for C38H30FNaN3O3 ([M+Na]+): 618.2169,
found: 618.2164; HPLC analysis (OD-H column, λ = 254 nm,
4.2.7. (R)-2-amino-4'-chloro-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3g)
o
20
White solid, 99% yield, 94% ee, mp 255.7-260.0 C, [α]D
-
1
21.0 (c 1.36, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.56
(d, J = 7.6 Hz, 6H), 7.27 (t, J = 7.2 Hz, 6H), 7.20 (t, J = 7.2 Hz,
3H), 6.80 (d, J = 4.4 Hz, 2H), 6.34 (t, J = 9.2 Hz, 1H), 4.71(s,
2H), 2.45 (d, J = 17.6 Hz, 1H), 2.35 (d, J = 17.2 Hz, 1H), 2.21 (d,
J = 15.6 Hz, 1H), 2.14 (d, J = 16.0 Hz, 1H), 1.08 (s, 3H), 1.06 (s,
3H); 13C NMR (100 MHz, CDCl3, ppm): δ 194.6, 176.4, 164.4,
159.3, 145.0, 141.4, 129.8, 129.5, 128.3, 127.8, 127.5, 126.9,
123.3, 117.3, 114.6, 110.7, 75.2, 59.8, 50.3, 47.6, 40.8, 32.0,
29.0, 27.4; IR (KBr, cm-1): ν 3453, 3363, 3202, 3054, 2964,
2193, 1730, 1672, 1595, 1492, 1447, 1344, 1267, 1215, 1170,
1138, 1048, 977, 887, 772, 726, 701; HRMS (ESI) calcd for
C38H30ClNaN3O3 ([M+Na]+): 634.1873, found: 634.1345; HPLC
analysis (OD-H column, λ = 254 nm, eluent: n-hexane/i-PrOH =
95/5, flow rate: 0.9 mL/min): tR = 24.37 min (minor), 35.49 min
(major).
eluent: n-hexane/i-PrOH = 95/5, flow rate: 0.9 mL/min): tR
29.55 min (minor), 34.51 min (major).
=
4.2.11. (R)-2-amino-5'-chloro-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3k)
o
20
White solid, 99% yield, 98% ee, mp 265.5-266.0 C, [α]D
-
1
43.4 (c 1.22, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.55
(d, J = 7.6 Hz, 6H), 7.29-7.24 (m, 6H), 7.20 (t, J = 7.2 Hz, 3H),
6.90 (d, J = 2.4 Hz, 1H), 6.82 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H),
6.31 (d, J = 8.4 Hz, 1H), 4.70 (s, 2H), 2.43 (d, J = 17.6 Hz, 1H),
2.38 (d, J = 17.6 Hz, 1H), 2.18 (d, J = 16.4 Hz, 1H), 2.11 (d, J =
16.4 Hz, 1H), 1.06 (s, 3H), 1.03 (s, 3H); 13C NMR (100 MHz,
CDCl3, ppm): δ 194.3, 176.8, 163.9, 158.3, 141.9, 141.4, 134.7,
129.7, 128.0, 127.5, 127.3, 126.9, 122.8, 117.2, 116.9, 111.4,
75.0, 61.5, 50.3, 47.3, 40.8, 32.1, 28.4, 27.7; IR (KBr, cm-1): ν
3395, 3318, 2958, 2186, 1717, 1672, 1595, 1473, 1447, 1351,
1318, 1286, 1254, 1221, 1164, 1106, 1054, 1003, 894, 811, 746,
701; HRMS (ESI) calcd for C38H30ClNaN3O3 ([M+Na]+):
634.1873, found: 634.1873; HPLC analysis (OD-H column, λ =
254 nm, eluent: n-hexane/i-PrOH = 95/5, flow rate: 0.9 mL/min):
tR = 29.26 min (minor), 36.01 min (major).
4.2.8. (R)-2-amino-5'-methoxy-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3h)
o
20
White solid, 99% yield, 99% ee, mp 259.9-260.2 C, [α]D
-
1
25.5 (c 2.00, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.57
(d, J = 7.6 Hz, 6H), 7.28-7.25 (m, 6H), 7.19 (t, J = 7.2 Hz, 3H),
6.50 (d, J = 2.0 Hz, 1H), 6.38 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H),
6.27 (d, J = 8.8 Hz, 1H), 4.65 (s, 2H), 3.62 (s, 3H), 2.45 (d, J =
17.6 Hz, 1H), 2.37 (d, J = 17.6 Hz, 1H), 2.18 (d, J = 16.4 Hz,
1H), 2.10 (d, J = 16.4 Hz, 1H), 1.07 (s, 3H), 1.03 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm): δ 194.2, 177.0, 163.6, 158.2,
155.5, 141.8, 136.5, 134.3, 129.8, 127.4, 126.7, 117.4, 116.4,
111.8, 111.4, 109.7, 74.8, 62.4, 55.3, 50.4, 47.6, 40.8, 32.1, 28.7,
27.5; IR (KBr, cm-1): ν 3389, 3196, 2958, 2193, 1710, 1672,
1601, 1485, 1447, 1344, 1318, 1280, 1215, 1170, 1054, 798, 740,
695; HRMS (ESI) calcd for C39H33NaN3O4 ([M+Na]+): 630.2369,
found: 630.2439; HPLC analysis (AS-H column, λ = 254 nm,
4.2.12. (R)-2-amino-5'-bromo-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3l)
eluent: n-hexane/EtOH = 90/10, flow rate: 0.9 mL/min): tR
11.65 min (minor), 15.45 min (major).
=
20
White solid, 97% yield, 99.2% ee, mp 261.2-262.1 oC, [α]D
-
1
40.2 (c 2.17, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.55
(d, J = 7.6 Hz, 6H), 7.27 (t, J = 7.2 Hz, 6H), 7.20 (t, J = 7.2 Hz,
3H), 7.04 (d, J = 2.0 Hz, 1H), 6.96 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz,
1H), 6.27 (d, J = 8.4 Hz, 1H), 4.72 (s, 2H), 2.43 (d, J = 18.0 Hz,
1H), 2.38 (d, J = 18.0 Hz, 1H), 2.18 (d, J = 16.0 Hz, 1H), 2.11 (d,
J = 16.4 Hz, 1H), 1.05 (s, 3H), 1.03 (s, 3H); 13C NMR (100 MHz,
CDCl3, ppm): δ 194.3, 176.6, 163.9, 158.4, 142.4, 141.4, 135.0,
130.1, 129.7, 127.5, 126.9, 125.6, 117.3, 115.5, 111.4, 75.0, 61.3,
50.3, 47.2, 40.8, 32.1, 28.4, 27.7; IR (KBr, cm-1): ν 3401, 3312,
2958, 2186, 1724, 1679, 1633, 1601, 1473, 1440, 1415, 1344,
1312, 1280, 1221, 1157, 1054, 900, 804, 733, 701; HRMS (EI)
calcd for C19H15BrN3O3 ([M-CPh3]+): 412.0297, found:
412.0294; HPLC analysis (OD-H column, λ = 254 nm, eluent: n-
hexane/i-PrOH = 95/5, flow rate: 0.9 mL/min): tR = 25.84 min
(minor), 34.32 min (major).
4.2.9. (R)-2-amino-5'-methyl-7,7-trimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3i)
o
20
White solid, 99% yield, 98% ee, mp 268.2-268.8 C, [α]D
-
1
32.5 (c 1.97, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.58
(d, J = 7.6 Hz, 6H), 7.26 (t, J = 7.6 Hz, 6H), 7.18 (t, J = 7.2 Hz,
3H), 6.72 (s, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 8.0 Hz,
1H), 4.62 (s, 2H), 2.44 (d, J = 17.2 Hz, 1H), 2.37 (d, J = 18.0 Hz,
1H), 2.17 (d, J = 17.2 Hz, 1H), 2.15 (s, 3H), 2.10 (d, J = 16.4 Hz,
1H), 1.06 (s, 3H), 1.03 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm): δ 194.2, 177.2, 163.5, 158.2, 141.9, 140.7, 132.9, 131.9,
129.8, 127.8, 127.4, 126.7, 123.2, 117.5, 115.7, 111.9, 74.8, 62.4,
50.4, 47.3, 40.9, 32.1, 28.6, 27.6, 20.9; IR (KBr, cm-1): ν 3395,
3196, 2958, 2186, 1710, 1672, 1595, 1492, 1447, 1351, 1324,

7
4.2.13. (R)-2-amino-6'-methoxy-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
3H), 6.84 (d, J = 0.8 Hz, 1H), 6.35 (s, 1H), 4.64 (s, 2H), 2.43 (d,
ACCEPTED MANUSCRIPT
J = 17.6 Hz, 1H), 2.37 (d, J = 17.6 Hz, 1H), 2.16 (d, J = 16.4 Hz,
1H), 2.10 (d, J = 16.4 Hz, 1H), 1.05 (s, 3H), 1.01 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm): δ 194.4, 177.1, 163.9, 158.3,
144.3, 141.3, 132.8, 131.4, 129.7, 127.5, 126.9, 123.1, 122.6,
117.2, 116.3, 111.4, 75.1, 61.5, 50.4, 46.9, 40.8, 32.1, 28.5, 27.6;
IR (KBr, cm-1): ν 3465, 3376, 2958, 2193, 1717, 1672, 1601,
1479, 1447, 1415, 1351, 1318, 1260, 1215, 1164, 1081, 1048,
1016, 932, 887, 740, 695; HRMS (ESI) calcd for C38H29ClN3O3
([M-H]+): 610.1897, found: 610.1904; HPLC analysis (OD-H
column, λ = 254 nm, eluent: n-hexane/i-PrOH = 95/5, flow rate:
0.9 mL/min): tR = 30.78 min (minor), 39.39 min (major).
4,3'-indoline] -3-carbonitrile (3m)
20
White solid, 99% yield, 99.2% ee, mp 260.1-260.3 oC, [α]D
-
1
21.0 (c 2.00, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.58
(d, J = 8.0 Hz, 6H), 7.28-7.23 (m, 6H), 7.19 (t, J = 7.2 Hz, 3H),
6.81 (d, J = 8.4 Hz, 1H), 6.38 (dd, J1 = 2.4 Hz, J2 = 8.4 Hz, 1H),
5.97 (d, J = 2.0 Hz, 1H), 4.59 (s, 2H), 3.42 (s, 3H), 2.42 (d, J =
17.6 Hz, 1H), 2.34 (d, J = 17.2 Hz, 1H), 2.16 (d, J = 16.0 Hz,
1H), 2.09 (d, J = 16.4 Hz, 1H), 1.04 (s, 3H), 1.01 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm): δ 194.4, 177.7, 163.4, 158.6,
158.1, 144.3, 141.7, 129.8, 127.4, 126.7, 125.2, 122.7, 117.5,
111.9, 107.2, 103.8, 74.8, 62.3, 55.0, 50.4, 46.8, 40.8, 32.0, 28.6,
27.5; IR (KBr, cm-1): ν 3440, 3389, 2958, 2186, 1724, 1679,
1621, 1601, 1498, 1447, 1351, 1318, 1215, 1151, 1106, 1054,
1016, 753, 733,701; HRMS (ESI) calcd for C39H32N3O4 ([M-
H]+): 606.2393, found: 606.2393; HPLC analysis (OD-H column,
λ = 254 nm, eluent: n-hexane/EtOH = 95/5, flow rate: 0.9
mL/min): tR = 20.70 min (minor), 26.36 min (major).
4.2.17. (R)-2-amino-6'-bromo-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3q)
20
White solid, 99% yield, 99.7% ee, mp 254.8-255.2 oC, [α]D
-
1
44.9 (c 2.17, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.55
(d, J = 8.0 Hz, 6H), 7.28 (t, J = 7.2 Hz, 6H), 7.21 (t, J = 7.2 Hz,
3H), 7.00 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz , 1H), 6.79 (d, J = 8.0 Hz,
1H), 6.48 (d, J = 1.6 Hz, 1H), 4.66 (s, 2H), 2.43 (d, J = 17.6 Hz,
1H), 2.37 (d, J = 17.6 Hz, 1H), 2.16 (d, J = 16.4 Hz, 1H), 2.10 (d,
J = 16.4 Hz, 1H), 1.05 (s, 3H), 1.01 (s, 3H); 13C NMR (100 MHz,
CDCl3, ppm): δ 194.4, 176.9, 163.9, 158.3, 144.5, 141.3, 131.9,
129.7, 127.5, 126.9, 125.4, 123.5, 120.8, 119.0, 117.2, 111.4,
75.1, 61.4, 50.3, 46.9, 40.8, 32.1, 28.5, 27.6; IR (KBr, cm-1): ν
3370, 3196, 2958, 2193, 1717, 1672, 1601, 1473, 1454, 1415,
1351, 1318, 1260, 1215, 1170, 1054, 1015, 887, 798, 733, 701;
HRMS (ESI) calcd for C38H29BrN3O3 ([M-H]+): 654.1409, found:
654.1392; HPLC analysis (OD-H column, λ = 254 nm, eluent: n-
hexane/i-PrOH = 95/5, flow rate: 0.9 mL/min): tR = 34.38 min
(minor), 42.30 min (major).
4.2.14. (R)-2-amino-6'-methyl-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3n)
20
White solid, 99% yield, 99.6% ee, mp 272.3-272.4 oC, [α]D
-
1
20.4 (c 1.97, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.57
(d, J = 8.0 Hz, 6H), 7.28-7.24 (m, 6H), 7.19 (t, J = 7.2 Hz, 3H),
6.80 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.16 (s, 1H),
4.56 (s, 2H), 2.43 (d, J = 17.6 Hz, 1H), 2.35 (d, J = 17.2 Hz, 1H),
2.16 (d, J = 16.0 Hz, 1H), 2.09 (d, J = 16.0 Hz, 1H), 2.00 (s, 3H),
1.05 (s, 3H), 1.01 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ
194.3, 177.5, 163.4, 158.1, 143.3, 141.9, 137.0, 130.1, 130.0,
127.3, 126.7, 123.2, 122.1, 117.4, 117.0, 112.0, 74.8, 62.7, 50.5,
47.0, 40.9, 32.1, 28.7, 27.5, 21.9; IR (KBr, cm-1): ν 3453, 3376,
2964, 2919, 2199, 1717, 1672, 1595, 1492, 1447, 1415, 1351,
1318, 1293, 1260, 1215, 1164, 1100, 1048, 939, 907, 804, 746,
733, 708; HRMS (ESI) calcd for C39H32N3O3 ([M-H]+):
590.2444, found: 590.2446; HPLC analysis (OD-H column, λ =
254 nm, eluent: n-hexane/i-PrOH = 95/5, flow rate: 0.9 mL/min):
tR = 27.31 min (minor), 35.71 min (major).
4.2.18. (R)-2-amino-7'-fluoro-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3r)
o
20
White solid, 99% yield, 99% ee, mp 231.7-232.4 C, [α]D
-
1
18.7 (c 1.97, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.55
(d, J = 7.6 Hz, 6H), 7.26 (t, J = 6.8 Hz, 6H), 7.19 (d, J = 7.2 Hz,
3H), 6.89 (td, J1 = 3.6 Hz, J2 = 7.6 Hz, 1H), 6.79 (dd, J1 = 0.8 Hz,
J2 = 7.2 Hz ,1H), 6.68-6.63 (m, 1H), 4.68 (s, 2H), 2.45 (d, J =
17.6 Hz, 1H), 2.37 (d, J = 17.6 Hz, 1H), 2.21 (d, J = 16.4 Hz,
1H), 2.14 (d, J = 16.4 Hz, 1H), 1.07 (s, 3H), 1.03 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm): δ 194.4, 176.8, 163.7, 158.3,
147.9, 145.5, 143.4, 135.8 (d, JC-F = 2.2 Hz), 130.4 (d, JC-F = 8.0
4.2.15. (R)-2-amino-6'-fluoro-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3o)
20
White solid, 99% yield, 99.1% ee, mp 261.1-261.3 oC, [α]D
-
1
16.8 (c 1.98, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.56
(d, J = 6.0 Hz, 6H), 7.27 (d, J = 6.4 Hz, 6H), 7.21 (d, J = 5.6 Hz,
3H), 6.86 (s, 1H), 6.56 (s, 1H), 6.13 (d, J = 10.4 Hz, 1H), 4.66 (s,
2H), 2.44 (d, J = 17.6 Hz, 1H), 2.38 (d, J = 17.6 Hz, 1H), 2.17 (d,
J = 14.8 Hz, 1H), 2.11 (d, J = 16.0 Hz, 1H), 1.06 (s, 3H), 1.03 (s,
3H); 13C NMR (100 MHz, CDCl3, ppm): δ 194.3, 177.4, 163.7,
162.8, 160.4, 158.2, 144.7 (d, JC-F = 11.7 Hz), 141.5, 141.4,
129.8, 129.7, 128.4 (d, JC-F = 2.9 Hz), 127.5, 127.4, 126.9, 123.1
(d, JC-F = 9.5 Hz), 117.2, 111.7, 109.1, 108.9, 104.9, 104.6, 75.1,
62.3, 50.4, 46.8, 40.9, 32.1, 28.5, 27.6; IR (KBr, cm-1): ν 3446,
3382, 2958, 2193, 1724, 1679, 1601, 1492, 1447, 1351, 1318,
1293, 1215, 1151, 1087, 1048, 945, 847, 746, 726, 701; HRMS
(ESI) calcd for C38H29FN3O3 ([M-H]+): 594.2193, found:
594.2192; HPLC analysis (OD-H column, λ = 254 nm, eluent: n-
hexane/i-PrOH = 95/5, flow rate: 0.9 mL/min): tR = 34.95 min
(minor), 44.32 min (major).
Hz), 129.3, 127.2 126.5, 124.4 (d, JC-F = 7.3 Hz), 118.7 (d, JC-F
=
2.9 Hz), 118.0, 117.8, 117.4, 111.8, 75.5, 61.8, 50.4, 47.4, 40.8,
32.1, 28.7, 27.4; IR (KBr, cm-1): ν 3446, 3195, 2958, 2193, 1723,
1672, 1601, 1485, 1454, 1351, 1318, 1235, 1221, 1157, 1054,
907, 868, 733, 708; HRMS (ESI) calcd for C38H29FN3O3 ([M-
H]+): 594.2193, found: 594.2178; HPLC analysis (OD-H column,
λ = 254 nm, eluent: n-hexane/i-PrOH = 95/5, flow rate: 0.9
mL/min): tR = 36.64 min (minor), 41.68 min (major).
4.3. General procedure for the preparation of the racemic
products 3a-3r
To a solution of isatylidene malononitrile 2 (0.10 mmol, 1.0
eq.),
1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-dimethylamino)
ethyl)thiourea (5 mol%) in dichloromethane (1 mL) was added
dimedone (0.12 mmol, 1.2 eq.) at 25 oC, and the resulting
mixture was stirred at this temperature until the starting materials
disappeared (monitored by TLC). The residue was directly
purified by flash column chromatography (4:1-20:1
CH2Cl2/EtOAc) to give the corresponding racemic product 3.
4.2.16. (R)-2-amino-6'-chloro-7,7-dimethyl-2',5-
dioxo-1'-trityl-5,6,7,8-tetrahydrospiro-[chromene-
4,3'-indoline] -3-carbonitrile (3p)
o
20
White solid, 99% yield, 99% ee, mp 257.6-258.1 C, [α]D
-
1
32.8 (c 2.03, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ 7.55
(d, J = 7.2 Hz, 6H), 7.28 (t, J = 7.2 Hz, 6H), 7.21 (t, J = 7.2 Hz,
4.4. General procedure for the one-pot three component reaction

8
Tetrahedron
ACCEPTED MANUSCRIPT
1952-1963; (f) Tan, F.; Xiao, W.-J.; Zeng, G.-B. Chin. J. Org.
Scheme 1d: To a solution of malononitrile (0.10 mmol, 1.0
Chem. 2017, 37, 824-840; (g) Xiao, Y.-L.; Zhou, Y.; Wang, J.;
Wang, J.-X.; Liu, H. Chin. J. Org. Chem. 2015, 35, 2035-2048; (h)
Narayan, R.; Potowski, M.; Jia, Z.-J.; Antonchick, A. P.;
Waldmann, H. Acc. Chem. Res. 2014, 47, 1296-1310; (i) Cheng,
D.-J.; Ishihara, Y.; Tan, B.; Barbas, C. F. ACS Catal. 2014, 4, 743-
762; (j) Chauhan P.; Chimni, S, S. Tetrahedron: Asymmetry 2013,
24, 343-356; (k) Hong, L.; Wang, R. Adv. Synth. Catal. 2013, 355,
1023-1052; (l) Dalpozzo, R.; Rartoli, G.; Bencivenni, G. Chem.
Soc. Rev. 2012, 41, 7247-7290; (m) Ball-Jones, N. R.; Badillo, J.
J.; Franz, A. K. Org. Biomol. Chem. 2012, 10, 5165-5181; (n)
Rios, R. Chem. Soc. Rev. 2012, 41, 1060-1074; (o) Singh, G. S.;
Desta, Z. Y. Chem. Rev. 2012, 112, 6104-6155; (p) Klein, J. E. M.
N. R.; Taylor, J. K. Eur. J. Org. Chem. 2011, 6821-6841.
eq.), N-trityl isatin (0.10 mmol, 1.0 eq.), chiral catalyst C15 (10
mol%), 4Å molecular sieves (50 mg) in 1 mL of dichloromethane
was added dimedone (0.12 mmol, 1.2 eq.) at 0 C. Then the
resulting mixture continued to stirred at this temperature for 24
hours (monitored by TLC). The residue was directly purified by
flash column chromatography (20:1 CH2Cl2/EtOAc) to give the
desired spiro product 3f, Knoevenagel condensation product 2f
and recovered N-trityl isatin.
o
4.5. General procedure for the transformation of product 3f and
characterization of compound 4
3. For example of asymmetric Diels-Alder reaction, see:
Zheng, H. F.; He, P.; Liu, Y. B.; Zhang, Y. L.; Liu, X. H.; Lin, L.
L.; Feng, X. M. Chem. Commun. 2014, 50, 8794-8796.
A mixture of the product 3f (346.6 mg, 0.6 mmol), 3 mL
triethyl orthoformate, and 1 mL acetic acid was stirred at 90 C
o
until the reaction was completed (monitored by TLC). The
resulting mixture was cooled to room temperature and added
water (10 mL), then extracted with CH2Cl2 (10 mL*3). The
organic phase was washed with water and then dried over
anhydrous Na2SO4. After concentrated under vacuum, the residue
was purified by column chromatography (2:1 petroleum
ether/EtOAc) and recrystallization to give the desired product 4.
4.
(a) Wang, J.-L.; Liu, D.-X.; Zhang, Z.-J.; Shan, S.-M.; Han, X.-B.;
Srinivasula, S. M.; Croce, C. M.; Alnemri, E. S.; Huang, Z.-W.
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Chernykh, V. P.; Shishkinb, O. V.; Shishkin, S. V. Tetrahedron
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2014, 46, 1143-1156; (d) J. Xie, X.-Y. Xing, F. Sha, Z.-Y. Wu,
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(R,E)-Ethyl-N-(3-cyano-7,7-dimethyl-2',5-dioxo-1'-
trityl-5,6,7,8-tetrahydrospiro[chromene-4,3'-
indolin] -2-yl)formimidate (4)
o
20
White solid, 90% yield, 99% ee, mp 250.5-250.8 C, [α]D
1
+14.4 (c 1.17, CH2Cl2); H NMR (400 MHz, CDCl3, ppm): δ
8.22 (s, 1H), 7.60 (d, J = 8.0 Hz, 6H ), 7.28-7.24 (m, 6H), 7.19 (t,
J = 6.8 Hz, 3H), 6.97-6.94 (m, 1H), 6.90-6.86 (m, 2H), 6.43-6.41
(m, 1H), 4.45-4.36 (m, 2H), 2.50 (d, J = 17.2 Hz, 1H), 2.43 (d, J
= 17.6 Hz, 1H), 2.19 (d, J = 16.4 Hz, 1H), 2.12 (d, J = 16.4 Hz,
1H), 1.37 (t, J = 7.2 Hz, 3H), 1.09 (s, 3H), 1.05 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm): δ 194.2, 176.4, 164.0, 159.7, 156.9,
143.5, 141.7, 132.2, 129.9, 127.6, 127.4, 126.7, 122.6, 116.1,
115.7, 111.4, 82.6, 75.1, 64.6, 50.5, 49.3, 41.0, 32.1, 28.7, 27.5,
13.8; IR (KBr, cm-1): ν 3448, 3058, 2961, 2213, 1732, 1673,
1615, 1466, 1362, 1304, 1251, 1186, 1089, 1043, 757, 725, 698;
HRMS (EI) calcd for C41H35N3O4 ([M-CPh3]+): 390.1454, found:
390.1444 ; HPLC analysis (AD-H column, λ = 254 nm, eluent: n-
hexane/i-PrOH = 30/1, flow rate: 0.9 mL/min): tR = 12.99 min
(minor), 14.79 min (major).
5.
6. (a) Zhang, L.-L.; Zhou, X.; Li, P.-F.; Liu, Z.T.; Liu, Y.; Sun, Y.;
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Acknowledgements
We are grateful for financial support from Science and
Technology
Commission
of
Shanghai
Municipality
(15ZR1409200), and the Fundamental Research Funds for the
Central Universities (222201814019).
References and notes
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