Enantioselective Hetero-Diels-Alder Reaction and the Synthesis of Spiropyrrolidone Derivatives

Article abstract of DOI:10.1021/acs.joc.8b01057

An efficient enantioselective hetero-Diels-Alder reaction was developed under catalysis of a chiral copper complex. A variety of spiropyrrolidones, which bear a tetra-substituted carbon stereocenter, can be obtained in good yields with excellent enantioselectivities by virtue of this method. Furthermore, a substrate-dependent reaction pathway was proposed on the basis of the isolated intermediates.

Full text of DOI:10.1021/acs.joc.8b01057

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Article
An Enantioselective Hetero-Diels-Alder Reaction and
the Synthesis of Spiropyrrolidone Derivatives therefor
Yekai Huang, Yanan Li, Jianan Sun, Jindong Li, Zhenggen Zha, and Zhiyong Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01057 • Publication Date (Web): 05 Jul 2018
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An Enantioselective Hetero-Diels-Alder Reaction and the
Synthesis of Spiropyrrolidone Derivatives therefor
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Yekai Huang, Yanan Li, Jianan Sun, Jindong Li, Zhenggen Zha* and Zhiyong Wang*
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Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter
Chemistry & Center for Excellence in Molecular Synthesis of Chinese Academy of Sciences,
Collaborative Innovation Center of Suzhou Nano Science and Technology & School of Chemistry
and Materials Science in University of Science and Technology of China
Hefei, Anhui 230026, P. R. China
*E-mail: zgzha@ustc.edu.cn; *E-mail: zwang3@ustc.edu.cn
Abstract: An efficient enantioselective hetero-Diels-Alder reaction was developed under catalysis
of a chiral copper complex. A variety of spiropyrrolidones, which bear a tetra-substituted carbon
stereocenter, can be obtained in good yields with excellent enantioselectivities by virtue of this
method. Furthermore, a substrate-dependent reaction pathway was proposed on the basis of the
isolated intermediates.
INTRODUCTION
The spiropyrrolidone skeleton as a privileged structure has been widely found in natural products
and medicinal compounds (Figure 1).1 For instance, this exists in potent histone deacetylase (HDAC)
inhibitor, which has the activity in inhibiting the proliferation of glioma U87MG, U251, SHG44,
and C6 cells, therefore becoming one of the classical anticancer agents. Recently, structure-function
relationship study indicated that modification on the spirochromane core moiety had a crucial effect
on the HDAC and antiproliferative activity. Therefore to develop an efficient method for
constructing chiral spiropyrrolidones is in great demand.
Figure 1. Chiral spiropyrrolidone scaffold in bioactive compounds.
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However, the traditional method to synthesize chiral spiropyrrolidones is to construct the racemic
isomers following the chiral separation. The other is to extract the compound from the
corresponding natural products by some biochemical techniques which is normally limited by the
raw material sources. Therefore, it is still a challenge to construct chiral spiropyrrolidones with a
simple and efficient method. As far as we know, the hetero-Diels-Alder (HDA) reaction plays an
important role in constructing optically active six-membered oxygen-containing carbocycles or
heterocycles.2, 3, 5, 6, 7 Various catalytic systems in HDA reaction, including Lewis acid catalysts,
Brønsted acid catalysts and organocatalysts, have been extensively employed to build a variety of
chiral pyrrolidone derivatives.4 For instance, cinchona alkaloid-derived amine and chiral phosphines
were shown to be efficient for the HDA reaction of 2,3-dioxopyrrolidines with allenoates.4a,b In
addition, aminocatalyst systems,4c,g carbine organocatalysts4d were also applied to [4+2]
cycloaddition reactions. Furthermore, the N,N’-dioxide/metal complex4e,f was successfully applied
to construct the chiral spiral rings in good yields with excellent enantioselectivities (Scheme 1).
Scheme 1. Previous Work and This Work on Hetero-Diels-Alder reaction of Danishefsky’s
diene with 2, 3-dioxopyrrolidines.
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In these HDA reactions, 2,3-dioxopyrrolidines13b were widely used in the construction of the chiral
annulations. We envisioned that our previous catalyst system, which demonstrated excellent results
in the traditional HDA reaction between Danishefsky’s diene13a and β,γ-unsaturated α-ketoesters or
glyoxals, may be capable of facilitating the construction of the chiral spiropyrrolidone skeleton by
employment of 2,3-dioxopyrrolidines. Herein we report an enantioselective hetero-Diels-Alder
reaction catalyzed by a copper complex,8 affording a variety of chiral spiropyrrolidones bearing a
tetra-substituted carbon stereocenter with great yields and high enantioselectivities.
RESULTS AND DISCUSSION
We began our study by choosing 1-benzyl-4-benzylidenepyrrolidine-2,3-dione and Danishefsky’s
diene as model substrates and using L1-Cu(OTf)2-Cs2CO3 as a catalyst (Table 1). The reaction was
carried out in different solvents, including CHCl3, CH3CN, EtOAc. To our delight, the best result
can be obtained in THF among these solvents (entries 1-5). This implied that ethers should favor
this reaction since THF is a kind of ether. Therefore we further investigated other different ethers
(entries 6-8). In terms of Table 1, diethyl ether presented the best result, which should be the optimal
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solvent for this reaction. Then, further exploration of different bases for this reaction was conducted
(entry 10-17). The experimental result showed that Cs2CO3 was the optimal base in terms of the
yield and the enantioselectivity. In view of the effect of temperature on the enantioselectivity of the
reaction, the reaction temperature was screened subsequently. When we lowered the temperature to
0 °C (entry 18), the enantioselectivity was slightly increased to 98% and the yield was kept at 85%.
However, when the temperature below the 0 °C, the reaction yield decreased significantly in spite
of a slight increase in enantioselectivity (entry 19). As a result, the optimized reaction conditions
were identified as below: L1-Cu(OTf)2 complex as the catalyst, Et2O as the reaction solvent,
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Cs2CO3 as the base, the HDA reaction being carried out at 0 °C.
Table 1 Optimization of the reaction conditionsa-c
entry
1
solvent
Toluene
CHCl3
CH3CN
EtOAc
THF
base
Cs2CO3
T (oC) yield (%)b ee (%)c
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
85
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Cs2CO3
3
Cs2CO3
4
Cs2CO3
5
Cs2CO3
6
1,4-dioxane
CPME
MTBE
Et2O
Cs2CO3
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Cs2CO3
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Cs2CO3
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Cs2CO3
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Et2O
K2CO3
Et2O
t-BuOK
DIPEA
Et2O
Et2O
Piperidine
Et3N
Et2O
Et2O
N-ethyl morpholine
DBU
Et2O
Et2O
DABCO
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Et2O
Et2O
Cs2CO3
Cs2CO3
0
85
75
98
99
-10
aUnless otherwise noted, all reactions were performed with 1a (0.1 mmol), 2a (0.2 mmol), L1 (2 mol %), Cs2CO3 (2 mol %)
and Cu(OTf)2 (2 mol%). bIsolated yield. cDetermined by chiral HPLC analysis. MTBE = Methyl tert-butyl ether. CPME =
Cyclopentyl methyl ether. DIPEA = Diisopropylethylamine. DBU = 1,8-Diisopropylethylamine. DBU = 1,8-
Diazabicyclo[5.4.0]undec-7-ene. DABCO = 1,4-diazabicyclooctane.
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With the optimal reaction conditions in hand, we next examined the substrate scope of 2,3-
dioxopyrrolidines for the reaction. All of the investigated reactions could be completed within 24 h
to afford the desired products in good yields with excellent enantioselectivities, most above 95% ee,
as shown in Table 2. First of all, the effect of the substitution was investigated. 2,3-dioxopyrrolidines
with meta-substituent at phenyl rings of R1 were tested to investigate the electronic effect.
Remarkably, it was found that electronic effect had little influence on the enantioselectivity but a
little influence on the yield. Both electron-donating and electron-withdrawing groups can survive
the reaction to give the desired products in moderate to good yields with excellent
enantioselectivities (entries 3b-3h). Moreover, the substrate bearing multi-substituents could also
be carried out smoothly to afford the desired product with excellent yield and enantioselectivity (3i).
However, the substitution position had an influence on the yields, while the ee value could be
maintained. For instance, fluoro-substituted groups at para position of the phenyl ring of R1
decreased the yield while the meta and ortho substitution gave the higher yields. In these cases,
however, the reaction ee values can be almost the same. (3e, 3f, 3j-3m). As for the bromo and methyl
substitution, hindrance effect had little influence on the reaction (3o, 3p). On the other hand, we
found that the substrate bearing 1-naphthyl group could give the desired product with excellent yield
and enantioselectivity (3n). To further investigate the scope of substrates, different R2 substituents
were tested and the corresponding products could be obtained in good yields with excellent
enantioselectivitis (3q, 3r). Moreover, the absolute configuration of product 3c was confirmed by
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X-ray crystallographic analysis.12
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Table 2. Scope of 2,3-dioxopyrrolidinesa-d
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time
(h)
yieldb
(%)
eec
entry R1
R2
3
(%)
1
C6H5
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Bn
Bn
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Bn
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m-MeC6H4
m-OMeC6H4
m-NO2C6H4
m-CF3C6H4
m-FC6H4
m-ClC6H4
m-BrC6H4
3,5-FC6H4
p-CF3C6H4
o-CF3C6H4
p-FC6H4
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4d
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7d
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3g
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3k
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o-FC6H4
Bn
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3o
3p
3q
3r
1-naphthyl
o-MeC6H4
o-BrC6H4
C6H5
Bn
Bn
Bn
propyl
C6H5
phenyl 18
aUnless otherwise noted, the reaction of 1 (0.25 mmol) and 2a (0.5 mmol) was performed in the presence of L1 (2 mol %),
Cs2CO3 (2 mol %) and Cu(OTf)2 (2 mol %) in Et2O (1.5 mL) at 0 °C. bIsolated yield. cDetermined by chiral HPLC analysis.
dWith 10 mol % catalyst.
To further evaluate the robust nature and practicability of this new method, a preparative scale
synthesis of product 3a was carried out. As shown in Scheme 2, the product 3a was obtained in 83%
yield with 98% ee.
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Scheme 2. Asymmetric Hetero-Diels-Alder Reaction on a gram scalea-c
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aThe reaction of 1a (5 mmol) and 2a (10 mmol) was performed in the presence of L1 (2 mol %), Cs2CO3 (2 mol %) and
Cu(OTf)2 (2 mol %) in Et2O (10 mL) at 0 °C. bIsolated yield. cDetermined by chiral HPLC analysis.
In order to gain more insights into what pathway the reaction was going through, some control
experiments were conducted. Normally, the reaction involved the traditional Diels-Alder
cycloaddition or a Mukaiyama-aldol reaction,9, 10, 11 when Lewis acid complex was chosen to
catalyzed oxo-Diels-Alder reaction. Here the substrate 1h, 2a and 2b were employed to study the
reaction process. For the HDA reaction of Danishefsky’s diene 2a with 1h, as shown in Scheme 3,
the intermediates 4 and 5 were detected by HRMS (see supporting information S3) before the
treatment of TFA. Moreover, the intermediates 5 can be isolated by silica gel chromatography and
1
identified by H NMR, 13C NMR, IR, and HRMS (see supporting information S56 and S4). As
expected, the ee vaule of the final product was well consistent with the Mukaiyama-aldol pathway.
In contrast, when the 2a was replaced by 2b as the diene, the cycloaddition intermediate 6 was
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obtained with 97% ee, which was also confirmed by H NMR, 13C NMR, IR, and HRMS (see
supporting information S57 and S4). This indicated that the HDA reaction of Danishefsky’s diene
2b with 1h proceeded a cycloaddition process. Thus, on the basis of the results above, the pathways
of this HDA reaction were greatly dependent on the diene substrate.
Scheme 3. The mechanism pathway of the Hetero-Diels-Alder reaction
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L
-Cu(OTf)2-Cs2CO3
(10 mol %)
TMSO
O
O
OTMS
OMe
O
O
Br
Et O, 0
2
OMe
℃
N
Bn
N
Bn
Br
1h
2a
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HO
O
O
TFA
OMe
O
O
Br
O
N
Bn
N
Bn
Br
3h
5
95% yield, 97% ee
97% ee
OMe
O
L
-Cu(OTf)2-Cs2CO3
(10 mol %)
O
O
OTBS
Br
OTBS
O
Et O, 0
2
℃
OMe
N
Bn
Br
N
Bn
6
1h
2b
dr > 20:1, 97% ee
O
TFA
O
Br
O
N
Bn
3h
95% yield, 97% ee
CONCLUSIONS
In conclusion, a copper-complex catalyzed asymmetric HDA reaction of Danishefsky’s diene with
2,3-dioxopyrrolidines was developed under mild conditions to give the spiropyrrolidones in good
yields with excellent enantioselectivities. This efficient method provides a facial access to construct
a tetra-substituted carbon stereocenter of spiropyrrolidone derivatives. The study of the reaction
mechanism indicated that the two reaction pathways were involved, which were depending equally
on the diene substrate. Furthermore, the gram scale synthesis can be carried out to afford the desired
product in 83% yield with 98% ee by using 2 mol % of the L1–Cu complex. Further studies to
expand the scope of this process and to develop more challenging asymmetric reactions are ongoing
in our laboratory.
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EXPERIMENTAL SECTION
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General Information: H NMR and 13C NMR were recorded on a 400MHz Nuclear Magnetic
Resonance Spectrometer (1H NMR: 400MHz, 13C NMR: 100MHz) using TMS as internal reference.
The chemical shifts (δ) and coupling constants (J) were expressed in ppm and Hz, respectively. UV-
Vis Spectrophotometry was carried out on infrared spectrometer. HPLC analysis was carried out on
HPLC with a multiple wavelength detector by commercial chiral columns. Optical rotations were
measured on a Polarimeter. HRMS (ESI) were recorded on a Q-TOF Premier. Commercially
available compounds were used without further purification. Solvents were purified according to
the standard procedures unless otherwise noted. Ligand, various pyrrolidones, and Danishefsky’s
diene were prepared according to literature procedures.
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General procedures of Hetero-Diels-Alder reaction: A mixture of Ligand (L, 2 mol %, 2.2 mg),
Cu(OTf)2 (2 mol %, 1.8 mg) and Cs2CO3 (2 mol %, 1.7 mg) in corresponding solvent (1.5 mL) was
stirred for 2 h at ambient atmosphere and the resulting mixture was cooled to 0 °C. After 30 min,
the corresponding pyrrolidone (0.25 mmol) and Danishefsky’s diene (0.5 mmol) were then added.
After reaction was finished (monitored by TLC), 5.0 equiv. TFA was added to quench the reaction.
The system was quenched by saturated sodium bicarbonate after 2 h and then extracted by ethyl
acetate. The organic phase was dried with anhydrous sodium sulfate, evaporated in vacuo.
Purification of the residue by column chromatograph (PE/EA= 10/1-3/1) afforded the desired HDA
adducts.
Experimental date of substrates
(E)-1-benzyl-4-benzylidenepyrrolidine-2,3-dione (1a)
Yellow solid, mp = 214-216 °C; 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.45-7.34 (m, 10H),
4.81 (s, 2H), 4.42 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 186.4, 160.5, 138.2, 134.6, 133.3, 131.5,
131.2, 129.4, 129.1, 128.5, 128.4, 124.7, 48.1, 46.4; HRMS (ESI-TOF) m/z: [M+H]＋ Calcd for
C18H16NO2 278.1181; found 278.1176.
(E)-1-benzyl-4-(3-methylbenzylidene)pyrrolidine-2,3-dione (1b)
1
Yellow solid, mp = 173-174 °C; H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.40-731 (m, 6H),
7.28-7.26 (m, 1H), 7.22-7.20 (m, 2H), 4.81 (s, 2H), 4.41 (s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 186.4, 160.2, 139.2, 138.5, 134.7, 133.3, 132.4, 132.3, 129.2, 129.1, 128.42, 128.35,
128.0, 124.5, 48.0, 46.4, 21.4; HRMS (ESI-TOF) m/z: [M+Na]＋ Calcd for C19H17NO2Na 314.1157;
found 314.1149.
(E)-1-benzyl-4-(3-methoxybenzylidene)pyrrolidine-2,3-dione (1c)
Yellow solid, mp = 169-170 °C; 1H NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.39-7.34 (m, 6H),
7.01-6.99 (m, 2H), 6.93 (s, 1H), 4.81 (s, 2H), 4.40 (s, 2H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 186.4, 160.5, 160.0, 138.1, 134.59, 134.57, 130.3, 129.1, 128.5, 128.4, 124.9, 123.4, 116.9, 116.8,
55.4, 48.1, 46.3; HRMS (ESI-TOF) m/z: [M+H]＋ Calcd for C19H18NO3 308.1287; found 308.1288.
(E)-1-benzyl-4-(3-nitrobenzylidene)pyrrolidine-2,3-dione (1d)
Yellow solid, mp = 185-187 °C; 1H NMR (400 MHz, CDCl3): δ 8.31-8.29 (m, 1H), 8.25 (s, 1H),
7.78-7.76 (m, 1H), 7.70-7.66 (m, 2H), 7.42-7.35 (m, 5H), 4.84 (s, 2H), 4.51 (s, 2H); 13C NMR (100
MHz, CDCl3): δ 186.3, 159.8, 148.6, 136.5, 134.8, 134.2, 130.5, 129.1, 128.50, 128.48, 127.0, 125.4,
124.8, 48.1, 46.1; HRMS (ESI-TOF) m/z: [M+H] ＋ Calcd for C18H15N2O4 323.1032; found
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(E)-1-benzyl-4-(3-(trifluoromethyl)benzylidene)pyrrolidine-2,3-dione (1e)
Yellow solid, mp = 186-188 °C; 1H NMR (400 MHz, CDCl3): δ 7.71-7.59 (m, 5H), 7.41-7.34 (m,
5H), 4.82 (s, 2H), 4.43 (s, 2H); 19F (376 MHz, CDCl3): δ -63.03; 13C NMR (100 MHz, CDCl3): δ
186.3, 160.0, 136.1, 134.4, 134.0, 133.7, 131.9 (q, 2JCF = 32.6 Hz, 1C), 130.0, 129.2, 128.5, 127.7
3
3
1
(q, JCF = 3.5 Hz, 1C), 127.5 (q, JCF = 3.8 Hz, 1C), 126.1, 123.4 (q, JCF = 270.9 Hz, 1C), 48.1,
46.1; HRMS (ESI-TOF) m/z: [M+H]＋ Calcd for C19H15F3NO2 346.1055; found 346.1054.
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(E)-1-benzyl-4-(3-fluorobenzylidene)pyrrolidine-2,3-dione (1f)
Yellow solid, mp = 195-196 °C; 1H NMR (400 MHz, CDCl3): δ 7.64 (s, 1H), 7.46-7.34 (m, 6H),
7.23-7.21 (m, 1H), 7.18-7.14 (m, 1H), 7.10-7.07 (m, 1H), 4.81 (s, 2H), 4.41 (s, 2H); 19F (376 MHz,
CDCl3): δ -110.96; 13C NMR (100 MHz, CDCl3): δ 186.4, 162.8 (d, JCF = 247.0 Hz, 1C), 160.2,
136.6 (d, 4JCF = 2.6 Hz, 1C), 135.3 (d, 3JCF = 7.5 Hz, 1C), 134.4, 131.0 (d, 3JCF = 8.2 Hz, 1C), 129.1,
128.49, 128.45, 127.2(d, 4JCF = 2.9 Hz, 1C), 125.6, 118.4 (d, 2JCF = 21.3 Hz, 1C), 117.2 (d, 2JCF
21.9 Hz, 1C), 48.1, 46.2; HRMS (ESI-TOF) m/z: [M+H]＋ Calcd for C18H15FNO2 296.1087; found
1
=
296.1083.
(E)-1-benzyl-4-(3-chlorobenzylidene)pyrrolidine-2,3-dione (1g)
Yellow solid, mp = 198-201 °C; 1H NMR (400 MHz, CDCl3): δ 7.61 (s, 1H), 7.44-7.27 (m, 9H),
4.82 (s, 2H), 4.42 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 186.3, 160.2, 136.4, 135.3, 135.0, 134.5,
131.3, 130.65, 130.56, 129.1, 128.5, 125.7, 48.1, 46.2; HRMS (ESI-TOF) m/z: [M+H]＋ Calcd for
C18H15ClNO2 312.0791; found 312.0791.
(E)-1-benzyl-4-(3-bromobenzylidene)pyrrolidine-2,3-dione (1h)
Yellow solid, mp = 203-205 °C; 1H NMR (400 MHz, CDCl3): δ 7.56-7.52 (m, 3H), 7.40-7.29 (m,
7H), 4.80 (s, 2H), 4.41 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 186.3, 160.1, 136.2, 135.2, 134.4,
134.1, 133.6, 130.7, 129.4, 129.1, 128.41, 128.38, 125.7, 123.3, 48.0, 46.1; HRMS (ESI-TOF) m/z:
[M+H]＋ Calcd for C18H15BrNO2 356.0286; found 356.0291.
(E)-1-benzyl-4-(3,5-difluorobenzylidene)pyrrolidine-2,3-dione (1i)
Yellow solid, mp = 185-187 °C; 1H NMR (400 MHz, CDCl3): δ 7.56 (s, 1H), 7.42-7.34 (m, 5H),
6.94-6.90 (m, 3H), 4.81 (s, 2H), 4.39 (s, 2H); 19F (376 MHz, CDCl3): δ -107.38; 13C NMR (100
MHz, CDCl3): δ 186.3, 163.2 (dd, 1JCF = 249.5 Hz, 3JCF = 12.4 Hz, 2C), 159.9, 136.1 (t, 3JCF = 9.5
4
2
Hz, 2C), 135.2 (t, JCF = 2.7 Hz, 1C), 134.3, 129.2, 128.55, 128.53, 126.6, 113.6 (dd, JCF = 18.9
Hz, 4JCF = 7.3 Hz, 2C), 106.7 (t, 2JCF = 25.1 Hz, 1C), 48.2, 46.0; HRMS (ESI-TOF) m/z: [M+H]＋
Calcd for C18H14F2NO2 314.0993; found 314.0994.
(E)-1-benzyl-4-(4-(trifluoromethyl)benzylidene)pyrrolidine-2,3-dione (1j)
Yellow solid, mp = 205-208 °C; 1H NMR (400 MHz, CDCl3): δ 7.71-7.69 (m, 3H), 7.54-7.52 (m,
2H), 7.41-7.34 (m, 5H), 4.82 (s, 2H), 4.43 (s, 2H); 19F (376 MHz, CDCl3): δ -63.12; 13C NMR (100
2
MHz, CDCl3): δ 186.4, 160.0, 136.6, 135.9, 134.3, 132.6 (q, JCF = 32.8 Hz, 1C), 131.1, 129.2,
128.5, 126.6, 126.2 (q, 3JCF = 3.8 Hz, 2C), 123.4 (q, 1JCF = 271.1 Hz, 1C), 48.1, 46.2; HRMS (ESI-
TOF) m/z: [M+H]＋ Calcd for C19H15F3NO2 346.1055; found 346.1056.
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(E)-1-benzyl-4-(2-(trifluoromethyl)benzylidene)pyrrolidine-2,3-dione (1k)
Yellow solid, mp = 180-183 °C; 1H NMR (400 MHz, CDCl3): δ 7.99 (m, 1H), 7.77-7.75 (m, 1H),
7.62-7.52 (m, 2H), 7.40-7.30 (m, 6H), 4.77 (s, 2H), 4.29 (m, 2H); 19F (376 MHz, CDCl3): δ -59.14;
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13C NMR (100 MHz, CDCl3): δ 186.0, 160.1, 134.4, 133.7 (q, JCF = 1.8 Hz, 1C), 132.1, 131.6,
3
130.34, 130.3 (q, 2JCF = 30.5 Hz, 1C), 129.4, 129.1, 128.5, 128.4, 127.8, 126.8 (q, JCF = 5.5 Hz,
1C), 123.5 (q, JCF = 272.4 Hz, 1C), 48.1, 45.6; HRMS (ESI-TOF) m/z: [M+H]＋ Calcd for
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C19H15F3NO2 346.1055; found 346.1053.
(E)-1-benzyl-4-(4-fluorobenzylidene)pyrrolidine-2,3-dione (1l)
Yellow solid, mp = 200-201 °C; 1H NMR (400 MHz, CDCl3): δ 7.66 (s, 1H), 7.45-7.34 (m, 7H),
7.16-7.12 (m, 2H), 4.81 (s, 2H), 4.39 (s, 2H); 19F (376 MHz, CDCl3): δ -105.86; 13C NMR (100
MHz, CDCl3): δ 186.3, 164.3 (d, 1JCF = 254.3 Hz, 1C), 160.5, 136.9, 134.5, 133.4 (d, 3JCF = 8.8 Hz,
2C), 129.7 (d, 4JCF = 3.2 Hz, 1C), 129.1, 128.5, 128.4, 124.2 (d, 5JCF = 2.5 Hz, 1C), 116.8 (d, 2JCF
21.9 Hz, 2C), 48.1, 46.2; HRMS (ESI-TOF) m/z: [M+H]＋ Calcd for C18H15FNO2 [M+H]＋
=
296.1087; found 296.1086.
(E)-1-benzyl-4-(2-fluorobenzylidene)pyrrolidine-2,3-dione (1m)
Yellow solid, mp = 200-202 °C; 1H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.47-7.42 (m, 1H),
7.40-7.29 (m, 6H), 7.22-7.18 (m, 1H), 7.17-7.12 (m, 1H), 4.79 (s, 2H), 4.37 (s, 2H); 19F (376 MHz,
CDCl3): δ -111.02; 13C NMR (100 MHz, CDCl3): δ 186.3, 161.9 (d, 1JCF = 254.7 Hz, 1C), 160.3,
134.5, 133.4 (d, 3JCF = 8.8 Hz, 1C), 130.5 (d, 4JCF = 1.5 Hz, 1C), 130.3 (d, 3JCF = 5.3 Hz, 1C), 129.1,
128.5, 128.4, 126.1 (d, 4JCF = 1.3 Hz, 1C), 124.8 (d, JCF = 3.7 Hz, 1C), 121.4 (d, JCF = 12.2 Hz,
1C), 116.5 (d, 2JCF = 21.9 Hz, 1C), 48.0, 46.3 (d, JCF = 5.8 Hz, 1C); HRMS (ESI-TOF) m/z: [M+H]
＋
3
2
Calcd for C18H15FNO2 296.1087; found 296.1086.
(E)-1-benzyl-4-(naphthalen-1-ylmethylene)pyrrolidine-2,3-dione (1n)
Yellow solid, mp = 189-191 °C; 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.15-8.13 (m, 1H),
7.95-7.88 (m, 2H), 7.63-7.55 (m, 2H), 7.51-7.45 (m, 2H), 7.38-7.31 (m, 5H), 4.79 (s, 2H), 4.38 (s,
2H); 13C NMR (100 MHz, CDCl3): δ 186.2, 160.7, 135.0, 134.7, 133.7, 132.3, 132.0, 129.9, 129.1,
129.0, 128.5, 128.4, 127.6, 127.4, 126.8, 126.7, 125.1, 123.4, 48.1, 46.3; HRMS (ESI-TOF) m/z:
[M+H]＋ Calcd for C22H18NO2 328.1338; found 328.1334.
(E)-1-benzyl-4-(2-methylbenzylidene)pyrrolidine-2,3-dione (1o)
Yellow solid, mp = 162-164 °C; 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.40-7.31 (m, 6H),
7.27 (s, 1H), 7.23-7.22 (m, 2H), 4.79 (s, 2H), 4.36 (s, 2H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 186.4, 160.7, 140.6, 135.8, 134.6, 132.0, 131.4, 131.3, 129.1, 128.50, 128.46, 128.37, 126.5, 125.2,
48.1, 46.3, 20.0; HRMS (ESI-TOF) m/z: [M+H]＋ Calcd for C19H18NO2 292.1338; found 292.1332.
(E)-1-benzyl-4-(2-bromobenzylidene)pyrrolidine-2,3-dione (1p)
Yellow solid, mp = 190-192 °C; 1H NMR (400 MHz, CDCl3): δ 8.01-8.00 (m, 1H), 7,67-7.65 (m,
1H), 7.39-7.25 (m, 8H), 4.78 (s, 2H), 4.33 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 186.2, 160.2,
136.6, 134.4, 134.0, 133.0, 132.1, 129.6, 129.1, 128.5, 128.4, 127.8, 127.3, 126.5, 48.0, 45.8; HRMS
(ESI-TOF) m/z: [M+H]＋ Calcd for C18H15BrNO2 356.0286; found 356.0284.
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(E)-4-benzylidene-1-propylpyrrolidine-2,3-dione (1q)
Yellow solid, mp = 158-159 °C; 1H NMR (400 MHz, CDCl3): δ 7.71-7.70 (m, 1H), 7.51 (m, 5H),
4.56 (d, 2H), 3.61 (t, 2H), 1.76 (m, 2H), 1.00 (t, 3H); 13C NMR (100 MHz, CDCl3): δ 186.7, 160.7,
137.8, 133.5, 131.5, 131.2, 129.4, 124.8, 47.0, 45.8, 20.4, 11.2; HRMS (ESI-TOF) m/z: [M+H]＋
Calcd for C14H16NO2 230.1181; found 230.1182.
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(E)-4-benzylidene-1-phenylpyrrolidine-2,3-dione (1r)
Yellow solid, mp = 176-178 °C; 1H NMR (400 MHz, CDCl3): δ 7.94-7.92 (m, 2H), 7.80 (s, 1H),
7.58-7.47 (m, 7H), 7.33-7.27 (m, 1H), 4.98 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 185.8, 159.3,
138.6, 138.1, 133.4, 131.8, 131.4, 129.5, 129.4, 126.8, 124.1, 119.5, 47.8; HRMS (ESI-TOF) m/z:
[M+H]＋ Calcd for C17H14NO2 264,1025; found 264.1024.
Experimental date of HDA adducts
(S,E)-2-benzyl-4-benzylidene-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3a)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow solid: 73.4
mg, 85% yield; mp = 45-47 °C; [α]D20 +265.1 (c = 1.30, CHCl3, 98% ee); HPLC: Daicel Chiralpak
AD-H, hexane: 2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23°C, UV = 240 nm, tR = 13.74
min (major), tR = 15.25 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.38-7.26 (m, 9H), 7.17-7.15
(m, 2H), 6.84 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.67 (d, J = 14.8, 1H), 4.51 (d, J = 14.8 Hz, 1H),
4.28 (d, J = 14.2 Hz, 1H), 4.04 (d, J = 14.2 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.79 (d, J = 16.9 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 189.7, 168.7, 160.5, 134.9, 134.4, 131.6, 129.2, 129.0, 128.75,
128.73, 128.6, 128.1, 128.0, 106.4, 83.7, 48.4, 46.8, 41.3; IR (film, ν/cm-1 ): 2922, 2852, 1702, 1676,
1596, 1399, 1268, 1224, 1028, 749, 696; HRMS (ESI-TOF) m/z: [M+Na]＋ Calcd for C22H19NO3Na
368.1263; found 368.1257.
(S,E)-2-benzyl-4-(3-methylbenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3b):
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 77.3 mg,
86% yield; [α]D20 +75.6 (c = 1.09, CHCl3, 98% ee); HPLC: Daicel Chiralpak IC, hexane: 2-propanol
= 40:60, flow rate = 0.6 mL/min, T = 23°C, UV = 215 nm, tR = 56.19 min (major), tR = 74.76 min
(minor); 1H NMR (400 MHz, CDCl3): δ 7.38-7.22 (m, 7H), 7.12-7.10 (m, 1H), 6.99-6.94 (m, 2H),
6.81 (s, 1H), 5.54 (d, J = 6.2 Hz, 1H), 4.67 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.29 (d,
J = 14.1 Hz, 1H), 4.04 (d, J = 14.1 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.78 (d, J = 16.9 Hz, 1H),
2.33 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 189.8, 168.7, 160.5, 138.4, 134.9, 134.3, 131.3, 129.7,
129.42, 129.39, 128.9, 128.6, 128.0, 127.9, 125.5, 106.3, 83.7, 48.4, 46.8, 41.2, 21.3; IR (film, ν/cm-
1
): 2923, 2854, 1692, 1597, 1440, 1400, 1270, 1223, 1029, 750, 698; HRMS (ESI-TOF) m/z:
[M+Na]＋ calcd for C23H21NO3Na 382.1419; found 382.1428.
(S,E)-2-benzyl-4-(3-methoxybenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3c):
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow solid: 73.2
mg, 78% yield; mp = 113-116 °C; [α]D20 +249.0 (c = 0.51, CHCl3, 98% ee); HPLC: Daicel Chiralpak
AD-H, hexane: 2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 16.56
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min (major), tR = 19.77 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.38-7.24 (m, 7H), 6.86-6.83
(m, 1H), 6.80 (s, 1H), 6.75-6.73 (m, 1H), 6.68 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8
Hz, 1H), 4.51 (d, J = 14.8 Hz, 1H), 4.28 (dd, J1 = 14.1 Hz, J2 =2.3 Hz, 1H), 4.04 (dd, J1 = 14.1 Hz,
J2 =2.0 Hz, 1H), 3.78 (s, 3H), 3.29 (d, J = 16.9 Hz, 1H), 2.78 (d, J = 16.9 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 189.7, 168.6, 160.5, 159.6, 135.6, 134.9, 132.0, 129.7, 129.2, 129.0, 128.0, 127.96,
121.0, 114.5, 114.0, 106.4, 83.7, 55.3, 48.4, 46.8, 41.2; IR (film, ν/cm-1 ): 2921, 2851, 1698, 1671,
1597, 1576, 1270, 1232, 1037, 786, 693; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for C23H21NO4Na
398.1368; found 398.1367.
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(S,E)-2-benzyl-4-(3-nitrobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3d):
The title compound was prepared according to the general working procedure (16 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow solid: 96.6
mg, 99% yield; mp = 51-53 °C; [α]D20 +186.7 (c = 1.44, CHCl3, 97% ee); HPLC: Daicel Chiralpak
IC, hexane: 2-propanol = 0:100, flow rate = 0.25 mL/min, T = 23°C, UV = 254 nm, tR = 269.60 min
(minor), tR = 297.44 min (major); 1H NMR (400 MHz, CDCl3): δ 8.17-8.15 (m, 1H), 8.02 (s, 1H),
7.58-754 (m, 1H), 7.51-7.49 (m, 1H), 7.39-7.26 (m, 6H), 6.91-6.90 (m, 1H), 5.58 (d, J = 6.4 Hz,
1H), 4.66 (d, J = 14.8 Hz, 1H), 4.55 (d, J = 14.8 Hz, 1H), 4.29 (dd, J1 = 14.3 Hz, J2 =2.3 Hz, 1H),
4.08 (dd, J1 = 14.3 Hz, J2 =2.1 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.79 (d, J = 16.9 Hz, 1H); 13
C
NMR (100 MHz, CDCl3): δ 189.2, 168.3, 160.4, 148.4, 135.9, 135.1, 134.6, 134.4, 129.8, 129.0,
128.2, 128.0, 126.7, 123.2, 123.1, 106.5, 83.3, 47.9, 46.9, 41.3; IR (film, ν/cm-1 ): 2922, 2852, 1703,
1645, 1597, 1526, 1349, 1268, 1223, 727, 670, 676; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for
C22H18N2O5Na 413.1113; found 413.1112.
(S,E)-2-benzyl-4-(3-(trifluoromethyl)benzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione
(3e):
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 87.8 mg,
20
85% yield; [α]D +168.4 (c = 1.23, CHCl3, 99% ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-
propanol = 70:30, flow rate = 1.0 mL/min, T = 23°C, UV = 230 nm, tR = 16.16 min (major), tR =
20.99 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.57-7.55 (m, 1H), 7.51-7.47 (m, 1H), 7.42-7.26
(m, 8H), 6.88 (s, 1H), 5.56 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H),
4.26 (d, J = 14.2 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.78 (d, J = 16.9 Hz,
1H); 19F (376 MHz, CDCl3): δ -62.85; 13C NMR (100 MHz, CDCl3): δ 189.4, 168.4, 160.4, 135.0,
134.7, 133.8, 131.6, 131.2 (q, 2JCF = 32.3 Hz, 1C), 129.3, 129.0, 128.1, 128.0, 127.7, 125.5 (q, 3JCF
= 3.9 Hz, 1C), 125.2 (q, 3JCF = 3.6 Hz, 1C), 123.6 (q, 1JCF = 270.9 Hz, 1C), 106.5, 83.4, 48.0, 46.8,
41.3; IR (film, ν/cm-1 ): 2923, 2854, 1706, 1677, 1598, 1329, 1269, 1165, 1121, 1073, 995, 910,
751, 697; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for C23H18F3NO3Na 436.1136; found 436.1135.
(S,E)-2-benzyl-4-(3-fluorobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3f)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 78.1 mg,
20
86% yield; [α]D +193.5 (c = 1.35, CHCl3, 99% ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-
propanol = 80:20, flow rate = 1.0 mL/min, T = 23°C, UV = 240 nm, tR = 32.29 min (minor), tR =
33.76 min (major); 1H NMR (400 MHz, CDCl3): δ 7.39-7.26 (m, 7H), 7.02-6.94 (m, 2H), 6.87-6.81
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(m, 2H), 5.55 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.26 (d, J =
14.2 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.27 (d, J = 16.9 Hz, 1H), 2.77 (d, J = 16.9 Hz, 1H); 19
F
(376 MHz, CDCl3): δ -112.06; 13C NMR (100 MHz, CDCl3): δ 189.4, 168.5, 162.7 (d, 1JCF = 245.6
Hz, 1C), 160.4, 136.4 (d, 3JCF = 7.6 Hz, 1C), 134.8, 133.1, 130.3 (d, 3JCF = 8.5 Hz, 1C), 129.0, 128.1,
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128.0, 127.97, 124.6 (d, JCF = 2.9 Hz, 1C), 115.45, 115.44 (d, JCF = 43.3 Hz, 1C), 106.4, 83.5,
48.2, 46.8, 41.3; IR (film, ν/cm-1 ): 2921, 2852, 1703, 1676, 1600, 1583, 1484, 1433, 1400, 1269,
1223, 751, 699; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for C22H18FNO3Na 386.1168; found
386.1167.
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(S,E)-2-benzyl-4-(3-chlorobenzylidene)-6-ozxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3g)
The title compound was prepared according to the general working procedure (24 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 89.3 mg,
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94% yield; [α]D +203.7 (c = 1.24, CHCl3, 97% ee); HPLC: Daicel Chiralpak IC, hexane: 2-
propanol = 0:100, flow rate = 0.25 mL/min, T = 23°C, UV = 230 nm, tR = 97.18 min (minor), tR =
103.89 min (major); 1H NMR (400 MHz, CDCl3): δ 7.39-7.26 (m, 8H), 7.15 (s, 1H), 7.04-7.02 (m,
1H), 6.78 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H),
4.26 (dd, J1 = 14.2 Hz, J2 =2.2 Hz, 1H), 4.03 (dd, J1 = 14.2 Hz, J2 = 1.8 Hz, 1H), 3.27 (d, J = 16.9
Hz, 1H), 2.77 (d, J = 16.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 189.4, 168.5, 160.4, 136.0,
134.8, 134.7, 133.3, 130.0, 129.0, 128.6, 128.1, 128.0, 127.8, 126.8, 106.5, 83.5, 48.1, 46.8, 41.3;
IR (film, ν/cm-1 ): 2923, 2854, 1705, 1677, 1596, 1268, 1225, 753; HRMS (ESI-TOF) m/z: [M+Na]
＋
calcd for C22H18ClNO3Na 402.0873; found 402.0874.
(S,E)-2-benzyl-4-(3-bromobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3h)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 95.5 mg,
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90% yield; [α]D +132.6 (c = 1.59, CHCl3, 97% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-
propanol = 90:10, flow rate = 0.5 mL/min, T = 23°C, UV = 240 nm, tR = 67.16 min (major), tR =
73.02 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.44-7.20 (m, 9H), 7.09-7.07 (m, 1H), 6.77 (s,
1H), 5.55 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.25 (d, J = 14.2
Hz, 1H), 4.02 (d, J = 14.2 Hz, 1H), 3.27 (d, J = 16.9 Hz, 1H), 2.76 (d, J = 16.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 189.4, 168.5, 160.4, 136.3, 134.8, 133.3, 131.6, 131.5, 130.2, 129.0, 128.1,
127.9, 127.7, 127.1, 122.8, 106.4, 83.5, 48.1, 46.8, 41.2; IR (film, ν/cm-1 ): 2922, 2852, 1703, 1672,
1595, 1399, 1266, 1223, 1029, 995, 781, 737, 699, 683; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd
for C22H18BrNO3Na 446.0368; found 446.0368.
(S,E)-2-benzyl-4-(3,5-difluorobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3i)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 87.7 mg,
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92% yield; [α]D +148.9 (c = 1.36, CHCl3, 98% ee); HPLC: Daicel Chiralpak IC, hexane: 2-
propanol = 60:40, flow rate = 0.8 mL/min, T = 23°C, UV = 240 nm, tR = 68.37 min (minor), tR =
93.28 min (major); 1H NMR (400 MHz, CDCl3): δ 7.40-7.31 (m, 4H), 7.28-7.26 (m, 2H), 6.79-6.73
(m, 2H), 6.71-6.66 (m, 2H), 5.56 (d, J = 6.2 Hz, 1H), 4.65 (d, J = 14.8 Hz, 1H), 4.54 (d, J = 14.8
Hz, 1H), 4.23 (dd, J1 = 14.3 Hz, J2 =2.4 Hz, 1H), 4.03 (dd, J1 = 14.3 Hz, J2 =2.2 Hz, 1H), 3.25 (d,
J = 16.9 Hz, 1H), 2.76 (dd, J1 = 16.9 Hz, J2 =0.3 Hz, 1H); 19F (376 MHz, CDCl3): δ -108.59; 13
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NMR (100 MHz, CDCl3): δ 189.2, 168.3, 162.9 (dd, 1JCF = 248.1 Hz, 3JCF =13.0 Hz, 2C), 160.4,
4
137.2 (t, 3JCF = 9.5 Hz, 1C), 134.7, 134.6, 129.0, 128.2, 128.0, 126.9 (t, JCF = 2.3 Hz, 1C), 111.5
(dd, 2JCF = 18.7 Hz, 4JCF = 7.2 Hz, 2C), 106.5, 104.0 (t, 2JCF = 25.2 Hz, 1C), 83.3, 48.0, 46.8, 41.3;
IR (film, ν/cm-1 ): 2293, 2853, 1705, 1677, 1619, 1589, 1433, 1399, 1269, 1225, 1118, 989, 847,
699; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for C22H17F2NO3Na 404.1074; found 404.1070.
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(S,E)-2-benzyl-4-(4-(trifluoromethyl)benzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione
(3j)
The title compound was prepared according to the general working procedure (17 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 67.2 mg,
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65% yield; [α]D +196.6 (c = 1.22, CHCl3, 96% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-
propanol = 80:20, flow rate = 1.0 mL/min, T = 23°C, UV = 230 nm, tR = 14.76 min (major), tR =
16.52 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.62-7.60 (m, 2H), 7.39-7.26 (m, 8H), 6.87 (s,
1H), 5.56 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.25 (d, J = 14.2
Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.78 (d, J = 16.9 Hz, 1H); 19F (376
MHz, CDCl3): δ -62.76; 13C NMR (100 MHz, CDCl3): δ 189.3, 168.4, 160.4, 137.8, 134.7, 134.4,
130.4(q, 2JCF = 32.6 Hz, 1C), 129.1, 128.9, 128.2, 128.0, 127.7, 125.7 (q, 3JCF = 3.7 Hz, 2C), 123.7
(q, 1JCF = 270.7 Hz, 1C), 106.5, 83.5, 48.1, 46.9, 41.3; IR (film, ν/cm-1 ): 2923, 2853, 1705, 1673,
1597, 1322, 1269, 1164, 1113, 1067, 699; HRMS (ESI-TOF) m/z: [M+Na] ＋ calcd for
C23H18F3NO3Na 436.1136; found 436.1130.
(S,E)-2-benzyl-4-(2-(trifluoromethyl)benzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione
(3k)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 100.2 mg,
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97% yield; [α]D +102.6 (c = 1.43, CHCl3, 97% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-
propanol = 80:20, flow rate = 1.0 mL/min, T = 23°C, UV = 240 nm, tR = 9.34 min (minor), tR =
11.74 min (major); 1H NMR (400 MHz, CDCl3): δ 7.69-7.67 (m, 1H), 7.52-7.49 (m, 1H), 7.44-7.29
(m, 5H), 7.22-7.16 (m, 4H), 5.56 (d, J = 6.2 Hz, 1H), 4.61 (d, J = 14.8 Hz, 1H), 4.49 (d, J = 14.8
Hz, 1H), 4.02 (dd, J1 = 14.2 Hz, J2 =2.4 Hz, 1H), 3.80 (dd, J1 = 14.2 Hz, J2 =2.2 Hz, 1H), 3.26 (d,
J = 16.8 Hz, 1H), 2.80 (d, J = 16.8 Hz, 1H); 19F (376 MHz, CDCl3): δ -60.41; 13C NMR (100 MHz,
2
CDCl3): δ 189.1, 168.7, 160.5, 134.9, 134.7, 132.8, 131.9, 129.3, 129.0, 128.95-128.06 (q, JCF
=
1
30.0 Hz, 1C), 128.4, 128.1, 127.9, 126.3 (q, 3JCF = 5.3 Hz, 1C), 125.8, 123.7 (q, JCF = 272.3 Hz,
1C), 106.6, 82.9, 47.3, 46.8, 41.1; IR (film, ν/cm-1 ): 2922, 2853, 1706, 1678, 1598, 1314, 1269,
1160, 1108, 1034, 769, 700; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for C23H18F3NO3Na 436.1136;
found 436.1136.
(S,E)-2-benzyl-4-(4-fluorobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3l)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 69.0 mg,
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76% yield; [α]D +206.9 (c = 1.11, CHCl3, 97% ee); HPLC: Daicel Chiralpak IC, hexane: 2-
propanol = 60:40, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 73.61 min (major), tR =
91.23 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.39-7.26 (m, 6H), 7.16-7.12 (m, 2H), 7.06-7.02
(m, 2H), 6.80 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.67 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H),
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4.25 (d, J = 14.0 Hz, 1H), 4.00 (d, J = 14.0 Hz, 1H), 3.28 (d, J = 17.0 Hz, 1H), 2.77 (d, J = 17.0 Hz,
1H); 19F (376 MHz, CDCl3): δ -111.53; 13C NMR (100 MHz, CDCl3): δ 189.6, 168.6, 162.5 (d, 1JCF
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= 248.7 Hz, 1C), 160.4, 134.8, 131.4 (d, JCF = 1.5 Hz, 1C), 130.6, 130.56, 130.5, 129.0, 128.1,
128.0, 115.8 (d, 2JCF = 21.7 Hz, 1C), 106.4, 83.6, 48.2, 46.8, 41.2; IR (film, ν/cm-1 ): 2922, 2852,
1703, 1678, 1597, 1509, 1400, 1270, 1224, 1029, 992, 700; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd
for C22H18FNO3Na 386.1168; found 386.1167.
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(S,E)-2-benzyl-4-(2-fluorobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3m)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 85.4 mg,
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94% yield; [α]D +138.0 (c = 1.21, CHCl3, 98% ee); HPLC: Daicel Chiralpak IC, hexane: 2-
propanol = 40:60, flow rate = 0.6 mL/min, T = 23°C, UV = 215 nm, tR = 46.53 min (major), tR =
55.94 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.38-7.24 (m, 7H), 7.14-7.05 (m, 3H), 6.95 (s,
1H), 5.55 (d, J = 6.3 Hz, 1H), 4.62 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.2
Hz, 1H), 3.95 (d, J = 14.2 Hz, 1H), 3.24 (d, J = 16.9 Hz, 1H), 2.81 (d, J = 16.9 Hz, 1H); 19F (376
MHz, CDCl3): δ -114.16; 13C NMR (100 MHz, CDCl3): δ 189.3, 168.7, 160.5, 160.0 (d, 1JCF = 249.3
Hz, 1C), 134.9, 134.0, 130.5 (d, 3JCF = 8.5 Hz, 1C), 129.4 (d, 4JCF = 2.7 Hz, 1C), 129.0, 128.1, 128.0,
124.2 (d, 3JCF = 3.6 Hz, 1C), 122.2 (d, 2JCF = 13.5 Hz, 1C), 121.6 (d, 3JCF = 4.3 Hz, 1C), 116.0 (d,
2JCF = 21.9 Hz, 1C), 106.5, 83.5, 48.1 (d, JCF = 4.5 Hz, 1C), 46.8, 41.3; IR (film, ν/cm-1 ): 2922,
2852, 1703, 1676, 1597, 1484, 1268, 1223, 1030, 990, 752, 700; HRMS (ESI-TOF) m/z: [M+Na]＋
calcd for C22H18FNO3Na 386.1168; found 386.1169.
(S,E)-2-benzyl-4-(naphthalen-1-ylmethylene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3n)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 89.0 mg,
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90% yield; [α]D +204.7 (c = 1.50, CHCl3, 97% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-
propanol = 80:20, flow rate = 1.0 mL/min, T = 23°C, UV = 240 nm, tR = 11.81 min (minor), tR =
14.46 min (major); 1H NMR (400 MHz, CDCl3): δ 7.86-7.80 (m, 3H), 7.55-7.48 (m, 3H), 7.42-7.38
(m, 2H), 7.34-7.25 (m, 3H), 7.22-7.20 (m, 3H), 5.59 (d, J = 6.2 Hz, 1H), 4.62 (d, J = 14.8 Hz, 1H),
4.44 (d, J = 14.8 Hz, 1H), 4.15 (dd, J1 = 14.2 Hz, J2 =2.3 Hz, 1H), 3.86 (dd, J1 = 14.2 Hz, J2 =2.1
Hz, 1H), 3.41 (d, J = 16.8 Hz, 1H), 2.90 (d, J = 16.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 189.7,
168.8, 160.5, 134.9, 134.1, 133.4, 131.08, 131.07, 129.1, 128.9, 128.6, 127.98, 127.94, 127.1, 126.8,
126.3, 125.8, 125.0, 123.8, 106.5, 83.4, 48.0, 46.8, 41.3; IR (film, ν/cm-1 ): 2921, 2851, 1703, 1672,
1596, 1398, 1267, 1029, 988, 778, 699; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for C26H21NO3Na
418.1419; found 418.1418.
(S,E)-2-benzyl-4-(2-methylbenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3o)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow solid: 77.3
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mg, 86% yield; [α]D +25.9 (c = 1.48, CHCl3, 96% ee); HPLC: Daicel Chiralpak OD-H, hexane:
2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 28.91 min (minor), tR =
37.97 min (major); 1H NMR (400 MHz, CDCl3): δ 7.37-7.12 (m, 9H), 7.00-6.99 (m, 2H), 5.55 (d,
J = 6.2 Hz, 1H), 4.65 (d, J = 14.8 Hz, 1H), 4.47 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.1 Hz, 1H), 3.88
(d, J = 14.1 Hz, 1H), 3.33 (d, J = 16.8 Hz, 1H), 2.77 (d, J = 16.8 Hz, 1H), 2.26 (s, 3H); 13C NMR
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(100 MHz, CDCl3): δ 189.8, 168.8, 160.5, 136.9, 134.9, 133.1, 132.2, 130.5, 128.9, 128.7, 128.01,
127.99, 127.8, 127.6, 125.9, 106.4, 83.5, 47.9, 46.8, 41.2, 19.6; IR (film, ν/cm-1 ): 2922, 2853, 1692,
1598, 1453, 1267, 1029, 748, 699; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for C23H21NO3Na
382.1419; found 382.1421.
(S,E)-2-benzyl-4-(2-bromobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3p)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 98.6 mg,
93% yield; mp = 46-48 °C; [α]D20 +167.3 (c = 1.38, CHCl3, 99% ee); HPLC: Daicel Chiralpak IC,
hexane: 2-propanol = 50:50, flow rate = 0.75 mL/min, T = 23°C, UV = 240 nm, tR = 54.89 min
(major), tR = 81.83 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.60-7.58 (m, 1H), 7.38-7.23 (m,
7H), 7.19-7.14 (m, 1H), 7.09-7.06 (m, 2H), 5.57 (dd, J1 = 6.2 Hz, J2 = 0.4 Hz, 1H), 4.64 (d, J = 14.8
Hz, 1H), 4.48 (d, J = 14.8 Hz, 1H), 4.13 (dd, J1 = 14.2 Hz, J2 = 2.4 Hz, 1H), 3.88 (dd, J1 = 14.2 Hz,
J2 = 2.2 Hz, 1H), 3.30 (d, J = 16.9 Hz, 1H), 2.83 (dd, J1 = 16.9 Hz, J2 = 0.4 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 189.4, 168.7, 160.5, 134.8, 134.2, 133.6, 133.2, 130.0, 129.0, 128.98, 128.5, 128.1,
128.0, 127.4, 124.3, 106.5, 83.3, 47.6, 46.8, 41.2; IR (film, ν/cm-1 ): 2921, 2851, 1705, 1674, 1596,
1432, 1398, 1266, 1223, 1025, 996, 750, 736, 699; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for
C22H18BrNO3Na 446.0368; found 446.0363.
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(S,E)-4-benzylidene-2-propyl-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3q)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 52.0 mg,
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70% yield; [α]D +331.7 (c = 1.10, CHCl3, 95% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-
propanol = 80:20, flow rate = 1.0 mL/min, T = 23°C, UV = 230 nm, tR = 9.44 min (major), tR =
10.62 min (minor); 1H NMR (400 MHz, CDCl3): δ 7.43-7.23 (m, 7H), 6.85-6.84 (m, 1H), 5.23 (dd,
J1 = 6.2 Hz, J2 = 0.6 Hz, 1H), 4.41 (dd, J1 = 14.0 Hz, J2 = 2.4 Hz, 1H), 4.14 (dd, J1 = 14.0 Hz, J2 =
2.1 Hz, 1H), 3.45-3.33 (m, 2H), 3.27 (d, J = 17.0 Hz, 1H), 2.74 (dd, J1 = 17.0 Hz, J2 = 0.6 Hz, 1H),
1.67-1.61 (m, 2H), 0.94 (t, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 189.9, 168.5, 160.5,
134.5, 132.1, 129.0, 128.80, 128.76, 128.6, 106.3, 83.9, 48.8, 44.5, 41.2, 20.2, 11.1; IR (film, ν/cm-
1 ): 2963, 2929, 2873, 1701, 1676, 1596, 1400, 1270, 1224, 1036, 994, 755, 727; HRMS (ESI-TOF)
m/z: [M+Na]＋ calcd for C18H19NO3Na 320.1263; found 320.1262.
(S,E)-4-benzylidene-2-phenyl-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3r)
The title compound was prepared according to the general working procedure (18 h) and purified
by column chromatography (PE / EA = 10/1-3/1) to give the product as a faint yellow oil: 71.2 mg,
86% yield; mp = 54-57 °C; [α]D20 +167.8 (c = 1.06, CHCl3, 95% ee); HPLC: Daicel Chiralpak OD-
H, hexane: 2-propanol = 70:30, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 35.43 min
(minor), tR = 43.24 min (major); 1H NMR (400 MHz, CDCl3): δ 7.73-7.71 (m, 2H), 7.45-7.28 (m,
8H), 7.24-7.20 (m, 1H), 6.91 (s, 1H), 5.57 (d, J = 6.2 Hz, 1H), 4.85 (d, J = 13.6 Hz, 1H), 4.62 (d, J
= 13.6 Hz, 1H), 3.35 (d, J = 17.0 Hz, 1H), 2.86 (d, J = 17.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
δ 189.6, 167.5, 160.3, 137.9, 134.3, 130.6, 129.5, 129.1, 128.83, 128.80, 125.8, 120.2, 106.5, 84.6,
49.9, 41.0; IR (film, ν/cm-1 ): 2922, 2853, 1706, 1665, 1595, 1493, 1396, 1272, 1221, 1203, 1037,
990, 755, 688; HRMS (ESI-TOF) m/z: [M+Na] ＋ calcd for C21H17NO3Na 354.1106; found
354.1105.
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(S,E)-1-benzyl-4-(3-bromobenzylidene)-3-hydroxy-3-((E)-4-methoxy-2-oxobut-3-en-1-
yl)pyrrolidin-2-one (5)
The title compound was prepared according to the general working procedure and purified by
column chromatography (PE / EA = 2:1) to give the product as a colorless oil. [α]D20 -99.3 (c = 1.37,
CHCl3, 97% ee); HPLC: Daicel Chiralpak IC, hexane: 2-propanol =50:50, flow rate = 0.75mL/min,
1
T = 23°C, UV = 240 nm, tR = 26.94 min (minor), tR = 46.16 min (major); H NMR (400 MHz,
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CD3COCD3): δ 7.53 (s, 1H), 7.48-7.45 (m, 1H), 7.37-7.26 (m, 7H), 6.86 (t, J = 2.4 Hz, 1H), 5.40-
5.38 (m, 1H), 4.66 (d, J = 14.9 Hz, 1H), 4.50 (d, J = 14.9 Hz, 1H), 4.41 (dd, J1 = 14.9 Hz, J2 = 2.4
Hz, 1H), 4.34 (dd, J1 = 14.9 Hz, J2 = 2.4 Hz, 1H), 3.54 (s, 3H), 3.15 (dd, J1 = 16.4 Hz, J2 = 3.5 Hz,
1H), 3.06 (d, J = 16.3 Hz, 1H), 2.55-2.50 (m, 2H); 13C NMR (100 MHz, CD3COCD3): δ 202.9,
172.3, 138.7, 137.6, 137.0, 132.3, 131.5, 131.4, 129.6, 128.6, 128.4, 128.1, 127.0, 123.1, 100.7,
79.4, 56.4, 49.2, 46.6, 46.3, 46.2; IR (film, ν/cm-1 ): 2900, 1727, 1696, 1306, 1197, 1110, 1062,
1007; HRMS (ESI-TOF) m/z: [M+Na]＋ calcd for C23H22BrNO4Na 478.0630; found 478.0630.
(5S,E)-2-benzyl-4-(3-bromobenzylidene)-9-((tert-butyldimethylsilyl)oxy)-7-methoxy-6-oxa-2-
azaspiro[4.5]dec-8-en-1-one (6)
The title compound was prepared according to the general working procedure and purified by
column chromatography (PE / EA= 5:1) to give the product as a colorless oil. [α]D20 -24.8 (c = 1.20,
CHCl3, 97% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol =90:10, flow rate = 1.0
mL/min, T = 23°C, UV = 240 nm, tR = 6.58 min (major), tR = 8.11 min (minor); 1H NMR (400 MHz,
CD3COCD3): δ 7.45-7.43 (m, 2H), 7.36-7.25 (m, 7H), 6.93-6.92 (m, 1H), 5.53 (m, 1H), 4.99-4.98
(m, 1H), 4.64 (d, J = 15.0 Hz, 1H), 4.55 (d, J = 15.0 Hz, 1H), 4.33 (dd, J1 = 14.3 Hz, J2 = 2.3 Hz,
1H), 4.21 (dd, J1 = 14.3 Hz, J2 = 2.3 Hz, 1H), 3.37 (m, 3H), 2.63-2.59 (m, 1H), 2.46-2.41 (m, 1H),
0.98-0.96 (m, 9H), 0.27-0.25 (m, 6H); 13C NMR (100 MHz, CD3COCD3): δ 171.6, 150.7, 139.1,
138.7, 137.4, 132.1, 131.3, 131.25, 129.5, 128.6, 128.3, 128.1, 126.1, 123.0, 103.8, 99.0, 77.9, 54.4,
48.8, 46.6, 35.8, 26.0, 18.6, -4.2; IR (film, ν/cm-1 ): 2928, 2857, 1707, 1682, 1253, 1178, 1132, 1064,
913, 838, 783, 757; HRMS (ESI-TOF) m/z: [M+H]＋ calcd for C29H37BrNO4Si 570.1675; found
570.1675.
ASSOCIATED CONTENT
Supporting Information
1
Preparation of substrates; H NMR and 13C NMR spectra for all the products; HPLC profiles and
crystallographic data of compound 3c (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org. Details of the crystal structure are available in the Cambridge
Crystallographic Data Centre with CCDC 1590154 number (www.ccdc.cam.ac.uk/data_request/cif).
AUTHOR INFORMATION
Corresponding Author
*E-mail: zgzha@ustc.edu.cn.
*Fax: 86-551-3631760. E-mail: zwang3@ustc.edu.cn
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We are grateful to the financial support from the National Natural Science Foundation of China
(21432009, 21672200, 21472177, 21772185) and the assistance of the product characterization
from the Chemistry Experiment Teaching Center of University of Science and Technology of China.
This work was supported by the Strategic Priority Research Program of the Chinese Academy of
Sciences, Grant No. XDB20000000.
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the supporting information of this article.
(13) For the synthesis of Danishefsky’s diene and 2,3-dioxopyrrolidines, see: (a) Danishefsky, S.;
Kitahara, T. Useful diene for the Diels-Alder reaction. J. Am. Chem. Soc. 1974, 96, 7807-7808. (b)
Southwick, P. L.; Crouch, R. T. The Condensation of Oxalic Esters with Esters of β-Alanine and N-
Substituted β-Aminopropionic Acids. Synthesis of Some Derivatives of 2,3-Dioxopyrrolidine and
2-Oxo-3-methoxy-3-pyrroline. J. Am. Chem. Soc., 1953, 75, 3413-3417.
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