An Enantioselective Hetero-Diels-Alder Reaction and the Synthesis of

Subscriber access provided by University of Massachusetts Amherst Libraries

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 Downloaded from http://pubs.acs.org on July 6, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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* 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: [email protected]; *E-mail: [email protected]

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.

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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.


Page 2 of 22

Page 3 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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



Page 4 of 22

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, Cs2CO3 as the base, the HDA reaction being carried out at 0 °C. Table 1 Optimization of the reaction conditionsa-c

entry

solvent

base

T (oC)

yield (%)b

ee (%)c

1

Toluene

Cs2CO3

r.t

85

85

2

CHCl3

Cs2CO3

r.t

83

89

3

CH3CN

Cs2CO3

r.t

80

59

4

EtOAc

Cs2CO3

r.t

84

94

5

THF

Cs2CO3

r.t

87

95

6

1,4-dioxane

Cs2CO3

r.t

85

95

7

CPME

Cs2CO3

r.t

88

96

8

MTBE

Cs2CO3

r.t

85

96

9

Et2O

Cs2CO3

r.t

87

97

10

Et2O

K2CO3

r.t

80

91

11

Et2O

t-BuOK

r.t

83

93

12

Et2O

DIPEA

r.t

87

93

13

Et2O

Piperidine

r.t

86

93

14

Et2O

Et3N

r.t

86

92

15

Et2O

N-ethyl morpholine

r.t

85

92

16

Et2O

DBU

r.t

84

94

17

Et2O

DABCO

r.t

90

95


Page 5 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


18

Et2O

Cs2CO3

0

85

98

19

Et2O

Cs2CO3

-10

75

99

a

Unless 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 = 1,8Diazabicyclo[5.4.0]undec-7-ene. DABCO = 1,4-diazabicyclooctane.

With the optimal reaction conditions in hand, we next examined the substrate scope of 2,3dioxopyrrolidines 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



Page 6 of 22

X-ray crystallographic analysis.12

Table 2. Scope of 2,3-dioxopyrrolidinesa-d

yieldb

eec

(%)

(%)

3a

85

98

18

3b

86

98

Bn

18

3c

78

98

m-NO2C6H4

Bn

16

3d

99

97

5

m-CF3C6H4

Bn

18

3e

85

99

6

m-FC6H4

Bn

18

3f

86

99

7d

m-ClC6H4

Bn

24

3g

94

97

8

m-BrC6H4

Bn

18

3h

90

97

9

3,5-FC6H4

Bn

18

3i

92

98

10d

p-CF3C6H4

Bn

17

3j

65

96

11

o-CF3C6H4

Bn

18

3k

97

97

12

p-FC6H4

Bn

18

3l

76

97

13

o-FC6H4

Bn

18

3m

94

98

14

1-naphthyl

Bn

18

3n

90

97

15

o-MeC6H4

Bn

18

3o

86

96

16

o-BrC6H4

Bn

18

3p

93

99

17

C6H5

propyl

18

3q

70

95

18d

C6H5

phenyl

18

3r

86

95

time

entry

R1

R2

1

C6H5

Bn

18

2

m-MeC6H4

Bn

3

m-OMeC6H4

4d

(h)

3

a

Unless 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. d With 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.


Page 7 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 2. Asymmetric Hetero-Diels-Alder Reaction on a gram scale a-c

a

The 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 identified by 1H NMR,

13

C 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 obtained with 97% ee, which was also confirmed by 1H NMR,

13

C 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



O O

L-Cu(OTf)2-Cs2CO3 (10 mol %)

OTMS Br

N Bn 1h

OMe

Et2O, 0 ℃

TMSO

2a

Br

HO

OMe

N O Bn

Br

3h

5

Br

97% ee

OMe

L-Cu(OTf)2-Cs2CO3 (10 mol %)

OTBS

1h

O

TFA

O

95% yield, 97% ee

N Bn

OMe

4

N O Bn

O

O

N O Bn

Br

O

O

Page 8 of 22

OMe

Et2O, 0 ℃

2b

O Br

O N O Bn 3h 95% yield, 97% ee

O Br

OTBS N O Bn 6 dr > 20:1, 97% ee

TFA

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.


Page 9 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


EXPERIMENTAL SECTION General Information: 1H 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. UVVis 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. 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) Yellow solid, mp = 173-174 °C; 1H 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



323.1030. (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 (q, 3JCF = 3.5 Hz, 1C), 127.5 (q, 3JCF = 3.8 Hz, 1C), 126.1, 123.4 (q, 1JCF = 270.9 Hz, 1C), 48.1, ＋ 46.1; HRMS (ESI-TOF) m/z: [M+H] Calcd for C19H15F3NO2 346.1055; found 346.1054. (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, 1JCF = 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 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 Hz, 2C), 135.2 (t, 4JCF = 2.7 Hz, 1C), 134.3, 129.2, 128.55, 128.53, 126.6, 113.6 (dd, 2JCF = 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 MHz, CDCl3): δ 186.4, 160.0, 136.6, 135.9, 134.3, 132.6 (q, 2JCF = 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.


Page 10 of 22

Page 11 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(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; 13 C NMR (100 MHz, CDCl3): δ 186.0, 160.1, 134.4, 133.7 (q, 3JCF = 1.8 Hz, 1C), 132.1, 131.6, 130.34, 130.3 (q, 2JCF = 30.5 Hz, 1C), 129.4, 129.1, 128.5, 128.4, 127.8, 126.8 (q, 3JCF = 5.5 Hz, ＋ 1C), 123.5 (q, 1JCF = 272.4 Hz, 1C), 48.1, 45.6; HRMS (ESI-TOF) m/z: [M+H] Calcd for 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, 3JCF = 3.7 Hz, 1C), 121.4 (d, 2JCF = 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] ＋ 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.



(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. (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/cm1 ): 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


Page 12 of 22

Page 13 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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. (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); 13C 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, 85% yield; [α]D20 +168.4 (c = 1.23, CHCl3, 99% ee); HPLC: Daicel Chiralpak OD-H, hexane: 2propanol = 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, 86% yield; [α]D20 +193.5 (c = 1.35, CHCl3, 99% ee); HPLC: Daicel Chiralpak OD-H, hexane: 2propanol = 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



(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); 19F (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, 128.0, 127.97, 124.6 (d, 4JCF = 2.9 Hz, 1C), 115.45, 115.44 (d, 2JCF = 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. (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, 94% yield; [α]D20 +203.7 (c = 1.24, CHCl3, 97% ee); HPLC: Daicel Chiralpak IC, hexane: 2propanol = 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, 90% yield; [α]D20 +132.6 (c = 1.59, CHCl3, 97% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2propanol = 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, 92% yield; [α]D20 +148.9 (c = 1.36, CHCl3, 98% ee); HPLC: Daicel Chiralpak IC, hexane: 2propanol = 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; 13C


Page 14 of 22

Page 15 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


NMR (100 MHz, CDCl3): δ 189.2, 168.3, 162.9 (dd, 1JCF = 248.1 Hz, 3JCF =13.0 Hz, 2C), 160.4, 137.2 (t, 3JCF = 9.5 Hz, 1C), 134.7, 134.6, 129.0, 128.2, 128.0, 126.9 (t, 4JCF = 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. (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, 65% yield; [α]D20 +196.6 (c = 1.22, CHCl3, 96% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2propanol = 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, 97% yield; [α]D20 +102.6 (c = 1.43, CHCl3, 97% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2propanol = 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, 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, 2JCF = 30.0 Hz, 1C), 128.4, 128.1, 127.9, 126.3 (q, 3JCF = 5.3 Hz, 1C), 125.8, 123.7 (q, 1JCF = 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, 76% yield; [α]D20 +206.9 (c = 1.11, CHCl3, 97% ee); HPLC: Daicel Chiralpak IC, hexane: 2propanol = 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),



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 = 248.7 Hz, 1C), 160.4, 134.8, 131.4 (d, 4JCF = 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. (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, 94% yield; [α]D20 +138.0 (c = 1.21, CHCl3, 98% ee); HPLC: Daicel Chiralpak IC, hexane: 2propanol = 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, 2 JCF = 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, 90% yield; [α]D20 +204.7 (c = 1.50, CHCl3, 97% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2propanol = 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 mg, 86% yield; [α]D20 +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


Page 16 of 22

Page 17 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(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. (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, 70% yield; [α]D20 +331.7 (c = 1.10, CHCl3, 95% ee); HPLC: Daicel Chiralpak AD-H, hexane: 2propanol = 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/cm1 ): 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 ODH, 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.



(S,E)-1-benzyl-4-(3-bromobenzylidene)-3-hydroxy-3-((E)-4-methoxy-2-oxobut-3-en-1yl)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, T = 23°C, UV = 240 nm, tR = 26.94 min (minor), tR = 46.16 min (major); 1H NMR (400 MHz, 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), 5.405.38 (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-2azaspiro[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 Preparation of substrates; 1H 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: [email protected]. *Fax: 86-551-3631760. E-mail: [email protected] Notes The authors declare no competing financial interest.


Page 18 of 22

Page 19 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ACKNOWLEDGMENTS 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. REFERENCES (1) For selected reports of pyrrospirone scaffold in medical chemistry, see: (a) Zhang, X. J.; Li, X.; Sun, H. P.; Jiang, Z. Y.; Tao, L.; Gao, Y.; Guo, Q. L.; You, Q. D. Synthesis and evaluation of novel aza-caged Garcinia xanthones. Org. Biomol. Chem., 2012, 10, 3288-3299; (b) Song, T. F.; Chen, M. X.; Chai, W. Y.; Zhang, Z. Z.; Lian, X. Y. New bioactive pyrrospirones C-I from a marine-derived fungus Penicillium sp. ZZ380. Tetrahedron 2018, 74, 884-891. (c) Thaler, F.; Moretti, L.; Amici, R.; Abate, A.; Colombo, A.; Carenzi, G.; Fulco, M. C.; Boggio, R.; Dondio, G.; Gagliardi, S.; Minucci, S.; Sartori, L.; Varasi, M.; Mercurio, C. Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors. European Journal of Medicinal Chemistry 2016, 108, 53-67. (2) For selected reviews on the hetero-Diels-Alder reaction, see: (a) Jørgensen, K. A. Catalytic Asymmetric Hetero-Diels-Alder Reactions of Carbonyl Compounds and Imines. Angew. Chem. Int. Ed. 2000, 39, 3558-3588. (b) Reymond, S. and Cossy, J. Copper-Catalyzed Diels-Alder Reactions. Chem. Rev., 2008, 108, 5359-5406. (c) Heravi, M. M.; Ahmadi, T.; Ghavidel, M.; Hiedari, B. and Hamidi, H. Recent applications of the hetero Diels-Alder reaction in the total synthesis of natural products. RSC Adv., 2015, 5, 101999-102075. (d) Pellissier, H. Asymmetric hetero-Diels-Alder reactions of carbonyl compounds. Tetrahedron 2009, 65, 2839-2877. (e) Moyano, A.; Rios, R. Asymmetric Organocatalytic Cyclization and Cycloaddition Reactions. Chem. Rev., 2011, 108, 4703-4832. (3) For examples of asymmetric HDA reactions of aldehydes with Danishefsky’s dienes, see: (a) Wang, B.; Feng, X. M.; Cui, X.; Liu, H.; Jiang, Y. Z. Highly efficient enantioselective synthesis of optically active dihydropyrones by chiral titanium(IV) (5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-bi-2naphthol) complexes. Chem. Commun. 2000, 0, 1605-1606. (b) Bednarsk, M.; Danishefsky, S. Interactivity of Chiral Catalysts and Chiral Auxiliaries in the Cycloaddition of Activated Dienes with Aldehydes: A Synthesis of L-Glucose. J. Am. Chem. Soc. 1986, 108, 7060-7067. (c) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. Asymmetric hetero-Diels-Alder reaction catalyzed by a chiral organoaluminum reagent. J. Am. Chem. Soc. 1988, 110, 310-312. (d) Long, J.; Hu, J. Y.; Shen, X. Q.; Ji, B. M.; Ding, K. L. Discovery of Exceptionally Efficient Catalysts for Solvent-Free Enantioselective Hetero-Diels-Alder Reaction. J. Am. Chem. Soc., 2002, 124, 10-11. (e) Anada, M.; Washio, T.; Shimada, N.; Kitagaki, S.; Nakajima, M.; Shiro, S. Hashimoto, M. A New Dirhodium(II) Carboxamidate Complex as a Chiral Lewis Acid Catalyst for Enantioselective Hetero-Diels-Alder Reactions*. Angew. Chem., Int. Ed. 2004, 43, 2665-2668. (f) Schaus, S. E.; Brånalt, J.; Jacobsen, E. N. Asymmetric Hetero-Diels-Alder Reactions Catalyzed by Chiral (Salen)Chromium(III) Complexes. J. Org. Chem. 1998, 63, 403-405. (g) Gong, L. Z.; Pu, L. The asymmetric hetero-DielsAlder reaction of enamide aldehydes with Danishefsky’s diene and an efficient synthesis of chiral binaphthyl ligands. Tetrahedron Letters. 2000, 41, 2327-2331. (h) Yu, Z. P.; Liu, X. H.; Dong, Z. H.; Xie, M. S.; Feng, X. M. An N,N’-Dioxide/In(OTf)3 Catalyst for the Asymmetric Hetero-Diels-



Alder Reaction Between Danishefsky's Dienes and Aldehydes: Application in the Total Synthesis of Triketide*. Angew. Chem. Int. Ed. 2008, 47, 1308-1311. (4) For recent of reports of HDA reaction of 2,3-dioxopyrrolidines, see: (a) Zhang, S.; Luo, Y. C.; Hu, X. Q.; Wang, Z. Y.; Liang, Y. M.; Xu, P. F. Enantioselective Amine-Catalyzed [4+2] Annulations of Allene Ketones and 2,3-Dioxopyrrolidine Derivatives: Synthesis of 4H-Pyran Derivatives. J. Org. Chem. 2015, 80, 7288-7294. (b) Wang, C.; Jia, H.; Zhang, C.; Gao, Z. Z.; Zhou, L. J.; Yuan, C. H.; Xiao, Y. M.; Guo, H. C. Phosphine-Catalyzed Enantioselective [2+4] Cycloaddition to Synthesize Pyrrolidin-2-one Fused Dihydropyrans Using α-Substituted Allenoates as C2 Synthons. J. Org. Chem. 2017, 82, 633-641. (c) Li, J. L.; Yang, K. C.; Li, Y.; Li, Q.; Zhu, H. P.; Han, B.; Peng, C.; Zhi, Y. G.; Gou, X. J. Asymmetric synthesis of bicyclic dihydropyrans via organocatalytic inverseelectron-demand oxo-Diels–Alder reactions of enolizable aliphatic aldehydes. Chem. Commun., 2016, 52, 10617-10620. (d) Li, J. L.; Fu, L.; Wu, J.; Yang, K. C.; Li, Q. Z.; Gou, X. J.; Peng, C.; Han, B.; Shen, X. D. Highly enantioselective synthesis of fused bicyclic dihydropyranones via lowloading N-heterocyclic carbene organocatalysis. Chem. Commun., 2017, 53, 6875-6878. (e) Lu, Y.; Zhou, Y. H.; Lin, L. L.; Zheng, H. F.; Fu, K.; Liu, X. H.; Feng, X. M. N,N’-Dioxide/nickel(II)catalyzed asymmetric Diels-Alder reaction of cyclopentadiene with 2,3-dioxopyrrolidines and 2alkenoyl pyridines. Chem. Commun., 2016, 52, 8255-8258. (f) Zheng, J. F.; Lin, L. L.; Fu, K.; Zhang, Y. L.; Liu, X. H.; Feng, X. M. Asymmetric Hetero-Diels-Alder Reaction of Danishefsky’s Diene with α-Ketoesters and Isatins Catalyzed by a Chiral N,N’-Dioxide/Magnesium(II) Complex. Chem. Eur. J. 2014, 20, 14493-14498. (g) Li, Q.; Zhou, L.; Shen, X. D.; Yang, K. C.; Zhang, X.; Dai, Q. S.; Leng, H. J.; Li, Q. Z.; Li, J. L. Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α-Haloaldehydes. Angew. Chem. Int. Ed. 2018, 57, 1913-1917. (5) For examples of asymmetric HDA reactions of aldehydes, see: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.; Krishnan, K. Asymmetric hetero Diels-Alder reactions of Danishefsky's diene and glyoxylate esters catalyzed by chiral bisoxazoline derived catalysts. Tetrahedron: Asymmetry, 1996, 7, 2165-2168. (b) Du, H. F.; Long, J.; Hu, J. Y.; Li, X.; Ding, K. L. 3,3’-Br2-BINOL-Zn Complex: A Highly Efficient Catalyst for the Enantioselective Hetero-Diels-Alder Reaction. Org. Lett., 2002, 4, 4349-4352. (c) Guin, J.; Rabalakos, C.; List, B. Highly Enantioselective Hetero-Diels-Alder Reaction of 1,3-Bis(silyloxy)-1,3-dienes with Aldehydes Catalyzed by Chiral Disulfonimide*. Angew. Chem. Int. Ed. 2012, 51, 8859-8863. (d) Du, H. F.; Ding, K. L. Enantioselective Catalysis of Hetero Diels-Alder Reaction and Diethylzinc Addition Using a Single Catalyst. Org. Lett., 2003, 5, 1091-1093. (e) Fan, Q.; Lin, L. L.; Liu, J.; Huang, Y. Z.; Feng, X. M.; Zhang, G. L. Highly Enantioselective Hetero-Diels-Alder Reaction of Brassard Diene with Aromatic Aldehydes. Org. Lett., 2004, 6, 2185-2188. (f) Tonoi, T.; Mikami, K. Chiral bis-trifluoromethanesulfonylamide as a chiral Brønsted acid catalyst for the asymmetric hetero Diels-Alder reaction with Danishefsky’s diene. Tetrahedron Lett. 2005, 46, 6355-6358. (g) Shen, J. F.; Liu, D. L; An, Q. J.; Liu, Y. G.; Zhang, W. B. The Synthesis of trans-Perhydroindolic Acids and their Application in Asymmetric Domino Reactions of Aldehyde Esters with β,γ-Unsaturated α-Keto Esters. Adv. Synth. Catal. 2012, 354, 3311-3325. (h) An, Q. J.; Shen, J. F.; Butt, N.; Liu, D. L; Liu, Y. G.; Zhang, W.-B. The Construction of 3-Methyl-4-arylpiperidines via a trans-Perhydroindolic Acid-Catalyzed Asymmetric Aza-DielsAlder Reaction. Adv. Synth. Catal., 2015, 357, 3627-3638. (6) For recent examples of chiral Lewis acid catalysts, see: (a) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Peri- and Enantioselectivity of Thermal, Scandium-, and [Pybox/Scandium]-


Page 20 of 22

Page 21 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Catalyzed Diels-Alder and Hetero-Diels-Alder Reactions of Methyl (E)-2-Oxo-4-aryl-butenoates with Cyclopentadiene. Chem. Eur. J. 2007, 13, 9478-9485. (b) Zhu, Y.; Chen, X. H.; Xie, M. S.; Dong, S. X.; Qiao, Z.; Lin, L. L.; Liu, X. H.; Feng, X. M. Asymmetric Diels-Alder and InverseElectron-Demand Hetero-Diels-Alder Reactions of β,γ-Unsaturated α-Ketoesters with Cyclopentadiene Catalyzed by N,N’-Dioxide Copper(II) Complex. Chem. Eur. J. 2010, 16, 1196311968. (c) Lin, L. L.; Kuang, Y. L.; Liu, X. H.; Feng, X. M. Indium(III)-Catalyzed Asymmetric Hetero-Diels-Alder Reaction of Brassard-Type Diene with Aliphatic Aldehydes. Org. Lett., 2011, 13, 3868-3871. (d) Zhao, B.; Loh, T. P. Asymmetric Hetero-Diels-Alder Reaction of Danishefsky’s Dienes with α-Carbonyl Esters Catalyzed by an Indium(III)-PyBox Complex. Org. Lett. 2013, 15, 2914-2917. (e) Zheng, J. F.; Lin, L. L.; Fu, K.; Zhang, Y. L.; Liu, X. H.; Feng, X. M. Asymmetric Hetero-Diels-Alder Reaction of Danishefsky’s Diene with α-Ketoesters and Isatins Catalyzed by a Chiral N,N’-Dioxide/Magnesium(II) Complex. Chem. Eur. J. 2014, 20, 14493-14498. (f) Hu, Y. B.; Xu, K.; Zhang, S.; Guo, F. F.; Zha, Z. G.; Wang, Z. Y. Copper-Catalyzed Enantioselective HeteroDiels-Alder Reaction of Danishefsky’s Diene with β,γ-Unsaturated α-Ketoesters. Org. Lett. 2014, 16, 3564-3567. (g) Li, Y. N.; Hu, Y. B.; Zhang, S.; Sun, J. N.; Li, L. J.; Zha, Z. G.; Wang, Z. Y. Copper-Catalyzed Enantioselective Hetero-Diels-Alder Reaction of Danishefsky’s Diene with Glyoxals. J. Org. Chem., 2016, 81, 2993-2999. (7) For recent examples of other catalysts, see: (a) Gao, T. P.; Lin, J. B.; Hu, X. Q.; Xu, P. F. A catalytic asymmetric hetero-Diels-Alder reaction of olefinic azlactones and isatins: facile access to chiral spirooxindole dihydropyranones. Chem. Commun., 2014, 50, 8934-8936. (b) Cui, H. L.; Chouthaiwale, P. V.; Yin, F.; Tanaka, F. Reaction-Based Mechanistic Investigations of Asymmetric Hetero-Diels-Alder Reactions of Enones with Isatins Catalyzed by Amine-Based Three-Component Catalyst Systems. Asian J. Org. Chem. 2016, 5, 153-161. (c) Yang, X. B.; Feng, J.; Zhang, J.; Wang, N.; Wang, L.; Liu, J. L.; Yu, X. Q. Highly Enantioselective Hetero-Diels-Alder Reaction of trans-1Methoxy-2-methyl-3-trimethylsiloxybuta-1,3-diene with Aromatic and Aliphatic Aldehydes Catalyzed by 3-Substituted BINOL-Titanium Complex. Org. Lett., 2008, 10, 1299-1302. (8) For the application of the ligands, see: (a) Lai, G. Y.; Guo, F. F.; Zheng, Y. Q.; Fang, Y.; Song, H. G.; Xu, K.; Wang, S. J.; Zha, Z. G.; Wang, Z. Y. Highly Enantioselective Henry Reactions in Water Catalyzed by a Copper Tertiary Amine Complex and Applied in the Synthesis of (S)-N-transFeruloyl Octopamine. Chem. Eur. J., 2011, 17, 1114-1117. (b) Xu, K.; Lai, G. Y.; Zha, Z. G.; Pan, S. S.; Chen, H. W.; Wang, Z. Y. A Highly anti-Selective Asymmetric Henry Reaction Catalyzed by a Chiral Copper Complex: Applications to the Syntheses of (+)-Spisulosine and a Pyrroloisoquinoline Derivative. Chem. Eur. J., 2012, 18, 12357-12362. (c) Zhang, S.; Xu, K.; Guo, F. F.; Hu, Y. B.; Zha, Z. G.; Wang, Z. Y. Enantioselective Copper(I/II)-Catalyzed Conjugate Addition of Nitro Esters to β,γ-Unsaturated α-Ketoesters. Chem. Eur. J., 2014, 4, 979-982. (d) Li, L. J.; Zhang, S.; Hu, Y. B.; Li, Y. N.; Li, C.; Zha, Z. G.; Wang, Z. Y. Highly Diastereo- and Enantioselective Michael Addition of Nitroalkanes to 2-Enoyl-Pyridine N-Oxides Catalyzed by Scandium(III)/Copper(II) Complexes. Chem. Eur. J., 2015, 21, 12885-12888. (e) Hu, Y. B.; Li, Y. N.; Zhang, S.; Li, C.; Li, L. J.; Zha, Z. G.; Wang, Z. Y. Org. Lett., 2015, 17, 4018 - 4021. (f) Li, Y. N.; Huang, Y. K.; Gui, Y.; Sun, J. N.; Li, J. D.; Zha, Z. G.; Wang, Z. Y. Copper-Catalyzed Enantioselective Henry Reaction of β,γ-Unsaturated α-Ketoesters with Nitromethane in Water. Org. Lett., 2017, 19, 6416 - 6419. (9) For both types of mechanisms of HDA reactions of aldehydes and Danishefsky’s diene, see: Roberson, M.; Jepsen, A. S.; Jørgensen, K. A. On the mechanism of catalytic enantioselective



hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral aluminum complexes-a concerted, step-wise or Mukaiyama-aldol pathway. Tetrahedron, 2001, 57, 907-913. (10) For the [4+2] cycloaddition pathway, see: (a) Bednarski, M.; Danishefsky, S. Mild Lewis Acid Catalysis: Eu(fod)3-Mediated Hetero-Diels-Alder Reaction. J. Am. Chem. Soc. 1983, 105, 37163717. (b) Zhang, X.; Du, H. F.; Wang, Z.; Wu, Y. D.; Ding, K. L. Experimental and Theoretical Studies on the Hydrogen-Bond-Promoted Enantioselective Hetero-Diels-Alder Reaction of Danishefsky's Diene with Benzaldehyde. J. Org. Chem. 2006, 71, 2862-2869. (11) For the Mukaiyama-aldol pathway, see: (a) Qian, C. T.; Wang, L. C. Asymmetric hetero-DielsAlder reaction of glyoxylate esters and Danishefsky’s diene catalyzed by chiral bis(oxazoline)lanthanide complexes. Tetrahedron Letters, 2000, 41, 2203-2206. (b) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. Chiral Hetero Diels-Alder Products by Enantioselective and Diastereoselective Zirconium Catalysis. Scope, Limitation, Mechanism, and Application to the Concise Synthesis of (+)-Prelactone C and (+)-9-Deoxygoniopypyrone. J. Am. Chem. Soc., 2003, 125, 3793-3798. (12) Details of the crystal structure analysis are provided free of charge from the CCDC 1590154 of the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif or from 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 NSubstituted 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.


Page 22 of 22

An Enantioselective Hetero-Diels-Alder Reaction and the Synthesis of

Recommend Documents