Organocatalytic Enantioselective Michael ... - ACS Publications

Subscriber access provided by University of South Dakota

Note

Organocatalytic Enantioselective Michael/Cyclization Domino Reaction between 3-Amideoxindoles and #,#-Unsaturated Aldehydes: One-Pot Preparation of Chiral Spirocyclic Oxindole-#-Lactams Peng Yang, Xiao Wang, Feng Chen, Zheng-Bing Zhang, Chao Chen, Lin Peng, and Li-Xin Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03090 • Publication Date (Web): 13 Mar 2017 Downloaded from http://pubs.acs.org on March 13, 2017

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 free 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 accessible to all readers and 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.

The Journal of Organic Chemistry 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 9

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

Organocatalytic Enantioselective Michael/Cyclization Domino Reaction between 3-Amideoxindoles and α,β-Unsaturated Aldehydes: One-Pot Preparation of Chiral Spirocyclic Oxindoleγ-Lactams Peng Yang,†,‡ Xiao Wang,†,‡ Feng Chen,†,‡ Zheng-Bing Zhang,†,‡ Chao Chen,†,‡ Lin Peng† and Li-Xin Wang*,† †

Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P.R. China ‡

University of Chinese Academy of Sciences, Beijing 100039, P.R. China

Supporting Information Placeholder

ABSTRACT: The first organocatalytic enantioselective Michael/Cyclization domino reaction between 3-amideoxindoles and α,βunsaturated aldehydes has been disclosed. After sequential oxidation with PCC, a direct and one-pot preparation of highly sterically hindered spirocyclic oxindole-γ-lactams was achieved in 51-81% yields with 75-97% ee and up to 80:20 dr.

Heterocyclic spirocyclic oxindoles are frequently occurred in nature and have now become an area of intensive interests in synthetic organic chemistry.1 Particularly, construction of heterocyclic spirocyclic-3,2’-oxindoles with a nitrogen atom at the C3 position, has emerged as appealing synthetic targets because of their wide spectra of significant bioactivities,2 such as inhibitor of acetylcholinesterase,2a antitumor activity2b antibacterial and anticancer activity2g (Figure 1).

on the functional transformation and analysis of the structural characteristics, we regarded that γ-lactams may be easily transformed from the oxidation of corresponding hemiaminals6 which might be obtained by a Michael/Cyclization reaction of amides or sulfonamides with α,β-unsaturated aldehydes.7 However, to the best of our knowledge, there has been no any report about enantioselective and organocatalytic preparation of optically enriched 3,2’-spirooxindoles bearing a γ-lactams moiety with our strategy and such a domino reaction device. Based on our Scheme 1. Strategy for the Construction of Spirocyclic Oxindole-γ-Lactams

Figure 1. Representative biologically active compounds containing the 3,2’-spiropyrrolidine oxindole skeleton. As a consequence, several methods3 to access structurally diverse heterocyclic spirooxindoles have been reported during the past years, including organometallic3a, 3b and organocatalytic means.3e In 2012, Ye’s group4 firstly synthesized a series of spirocyclic oxindole-γ-lactams via NHC-catalyzed [3 + 2] annulation of enals with oxindole imines and successfully used them as effective precursors for various heterocyclic spirocyclic-3,2’-oxindoles. Since then, catalytic asymmetric syntheses of oxindole-γ-lactams have aroused extensive attentions from several research groups,5 such as NHC-catalyzed [3 + 2] annulations of α,β-unsaturated aldehydes with isatinimines5a, 5d, 5e and Michael/cyclization of 3-amideoxindoles with olefinic azlactones5b or α,β-unsaturated acyl phosphonates (Scheme 1).5c Nevertheless, considering the importance of the spirocyclic-3,2’-oxindoles in pharmaceuticals, the development of novel and efficient synthetic methods is still desirable. Based

ACS Paragon Plus Environment


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

persistent research program toward the exploitation of organocatalytic domino reactions8 and our interests in the constructions of spirooxindoles,9 herein we wish to present the first organocatalytic asymmetric Michael/Cyclization reaction of 3amideoxindoles and α,β-unsaturated aldehydes with classical α,α-diphenylprolinol silyl ether as catalyst, pyridinium chlorochromate (PCC) as oxidant, providing spirocyclic oxindole-γlactams in good yields (up to 81%) with good diastereoselectivities (up to 80:20 dr) and excellent enantioselectivities (up to 97% ee). At the outset of our investigation, some important clues had to be expounded: in the presence of catalytic pyrrolidine and TFA, the expected Michael/Cyclization process was ready to afford the expected hemiaminals, which were obtained as complex mixtures composed of a variety of isomers. This result might attribute to the poor stereoselectivity of the Cyclization process. Fortunately, when PCC (2.5 equiv.) was added to the hemiaminal mixture without separation, the desired γlactams were obtained as two diastereomers in one pot. Table 1. Evaluation of Catalysts and Solventsa

entry

cat.

solvent

yieldb (%)

drc

Page 2 of 9

for 12 h. The domino and one pot process afforded the desired product 4a in 25% yield with 39:61 dr and 24% ee. Other chiral secondary amine catalysts were investigated sequentially (Table 1, entries 2-5), and α,α-diarylprolinol silyl ether catalysts 1c-1e, which might performed iminium-ion activation and contained two aromatic groups, gave the best and similar results (49-54% yield, 36:64-37:63 dr and 86-92% ee; Table 1, entries 3-5). Considering the complexity of the structure, the simplest 1c was selected as the optimal catalyst. A survey of solvents indicated that ethers gave moderate diastereoselectivities and excellent enantioselectivities (21-50% yield, up to 36:64 dr and 92-96% ee; Table 1, entries 11-13). MTBE and THF afforded the highest enantioselectivitiy (96% ee; Table 1, entries 11, 13), while THF gave better yield (50% yield; Table 1, entry 13). Other solvents, such as toluene, dimethyl carbonate and chlorinated solvents, gave inferior results (Table 1, entries 6-10). Table 2. Optimization of Reaction Conditionsa

entry

additives

temp (oC)

time (d)

yieldb (%)

drc

eed (%)

1

none

25

2

10

33/67

87/90

2

benzoic acid

25

2

63

42/58

85/90

3

TFA

25

2

50

36/64

95/96

eed (%)

4

p-TsOH

25

2

6.2

21/79

19/76

5

D-CSA

25

2

2.4

20/80

38/78

TFA

40

1

51

42/58

92/95

1

1a

DCM

25

39/61

24/21

6

2

1b

DCM

19

98/2

6/0

7

TFA

10

4

48

37/63

95/96

89/92

8

TFA

0

8

31

36/64

95/95

3 4 5 6

1c 1d 1e 1c

DCM DCM DCM DCE

52 49 54 40

36/64 37/63 36/64 33/67

TFA

25

2

55

36/64

95/96

86/90

10

f

TFA

25

2

51

33/67

91/95

90/93

11g

TFA

25

4

41

31/69

85/91

89/92

7

1c

chloroform

38

38/62

56/73

8

1c

CCl4

38

36/64

54:69

9

1c

toluene

16

62/38

94/95

10

1c

dimethyl carbonate

34

47/53

89/91

11

1c

MTBE

32

43/57

94/96

12

1c

diethyl ether

21

42/58

92/95

13

1c

THF

50

36/64

95/96

a

Unless otherwise noted, reactions were performed with 2a (0.2 mmol), 3a (0.3 mmol) and 1 (0.06 mmol) in solvent (1.0 mL) at 25 °C for 2 days, then oxidized by PCC (0.5 mmol) for 12 h. b Combined yield of both diastereomers. c, dDetermined by chiral HPLC.

Based on the preliminary results, N-(1-methyl-2oxoindolin-3-yl) formamide 2a (0.2 mmol) was selected as model substrate with cinnamaldehyde 3a (0.3 mmol) in the presence of L-proline 1a in DCM at 25 oC (Table 1, entry 1) and the residue was subsequently oxidized by PCC (0.5 mmol)

9

e

a

Unless otherwise noted, reactions were performed with 2a (0.2 mmol), 3a (0.3 mmol) and 1c (0.06 mmol) in THF (1.0 mL) at 25 °C, then oxidized by PCC (0.5 mmol) for 12 h. bCombined yield of both diastereomers. c, dDetermined by chiral HPLC. ePerformed at 25 mol% catalyst loading. fPerformed at 20 mol% catalyst loading. gPerformed at 10 mol% catalyst loading.

To further optimize the reaction, other parameters were studied, and the results were listed in Table 2. The acidity of additives had obvious effects on yields and stereoselectivities (Table 2, entries 1-5) and TFA still gave the highest enantioselectivity. Reaction temperature and catalyst loadings also showed obvious effects. Lower temperature had no obvious improvement on stereoselectivities, while yields were significantly lowered (Table 2, entries 7, 8). When 25 mol% α,αdiphenylprolinol silyl ether 1c used, a slight improvement of yield was observed without loss of stereocontrol (55% yield, 36:64 dr, 96% ee; Table 2, entry 9). However, poor enantioselectivities were observed when the catalyst loading was reduced furtherly (Table 2, entries 10, 11).

2


Page 3 of 9

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


Table 3. Scope of 3-Amideoxindoles with α,β-Unsaturated Aldehydesa

entry

2

3

4/yieldb (%)

drc

eed (%)

1

2a

R = Ph (3a)

4a/55

36/64

95/96

2

2a

R = 4-FC6H4 (3b)

4b/60

35/65

93/95

3

2a

R = 4-ClC6H4 (3c)

4c/63

36/64

93/95

4

2a

R = 4-BrC6H4 (3d)

4d/61

36/64

93/95

5

2a

R = 4-MeC6H4 (3e)

4e/64

25/75

92/95

6

2a

R = 2-BrC6H4 (3f)

4f/51

42/58

97/95

e

2a

R = 2-MeOC6H4 (3g)

4g/51

45/55

87/93

8e

2a

R = 2-NO2C6H4 (3h)

4h/77

38/62

93/95

9

2b

R = Ph (3a)

4i/63

27/73

92/95

10

2c

R = Ph (3a)

4j/81

20/80

92/94

11

2d

R = Ph (3a)

4k/59

28/72

93/96

12

2e

R = Ph (3a)

4l/n.r

nd

nd

13

2f

R = Ph (3a)

4m/n.r

nd

nd

14

2a

R = Me (3i)

4n/trace

nd

nd

7

a

Unless otherwise noted, reactions were performed with 2 (0.2 mmol), 3 (0.3mmol) and 1c (0.06 mmol) in THF (1.0 mL) at 25 °C for 2 days, then oxidized by PCC (0.5 mmol) for 12 h. b Combined yield of both diastereomers. c, dDetermined by chiral HPLC. ePerformed in 1,4-dioxane.

Under the optimal conditions, the substrate scope was evaluated, and the results were presented in Table 3. Substituents on aromatic rings of α,β-unsaturated aldehydes, regardless of the electronic characteristics and substituted position, were well tolerable and provided the desired products 4a-h in 51-77% yields with up to 25:75 dr in 87-97% ee (Table 3, entries 1-8). Substituents on nitrogen atoms of oxindoles slightly affected yields and diastereoselectivities (59-81% yield, 28:72-20:80 dr, 92-95% ee; Table 3, entries 9-11). The electronic properties of the substituents on amides had obvious effects. When other carbonyl substituted amides were used, the reaction did not occur under the same optimized conditions (Table 3, entries 12, 13). Aliphatic α,β-unsaturated aldehyde was also investigated, but no reaction was observed (Table 3, entry 14). To further investigate the generality of this asymmetric reaction, 3-sulfonamide oxindoles were used as nucleophiles. Surprisingly, the reaction of 5 with α,β-unsaturated aldehydes 3 was conducted smoothly under the previously optimized conditions (Table 4). Similar as the former substrates, different α,β-unsaturated aldehydes were also examined (Table 4, entries 1-6), and the desired γ-lactams 6a-f were obtained in 58-

71% yield, up to 22:78 dr in 75-91% ee. When the substituents on nitrogen atoms of oxindoles were replaced by ethyl or benzyl, satisfactory results were also obtained (61-67% yield, 28:72-24:76 dr, 83-90% ee; Table 4, entries 7, 8). Substituents on the aromatic ring of oxindoles afforded the desired products with moderate yields and diastereoselectivities, and excellent enantioselectivities (59-66% yield, 47:53-24:76 dr, 78-93% ee; Table 4, entries 9-11). No detectable reaction was observed when aliphatic α,β-unsaturated aldehydes were used under the optimal reaction conditions. Based on those results, we established the optimal reaction conditions: 0.2 mmol 2a and 0.3 mmol 3a in 1.0 mL THF in the presence of 25 mol% 1c and 25 mol% TFA at 25 oC for 2 d, then oxidized by PCC (0.5 mmol) for 12 h. Table 4. Scope of 3-Sulfonamide Oxindoles with α,βUnsaturated Aldehydesa

entry

5

3

6/yieldb (%)

drc

eed (%)

1

5a

R = Ph (3a)

6a/70

25/75

80/88

2

5a

R = 4-FC6H4 (3b)

6b/66

24/76

84/91

3

5a

R = 4-ClC6H4 (3c)

6c/58

27/73

85/88

4

5a

R = 4-BrC6H4 (3d)

6d/71

44/56

87/81

5

5a

R = 4-MeC6H4 (3e)

6e/64

22/78

75/85

6

5a

R = 4-NO2C6H4 (3j)

6f/71

39/61

89/85

7

5b

R = 4-FC6H4 (3b)

6g/61

28/72

83/90

8

5c

R = 4-FC6H4 (3b)

6h/67

24/76

84/90

9

5d

R = 4-FC6H4 (3b)

6i/66

47/53

82/86

10

5e

R = 4-FC6H4 (3b)

6j/59

24/76

78/89

5f

R = 4-FC6H4 (3b)

6k/60

31/69

81/93

11 a

Unless otherwise noted, reactions were performed with 5 (0.2 mmol), 3 (0.3mmol) and 1c (0.06 mmol) in THF (1.0 mL) at 25 °C for 2 days, then oxidized by PCC (0.5 mmol) for 12 h. b Combined yield of both diastereomers. c, dDetermined by chiral HPLC.

Differently, the absolute configuration of the major products identified as (3S, 3’S) by single-crystal X-ray analysis of the major isomer of 4d (see the Supporting Information), which showed our target product maintained in an unfavorable state with more crowded steric hindrance compared with previous report5. Based on those experimental results, a plausible mechanism was proposed and illustrated in scheme 2. 4Bromocinnamaldehyde, which was used as Michael acceptor, was firstly activated by 1c in the presence of acid additives to form the iminium-ion intermediate 7, and reacted with 3amideoxindole 2a via transition state 1 to afford the major product 4d. In which, the aromatic ring A maintained the least steric hindrance with the controlling group of OTMS, but had a considerable steric hindrance with aromatic ring B. Except

3



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

for that, there might be another transition state 2. In which, the aromatic ring A had some steric repulsion with the -OTMS, while the hindrance with aromatic ring B was released effectively. Because of the two possible transition states, the diastereoselectivity of this reaction was confined.

Scheme 2. Proposed Transition State for This Transformation In conclusion, the first organocatalytic Michael/Cyclization reaction of 3-amideoxindoles with α,β-unsaturated aldehydes has been successfully developed. After sequential and one pot oxidation with PCC, this methodology provided a new approach to construct highly sterically hindered spirocyclic oxindole-γ-lactams in good yields (up to 81%) with moderate regioselectivities (up to 80:20 dr) and excellent enantioselectivities (up to 97% ee). EXPERIMENTAL SECTION General Methods and Materials. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance (300 MHz for 1H NMR, 75 MHz for 13C NMR) instrument. Data for 1H NMR are reported as chemical shift (ppm, tetramethylsilane as the internal standard), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz). Data for 13C NMR are reported as chemical shift. Flash column chromatography was carried out using silica gel eluting with ethyl acetate and petroleum ether. High-resolution mass spectra (HRMS) analyses were obtained with the Bruker SolariX 70 Fourier-transform mass spectrometer. Reactions were monitored by TLC and visualized with ultraviolet light. Enantiomeric excess was determined by HPLC analysis on chiralpak ADH, AS-H, or IC-H columns. Optical rotations were measured at 589 nm at 20 oC. Melting points were recorded on a Buchi Melting Point B-545. 3-Amideoxindoles (2a-d) were prepared according to the reported procedures.10 Unless otherwise noted, materials were purchased from commercial suppliers and used without further purification. Synthesis of Substrates 5a-f. 4-methyl-N-(1-methyl-2-oxoindolin-3yl)benzenesulfonamide (5a). A solution of 3-amino-1-methylindolin-2-one hydrochloride (2.5 g, 12.6 mmol) in CHCl3 (50 mL) was added saturated sodium bicarbonate (25 mL) under nitrogen atmosphere. The mixture was stirred at room temperature for 10 min and the organic layer was separated to a 100 mL flask under nitrogen atmosphere. Pyridine (1.2 equiv.) and ptoluenesulfonyl chloride (1.1 equiv.) was added sequentially. After 1.5 h, the mixture was washed with water (50 mL x 2), the organic layer was dried by Na2SO4 and concentrated. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 5:1-3:1) to give 5a (2.83 g, 71% yield) as a white solid. Mp 185-187 oC; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 6.98 – 6.89 (m, 2H), 6.74 (d, J = 7.3 Hz, 1H), 4.96 (d, J = 8.6 Hz, 1H), 3.07 (s, 3H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO) δ 173.0, 143.6, 142.6, 139.4, 129.4, 129.1, 126.6, 126.2, 124.0, 122.1, 108.6, 54.5, 26.1, 21.0. N-(1-ethyl-2-oxoindolin-3-yl)-4-methylbenzenesulfonamide (5b). The method for the synthesis of 5b was similar to that for 5a. Product 5b (0.92 g, 56% yield) was obtained from 3-amino-1-ethylindolin-2-one hydrochloride (1.06 g, 5.0 mmol) as a white solid. Mp 173-174 oC; 1H NMR (300 MHz, Chloroform-d) δ 7.82 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.31 – 7.7.26 (m, 3H), 7.02 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.44 (s, 1H), 4.76 (d, J = 3.8 Hz, 1H), 3.74 – 3.60 (m, 2H), 2.42 (s, 3H),

Page 4 of 9

1.21 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.1, 143.7, 142.6, 137.1, 129.6, 127.5, 125.8, 125.4, 123.0, 108.5, 55.2, 35.1, 21.6, 12.4. N-(1-benzyl-2-oxoindolin-3-yl)-4-methylbenzenesulfonamide (5c). The method for the synthesis of 5c was similar to that for 5a. Product 5c (5.81 g, 74% yield) was obtained from 3-amino-1-benzylindolin-2-one hydrochloride (5.50 g, 20.0 mmol) as a white solid. Mp 176-177 oC; 1H NMR (300 MHz, DMSO-d6) δ 8.61 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.30 – 7.21 (m, 5H), 7.13 – 7.11 (m, 1H), 6.82 (t, J = 7.1 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 5.12 (d, J = 8.6 Hz, 1H), 4.81 (dd, J = 22.9, 15.9 Hz, 2H), 2.39 (s, 3H); 13C NMR (75 MHz, DMSO) δ 173.2, 142.6, 142.6, 139.4, 135.9, 129.4, 128.9, 128.5, 127.3, 126.6, 126.3, 124.2, 122.2, 109.2, 54.5, 42.8, 21.0. N-(5-bromo-1-methyl-2-oxoindolin-3-yl)-4-methylbenzenesulfonamide (5d). The method for the synthesis of 5d was similar to that for 5a. Product 5d (1.58 g, 63% yield) was obtained from 3-amino-5-bromo-1methylindolin-2-one hydrochloride (1.77 g, 6.36 mmol) as a white solid. Mp 162-163 oC; 1H NMR (300 MHz, Chloroform-d) δ 7.78 (d, J = 8.3 Hz, 2H), 7.43 – 7.40 (m, 1H), 7.32 – 7.26 (m, 3H), 6.68 (d, J = 8.3 Hz, 1H), 5.65 (d, J = 5.9 Hz, 1H), 4.76 (d, J = 5.9 Hz, 1H), 3.14 (s, 3H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.1, 144.1, 142.6, 137.0, 132.5, 129.8, 128.8, 127.4, 126.8, 115.9, 109.9, 54.9, 26.7, 21.6. 4-methyl-N-(1,5,7-trimethyl-2-oxoindolin-3-yl)benzenesulfonamide (5e). The method for the synthesis of 5e was similar to that for 5a. Product 5e (1.21 g, 79% yield) was obtained from 3-amino-1,5,7-trimethylindolin-2one hydrochloride (1.01 g, 4.45 mmol) as a white solid. Mp 186-187 oC; 1 H NMR (300 MHz, Chloroform-d) δ 7.68 (d, J = 8.3 Hz, 2H), 7.26 – 7.22 (m, 2H), 6.62 (s, 1H), 6.45 (s, 1H), 5.46 – 5.29 (m, 1H), 4.92 (d, J = 7.9 Hz, 1H), 3.05 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.22 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 144.1, 143.3, 140.0, 138.4, 136.6, 129.2, 127.4, 125.6, 118.7, 106.9, 55.0, 26.4, 21.7, 21.6, 17.7. N-(1,5-dimethyl-2-oxoindolin-3-yl)-4-methylbenzenesulfonamide (5f). The method for the synthesis of 5f was similar to that for 5a. Product 5f (0.89 g, 55% yield) was obtained from 3-amino-1,5-dimethylindolin-2-one hydrochloride (1.04 g, 4.89 mmol) as a white solid. Mp 185-187 oC; 1H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.08 – 7.05 (m, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.25 (s, 1H), 4.87 (d, J = 8.6 Hz, 1H), 3.04 (s, 3H), 2.42 (s, 3H), 2.09 (s, 3H); 13C NMR (75 MHz, DMSO) δ 172.8, 142.7, 141.3, 139.5, 130.9, 129.4, 129.0, 126.7, 125.9, 124.9, 108.2, 54.5, 26.2, 20.9, 20.4. General Procedure for the Synthesis of Compounds 4 and 6. A solution of 3-amideoxindoles 2 (0.2 mmol, 1.0 equiv.), α,β-unsaturated aldehydes 3 (0.3 mmol, 1.5 equiv.), (S)-α,α-diphenylprolinol silyl ether 1c (0.05 mmol, 16.3 mg, 0.25 equiv.) and trifluoroacetic acid (0.05 mmol, 3.8 uL, 0.25 equiv.) in THF (1.0 mL) was stirred at room temperature. After 2 days later, PCC (0.5 mmol, 108 mg, 2.5 equiv.) was added and the mixture was stirred for 12 h again. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (8:1 - 5:1) as eluent to afford the products 4. The method for the synthesis of 6 was similar to that for 4. (3S,3'S)-1-methyl-2,5'-dioxo-3'-phenylspiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4a). Yellow oil; 38% yield, [α]D20 = +21.0 (c = 1.11, CH2Cl2); dr = 36/64. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 96% ee: tmajor = 22.0 min, tminor = 18.7 min); 1H NMR (300 MHz, Chloroform-d) 9.04 (s, 1H), 7.15 – 7.09 (m, 4H), 6.96 – 6.89 (m, 4H), 6.61 (d, J = 7.8 Hz, 1H), 4.14 – 4.07 (m, 1H), 3.37 (dd, J = 17.5, 12.5 Hz, 1H), 3.19 (s, 3H), 3.09 (dd, J = 17.5, 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 173.4, 158.4, 143.3, 133.2, 129.9, 128.1, 128.0, 127.6, 124.4, 123.3, 122.4, 108.5, 68.8, 47.5, 35.3, 26.6; HRMS (ESI-FT): Exact mass calcd for C19H17N2O3 [M+H]+: 321.1234, Found 321.1233. 1-methyl-2,5'-dioxo-3'-phenylspiro[indoline-3,2'-pyrrolidine]-1'carbaldehyde (4a'). White solid; Mp 91-93 oC; 17% yield, [α]D20 = -8.2 (c = 0.55, CH2Cl2); dr = 36/64. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 95% ee: tmajor = 16.8 min, tminor = 23.8 min); 1H NMR (300 MHz, Chloroform-d) δ 9.12 (s, 1H), 7.34 – 7.31 (m, 2H), 7.19 – 7.14 (m, 4H), 6.83 (d, J = 7.1 Hz, 2H), 6.65 (d, J = 7.7 Hz, 1H), 3.82 (dd, J = 13.7, 7.3 Hz, 1H), 3.66 (dd, J = 16.6, 13.8 Hz, 1H), 2.85 (dd, J = 16.6, 7.3 Hz, 1H), 2.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.6, 172.2, 159.4, 143.6, 131.8, 123.0, 128.4, 128.2, 127.7, 126.4, 123.2, 122.0, 108.6, 69.6, 49.4, 34.5, 25.8. (3S,3'S)-3'-(4-fluorophenyl)-1-methyl-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4b). White solid; Mp 167-170 oC; 40%

4


Page 5 of 9

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


yield, [α]D20 = -17.0 (c = 0.80, CH2Cl2); dr = 35/65. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 95% ee: tmajor = 19.3 min, tminor = 16.7 min); 1H NMR (300 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.18 (t, J = 1.3 Hz, 1H) 6.98-6.88 (m, 4H) 6.79 (t, J = 8.6 Hz, 2H) 6.64 (d, J = 7.9 Hz, 1H), 4.09 (dd, J = 12.5, 8.0 Hz, 1H), 3.31 (dd, J = 17.4, 12.6 Hz, 1H), 3.20 (s, 3H), 3.08 (dd, J = 17.4, 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 174.3, 173.2, 162.3 (d, JC, F = 246.2 Hz) 158.3, 143.3, 130.2, 129.3 (d, JC, F = 8.2 Hz), 128.9 (d, JC, F = 3.2 Hz), 124.2, 123.2, 122.6, 115.2 (d, JC, F = 21.5 Hz), 108.8, 68.8, 47.1, 35.5, 26.7; HRMS (ESI-FT): Exact mass calcd for C19H15FN2NaO3 [M+Na]+: 361.0959, Found 361.0950. 3'-(4-fluorophenyl)-1-methyl-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4b'). White solid; Mp 128-130 oC; 20% yield, [α]D20 = -17.0 (c = 0.80, CH2Cl2); dr = 35/65. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 93% ee: tmajor = 14.6 min, tminor = 21.0 min); 1H NMR (300 MHz, Chloroform-d) δ 9.10 (s, 1H), 7.37 – 7.31 (m, 2H), 7.19 – 7.16 (m, 1H), 6.84 – 6.80 (m, 4H), 6.68 (d, J = 9.8 Hz, 1H), 3.80 (dd, J = 13.7, 7.5 Hz, 1H), 3.59 (dd, J = 16.8, 13.7 Hz, 1H), 2.91 – 2.79 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.3, 172.2, 162.6 (d, JC,F = 246.2 Hz), 159.3, 143.5, 130.1, 129.4 (d, JC,F = 8.2 Hz), 127.5 (d, JC,F = 3.2 Hz), 126.1, 123.3, 122.0, 115.2 (d, JC,F = 21.4 Hz), 108.7, 69.5, 48.7, 34.6, 25.9. (3S,3'S)-3'-(4-chlorophenyl)-1-methyl-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4c). White solid; Mp 150-151 oC; 40% yield, [α]D20 = -14.2 (c = 0.71, CH2Cl2); dr = 36/64. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 95% ee: tmajor = 20.1 min, tminor = 17.2 min); 1H NMR (300 MHz, Chloroform-d) δ 9.03 (s, 1H), 7.19 – 7.16 (m, 1H) 7.07 (d, J = 8.5 Hz, 2H), 7.01 – 6.86 (m, 4H), 6.65 (d, J = 7.9 Hz, 1H), 4.08 (dd, J = 12.6, 8.1 Hz, 1H), 3.31 (dd, J = 17.4, 12.7 Hz, 1H), 3.20 (s, 3H), 3.07 (dd, J = 17.4, 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 174.1, 173.1, 158.3, 143.3, 134.0, 131.7, 130.3, 129.0, 128.4, 124.1, 123.2, 122.6, 108.8, 68.7, 47.1, 35.4, 26.7; HRMS (ESI-FT): Exact mass calcd for C19H16ClN2O3 [M+H]+: 355.0844, Found 355.0844. 3'-(4-chlorophenyl)-1-methyl-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4c'). White solid; Mp 135-136 oC; 23% yield, [α]D20 = -87.3 (c = 1.20, CH2Cl2); dr = 36/64. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 93% ee: tmajor = 15.2 min, tminor = 21.9 min); 1H NMR (300 MHz, Chloroform-d) δ 9.10 (s, 1H), 7.35 – 7.31 (m, 2H), 7.19 – 7.11 (m, 3H), 6.77 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 7.7 Hz, 1H), 3.79 (dd, J = 13.7, 7.5 Hz, 1H), 3.59 (dd, J = 16.8, 13.7 Hz, 1H), 2.88 – 2.80 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.2, 172.1, 159.3, 143.5, 134.3, 130.4, 130.2, 129.1, 128.4, 126.0, 123.4, 122.0, 108.8, 69.4, 48.7, 34.5, 26.0. (3S,3'S)-3'-(4-bromophenyl)-1-methyl-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4d). White solid; Mp 155-157 oC; 42% yield, [α]D20 = -31.4 (c = 1.05, CH2Cl2); dr = 36/64. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 95% ee: tmajor = 18.9 min, tminor = 16.0 min); 1H NMR (300 MHz, Chloroform-d) δ 9.02 (s, 1H), 7.24 – 7.19 (m, 3H), 6.98 – 6.92 (m, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 7.9 Hz, 1H), 4.06 (dd, J = 12.6, 8.1 Hz, 1H), 3.30 (dd, J = 17.4, 12.6 Hz, 1H), 3.19 (s, 3H), 3.06 (dd, J = 17.4, 8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 174.1, 173.1, 158.2, 143.3, 133.3, 131.3, 130.3, 129.3, 124.1, 123.2, 122.6, 122.1, 108.8, 68.6, 47.1, 35.3, 26.7; HRMS (ESI-FT): Exact mass calcd for C19H16BrN2O3 [M+H]+: 399.0339, Found 399.0336. 3'-(4-bromophenyl)-1-methyl-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4d'). White solid; Mp 137-139 oC; 19% yield, [α]D20 = -44.5 (c = 1.10, CH2Cl2); dr = 36/64. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 93% ee: tmajor = 14.3 min, tminor = 20.4 min); 1H NMR (300 MHz, Chloroform-d) δ 9.09 (s, 1H), 7.37 – 7.29 (m, 4H), 7.16 (t, J = 7.6 Hz, 1H), 6.70 (t, J = 8.3 Hz, 3H), 3.77 (dd, J = 13.7, 7.5 Hz, 1H), 3.58 (dd, J = 16.7, 13.7 Hz, 1H), 2.87 – 2.79 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 175.1, 172.1, 159.3, 143.6, 131.4, 131.0, 130.2, 129.5, 126.1, 123.4, 122.6, 122.0, 108.8, 69.3, 48.8, 34.5, 26.0. (3S,3'S)-1-methyl-2,5'-dioxo-3'-(p-tolyl)spiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4e). White solid; Mp 175-177 oC; 48% yield, [α]D20 = -19.5 (c = 0.88, CH2Cl2); dr = 25/75. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 20/80,

flow rate 1.0 mL/min, λ = 254 nm, 95% ee: tmajor = 17.9 min, tminor = 12.6 min); 1H NMR (300 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.19 – 7.14 (m, 1H), 7.00 – 6.83 (m, 4H), 6.82 (d, J = 8.1, 2H), 6.63 (d, J = 7.8 Hz, 1H), 4.07 (dd, J = 12.6, 8.0 Hz, 1H), 3.34 (dd, J = 17.5, 12.5 Hz, 1H), 3.20 (s, 3H), 3.06 (dd, J = 17.5, 8.0 Hz, 1H), 2.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.7, 173.4, 158.4, 143.3, 137.8, 130.0, 129.9, 128.8, 127.5, 124.5, 123.3, 122.4, 108.6, 68.8, 47.3, 35.5, 26.6, 21.0; HRMS (ESI-FT): Exact mass calcd for C20H18N2NaO3 [M+Na]+: 357.1210, Found 357.1198. 1-methyl-2,5'-dioxo-3'-(p-tolyl)spiro[indoline-3,2'-pyrrolidine]-1'carbaldehyde (4e'). White solid; Mp 126-127 oC; 16% yield, [α]D20 = +5.0 (c = 0.84, CH2Cl2); dr = 25/75. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm, 92% ee: tmajor = 11.2 min, tminor = 19.0 min); 1H NMR (300 MHz, Chloroform-d) δ 9.11 (s, 1H), 7.36 – 7.26 (m, 2H), 7.18-7.13 (m, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 8.1 Hz, 2H), 6.66 (d, J = 7.6 Hz, 1H), 3.79 (dd, J = 13.8, 7.3 Hz, 1H), 3.63 (dd, J = 16.6, 13.8 Hz, 1H), 2.86 – 2.76 (m, 4H), 2.25 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.7, 172.4, 159.4, 143.6, 138.2, 129.9, 128.9, 128.7, 127.6, 126.6, 123.2, 122.0, 108.6, 69.6, 49.1, 34.7, 25.9, 21.0. (3S,3'S)-3'-(2-bromophenyl)-1-methyl-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4f). White solid; Mp 164-166 oC; 51% yield, [α]D20 = -18.1 (c = 0.63, CH2Cl2); dr = 42/58. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, major diastereomer 95% ee: tmajor = 21.7 min, tminor = 19.6 min; minor diastereomer 97% ee: tmajor = 17.0 min, tminor = 25.6 min); 1H NMR (300 MHz, Chloroform-d) δ (major diastereomer + minor diastereomer) 9.11 (s, 0.46 H, Minor), 9.06 (s, 0.54H, Major), 7.38-7.30 (m, 2H, Major + Minor), 7.30 – 7.07 (m, 4H, Major + Minor ), 6.77 – 6.10 ( m, 2H, Major + Minor), 4.61 (dd, J = 12.4, 8.3 Hz, 0.46H, Minor), 4.45 (dd, J = 9.4, 4.5 Hz, 0.54H, Major), 3.59 (dd, J = 18.0, 9.4 Hz, 0.53H, Major), 3.39 (dd, J = 17.4, 12.4 Hz, 0.46H, Minor), 3.26 (s, 1.69 H, Major), 2.91(s, 1.40H, Minor) 3.04 – 2.99 (m, 0.57H, Major), 2.98 – 2.96 (m, 0.45H, Minor); 13C NMR (75 MHz, CDCl3) δ 176.2, 175.1, 174.2, 172.5, 159.4, 159.3, 144.2, 143.2, 136.7, 133.1, 133.0, 132.7, 130.0, 129.8, 129.7, 129.5, 129.4, 128.2, 127.5, 127.4, 126.8, 125.8, 125.6, 123.84, 123.78, 123.6, 123.0, 122.0, 108.5, 108.5, 69.7, 68.4, 45.7, 43.3, 36.9, 36.8, 26.7, 26.1; HRMS (ESI-FT): Exact mass calcd for C19H16BrN2O3 [M+H]+: 399.0339, Found 399.0338. (3S,3'S)-3'-(2-methoxyphenyl)-1-methyl-2,5'-dioxospiro[indoline3,2'-pyrrolidine]-1'-carbaldehyde (4g). White solid; Mp 139-141 oC; 26% yield, [α]D20 = +0.3 (c = 0.85, CH2Cl2); dr = 45/55. The ee was determined by chiral HPLC (Chiralcel AD-H column, i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, 93% ee: tmajor = 23.7 min, tminor = 25.2 min); 1 H NMR (300 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.15 – 7.00 (m, 3H), 6.82 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 8.1 Hz, 2H), 6.62 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 7.3 Hz, 1H), 4.28 (dd, J = 9.0, 7.4 Hz, 1H), 3.48 (s, 3H), 3.30 – 3.16 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 176.3, 174.6, 159.2, 157.4, 143.8, 129.4, 129.1, 127.9, 124.8, 124.7, 123.7, 121.8, 120.3, 110.3, 107.9, 68.5, 54.8, 40.1, 35.4, 26.6; HRMS (ESI-FT): Exact mass calcd for C20H19N2O4 [M+H]+: 351.1339, Found 351.1336. 3'-(2-methoxyphenyl)-1-methyl-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4g'). White solid; Mp 191-192 oC; 25% yield, [α]D20 = +61.6 (c = 1.00, CH2Cl2); dr = 45/55. The ee was determined by chiral HPLC (Chiralcel AD-H column, i-PrOH/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, 87% ee: tmajor = 28.0 min, tminor = 34.5 min); 1H NMR (300 MHz, Chloroform-d) δ 9.11 (s, 1H), 7.37 – 7.31 (m, 2H), 7.25 – 7.22 (m, 1H), 7.16 – 7.10 (m, 2H), 6.89 (m, 1H), 6.64 – 6.58 (m, 2H), 4.56 (dd, J = 13.3, 8.1 Hz, 1H), 3.53 (dd, J = 17.2, 13.3 Hz, 1H), 3.21 (s, 3H), 2.85 – 2.76 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.0, 172.7, 159.4, 157.6 143.2, 129.3, 129.1, 128.1, 127.1, 122.8, 122.6, 120.9, 120.3, 110.1, 108.1, 69.6, 54.8, 40.3, 35.2, 25.9. (3S,3'S)-1-methyl-3'-(2-nitrophenyl)-2,5'-dioxospiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4h). Pale yellow solid; Mp 152-154 oC; 77% yield, [α]D20 = +1.4 (c = 0.60, CH2Cl2); dr = 38/62. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, major diastereomer 95% ee: tmajor = 42.8 min, tminor = 19.4 min; minor diastereomer 93% ee: tmajor = 34.1 min, tminor = 25.6 min); 1H NMR (300 MHz, Chloroform-d) δ (major diastereomer + minor diastereomer): 9.08 (s, 0.47 H, Minor), 9.04 (s, 0.52H, Major), 7.76 – 7.67 (m, 2H, Major + Minor), 7.51 – 7.38 (m, 2H, Major + Minor), 7.34 – 7.13 (m, 2H, Major + Minor), 6.79 – 5.96 (m, 2H, Major + Minor), 4.85 (dd, J = 11.9, 8.1 Hz, 0.51H), 4.72 (dd, J = 9.6, 3.2 Hz,

5



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

0.51H), 3.69 (dd, J = 18.1, 9.6 Hz, 0.64H, Major), 3.53 (dd, J = 17.2, 11.9 Hz, 0.51H, Minor), 3.29 (s, 1.61H, Major), 2.84 (s, 1.45H, Minor), 3.15 – 2.95 (m, 1H, Major + Minor); 13C NMR (75 MHz, CDCl3) δ 176.0, 174.6, 174.1, 172.1, 159.3, 159.1, 150.6, 149.2, 144.4, 143.0, 133.2, 133.1, 132.3, 130.5, 123.0, 129.4, 129.2, 129.1, 128.3, 126.9, 125.2, 124.7, 124.5, 123.9, 123.6, 123.2, 122.7, 121.9, 108.8, 108.8, 69.5, 68.4, 41.1, 39.0, 36.6, 35.4, 26.8, 26.1; HRMS (ESI-FT): Exact mass calcd for C19H16N3O5 [M+H]+: 366.1085, Found 366.1082. (3S,3'S)-1-ethyl-2,5'-dioxo-3'-phenylspiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4i). White solid; Mp 150-152 oC; 46% yield, [α]D20 = -13.0 (c = 1.02, CH2Cl2); dr = 27/73. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 95% ee: tmajor = 22.9 min, tminor = 17.6 min); 1H NMR (300 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.14 – 7.08 (m, 4H), 7.00 - 6.89 (m, 4H), 6.63 (d, J = 7.8, Hz, 1H), 4.12 (dd, J = 12.8, 8.0 Hz, 1H), 3.80-3.70 (m, 2H), 3.38 (dd, J = 17.5, 12.8 Hz, 1H), 3.07 (dd, J = 17.5, 8.0 Hz, 1H), 1.25 – 1.17 (q, 3H); 13C NMR (75 MHz, CDCl3) δ 174.6, 172.9, 158.3, 142.4, 133.0, 129.9, 128.1, 128.1, 127.8, 124.7, 123.5, 122.2, 108.7, 68.8, 47.6, 35.3, 35.2, 12.1; HRMS (ESI-FT): Exact mass calcd for C20H18N2NaO3 [M+Na]+: 357.1210, Found 357.1202. 1-ethyl-2,5'-dioxo-3'-phenylspiro[indoline-3,2'-pyrrolidine]-1'carbaldehyde (4i'). White solid; Mp 110-112 oC; 17% yield, [α]D20 = -7.6 (c = 1.05, CH2Cl2); dr = 27/73. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 92% ee: tmajor = 24.3 min, tminor = 16.5 min); 1H NMR (300 MHz, Chloroform-d) δ 9.11 (s, 1H), 7.36 – 7.33 (m, 2H), 7.21 – 7.14 (m, 4H), 6.84 (d, J = 7.1 Hz, 2H), 6.69 – 6.66 (m, 1H), 3.84 (dd, J = 13.7, 7.3 Hz, 1H), 3.75 – 3.51 (m, 2H), 3.17 (m, 1H), 2.84 (dd, J = 16.6, 7.3 Hz, 1H), 0.55 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.7, 171.7, 159.3, 142.7, 131.7, 129.9, 128.4, 128.3, 127.9, 126.6, 123.0, 122.2, 108.7, 69.4, 49.3, 34.5, 34.4, 11.6. (3S,3'S)-2,5'-dioxo-1,3'-diphenylspiro[indoline-3,2'-pyrrolidine]-1'carbaldehyde (4j). White solid; Mp 129-131 oC; 81% yield, [α]D20 = -20.9 (c = 1.30, CH2Cl2); dr = 20/80. The ee was determined by chiral HPLC (Chiralcel AD-H column, i-PrOH/hexane = 50/50, flow rate 0.6 mL/min, λ = 254 nm, major diastereomer 94% ee: tmajor = 12.9 min, tminor = 41.7 min; minor diastereomer 92% ee: tmajor = 15.6 min, tminor = 10.6 min); 1H NMR (300 MHz, Chloroform-d) δ (major diastereomer + minor diastereomer) 9.18 (s, 0.25H, Minor), 9.12 (s, 0.75H, Major), 7.52 – 7.28 (m, 5H, Major + Minor), 7.26 – 7.15 (m, 3H, Major + Minor), 7.09 – 6.68 (m, 5H, Major + Minor), 6.51 – 6.49 (m, 1H, Major + Minor), 4.24 (dd, J = 13.1, 7.9 Hz, 0.80H, Major), 3.93 (dd, J = 13.8, 7.5 Hz, 0.25H, Minor), 3.70 (dd, J = 16.9, 13.7 Hz, 0.27H, Minor), 3.47 (dd, J = 17.4, 13.1 Hz, 0.75H, Major), 3.10 (dd, J = 17.4, 8.0 Hz, 0.75H, Major), 2.89 (dd, J = 16.9, 7.6 Hz, 0.24H, Minor); 13C NMR (75 MHz, CDCl3) δ 175.6, 174.4, 172.8, 159.5, 158.4, 143.6, 132.9, 129.9, 129.9, 129.7, 129.5, 128.6, 128.4, 128.3, 128.0, 127.8, 126.7, 126.5, 124.2, 123.7, 123.4, 122.9, 122.3, 109.8, 69.1, 49.7, 48.1, 35.1, 34.3; HRMS (ESI-FT): Exact mass calcd for C24H19N2O3 [M+H]+: 383.1390, Found 383.1391. (3S,3'S)-1-benzyl-2,5'-dioxo-3'-phenylspiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (4k). White solid; Mp 158-160 oC; 40% yield, [α]D20 = -18.4 (c = 1.43, CH2Cl2); dr = 28/72. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm,96% ee: tmajor = 15.5 min, tminor = 17.4 min); 1H NMR (300 MHz, Chloroform-d) δ 9.09 (s, 1H), 7.28 – 7.26 (m, 3H), 7.18 – 7.04 (m, 7H), 6.97 – 6.95 (m, 2H), 6.94 – 6.90 (m, 1H), 6.45 (d, J = 7.7 Hz, 1H), 4.91 (d, J = 1.8 Hz, 2H), 4.17 (dd, J = 12.8, 8.0 Hz, 1H), 3.40 (dd, J = 17.5, 12.8 Hz, 1H), 3.10 (dd, J = 17.5, 8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 173.4, 158.4, 142.6, 134.9, 132.9, 129.9, 128.7, 128.3, 128.1, 128.0, 127.6, 127.1, 124.5, 123.4, 122.5, 109.8, 68.9, 48.0, 44.3, 35.7; HRMS (ESI-FT): Exact mass calcd for C25H20N2NaO3 [M+Na]+: 419.1366, Found 419.1352. 1-benzyl-2,5'-dioxo-3'-phenylspiro[indoline-3,2'-pyrrolidine]-1'carbaldehyde (4k'). White solid; Mp 155-157 oC; 19% yield, [α]D20 = 94.6 (c = 0.72, CH2Cl2); dr = 28/72. The ee was determined by chiral HPLC (Chiralcel IC column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 93% ee: tmajor = 16.1 min, tminor = 18.9 min); 1H NMR (300 MHz, Chloroform-d) δ 9.14 (s, 1H), 7.38 – 7.31 (m, 2H), 7.23 – 7.10 (m, 7H), 6.95 (d, J = 7.3, 2H), 6.49 (d, J = 6.6 Hz, 2H), 6.43 (d, J = 6.0 Hz, 1H), 4.85 (d, J = 16.1 Hz, 1H), 4.37 (d, J = 16.1 Hz, 1H), 3.94 (dd, J = 13.9, 7.5 Hz, 1H), 3.74 (dd, J = 16.8, 13.8 Hz, 1H), 2.90 (dd, J = 16.8, 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 175.5, 172.6, 159.5, 143.1, 134.5,

Page 6 of 9

132.0, 130.0, 128.7, 128.6, 128.5, 128.3, 127.2, 126.4, 126.3, 123.3, 122.1, 110.0, 69.5, 49.0, 43.8, 34.8. (3S,3'S)-1-methyl-2,5'-dioxo-3'-phenylspiro[indoline-3,2'pyrrolidine]-1'-carbaldehyde (6a). White solid; Mp 221-223 oC; 70% yield, [α]D20 = -0.5 (c = 0.50, CH2Cl2); dr = 25/75. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, major diastereomer 88% ee: tmajor = 35.2 min, tminor = 16.2 min; minor diastereomer 80% ee: tmajor = 24.5 min, tminor = 42.7 min); 1 H NMR (300 MHz, Chloroform-d) δ(major diastereomer + minor diastereomer) 7.92 (d, J = 8.4 Hz, 1.43H, Major), 7.85 (d, J = 8.4 Hz, 0.57 H, Minor), 7.32 – 711 (m, 5H, Major + Minor), 7.09 – 6.57 (m, 3H, Major + Minor), 6.97 – 6.86 (m, 1.52H, Major), 6.78 – 6.75 (m, 0.60 H, Minor), 6.64 (d, J = 7.8 Hz, 0.29H, Minor), 6.58 (d, J = 7.6 Hz, 0.74H, Major), 4.07 (dd, J = 13.4, 7.8 Hz, 0.79H, Major), 3.77 (dd, J = 13.9, 7.5 Hz, 0.29H, Minor), 3.51 (dd, J = 16.2, 13.9 Hz, 0.29H, Minor), 3.27 (dd, J = 17.1, 13.3 Hz, 0.78H, Major), 3.18 (s, 2.21 H, Major), 2.77 (s, 0.81H, Minor), 2.82 (dd, J = 17.0 Hz, 7.9 Hz, 0.79 H, Major), 2.63 (dd, J = 16.2, 7.4 Hz, 0.31H, Minor), 2.44 (s, 3H, Major + Minor); 13C NMR (75 MHz, CDCl3) δ 174.0, 173.0, 172.7, 172.0, 145.4, 145.3, 142.6, 135.0, 132.6, 131.7, 130.1, 129.4, 129.24, 129.17, 128.4, 128.1, 128.0, 127.9, 127.8, 125.5, 123.8, 123.2, 122.7, 122.5, 108.6, 108.5, 73.6, 73.1, 50.5, 48.8, 34.9, 34.2, 26.6, 25.9, 21.7; HRMS (ESI-FT): Exact mass calcd for C25H22N2NaO4S [M+Na]+: 469.1193, Found 469.1176. (3S,3'S)-3'-(4-fluorophenyl)-1-methyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6b). White solid; Mp 219-220 oC; 50% yield, [α]D20 = -22.3 (c = 1.73, CH2Cl2); dr = 24/76. The ee was determined by chiral HPLC (Chiralcel AS-H column, EtOH/hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm, 91% ee: tmajor = 10.5 min, tminor = 16.0 min); 1H NMR (300 MHz, Chloroform-d) δ 7.91 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.22 – 7.16 (m, 2H), 7.02 – 6.99 (m, 1H), 6.85 – 6.82 (m, 2H), 6.77 – 6.71 (m, 2H), 6.62 (d, J = 7.8 Hz, 1H), 4.04 (dd, J = 13.4, 7.8 Hz, 1H), 3.25 – 3.15 (m, 4H), 2.81 (dd, J = 17.0, 7.8 Hz, 1H), 2.43 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 173.9, 171.7, 162.2 (d, JC, F = 246.3 Hz), 145.4, 142.6, 134.9, 130.3, 129.5, 129.3 (d, JC, F = 7.5 Hz), 129.4, 129.3, 128.4 (d, JC, F = 3.3 Hz), 125.3, 123.7, 122.6, 115.0 (d, JC, F = 21.5 Hz), 108.8, 73.0, 48.2, 35.2 26.6, 21.7; HRMS (ESI-FT): Exact mass calcd for C25H21FN2NaO4S [M+Na]+: 487.1098, Found 487.1079. 3'-(4-fluorophenyl)-1-methyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6b'). White solid; Mp 155-156 oC; 16% yield, [α]D20 = +22.9 (c = 0.67, CH2Cl2); dr = 24/76. The ee was determined by chiral HPLC (Chiralcel AS-H column, EtOH/hexane = 20/80, flow rate 1.0 mL/min, λ = 254 nm, 84% ee: tmajor = 12.3 min, tminor = 9.7 min); 1H NMR (300 MHz, Chloroform-d) δ 7.84 (d, J = 8.4, 2H), 7.41 – 7.30 (m, 4H), 7.23 – 7.21 (m, 1H), 6.84 – 6.74 (m, 4H), 6.68 (d, J = 7.7 Hz, 1H), 3.75 (dd, J = 13.9, 7.5 Hz, 1H), 3.45 (dd, J = 16.3, 13.9 Hz, 1H), 2.83 (s, 3H), 2.66 (dd, J = 16.3, 7.6 Hz, 1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.9, 172.4, 162.6 (d, JC,F = 246.2 Hz), 145.4, 143.4, 134.9, 130.2, 129.6 (d, JC,F = 8.2 Hz), 129.4, 129.3, 129.2, 127.5 (d, JC.F = 3.2 Hz), 127.4, 123.3, 122.7, 115.1 (d, JC,F = 21.4 Hz), 108.6, 73.4, 49.7, 34.5, 26.0, 21.7. (3S,3'S)-3'-(4-chlorophenyl)-1-methyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6c). White solid; Mp 214-216 oC; 40% yield, [α]D20 = -35.3 (c = 0.80, CH2Cl2); dr = 27/73. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm,88% ee: tmajor = 37.4 min, tminor = 15.5 min); 1H NMR (300 MHz, Chloroform-d) δ 7.90 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.26 – 7.23 (m, 1H), 7.18 – 7.16 (m, 1H), 7.05 – 7.00 (m, 3H), 6.81 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 7.8 Hz, 1H), 4.04 (dd, J = 13.4, 7.8 Hz, 1H), 3.25 – 3.15 (m, 4H), 2.85 – 2.76 (m, 1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.8, 171.5, 145.5, 142.7, 134.9, 134.0, 131.2, 130.4, 129.4, 129.3, 129.2, 128.2, 125.2, 123.7, 122.6, 109.0, 72.9, 48.3, 35.1, 26.7, 21.7; HRMS (ESI-FT): Exact mass calcd for C25H21ClN2NaO4S [M+Na]+: 503.0803, Found 503.0781. 3'-(4-chlorophenyl)-1-methyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6c'). White solid; Mp 149-150 oC; 18% yield, [α]D20 = -0.4 (c = 1.00, CH2Cl2); dr = 27/73. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 85% ee: tmajor = 23.6 min, tminor = 44.2 min); 1H NMR (300 MHz, Chloroform-d) δ 7.83 (d, J = 8.3 Hz, 2H), 7.41 – 7.30 (m, 4H), 7.23 – 7.18 (m, 1H), 7.11 – 7.08 (m, 2H), 6.72 – 6.68 (m, 3H), 3.74 (dd, J = 13.8, 7.5 Hz, 1H), 3.45 (dd, J = 16.3, 13.8 Hz, 1H), 2.84 (s, 3H), 2.62 (dd, J = 16.2, 7.5 Hz, 1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ

6


Page 7 of 9

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


172.8, 172.3, 145.4, 143.3, 134.8, 134.3, 130.32, 130.29, 129.3, 129.23, 129.20, 128.3, 127.3, 123.3, 122.7, 108.7, 73.2, 49.7, 34.3, 26.0, 21.7. (3S,3'S)-3'-(4-bromophenyl)-1-methyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6d). White solid; Mp 202-205 oC; 42% yield, [α]D20 = -14.5 (c = 0.94, CH2Cl2); dr = 44/56. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 81% ee: tmajor = 23.5 min, tminor = 44.3 min); 1H NMR (300 MHz, Chloroform-d) δ 7.90 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.24 – 7.16 (m, 4H), 7.02 (t, J = 0.8 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 7.8 Hz, 1H), 4.02 (dd, J = 13.4, 7.8 Hz, 1H), 3.25 – 3.14 (m, 4H), 2.80 (dd, J = 17.0, 7.8 Hz, 1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.8, 171.5, 145.5, 142.7, 134.9, 131.7, 131.2, 130.4, 129.5, 129.4, 129.3, 125.1, 123.7, 122.6, 122.2, 109.0, 72.8, 48.3, 35.0, 26.7, 21.7; HRMS (ESI-FT): Exact mass calcd for C25H21BrN2NaO4S [M+Na]+: 547.0298, Found 547.0271. 3'-(4-bromophenyl)-1-methyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6d'). White solid; Mp 156-158 oC; 29% yield, [α]D20 = -4.9 (c = 0.89, CH2Cl2); dr = 44/56. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 87% ee: tmajor = 38.7 min, tminor = 15.8 min); 1H NMR (300 MHz, Chloroform-d) δ 7.83 (d, J = 8.4 Hz, 2H), 7.41 – 7.30 (m, 4H), 7.26 – 7.18 (m, 3H), 6.71 – 6.63 (m, 3H), 6.65 (d, J = 7.9 Hz, 1H), 3.73 (dd, J = 13.8, 7.4 Hz, 1H), 3.44 (dd, J = 16.2, 13.9 Hz, 1H), 2.85 (s, 3H), 2.62 (dd, J = 16.2, 7.5 Hz, 1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.8, 172.3, 145.4, 143.4, 134.9, 131.3, 130.9, 130.3, 129.6, 129.3, 129.2, 127.3, 123.4, 122.7, 122.6, 108.8, 73.2, 49.8, 34.3, 26.0, 21.7. (3S,3'S)-1-methyl-3'-(p-tolyl)-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6e). White solid; Mp 204-205 oC; 64% yield, [α]D20 = -24.5 (c = 1.20, CH2Cl2); dr = 22/78. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, major diastereomer 85% ee: tmajor = 41.5 min, tminor = 16.3 min; minor diastereomer 75% ee: tmajor = 27.2 min, tminor = 56.9 min); 1 H NMR (300 MHz, Chloroform-d) δ (major diastereomer + minor diastereomer) 7.91 (d, J = 8.3 Hz, 1.52H, Major), 7.85 (d, J = 8.3 Hz, 0.47H, Minor), 7.32 – 7.16 (m, 4H, Major + Minor), 7.00 – 6.59 (m, 6H), 4.04 (dd, J = 13.4, 7.8 Hz, 0.79H, Major), 3.74 (dd, J = 13.9, 7.5 Hz, 0.24H, Minor), 3.48 (dd, J = 16.2, 13.9 Hz, 0.25H, Minor), 3.23 (dd, J = 17.0, 13.4 Hz, 0.81H, Major), 3.18 (s, 2.40H, Major), 2.80 (s, 0.75H, Minor), 2.79 (dd, J = 17.0, 7.7 Hz, 0.74H, Major), 2.60 (dd, J = 16.3, 7.5 Hz, 0.28H, Minor), 2.43(s, 3H, Major + Minor), 2.23 (s, 0.74H, Minor), 2.16(s, 2.3H, Major); 13C NMR (75 MHz, CDCl3) δ 174.1, 173.1, 172.8, 172.1, 145.30, 145.26, 142.7, 138.1, 137.8, 135.0, 130.0, 129.5, 129.3, 129.2, 129.2, 128.7, 128.7, 127.7, 127.7, 125.6, 123.8, 123.1, 122.7, 122.4, 108.7, 108.5, 73.5, 73.1, 50.2, 48.6, 35.2, 34.4, 26.6, 25.9, 21.7, 21.0, 20.9; HRMS (ESI-FT): Exact mass calcd for C26H24N2NaO4S [M+Na]+: 483.1349, Found 483.1330. (3S,3'S)-1-methyl-3'-(4-nitrophenyl)-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6f). White solid; Mp 204-205 oC; 71% yield, [α]D20 = -0.2 (c = 1.03, CH2Cl2); dr = 39/61. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, major diastereomer 85% ee: tmajor = 30.3 min, tminor = 52.7 min; minor diastereomer 89% ee: tmajor = 49.3 min, tminor = 22.4 min);1H NMR (300 MHz, Chloroform-d) δ (major diastereomer + minor diastereomer) 7.94 – 7.88 (m, 4H, Major + Minor), 7.33 – 7.19 (m, 4H, Major + Minor), 7.09 – 6.98 (m, 3H, Major + Minor), 6.70 (d, J = 7.7 Hz, 0.24H, Minor), 6.64 (d, J = 7.7 Hz, 0.76H, Major), 4.17 (dd, J = 13.2, 7.7 Hz, 0.79H, Major), 3.88 (dd, J = 13.6, 7.6 Hz, 0.23H, Minor), 3.51 (dd, J = 16.3, 13.7 Hz, 0.23H), 3.28 (dd, J = 17.0, 13.3 Hz, 0.75H), 3.21 (s, 2.32H, Major), 2.83 (s, 0.65H, Minor), 2.87 (dd, J = 17.0, 7.9 Hz, 0.79H, Major), 2.70 (dd, J = 16.3, 7.6 Hz, 0.25H, Minor), 2.44 (s, 3H, Major + Minor); 13C NMR (75 MHz, CDCl3) δ 173.6, 172.6, 171.7, 170.9, 147.5, 145.7, 142.6, 140.2, 139.5, 134.7, 130.8, 130.7, 129.4, 129.33, 129.26, 129.1, 128.8, 124.7, 123.7, 123.6, 123.2, 123.1, 122.9, 122.8, 109.1, 108.9, 73.0, 72.6, 49.8, 48.3, 34.8, 34.2, 26.8, 26.1, 21.7; HRMS (ESI-FT): Exact mass calcd for C25H21N3NaO6S [M+Na]+: 514.1043, Found 514.1023. (3S,3'S)-1-ethyl-3'-(4-fluorophenyl)-5-methyl-1'-tosylspiro[indoline3,2'-pyrrolidine]-2,5'-dione (6g). White solid; Mp 209-210 oC; 61% yield, [α]D20 = -55.9 (c = 1.02, CH2Cl2); dr = 28/72. The ee was determined by chiral HPLC (Chiralcel AD-H column, i-PrOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, major diastereomer 90% ee: tmajor = 10.6 min, tminor = 50.1 min; minor diastereomer 83% ee: tmajor = 36.7 min, tminor = 11.9 min); 1H NMR (300 MHz, Chloroform-d) δ (major diastereomer + minor diastereomer) 7.92 (d, J = 8.4 Hz, 1.47H, Major), 7.84 (d, J = 8.4 Hz,

0.53H, Minor), 7.32 – 7.19 (m, 4H, Major + Minor), 6.99 – 6.62 (m, 6H, Major + Minor), 4.03 (dd, J = 13.5, 7.8 Hz, 0.75H, Major), 3.46 (dd, J = 16.3, 13.9 Hz, 0.26H, Minor), 3.77 – 3.57 (m, 2H, Major + Minor), 3.26 – 3.15 (m, 1H, Major + Minor), 2.80 (dd, J = 17.0, 7.8 Hz, 0.73H, Major), 2.62 (dd, J = 16.3, 7.5 Hz, 0.27H, Minor), 2.43 (s, 3H, Major + Minor), 1.18 (t, J = 7.2 Hz, 2.33H, Major), 0.70 (t, J = 7.2 Hz, 0.78H, Minor); 13C NMR (75 MHz, CDCl3) δ 173.5, 172.5, 172.4, 171.7, 162.7 (d, JC, F = 246.3 Hz, Minor), 162.3 (d, JC, F = 246.1 Hz, Major), 145.4, 142.6, 141.8, 135.0, 130.24, 130.20, 129.74 (d, JC, F = 8.1 Hz, Minor), 129.68 (d, JC, F = 8.2 Hz, Major), 129.4, 129.3, 129.2, 128.3 (d, JC, F = 3.2 Hz, Major), 127.6 (d, JC, F = 8.9 Hz, Minor), 125.6, 124.0, 123.1, 123.0, 122.4, 115.1 (d, JC, F = 21.4 Hz, Minor), 114.9 (d, JC, F = 21.4 Hz, Major), 108.9, 108.7, 73.1, 72.9, 49.5, 48.2, 35.3, 35.2, 34.5, 34.4, 21.7, 12.1, 11.7; HRMS (ESI-FT): Exact mass calcd for C26H24FN2O4S [M+H]+: 479.1435, Found 479.1429. (3S,3'S)-1-benzyl-3'-(4-fluorophenyl)-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6h). White solid; Mp 184-185 oC; 67% yield, [α]D20 = -55.9 (c = 1.02, CH2Cl2); dr = 24/76. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, major diastereomer 90% ee: tmajor = 24.1 min, tminor = 13.7 min; minor diastereomer 84% ee: tmajor = 21.5 min, tminor = 33.8 min); 1 H NMR (300 MHz, Chloroform-d) δ (major diastereomer + minor diastereomer) 7.94 (d, J = 8.4 Hz, 1.6H, Major), 7.81 (d, J = 8.4 Hz, 0.4H, Minor), 7.42 – 7.26 (m, 6H, Major + Minor), 7.15 – 7.12 (m, 3H, Major + Minor), 7.02 – 6.81 (m, 3H, Major + Minor), 6.72 – 6.69 (m, 2H, Major + Minor), 6.52 – 6.48 (m, 1H, Major + Minor), 4.98 – 4.45 (m, 2H, Major + Minor), 4.08 (dd, J = 13.6 Hz, 7.9 Hz, 0.85H, Major), 3.86 (dd, J = 13.9, 7.5 Hz, 0.19H, Minor), 3.21 (dd, J = 17.0, 13.6 Hz, 0.79H, Major), 3.52 (dd, J = 16.3, 13.9 Hz, 0.18H, Minor), 2.82 (dd, J = 17.0, 7.8 Hz, 0.79H, Major), 2.66 (dd, J = 16.3, 7.5 Hz, 0.20H, Minor), 2.44 (s, 3H, Major + Minor); 13C NMR (75 MHz, CDCl3) δ 174.0, 173.2, 172.3, 171.6, 162.8 (d, JC, F = 246 Hz, Minor), 162.3(d, JC, F = 246 Hz, Major), 145.44, 145.39, 143.1, 142.0, 135.0, 134.94, 134.87, 134.7, 130.3, 130.0 (d, JC, F = 8.3 Hz, Minor), 129.9 (d, JC, F = 8.3 Hz, Major), 129.4, 129.29, 129.25, 129.2, 128.7, 128.6, 128.2 (d, JC, F = 3.8 Hz, Major), 127.7 (d, JC,F = 3.7 Hz, Minor), 127.6, 127.4, 127.2, 126.5, 123.9, 123.3, 122.9, 122.6, 115.5 (d, JC, F = 21.8 Hz, Minor) , 115.1 (d, JC, F = 21.0 Hz, Major), 110.0, 109.9, 73.1, 73.0, 49.4, 48.6, 44.4, 44.0, 35.6, 34.7, 21.7; HRMS (ESI-FT): Exact mass calcd for C31H26FN2O4S [M+H]+: 541.1597, Found 541.1570. (3S,3'S)-5-bromo-3'-(4-fluorophenyl)-1-methyl-1'tosylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione (6i). White solid; Mp 189-190 oC; 35% yield, [α]D20 = -8.2 (c = 0.55, CH2Cl2); dr = 47/53. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 86% ee: tmajor = 19.5 min, tminor = 40.9 min); 1H NMR (300 MHz, Chloroform-d) δ 7.84 (d, J = 8.4 Hz, 2H), 7.36 – 7.31 (m, 3H), 7.15 (d, J = 1.8, 1H), 6.88 – 6.53 (m, 4H), 6.52 (d, J = 8.3 Hz, 1H), 4.05 (dd, J = 13.1, 7.8 Hz, 1H), 3.21 – 3.10 (m, 4H), 2.85 (dd, J = 17.1, 8.0 Hz, 1H) , 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.4, 171.3, 162.4 (d, JC, F = 246.7 Hz), 145.7, 141.8, 134.6, 133.1, 129.5, 129.4 (d, JC, F = 8.1 Hz), 129.4, 129.3, 128.0 (d, JC, F = 3.3 Hz), 127.2, 126.9, 115.3 (d, JC, F = 21.5 Hz), 115.1, 110.3, 72.6, 48.1, 35.0, 26.8, 21.8; HRMS (ESI-FT): Exact mass calcd for C25H21BrFN2O4S [M+H]+: 543.0384, Found 543.0373. 5-bromo-3'-(4-fluorophenyl)-1-methyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6i'). White solid; Mp 226-227 oC; 31% yield, [α]D20 = +4.3 (c = 1.12, CH2Cl2); dr = 47/53. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 82% ee: tmajor = 36.7 min, tminor = 13.9 min); 1H NMR (300 MHz, Chloroform-d) δ 7.79 (d, J = 8.4 Hz, 2H), 7.51 – 7.48 (m, 1H), 7.38 – 7.33 (m, 3H), 6.87 – 6.77 (m, 4H), 6.56 (d, J = 8.3 Hz, 1H), 3.70 (dd, J = 13.8, 7.4 Hz, 1H), 3.46 (dd, J = 16.2, 13.9 Hz, 1H), 2.81 (s, 3H), 2.64 (dd, J = 16.2, 7.4 Hz, 1H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ172.5, 172.0, 162.7 (d, JC,F = 247 Hz), 145.6, 142.6, 134.9, 133.1, 129.6 (d, JC,F = 8.2 Hz), 129.4, 129.1, 129.0, 127.1 (d, JC,F = 3.2 Hz), 126.0, 115.5 (d, JC,F = 3.2 Hz), 115.1, 110.1, 72.9, 49.6, 34.5, 26.1, 21.8. (3S,3'S)-3'-(4-fluorophenyl)-1,5-dimethyl-1'-tosylspiro[indoline3,2'-pyrrolidine]-2,5'-dione (6j). White solid; Mp 195-198 oC; 45% yield, [α]D20 = -19.2 (c = 1.05, CH2Cl2); dr = 24/76. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 89% ee: tmajor = 27.7 min, tminor = 14.9 min); 1H NMR (300 MHz, Chloroform-d) δ 7.89 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.02 – 6.99 (m, 1H), 6.92 (s, 1H), 6.87 – 6.82 (m, 2H), 6.78 – 6.72 (m, 2H), 6.51 (d, J = 8.0 Hz, 1H), 4.04 (dd, J = 13.4, 7.9 Hz, 1H), 3.24 – 3.14 (m, 4H), 2.81 (dd, J = 17.0, 7.9 Hz, 1H), 2.44 (s, 3H), 2.27 (s, 3H);

7


The Journal of Organic Chemistry C NMR (75 MHz, CDCl3) δ 173.8, 171.7, 162.3 (d, JC, F = 246 Hz), 145.4, 140.3, 135.0, 132.1, 130.6, 129.5 (d, JC, F = 8.2 Hz), 129.4, 129.2, 128.5 (d, JC, F = 3.3 Hz), 125.2, 124.5, 115.0 (d, JC, F = 21.4 Hz), 108.6, 73.1, 48.1, 35.2, 26.7, 21.7, 21.1; HRMS (ESI-FT): Exact mass calcd for C26H24FN2O4S [M+H]+: 479.1435, Found 479.1430. 3'-(4-fluorophenyl)-1,5-dimethyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6j'). White solid; Mp 259-261 oC; 14% yield, [α]D20 = -2.6 (c = 0.75, CH2Cl2); dr = 24/76. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 78% ee: tmajor = 25.1 min, tminor = 41.0 min); 1H NMR (300 MHz, Chloroform-d) δ 7.83 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.17 – 7.14 (m, 2H), 6.84 – 6.72 (m, 4H), 6.56 (d, J = 8.5 Hz, 1H), 3.73 (dd, J = 13.9, 7.5 Hz, 1H), 3.44 (dd, J = 16.3, 13.9 Hz, 1H), 2.80 (s, 3H), 2.61 (dd, J = 16.2, 7.5 Hz, 1H), 2.44 (s, 3H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ172.8, 172.4, 162.6 (d, JC,F = 246 Hz), 145.3, 141.0, 135.0, 132.8, 130.5, 129.6 (d, JC,F = 8.2 Hz), 129.2, 129.1, 127.6 (d, JC,F = 3.2Hz), 127.3, 123.5, 115.0 (d, JC,F = 21.3 Hz), 108.4, 73.4, 49.6, 34.5, 26.0, 21.7, 21.2. (3S,3'S)-3'-(4-fluorophenyl)-1,5,7-trimethyl-1'-tosylspiro[indoline3,2'-pyrrolidine]-2,5'-dione (6k). White solid; Mp 220-222 oC; 44% yield, [α]D20 = 16.5 (c = 1.10, CH2Cl2); dr = 31/69. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 93% ee: tmajor = 189.0 min, tminor = 43.8 min); 1H NMR (300 MHz, Chloroform-d) δ 7.96 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.88 – 6.74 (m, 4H), 6.55 (s, 1H), 6.30 (s, 1H), 4.09 (dd, J = 13.1, 9.1 Hz, 1H), 3.20 (s, 3H), 3.15 – 3.09 (m, 1H), 2.88 (dd, J = 17.6 Hz, 9.2 Hz, 1H), 2.43 – 2.41 (m, 3H), 2.23 (d, J = 5.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ175.2, 171.9, 162.1 (d, JC,F = 245.9 Hz), 145.4, 143.2, 140.1, 134.6, 134.1, 129.5, 129.31, 129.27, 129.2, 129.1, 128.8 (d, JC,F = 8.2 Hz), 126.6, 120.9, 115.1 (d, JC,F = 21.4 Hz), 108.4, 73.8, 48.5, 36.8, 26.7, 21.7, 21.6, 19.4; HRMS (ESI-FT): Exact mass calcd for C27H26FN2O4S [M+H]+: 493.1592, Found 493.1583. 3'-(4-fluorophenyl)-1,5,7-trimethyl-1'-tosylspiro[indoline-3,2'pyrrolidine]-2,5'-dione (6k'). White solid; Mp 210-212 oC; 16% yield, [α]D20 = 60.5 (c = 1.04, CH2Cl2); dr = 31/69. The ee was determined by chiral HPLC (Chiralcel IC column, EtOH/hexane = 50/50, flow rate 0.7 mL/min, λ = 254 nm, 81% ee: tmajor = 54.8 min, tminor = 137.2 min); 1H NMR (300 MHz, Chloroform-d) δ 7.89 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.86 – 6.74 (m, 5H), 6.32 (s, 1H), 3.97 (dd, J = 13.9, 7.7 Hz, 1H), 3.43 (dd, J = 16.4, 13.8 Hz, 1H), 2.77 (s, 3H), 2.65 (dd, J = 16.4, 7.9 Hz, 1H) , 2.44 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.0, 172.2, 162.6 (d, JC, F = 246.2 Hz), 145.4, 143.6, 134.6, 140.3, 134.7, 129.7 (d, JC, F = 8.1 Hz), 129.6, 129.1, 128.0 (d, JC, F = 3.2 Hz), 126.6, 121.3, 115.0 (d, JC, F = 21.3 Hz), 107.3, 73.9, 45.3, 34.1, 25.8, 21.8, 21.7, 17.5. 13

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

ASSOCIATED CONTENT Supporting Information Copies of NMR spectra and HPLC analysis spectra of all compounds, X-ray structural data (CIF) for compound 4a. This material is available free of charge via the Internet at http:// pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Notes The authors declare no competing financial interest.

REFERENCES 1. (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748; (b) Arulananda Babu, S.; Padmavathi, R.; Ahmad Aslam, N.; Rajkumar, V. Stud. Nat. Prod. Chem. 2015, 46, 227; (c) Yu, B.; Yu, D. Q.; Liu, H. M. Eur. J. Med. Chem. 2015, 97, 673; (d) Santos, M. M. M.

Page 8 of 9

Tetrahedron 2014, 70, 9735; (e) Kumar, A.; Gupta, G.; Bishnoi, A. K.; Saxena, R.; Saini, K. S.; Konwar, R.; Kumar, S.; Dwivedi, A. Bioorg. Med. Chem. 2015, 23, 839; (f) Bergonzini, G.; Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 971; (g) Silvi, M.; Chatterjee, I.; Liu, Y.; Melchiorre, P. Angew. Chem. Int. Ed. 2013, 52, 10780; (h) Jayakumar, S.; Muthusamy, S.; Prakash, M.; Kesavan, V. Eur. J. Org. Chem. 2014, 2014, 1893; (i) McInturff, E. L.; Mowat, J.; Waldeck, A. R.; Krische, M. J. J. Amer. Chem. Soc. 2013, 135, 17230; (j) Zhu, X.-Q.; Wu, J.-S.; Xie, J.-W. Tetrahedron 2016, 72, 8327; (k) Zhao, B.-L.; Du, D.-M. Adv. Synth. Catal. 2016, 358, 3992. 2. (a) Ali, M. A.; Ismail, R.; Choon, T. S.; Yoon, Y. K.; Wei, A. C.; Pandian, S.; Kumar, R. S.; Osman, H.; Manogaran, E. Bioorg. Med. Chem. Lett. 2010, 20, 7064; (b) Thangamani, A. Eur. J. Med. Chem. 2010, 45, 6120; (c) Puerto Galvis, C. E.; Kouznetsov, V. V. Org. Biomol. Chem. 2013, 11, 7372; (d) Girgis, A. S. Eur. J. Med. Chem. 2009, 44, 91; (e) Maheswari, S. U.; Balamurugan, K.; Perumal, S.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2010, 20, 7278; (f) Kia, Y.; Osman, H.; Kumar, R. S.; Murugaiyah, V.; Basiri, A.; Perumal, S.; Wahab, H. A.; Bing, C. S. Bioorg. Med. Chem. 2013, 21, 1696; (g) Arun, Y.; Bhaskar, G.; Balachandran, C.; Ignacimuthu, S.; Perumal, P. T. Bioorg. Med. Chem. Lett. 2013, 23, 1839. 3. (a) MacDonald, J. P.; Shupe, B. H.; Schreiber, J. D.; Franz, A. K. Chem. Commun. 2014, 50, 5242; (b) Muthusamy, S.; Kumar, S. G. Org. Biomol. Chem. 2016, 14, 2228; (c) Wang, D.-C.; Song, H.; Xu, C.-Y.; Dong, H.; Liu, J. Chin. Chem. Lett. 2015, 26, 1050; (d) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104; (e) Tian, L.; Hu, X. Q.; Li, Y. H.; Xu, P. F. Chem. Commun. 2013, 49, 7213; (f) Wu, G.; Ouyang, L.; Liu, J.; Zeng, S.; Huang, W.; Han, B.; Wu, F.; He, G.; Xiang, M. Mol. Divers. 2013, 17, 271; (g) Haddad, S.; Boudriga, S.; Akhaja, T. N.; Raval, J. P.; Porzio, F.; Soldera, A.; Askri, M.; Knorr, M.; Rousselin, Y.; Kubicki, M. M.; Rajani, D. New J. Chem. 2015, 39, 520; (h) Kathirvelan, D.; Haribabu, J.; Reddy, B. S.; Balachandran, C.; Duraipandiyan, V. Bioorg. Med. Chem. Lett. 2015, 25, 389; (i) Zheng, H.; Liu, X.; Xu, C.; Xia, Y.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2015, 54, 10958. (j) Zhao, X.; Liu, X.; Xiong, Q.; Mei, H.; Ma, B.; Lin, L.; Feng, X. Chem. Commun. 2015, 51, 16076. (k) Cao, W.; Liu, X.; Guo, J.; Lin, L.; Feng, X. Chem. Eur. J. 2015, 21, 1632. (l) Wang, G.; Liu, X.; Huang, T.; Kuang, Y.; Lin, L.; Feng, X. Org. Lett. 2013, 15, 76. 4. Zhang, B.; Feng, P.; Sun, L. H.; Cui, Y.; Ye, S.; Jiao, N. Chem. Eur. J. 2012, 18, 9198. 5. (a) Lv, H.; Tiwari, B.; Mo, J.; Xing, C.; Chi, Y. R. Org. Lett. 2012, 14, 5412; (b) Cui, B. D.; Zuo, J.; Zhao, J. Q.; Zhou, M. Q.; Wu, Z. J.; Zhang, X. M.; Yuan, W. C. J. Org. Chem. 2014, 79, 5305; (c) Chen, L.; Wu, Z. J.; Zhang, M. L.; Yue, D. F.; Zhang, X. M.; Xu, X. Y.; Yuan, W. C. J. Org. Chem. 2015, 80, 12668; (d) Jiang, D.; Dong, S.; Tang, W.; Lu, T.; Du, D. J. Org. Chem. 2015, 80, 11593; (e) Chen, K. Q.; Li, Y.; Zhang, C. L.; Sun, D. Q.; Ye, S. Org. Biomol. Chem. 2016, 14, 2007. 6. (a) Talavera, G.; Reyes, E.; Vicario, J. L.; Carrillo, L.; Uria, U. Adv. Synth. Catal. 2013, 355, 653; (b) Claire Bouix, P. B., Jacques Eustache. Tetrahedron Lett. 1998, 39, 825. 7. (a) Chung, J. Y. L.; Wasicak, J. T.; Arnold, W. A.; May, C. S.; Nadzan, A. M.; Holladay, M. W. J. Org. Chem. 1990, 55, 270; (b) Rios, R.; Ibrahem, I.; Vesely, J.; Sundén, H.; Córdova, A. Tetrahedron Lett. 2007, 48, 8695; (c) Wang, P.; Naduthambi, D.; Mosley, R. T.; Niu, C.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Bioorg. Med. Chem. Lett. 2011, 21, 4642; (d) Breistein, P.; Johansson, J.; Ibrahem, I.; Lin, S.; Deiana, L.; Sun, J.; Cordova, A. Adv. Synth. Catal. 2012, 354, 1156; (e) Fatas, P.; Gil, A. M.; Calaza, M. I.; Jimenez, A. I.; Cativiela, C. Chirality 2012, 24, 1082. 8. (a) Zhou, J.; Wang, Q. L.; Peng, L.; Tian, F.; Xu, X. Y.; Wang, L. X. Chem. Commun. 2014, 50, 14601; (b) Zhou, J.; Jia, L.-N.; Wang, Q.-L.; Peng, L.; Tian, F.; Xu, X.-Y.; Wang, L.-X. Tetrahedron 2014, 70, 8665; (c) Wang, L. L.; Peng, L.; Bai, J. F.; Huang, Q. C.; Xu, X. Y.; Wang, L. X. Chem. Commun. 2010, 46, 8064. 9. (a) Wang, L. L.; Bai, J. F.; Peng, L.; Qi, L. W.; Jia, L. N.; Guo, Y. L.; Luo, X. Y.; Xu, X. Y.; Wang, L. X. Chem. Commun. 2012, 48, 5175; (b) Wang, Q. L.; Peng, L.; Wang, F. Y.; Zhang, M. L.; Jia, L. N.; Tian, F.; Xu, X. Y.; Wang, L. X. Chem. Commun. 2013, 49, 9422; (c) Qi, L. W.; Yang, Y.; Gui, Y. Y.; Zhang, Y.; Chen, F.; Tian, F.; Peng, L.; Wang, L. X. Org. Lett. 2014, 16, 6436; (d) Zhou, J.; Jia, L.-N.; Peng, L.; Wang, Q.-L.; Tian, F.; Xu, X.-Y.; Wang, L.-X. Tetrahedron 2014, 70, 3478; (e) Guo, Y.; Zhang, Y.; Qi, L.; Tian, F.; Wang, L. RSC Adv. 2014, 4, 27286. 10. Cui, B. D.; Han, W. Y.; Wu, Z. J.; Zhang, X. M.; Yuan, W. C. J. Org. Chem. 2013, 78, 8833.

8


Page 9 of 9


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

9


Organocatalytic Enantioselective Michael ... - ACS Publications

Recommend Documents