Cu(I)-Catalyzed Asymmetric Mannich Reaction of Glycine Schiff Bases

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Cu(I)-Catalyzed Asymmetric Mannich Reaction of Glycine Schiff Bases to Ketimines Ying Fan, Jian Lu, Feng Sha, Qiong Li, and Xin-Yan Wu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01566 • Publication Date (Web): 26 Aug 2019 Downloaded from pubs.acs.org on August 26, 2019

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The Journal of Organic Chemistry

Cu(I)-Catalyzed Asymmetric Mannich Reaction of Glycine Schiff Bases to Ketimines Ying Fan, Jian Lu, Feng Sha, Qiong Li, Xin-Yan Wu* Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China E-mail: [email protected]

ABSTRACT: A copper-catalyzed asymmetric Mannich reaction between glycine Schiff bases and ketimines has been developed. This method afforded 2-oxindole-based chiral syn-α,β-diamino acid derivatives in high yields (89-99%) with good-to-excellent diastereoselectivities (up to 98:2 dr) and excellent enantioselectivities (95-99% ee). INTRODUCTION The asymmetric Mannich reaction is an important synthetic strategy for the construction of optically active amine compounds as well as for the formation of chiral C-C bonds in organic chemistry.1 Over the past decades, much efforts have been devoted to developing this synthetic transformation. Among the nucleophiles developed, glycine Schiff bases are one of the mostly used due to their commercial availability to afford chiral α,βdiamino acids.2 Recently, progresses have been made towards the enantioselective Mannich reaction between glycine Schiff bases and imines, catalyzed by both chiral metal complexes3 and organocatalysts.4 Nevertheless, the electrophiles used for this reaction are still limited to aldimines. The addition of glycine Schiff bases to ketimines remains a challenging task mainly because of the steric repulsion around the vicinal stereocenters.5 To date, there were only two reports demonstrating the asymmetric Mannich reaction between glycine Schiff bases and ketimines. In 2018, Deng and co-workers described for the first time the enantioselective Mannich reaction of glycine Schiff bases to ketimines, using copper(I)/Ph-Phosferrox complex as the chiral catalyst.3h Zhang and co-workers reported a copper(II)/RuPHOX-catalyzed asymmetric Mannich-type reaction between glycine Schiff bases and cyclic ketimines.3i In both reports, anti-selective adducts have

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been obtained. However, the development of new chiral catalytic systems for the enantioselective Mannich reaction of glycine Schiff bases to ketimines is still in demand. The chiral 3-substituted 3-amino-2-oxindoles are a popular building unit for many pharmaceuticals and bioactive natural products.6 As a result, efforts have been devoted to the asymmetric synthesis of these scaffolds. The addition of different nucleophiles to isatin-derived ketimines appeared to be the most employed, producing 3-substituted 3amino-2-oxindoles efficiently.7 However, the exploration of other nucleophiles for this reaction, resulting in the structural diversification of chiral 3-substituted 3-amino-2oxindoles, is still necessary. With our continuing interest in the asymmetric synthesis of 3-substituted 3-amino-2-oxindoles,8 herein we describe a copper(I)-catalyzed asymmetric Mannich reaction between glycine Schiff bases and isatin-derived ketimines, producing 3,3-disubstituted-2-oxindoles with a syn-α,β-diamino acid motif. RESULTS AND DISCUSSION Initially, Mannich reaction of glycine ester 1a with isatin-derived ketimine 2a was carried out as a model reaction to screen a suitable chiral cyclohexane-based N,P-ligand (Figure 1). The reaction was performed with 5.0 mol% of CuI and 6.0 mol% of chiral ligand, with 10 mol% of Et3N as the base in 2.0 mL of CH2Cl2 at 25 °C. As shown in Table 1, the reaction proceeded smoothly with our catalytic system, affording the syn-adduct in moderate-to-excellent yields. Chiral ligand L1 yielded a racemic product with a good diastereoselectivity (entry 1). With ligands L2-L4, low diastereoselectivities and enantioselectivities were obtained (entries 2-4). To improve the stereoselectivity, amidophosphine ligands with an additional chiral scaffold were probed (entries 5-10). To our delight, excellent enantioselectivities and good diastereoselectivities were obtained by using ligands L6-L10 (entries 6-10). Ligand L7 produced a highest 87:13 dr and 95% ee. Subsequently, ligands L11-L14 with the same amino acid scaffold as ligand L7 were examined (entries 11-14). Among them, ligand L11 gave the best result, providing the Mannich adduct 3aa in 99% yield with 87:13 dr (syn/anti) and 97% ee for syn-product (entry 11). Remarkably, the anti-adducts were achieved in 95% ee as the major product with ligand L15, a diastereomer of ligand L7 (entry 15). Considering the favorable yield and stereoselectivity obtained, ligand L11 was chosen as the optimal ligand for further study.


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Figure 1. Structures of the chiral phosphine ligands screened Table 1. Screening of the chiral ligands for the Mannich reactiona

a

Entry

Ligand

Time (h)

Yield (%)b

Drc

Ee (%)d

1

L1

48

40

17:83

0

2

L2

48

76

60:40

22

3

L3

48

82

38:62

36

4

L4

48

59

50:50

20

5

L5

48

85

56:44

18

6

L6

12

99

82:18

91

7

L7

12

99

87:13

95

8

L8

24

99

86:14

90

9

L9

24

99

85:15

93

10

L10

48

89

74:26

84

11

L11

18

99

87:13

97

12

L12

18

99

86:14

94

13

L13

12

99

84:16

92

14

L14

12

99

84:16

92

15

L15

12

99

24:76

-73 e

The reactions were carried out with Schiff base 1a (0.22 mmol), ketimine 2a (0.2 mmol), 5.0 mol%



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CuI, 6.0 mol% chiral ligand, and 10 mol% Et3N in 2.0 mL of CH2Cl2 at 25 °C. bIsolated yield containing two diastereomers. cDr values refer to syn/anti ratio, determined by chiral HPLC analysis. d

Ee values of syn-adducts, determined by chiral HPLC analysis. eThe ee value for anti-adduct is 95%.

Subsequently, we concentrated on the screening of copper salts with ligand L11, and the results were summarized in Table 2. In general, the cuprous salts produced better reactivities and stereoselectivities than the cupric salts (entries 1-7 vs. entries 9 and 10). The monovalent copper salts such as CuI, CuBr and CuCl gave Mannich adducts 3aa in nearly quantitative yields with 87:13 dr and 97% ee. In particular, CuBr exhibited the best reactivity (entry 2 vs. entries 1 and 3). When using Cu(CH3CN)4BF4 and Cu(CH3CN)4PF6 as a precatalyst, the reaction rate was increased and a similar stereoselectivity was obtained (entries 4 and 5 vs. entry 2). In the presence of CuOAc and CuTC, the yields and stereoselectivities were declined (entries 6 and 7 vs. entry 2). The results mentioned above suggested that the anion of the precatalyst affected the reaction rate. When Cu(OAc)2 was used, a longer reaction time was required (entry 8). The model reaction became sluggish and no product was determined for 3 days when CuBr2 and Cu(OTf)2 were used (entries 9 and 10). According to the results listed in Table 2, CuBr was selected as the precatalyst for subsequent optimization. Table 2. Screening of copper salts for the Mannich reactiona

Entry

Copper salt

Time (h)

Yield (%)b

Drc

Ee (%)d

1

CuI

18

99

87:13

97

2

CuBr

12

99

87:13

97

3

CuCl

24

98

87:13

97

4

Cu(CH3CN)4BF4

8

99

86:14

97

5

Cu(CH3CN)4PF6

8

99

86:14

96

6

CuOAc

48

95

86:14

95

7

CuTC

24

93

74:26

95

8

Cu(OAc)2

72

92

73:27

94

9

CuBr2

72

trace

nde

nd


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10 a

Cu(OTf)2

72

trace

nd

nd

The reactions were carried out with Schiff base 1a (0.22 mmol), ketimine 2a (0.2 mmol), 5.0 mol%

copper salt, 6.0 mol% L11, and 10 mol% Et3N in 2.0 mL of CH2Cl2 at 25 °C. bIsolated yield containing two diastereomers. cDr values refer to syn/anti ratio, determined by chiral HPLC analysis. dEe values of syn-adducts, determined by chiral HPLC analysis. end = not determined.

Next, the solvent effect was investigated (Table 3). In all the solvents screened, the model reaction completed smoothly, affording Mannich adducts 3aa in nearly quantitative yields (entries 1-13). In toluene and its analogues, the products were obtained in good diastereoselectivities and excellent enantioselectivities (entries 1-6). Use of ether solvents led to the slightly declined stereoselectivities (entries 8-10 vs. entry 3), and a similar result was obtained in EtOAc (entry 11). With CH3CN as a solvent, the enantioselectivity decreased obviously (entry 12 vs. entry 3). However, the reaction provided only 29% ee in DMF (entry 13). These results suggested that o-xylene, p-xylene and mesitylene turned out to be the most effective solvents for the model reaction, providing adducts 3aa in 99% yield with 90:10 dr and 99% ee (entries 2-4). Then, we chose p-xylene as solvent for the Mannich reaction. The base, the catalyst loading, the molar ratio of chiral ligand L11 to CuBr and the reaction temperature were then optimized. When 10 mol% of K2CO3 was used as the base instead of Et3N, the diastereoselectivity decreased slightly (entry 14 vs. entry 3). Increment of the amount of Et3N used led to a faster the reaction rate, but an unchanged yield and stereoselectivity (entries 3, 15 and 16). When the catalyst loading was reduced from 5.0 mol% to 2.5 mol%, excellent yield and stereoselectivity were obtained (entry 17). Further decrease of the catalyst loading to 1.0 mol% resulted in a considerably declined yield and stereoselectivity, due to a poor conversion rate (entry 18 vs. entry 17). When the molar ratio of ligand L11 to CuBr was changed from 1.2:1 to 2:1, the reaction rate became even slower (entry 19 vs. entry 3). Change in reaction temperature also had an influence on the reaction rate. When the reaction was carried out in toluene at 0 °C, 24 hours were required to complete the reaction (entry 20). Based on the results mentioned above, the optimal reaction condition was established to be the presence of 2.5 mol% of CuBr and 3.0 mol% of chiral ligands L11 in p-xylene at 25 °C, with 10 mol% of Et3N as the base.



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Table 3. The effect of solvent on the Mannich reactiona

Entry

Solvent

Time (h)

Yield (%) b

Dr c

Ee (%) d

1

toluene

6

99

89:11

99

2

o-xylene

6

99

90:10

99

3

p-xylene

6

99

90:10

99

4

mesitylene

6

99

90:10

99

PrPh

6

99

89:11

98

BuPh

6

99

87:13

97

7

CH2Cl2

12

99

87:13

97

8

Et2O

6

99

90:10

97

9

MTBE

6

99

89:11

98

10

THF

18

99

85:15

95

11

EtOAc

12

99

88:12

96

12

CH3CN

18

98

83:17

82

13

DMF

18

99

78:22

29

14 e

p-xylene

6

99

89:11

99

f

p-xylene

10

99

90:10

98

16 g

p-xylene

4

99

90:10

99

17 h

p-xylene

8

99

91:9

99

18 i

p-xylene

120

39

74:26

81

19 j

p-xylene

48

97

90:10

98

20 k

toluene

24

99

91:9

99

5

i

6

t

15

a

Unless noted otherwise, the reactions were carried out with Schiff base 1a (0.22 mmol), ketimine 2a

(0.2 mmol), 5.0 mol% CuBr, 6.0 mol% L11, and 10 mol% Et3N at 25 °C in 2.0 mL of solvent. bIsolated yield containing two diastereomers. cDr values refer to syn/anti ratio, determined by chiral HPLC analysis. dEe values of syn-adducts, determined by chiral HPLC analysis. eK2CO3 was used as base instead of Et3N. f5 mol% Et3N was used. g20 mol% Et3N was used. h2.5 mol% catalyst, 0.3 mmol scale. i

1.0 mol% catalyst, 0.7 mmol scale. jThe molar ratio of ligand L11 to CuBr was 2:1. kThe reaction

temperature was 0 °C.


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With the optimized reaction condition in hand, the substrate scope of the Mannich reaction was examined (Table 4). Initially, ketimines bearing different substituents at 1position of 2-oxindole were probed (entries 1-4). The results indicated that N-protecting group played an important role for the Mannich reaction. N-benzyl substituted ketimine gave a higher diastereoselectivity than N-methyl substrate, while the yield and enantioselectivity decreased slightly (entry 2 vs. entry 1). When N-benzhydryl and NH free substrates were introduced, the results were unfavorable (entries 3 and 4). Subsequently, glycine Schiff bases with different ester groups were examined. Methyl and ethyl glycinates provided a similar result (entries 1 and 5). When benzyl glycinate was used, the diastereoselectivity increased slightly, whereas the enantioselectivity decreased (entry 6 vs. entry 1). The sterically bulky tert-butyl glycine ester was unreactive under the typical reaction conditions, probably due to a steric hindrance. Then, ketimines derived from N-methyl isatins with different substituents at 5-, 6- or 7-position were investigated (entries 7-18). To our delight, the Mannich reaction tolerated all the ketimines examined, providing excellent yields with up to 94:6 dr and 95-99% ee. Generally, the substrates bearing electron-donating groups gave better enantioselectivity than those with electron-withdrawing groups at the same position (entries 9 and 10 vs. entries 7 and 8, entry 13 vs. entries 11 and 12, entry 18 vs. entries 14-17). In addition, 7substituted isatin-derived ketimines provided better results than 5- and 6-substituted analogues (entry 15 vs. entries 7 and 11, entry 16 vs. entries 8 and 12). In order to further improve the diastereoselectivity, ketimines derived from N-benzyl isatins were also evaluated (entries 19-27). It appeared that the ester groups of glycine Schiff bases had a negligible effect on the diastereoselectivity, which differed from Nmethyl substituted ketimines (entries 2, 19 and 20 vs. entries 1, 5 and 6). Moreover, all N-benzyl substituted ketimines provided the corresponding products in excellent yields, enantioselectivities and diastereoselectivities, regardless of the electronic properties and the substitution position (entries 21-27). Isatin-derived ketimines with other protecting groups on the imine nitrogen were also examined under the typical reaction conditions. However, the asymmetric catalytic system was ineffective for the N-PMP and N-benzhydryl analogues, while no desire adduct could be obtained using N-Cbz imine. Ketoimine-based glycine esters 1 have been selected as nucleophiles in our study because they are more commercially available than the corresponding aldimino ester. To further examine the substrate tolerance, we synthesized an aldimino ester by the condensation between benzaldehyde and methyl



Page 8 of 29

glycinate. However, the typical reaction conditions are not suitable for the this aldimino ester, the reaction is sluggish and only trace product can be detected after 3 days.

Table 4. Substrate scope of the asymmetric Mannich reactiona

Time (h)

Yield (%)

Dr

Ee (%)d

Me

8

3aa, 99

91:9

99

H

Bn

12

3ab, 96

95:5

98

Me

H

CHPh2

24

3ac, 60

84:16

77

4

Me

H

H

24

3ad, 48

63:37

64

5

Et

H

Me

8

3ba, 99

90:10

99

6

Bn

H

Me

8

3ca, 99

94:6

98

7

Me

5-Cl

Me

4

3ae, 99

80:20

96

8

Me

5-Br

Me

4

3af, 99

78:22

96

9

Me

5-Me

Me

6

3ag, 99

92:8

99

10

Me

5-MeO

Me

8

3ah, 98

86:14

97

11

Me

6-Cl

Me

6

3ai, 95

84:16

97

12

Me

6-Br

Me

8

3aj, 89

85:15

95

13

Me

6-MeO

Me

6

3ak, 93

82:18

98

14

Me

7-F

Me

4

3al, 99

90:10

98

15

Me

7-Cl

Me

4

3am, 99

92:8

98

16

Me

7-Br

Me

4

3an, 99

93:7

98

17

Me

7-CF3

Me

4

3ao, 99

93:7

97

18

Me

7-Me

Me

4

3ap, 99

94:6

99

19

Et

H

Bn

12

3bb, 92

96:4

98

20

Bn

H

Bn

12

3cb, 91

96:4

98

21

Me

5-Cl

Bn

6

3aq, 99

90:10

95

22

Me

5-Me

Bn

8

3ar, 99

97:3

99

23

Me

6-Cl

Bn

6

3as, 99

94:6

96

24

Me

6-MeO

Bn

8

3at, 97

95:5

99

Entry

R

1

2

R

1

Me

H

2

Me

3

R

3

b


c

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a

25

Me

7-Cl

Bn

6

3au, 99

97:3

97

26

Me

7-Br

Bn

6

3av, 99

98:2

98

27

Me

7-Me

Bn

6

3aw, 99

98:2

99

The reactions were carried out with glycine Schiff bases 1 (0.33 mmol), ketimines 2 (0.3 mmol), 2.5

mol% CuBr, 3.0 mol% L11, and 10 mol% Et3N in 3.0 mL of p-xylene at 25 °C. bIsolated yield containing two diastereomers. cDr values refer to syn/anti ratio, determined by both 1H NMR spectroscopy (syn/anti < 95:5) and chiral HPLC analysis. dEe values of syn-adducts, determined by chiral HPLC analysis.

The absolute configuration of product 3ab was determined to be (2R,3’S) by X-ray analysis (see ESI† for details), and those of other adducts were assigned tentatively by analogy. To rationalize the stereochemical result of this asymmetric Mannich reaction, a possible transition-state model is proposed based on our experimental results and the related literature reports.3d, 3e, 3j, 9 The nucleophile can be activated by coordinating with the copper-L11 complex. Simultaneously, the ketimine could be activated by the intermolecular H-bonding between its N-Boc group and the sulfamide moiety of the chiral catalyst. The favorable orientation as shown in Figure 2 led to Si-face attack and resulted in syn-selective product 3 with (2R,3’S)-configuration.

Figure 2. Proposed transition state leading to the syn-adduct

To demonstrate the synthetic applicability of this protocol, a gram-scale synthesis of compound 3ab was conducted under the typical reaction condition. The desired adducts were achieved in 98% yield with 96:4 dr and 98% ee without any loss in yield and stereoselectivity (Scheme 1).



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Scheme 1. Gram-scale synthesis of Mannich adduct 3ab

Furthermore, the transformation of 3ab was carried out. Oxindole-based Cβtetrasubstituted α,β-diamino acid derivative 4 was obtained in nearly quantitative yield by treatment with 1 M HCl, and the optically active compound 5 was achieved in 99% yield via a sequential deprotection of 3ab by acidity adjustment (Scheme 2a). In addition, 3ab could be easily converted to compound 6 in excellent yield and enantioselectivity by Pd/C-catalyzed hydrogenation. Debenzylation of adduct 3ab offered an alternative approach to the synthesis of Mannich adduct 3ad in 68% yield with 96:4 dr and 98% ee (Scheme 2b). a) Hydrolysis and deprotection of Mannich adduct 3ab

b) Hydrogenation and debenzylation of Mannich adduct 3ab


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Scheme 2. Transformations of Mannich adduct 3ab

CONCLUSION In conclusion, we have developed a copper-catalyzed asymmetric Mannich reaction of glycine Schiff bases with isatin-derived ketimines, producing a wide range of 3substituted 3-amino-2-oxindoles efficiently in high yields (89-99%) with good-toexcellent diastereoselectivities (up to 98:2 dr) and excellent enantioselectivities (95-99% ee). Notably, this method provided Cβ-tetrasubstituted syn-α,β-diamino acid derivatives for the first time via catalytic asymmetric Mannich reaction of glycine Schiff bases to ketimines. EXPERIMENTAL SECTION General information. Melting points were taken without correction. Optical rotations were measured on a WZZ-2A digital polarimeter at the wavelength of the sodium D-line (589 nm). The NMR spectra were recorded on Bruker 400 spectrometer. 1H NMR spectra were referenced to tetramethylsilane (δ 0.00 ppm). 13C{1H} NMR spectra were referenced to the carbon signals of CDCl3 (δ 77.0 ppm). 31P{1H} NMR spectra were referenced to 85% H3PO4 (δ 0.0 ppm). IR spectra were recorded on Nicolet Magna-1 550 spectrometer. High Resolution Mass spectra (HRMS) were recorded on Micromass GCT with Electron Spray Ionization (ESI-TOF) resource. HPLC analysis was performed on Waters equipment using Daicel Chiralpak AD-H column, Chiralpak AS-H column or Chiralcel OD-H column. Toluene, o-xylene, p-xylene, mesitylene, iPrPh, tBuPh, ethyl ether, MTBE and THF were freshly distilled from sodium-benzophenone. Ethyl acetate and CH2Cl2 were freshly distilled from CaH2. CH3CN was distilled from P2O5. DMF were dried over



CaH2 and distilled under reduced pressure. Analytical thin-layer chromatography (TLC) was performed on glass plates coated with 10-40 μm. Silica gel column chromatography was performed, using silica gel (300-400 mesh) eluted with petroleum ether and ethyl acetate. Chiral cyclohexane-based N,P-ligands L1-L15 were prepared according to literature procedure.10 Isatin-derived ketimines were synthesized by following the literature procedure.11 Characterization of the New Chiral Ligands L11-L13 (S)-N-((1R,2R)-2-(diphenylphosphanyl)cyclohexyl)-3-methyl-2-((4-nitrophenyl) sulfonamido)butanamide (L11). Yellow solid, 91% yield (182.4 mg), mp 155.0-156.7 oC, [α]D25 -9.8 (c 2.04, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 8.26 (dt, J = 8.8, 1.6 Hz, 2H), 8.02 (dt, J = 8.8, 2.0 Hz, 2H), 7.45-7.36 (m, 5H), 7.33-7.24 (m, 3H), 7.22-7.15 (m, 2H), 5.60 (d, J = 8.0 Hz, 1H), 5.55 (d, J = 8.4 Hz, 1H), 3.62-3.51 (m, 1H), 3.43 (dd, J = 8.4, 4.0 Hz, 1H), 2.15-2.01 (m, 2H), 1.95-1.84 (m, 1H), 1.64 (d, J = 9.6 Hz, 3H), 1.27-1.10 (m, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.87-0.80 (m, 1H), 0.78 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.2, 149.9, 145.6, 136.6 (d, J = 13.1 Hz), 134.5 (d, J = 16.3 Hz), 134.1 (d, J = 20.1 Hz), 132.4 (d, J = 17.6 Hz), 129.2, 129.0 (d, J = 5.8 Hz), 128.6, 128.4, 128.3 (d, J = 7.4 Hz), 124.5, 61.59, 51.9 (d, J = 16.1 Hz), 39.8 (d, J = 16.3 Hz), 34.3 (d, J = 6.8 Hz),, 32.3, 27.7, 25.8 (d, J = 3.7 Hz),, 24.6, 19.2, 16.8; 31P{1H} NMR (162 MHz, CDCl3, 85% H3PO4): δ -8.30; IR (KBr, cm-1): ν 3442, 2933, 2852, 1663, 1535, 1440, 1352, 1168, 1094, 849, 740, 700, 618; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H35N3O5PS 568.2030, found 568.2048. (S)-N-((1R,2R)-2-(diphenylphosphanyl)cyclohexyl)-3-methyl-2-(phenylsulfonamido) butanamide (L12). White solid, 92% yield (84.5 mg), mp 144.2-146.1 oC, [α]D25 -30.3 (c 1.41, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J = 8.0, 1.6 Hz, 2H), 7.54-7.45 (m, 5H), 7.44-7.37 (m, 3H), 7.36-7.28 (m, 5H), 5.86 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 7.6 Hz, 1H), 3.72-3.62 (m, 1H), 3.37 (dd, J = 7.6, 4.0 Hz, 1H), 2.17 (td, J = 9.6, 2.4 Hz, 1H), 2.09 (dt, J = 12.4, 4.0 Hz, 1H), 2.04-1.95 (m, 1H), 1.73-1.65 (m, 1H), 1.65-1.53 (m, 2H), 1.37-1.18 (m, 2H), 1.18-1.07 (m, 1H), 1.03-0.91 (m, 1H), 0.76 (d, J = 6.8 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.7, 139.6, 137.0 (d, J = 13.3 Hz), 135.6 (d, J = 16.3 Hz), 134.2 (d, J = 20.4 Hz), 132.9 (d, J = 2.7 Hz), 132.7, 129.1, 128.9, 128.8 (d, J = 6.4 Hz), 128.6, 128.2 (d, J = 7.4 Hz), 127.1, 61.7, 51.6 (d, J = 16.4 Hz), 39.3 (d, J = 16.0 Hz), 33.1 (d, J = 7.3 Hz), 31.2, 27.4 (d, J = 4.9 Hz), 25.4 (d, J = 5.4 Hz), 24.2, 19.1, 16.8; 31P{1H} NMR (162 MHz, CDCl3, 85% H3PO4): δ -8.81; IR (KBr, cm-1): ν 3274, 3063, 2933, 2852, 1745, 1657, 1528, 1440, 1331, 1162, 1094, 754, 693,


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598, 557; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H36N2O3PS 523.2179, found 523.2190. (S)-N-((1R,2R)-2-(diphenylphosphanyl)cyclohexyl)-3-methyl-2-(naphthalene-2sulfonamido)butanamide (L13). White solid, 89% yield (89.6 mg), mp 164.2-166.6 oC, [α]D25 -31.0 (c 1.01, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 1.2 Hz, 1H), 7.97-7.90 (m, 2H), 7.85-7.77 (m, 2H), 7.62-7.54 (m, 2H), 7.41-7.33 (m, 5H), 7.32-7.21 (m, 5H), 5.83 (d, J = 8.0 Hz, 1H), 5.02 (d, J = 8.0 Hz, 1H), 3.67-3.56 (m, 1H), 3.46 (dd, J = 7.6, 4.0 Hz, 1H), 2.11-1.95 (m, 3H), 1.66-1.58 (m, 1H), 1.56-1.41 (m, 2H), 1.29-1.17 (m, 1H), 1.16-1.04 (m, 1H), 1.02-0.90 (m, 1H), 0.90-0.80 (m, 1H), 0.76 (d, J = 6.8 Hz, 3H), 0.70 (d, J = 6.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.8, 136.9 (d, J = 13.4 Hz), 136.3, 135.5 (d, J = 16.3 Hz), 134.8, 134.2 (d, J = 20.4 Hz), 132.7 (d, J = 18.6 Hz), 132.0, 129.6, 129.3, 128.8, 128.7, 128.7, 128.6, 128.5, 128.2 (d, J = 7.4 Hz), 127.9, 127.6, 122.3, 61.8, 51.6 (d, J = 16.6 Hz), 39.2 (d, J = 16.1 Hz), 33.1 (d, J = 6.8 Hz), 31.1, 27.3 (d, J = 3.6 Hz), 25.4 (d, J = 4.9 Hz), 24.2, 19.2, 16.8;

31

P{1H} NMR (162 MHz,

CDCl3, 85% H3PO4): δ -8.75; IR (KBr, cm-1): ν 3462, 3062, 2933, 2852, 1657, 1528, 1434, 1331, 1162, 1128, 1073, 748, 700, 659, 550; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H38N2O3PS 573.2335, found 573.2332. General Procedure for the Asymmetric Mannich Reaction of Glycine Schiff Bases to Ketimines Under a nitrogen atmosphere, CuBr (0.0075 mmol, 1.1 mg) and ligand L11 (0.009 mmol, 5.1 mg) dissolved in p-xylene (1.5 mL) were added to a flame-dried Schlenk tube equipped a stir bar, and the mixture was stirred at 25 oC for 1 hour. Then, glycine Schiff base 1a (0.33 mmol, 83.6 mg) were added followed by Et3N (0.03 mmol, 4.16 μL) and isatin-derived ketimine 2a (0.3 mmol, 78.1 mg) in p-xylene (1.5 mL) were added. The resulting mixture was stirred at the same temperature until the reaction completed (monitored by TLC). The solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography (2:1 to 6:1 petroleum ether/ethyl acetate) to give the desire product 3aa. methyl

(R)-2-((S)-3-((tert-butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)-2-

((diphenylmethylene)amino)acetate (3aa).3h White solid, 99% yield (153.5 mg), mp 211.8 o

C, 91:9 syn/anti, 99% ee for syn-isomer, [α]D25 +139.8 (c 2.12, CH2Cl2); 1H NMR (400

MHz, CDCl3): δ 7.49 (s, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.37-7.27 (m, 6H), 7.15 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.84 (s, 3H), 6.58 (s, 1H), 4.23 (s, 1H), 3.75 (s, 3H), 3.16 (s, 3H), 1.32 (s, 9H); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2propanol = 90/10, flow rate: 0.9 mL/min): tR = 14.2 min (syn-major), 20.2 min (anti-



minor), 26.3 min (syn-minor), 29.7 min (anti-major). methyl

(R)-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-2-oxoindolin-3-yl)-2-

((diphenylmethylene)amino)acetate (3ab).3h White solid, 96% yield (169.8 mg), mp 211.1-213.4 oC, 95:5 syn/anti, 98% ee for syn-isomer, [α]D25 +146.8 (c 2.58, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 6.8 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.37-7.25 (m, 5H), 7.16 (q, J = 7.6 Hz, 4H), 7.11 (s, 1H), 7.05 (t, J = 7.2 Hz, 2H), 6.95 (t, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.72 (s, 2H), 6.62 (d, J = 7.6 Hz, 1H), 5.04 (s, 1H), 4.75 (s, 1H), 4.30 (s, 1H), 3.73 (s, 3H), 1.35 (s, 9H); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 80/20, flow rate: 0.9 mL/min): tR = 7.8 min (syn-major), 13.2 min (anti-minor), 18.6 min (syn-minor), 53.4 min (anti-major). methyl

(R)-2-((S)-1-benzhydryl-3-((tert-butoxycarbonyl)amino)-2-oxoindolin-3-yl)-2-

((diphenylmethylene)amino)acetate (3ac). White solid, 60% yield (119.9 mg), mp 89.5119.0 oC, 84:16 syn/anti, 77% ee for syn-isomer, [α]D25 +121.7 (c 1.31, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 6.0 Hz, 1H, major and minor), 7.42 (q, J = 7.6 Hz, 1H, major and minor), 7.37 (t, J = 7.6 Hz, 1H, major and minor), 7.34-7.23 (m, 8H, major and minor), 7.23-7.03 (m, 8H, major and minor), 7.00 (t, J = 7.6 Hz, 1H, major and minor), 6.97-6.87 (m, 2H, major and minor), 6.83 (s, 1H, major and minor), 6.65-6.51 (m, 2H, major and minor), 6.39 (s, 1H, major and minor), 4.39 (s, 0.16H, minor), 4.19 (s, 0.84H, major), 3.67 (s, 2.52H, major), 3.58 (s, 0.48H, minor), 1.35 (s, 9H, major and minor); 13

C{1H} NMR (100 MHz, CDCl3): δ (major and minor) 174.5, 173.2, 169.4, 153.9, 139.1,

138.5, 137.4, 135.2, 130.9, 129.2, 129.1, 129.0, 128.8, 128.5, 128.4, 128.3, 128.2, 128.2, 128.1, 128.0, 127.5, 127.4, 127.1, 123.9, 121.9, 111.4, 79.9, 68.4, 63.9, 62.9, 58.6, 52.4, 29.7, 28.2; IR (KBr, cm-1): ν 3422, 2926, 1725, 1616, 1487, 1351, 1263, 1175, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C42H40N3O5 666.2963, found 666.2953; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 6.3 min (syn-major), 14.4 min (syn-minor), 25.4 min (anti-minor), 42.9 min (anti-major). methyl

(R)-2-((S)-3-((tert-butoxycarbonyl)amino)-2-oxoindolin-3-yl)-2-((diphenyl-

methylene)amino)acetate (3ad). White solid, 48% yield (71.6 mg), mp 115.0-119.8 oC, 63:37 syn/anti, 64% ee for syn-isomer, [α]D25 +12.2 (c 0.36, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.91 (s, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.44-7.36 (m, 4H), 7.27 (t, J = 7.6 Hz, 2H), 7.18 (q, J = 7.6 Hz, 2H), 6.97 (t, J = 7.2 Hz, 3H), 6.82 (d, J = 7.6 Hz, 1H), 6.43 (s, 1H), 4.41 (s, 1H), 3.63 (s, 3H), 1.27 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.3, 173.8, 169.4, 154.0, 141.4, 138.8, 135.5, 130.9, 129.2, 1291, 129.1, 128.7, 128.0, 127.4,


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123.6, 122.4, 109.7, 80.5, 68.7, 63.6, 52.4, 28.0; IR (KBr, cm-1): ν 3462, 2926, 1725, 1616, 1487, 1372, 1257, 1168, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H30N3O5 500.2180, found 500.2169; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 70/30, flow rate: 0.5 mL/min): tR = 23.7 min (syn-major), 81.2 min (anti-minor), 88.2 min (syn-minor), 104.0 min (anti-major). ethyl


((diphenylmethylene)amino)acetate (3ba).3h White solid, 99% yield (158.1 mg), mp 167.6-195.5 oC, 90:10 syn/anti, 99% ee for syn-isomer, [α]D25 +146.2 (c 2.28, CH2Cl2); 1

H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 6.0 Hz, 2H, major and minor), 7.44-7.27 (m,

7H, major and minor), 7.17 (d, J = 7.2 Hz, 1H, major and minor), 7.00 (t, J = 7.2 Hz, 1H, major and minor), 6.91-6.74 (m, 3H, major and minor), 6.61 (s, 0.57H, major),4.40 (s, 0.10H, minor), 4.21 (s, 0.90H, major), 4.23 (q, J = 7.2 Hz, 1.80H, major), 4.06-3.94 (m, 0.20H, minor), 3.24 (s, 0.30H, minor), 3.16 (s, 2.70H, major), 1.33 (s, 9H, major and minor), 1.27 (t, J = 7.2 Hz, 2.70H, major), 1.07 (t, J = 7.2 Hz, 0.30H, minor); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.8 mL/min): tR = 12.5 min (syn-major), 20.6 min (syn-minor), 25.9 min (anti-minor), 31.8 min (anti-major). benzyl


((diphenylmethylene)amino)acetate (3ca).3h White solid, 99% yield (176.8 mg), mp 98.6161.6 oC, 94:6 syn/anti, 98% ee for syn-isomer, [α]D25 +115.8 (c 2.98, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 6.4 Hz, 2H), 7.41-7.23 (m, 10H), 7.20 (t, J = 7.6 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 7.2 Hz, 2H), 6.62 (s, 1H), 5.20 (s, 2H), 4.22 (s, 1H), 3.14 (s, 3H), 1.32 (s, 9H); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 18.2 min (syn-major), 24.5 min (anti-minor), 38.8 min (anti-major), 54.8 min (syn-minor). methyl (R)-2-((S)-3-((tert-butoxycarbonyl)amino)-5-chloro-1-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3ae). White solid, 99% yield (164.3 mg), mp 159.5-185.9 oC, 80:20 syn/anti, 96% ee for syn-isomer, [α]D25 +82.2 (c 2.59, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.49-7.34 (m, 6H, major and minor), 7.28 (dd, J = 8.0, 1.6 Hz, 3H, major and minor), 7.15 (s, 1H, major and minor), 6.99-6.89 (m, 2H, major and minor), 6.79 (d, J = 8.4 Hz, 1H, major and minor), 6.68 (s, 1H, major and minor), 4.39 (s, 0.20H, minor), 4.32 (s, 0.80H, major), 3.76 (s, 2.40H, major), 3.65 (s, 0.60H, minor), 3.26 (s, 0.60H, minor), 3.16 (s, 2.40H, major), 1.33 (s, 9H, major and minor); HPLC analysis



(AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 9.5 min (syn-major), 10.5 min (anti-minor), 12.8 min (syn-minor), 16.5 min (antimajor). methyl (R)-2-((S)-5-bromo-3-((tert-butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3af). White solid, 99% yield (177.4 mg), mp 83.196.0 oC, 78:22 syn/anti, 96% ee for syn-isomer, [α]D25 +53.5 (c 1.36, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J = 5.2, 2.0 Hz, 2H, major and minor), 7.42-7.33 (m, 4H, major and minor), 7.29 (t, J = 7.6 Hz, 3H, major and minor), 6.99-6.88 (m, 2H, major and minor), 6.74 (d, J = 8.4 Hz, 0.78H, major), 6.66 (d, J = 8.0 Hz, 0.32H, minor), 6.45 (s, 0.59H, major), 4.37 (s, 0.22H, minor), 4.31 (s, 0.78H, major), 3.77 (s, 2.34H, major), 3.67 (s, 0.66H, minor), 3.26 (s, 0.66H, minor), 3.15 (s, 2.34H, major), 1.33 (s, 9H, major and minor);

13

C{1H} NMR (100 MHz, CDCl3): δ (major and minor) 173.7, 173.6, 170.0,

169.2, 153.7, 153.5, 143.4, 138.4, 135.2, 131.9, 131.0, 129.2, 129.0, 128.8, 128.7, 128.6, 128.1, 128.0, 127.4, 127.3, 126.6, 126.4, 115.0, 114.8, 109.1, 80.4, 68.6, 68.4, 64.0, 63.3, 52.6, 28.0, 26.6; IR (KBr, cm-1): ν 3462, 2926, 1725, 1609, 1487, 1364, 1269, 1168, 760, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C30H3179BrN3O5 592.1442, found 592.1460; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 10.9 min (syn-major), 12.2 min (anti-minor), 15.7 min (synminor), 19.8 min (anti-major). methyl

(R)-2-((S)-3-((tert-butoxycarbonyl)amino)-1,5-dimethyl-2-oxoindolin-3-yl)-2-

((diphenylmethylene)amino)acetate (3ag).3h White solid, 99% yield (158.3 mg), mp 166.8-179.2 oC, 92:8 syn/anti, 99% ee for syn-isomer, [α]D25 +112.5 (c 2.52, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 7.2 Hz, 2H, major and minor), 7.43-7.32 (m, 4H, major and minor), 7.27 (t, J = 8.0 Hz, 2H, major and minor), 7.13 (d, J = 7.6 Hz, 1H, major), 7.02 (d, J = 8.0 Hz, 1H, minor), 6.96 (s, 1H, major and minor), 6.94-6.83 (m, 2H, major and minor), 6.74 (d, J = 7.6 Hz, 0.92H, major), 6.66 (d, J = 8.0 Hz, 0.08H, minor), 6.53 (s, 0.53H, major), 4.37 (s, 0.08H, minor), 4.27 (s, 0.92H, major), 3.76 (s, 2.76H, major), 3.63 (s, 0.24H, minor), 3.24 (s, 0.24H, minor), 3.15 (s, 2.76H, major), 2.29 (s, 0.24H, minor), 2.26 (s, 2.76H, major), 1.32 (s, 9H, major and minor); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 9.8 min (syn-major), 14.3 min (anti-minor), 17.6 min (syn-minor), 22.4 min (antimajor). methyl (R)-2-((S)-3-((tert-butoxycarbonyl)amino)-5-methoxy-1-methyl-2-oxoindolin-3yl)-2-((diphenylmethylene)amino)acetate (3ah).3h White solid, 98% yield (159.9 mg), mp


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82.4-101.7 oC, 86:14 syn/anti, 97% ee for syn-isomer, [α]D25 +110.5 (c 2.52, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.56-7.44 (m, 2H, major and minor), 7.44-7.33 (m, 4H, major and minor), 7.30 (t, J = 7.6 Hz, 2H, major and minor), 6.85 (dd, J = 8.4, 2.8 Hz, 3H, major and minor), 6.77 (dd, J = 10.8, 2.4 Hz, 1H, major and minor), 6.69 (d, J = 8.4 Hz, 1H, major and minor), 6.58 (s, 0.49H, major), 4.38 (s, 0.14H, minor), 4.24 (s, 0.86H, major), 3.76 (s, 2.58H, major), 3.74 (s, 0.42H, minor), 3.63 (s, 3H), 3.24 (s, 0.42H, minor), 3.14 (s, 2.58H, major), 1.34 (s, 9H, major and minor); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 80/20, flow rate: 0.9 mL/min): tR = 9.8 min (syn-major), 13.8 min (anti-minor), 26.9 min (anti-major), 47.9 min (syn-minor). methyl (R)-2-((S)-3-((tert-butoxycarbonyl)amino)-6-chloro-1-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3ai).3h White solid, 95% yield (155.8 mg), mp 153.0-163.3 oC, 84:16 syn/anti, 97% ee for syn-isomer, [α]D25 +81.9 (c 2.21, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.2 Hz, 2H), 7.43-7.35 (m, 4H), 7.30 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.93-6.98 (m, 2H), 6.79 (d, J = 7.6 Hz, 1H), 6.31 (s, 1H), 4.39 (s, 1H), 3.59 (s, 3H), 3.25 (s, 3H), 1.22 (s, 9H); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 8.3 min (syn-major), 9.4 min (syn-minor), 10.4 min (anti-minor), 13.5 min (anti-major). methyl (R)-2-((S)-6-bromo-3-((tert-butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3aj).3h White solid, 89% yield (158.2 mg), mp 142.5-146.6 oC, 85:15 syn/anti, 95% ee for syn-isomer, [α]D25 +71.1 (c 1.68, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 6.4 Hz, 2H, major and minor), 7.43-7.36 (m, 4H, major and minor), 7.31 (q, J = 7.6 Hz, 2H, major and minor), 7.16 (d, J = 7.2 Hz, 1H, major and minor), 7.02 (d, J = 8.0 Hz, 2H, major and minor), 6.96-6.86 (m, 2H, major and minor), 6.69 (s, 0.64H, major), 4.38 (s, 0.15H, minor), 4.29 (s, 0.85H, major), 3.74 (s, 2.55H, major), 3.59 (s, 0.45H, minor), 3.22 (s, 0.45H, minor), 3.15 (s, 2.55H, major), 1.32 (s, 9H, major and minor); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 8.0 min (syn-major), 8.9 min (syn-minor), 10.1 min (anti-minor), 13.2 min (anti-major). methyl (R)-2-((S)-3-((tert-butoxycarbonyl)amino)-6-methoxy-1-methyl-2-oxoindolin-3yl)-2-((diphenylmethylene)amino)acetate (3ak).3h White solid, 93% yield (152.3 mg), mp 99.6-112.6 oC, 82:18 syn/anti, 98% ee for syn-isomer, [α]D25 +85.3 (c 2.46, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 8.0 Hz, 0.36H, minor), 7.48 (d, J = 7.2 Hz, 1.64H, major), 7.43-7.32 (m, 4H, major and minor), 7.29 (t, J = 8.0 Hz, 2H, major and minor),



7.21 (d, J = 8.0 Hz, 0.18H, minor), 7.05 (d, J = 8.0 Hz, 0.82H, major), 7.02-6.98 (m, 0.36H, minor), 6.95-6.84 (m, 1.64H, major), 6.69 (s, 0.68H, major), 6.50 (dd, J = 8.4, 2.0 Hz, 1H, major and minor), 6.45 (s, 0.82H, major), 6.37 (d, J = 2.0 Hz, 0.18H, minor), 4.38 (s, 0.18H, minor), 4.26 (s, 0.82H, major), 3.83 (s, 2.46H, major), 3.78 (s, 0.54H, minor), 3.74 (s, 2.46H, major), 3.57 (s, 0.54H, minor), 3.22 (s, 0.54H, minor), 3.15 (s, 2.46H, major), 1.32 (s, 9H, major and minor); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 13.6 min (syn-major), 18.2 min (anti-minor), 21.5 min (syn-minor), 31.7 min (anti-major). methyl (R)-2-((S)-3-((tert-butoxycarbonyl)amino)-7-fluoro-1-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3al). White solid, 99% yield (159.2 mg), mp 205.5-208.4 oC, 90:10 syn/anti, 98% ee for syn-isomer, [α]D25 +112.1 (c 2.59, CH2Cl2); 1

H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 7.6 Hz, 2H, major and minor), 7.44-7.34 (m,

4H, major and minor), 7.31 (t, J = 7.6 Hz, 2H, major and minor), 7.11-7.02 (m, 1H, major and minor), 6.98-6.83 (m, 4H, major and minor), 6.75 (s, 0.64H, major), 4.37 (s, 0.10H, minor), 4.26 (s, 0.87H, major), 3.74 (s, 2.70H, major), 3.62 (s, 0.30H, minor), 3.47 (s, 0.30H, minor), 3.38 (s, 2.70H, major), 1.33 (s, 9H, major and minor); 13C{1H} NMR (100 MHz, CDCl3): δ (major and minor) 174.3, 173.9, 173.5, 169.8, 153.8, 153.6, 147.6 (d, J = 242.0 Hz), 138.6, 138.4, 135.3, 135.2, 131.0, 129.1, 128.9, 128.9, 128.7, 128.6, 128.1, 128.1, 127.4, 127.2, 122.9 (d, J = 6.3 Hz), 119.1, 117.2 (d, J = 18.0 Hz), 80.3 (d, J = 18.3 Hz), 68.8, 68.4, 64.2, 63.35 , 52.5, 29.0, 28.0; IR (KBr, cm-1): ν 3422, 2926, 1718, 1630, 1487, 1364, 1277, 1168, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C30H31FN3O5 532.2242, found 532.2253; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 9.6 min (syn-major), 13.4 min (anti-minor), 22.3 min (syn-minor), 24.6 min (anti-major). methyl (R)-2-((S)-3-((tert-butoxycarbonyl)amino)-7-chloro-1-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3am).3h White solid, 99% yield (164.3 mg), mp 195.8-199.3 oC, 92:8 syn/anti, 98% ee for syn-isomer, [α]D25 +135.2 (c 2.76, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 7.2 Hz, 2H, major and minor), 7.44-7.35 (m, 4H, major and minor), 7.31 (t, J = 7.2 Hz, 2H, major and minor), 7.26 (d, J = 7.6 Hz, 1H, major and minor), 7.05 (d, J = 7.2 Hz, 1H, major and minor), 6.92 (t, J = 7.6 Hz, 1H, major and minor), 6.89-6.83 (m, 2H, major and minor), 6.77 (s, 0.62H, major), 4.34 (s, 0.08H, minor), 4.26 (s, 0.92H, major), 3.74 (s, 2.76H, major), 3.64 (s, 0.24H, minor), 3.64 (s, 0.24H, minor), 3.53 (s, 2.76H, major), 1.34 (s, 9H, major and minor); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 8.1 min (syn-major), 11.3 min (anti-minor), 16.5 min (syn-minor), 23.6 min (anti-


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major). methyl (R)-2-((S)-7-bromo-3-((tert-butoxycarbonyl)amino)-1-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3an). White solid, 99% yield (177.5 mg), mp 189.5-192.8 oC, 93:7 syn/anti, 98% ee for syn-isomer, [α]D25 +144.8 (c 1.03, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 6.4 Hz, 2H), 7.46-7.35 (m, 5H), 7.32 (t, J = 7.6 Hz, 2H), 7.09 (d, J = 7.2 Hz, 1H), 6.87 (dd, J = 6.8, 2.0 Hz, 3H), 6.77 (s, 1H), 4.33 (s, 0.07H, minor), 4.27 (s, 0.93H, major), 3.73 (s, 2.79H, major), 3.66 (s, 0.21H, minor), 3.65 (s, 0.21H, minor), 3.54 (s, 2.79H, major), 1.33 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (major and minor) 174.7, 173.5, 169.9, 153.5, 141.6, 138.3, 135.0, 134.6, 131.8, 131.0, 129.9, 129.1, 128.9, 128.8, 128.6, 128.5, 128.1, 128.0, 127.2, 127.0, 123.4, 121.9, 102.3, 80.1, 68.8, 68.3, 63.6, 62.9, 52.5, 30.1, 28.0; IR (KBr, cm-1): ν 3422, 2926, 1725, 1609, 1467, 1372, 1263, 1168, 740, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C30H3179BrN3O5 592.1442, found 592.1454; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 8.1 min (syn-major), 11.4 min (anti-minor), 15.7 min (syn-minor), 24.1 min (anti-major). methyl

(R)-2-((S)-3-((tert-butoxycarbonyl)amino)-1-methyl-2-oxo-7-(trifluoromethyl)

indolin-3-yl)-2-((diphenylmethylene)amino)acetate (3ao). White solid, 99% yield (174.2 mg), mp 187.5-190.4 oC, 93:7 syn/anti, 97% ee for syn-isomer, [α]D25 +119.9 (c 2.75, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 1H), 7.46-7.36 (m, 6H), 7.34 (d, J = 6.8 Hz, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.92-6.86 (m, 2H), 6.71 (s, 1H), 4.36 (s, 0.07H, minor), 4.34 (s, 0.93H, major), 3.75 (s, 2.79H, major), 3.65 (s, 0.21H, minor), 3.50 (s, 0.21H, minor), 3.37 (s, 2.79H, major), 1.32 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ (major and minor) 175.4, 173.8, 169.5, 153.5, 142.6, 138.3, 135.2, 130.1 (q, J = 209.1 Hz), 128.9, 128.8, 128.6, 128.1, 128.0, 127.2, 127.1, 126.3, 125.1, 122.4, 121.7, 112.1 (d, J = 32.6 Hz), 80.4, 68.4, 62.7, 62.0, 52.7, 29.3, 28.1; IR (KBr, cm-1): ν 3415, 2920, 1725, 1603, 1460, 1331, 1263, 1168, 748, 700; HRMS (ESITOF) m/z: [M + H]+ calcd for C31H31F3N3O5 582.2210, found 582.2218; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 7.7 min (syn-major), 9.6 min (anti-minor), 12.9 min (syn-minor), 21.1 min (antimajor). methyl

(R)-2-((S)-3-((tert-butoxycarbonyl)amino)-1,7-dimethyl-2-oxoindolin-3-yl)-2-

((diphenylmethylene)amino)acetate (3ap).3h White solid, 99% yield (157.8 mg), mp 192.7-195.8 oC, 94:6 syn/anti, 99% ee for syn-isomer, [α]D25 +155.8 (c 2.66, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 6.8 Hz, 2H), 7.44-7.28 (m, 6H), 7.04 (d, J = 7.6



Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.81 (dd, J = 7.6, 1.2 Hz, 2H), 6.60 (s, 0.63H, major), 4.32 (s, 0.06H, minor), 4.18 (s, 0.94H, major), 3.74 (s, 2.82H, major), 3.63 (s, 0.18H, minor), 3.53 (s, 0.18H, minor), 3.43 (s, 2.82H, major), 2.57 (s, 2.82H, major), 2.54 (s, 0.18H, minor), 1.34 (s, 9H); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 11.1 min (synmajor), 15.4 min (anti-minor), 25.0 min (syn-minor), 37.6 min (anti-major). ethyl


((diphenylmethylene)amino)acetate (3bb). White solid, 92% yield (163.9 mg), mp 161.8174.6 oC, 96:4 syn/anti, 98% ee for syn-isomer, [α]D25 +149.6 (c 0.92, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.38-7.24 (m, 5H), 7.23 (s, 1H), 7.22-7.06 (m, 5H), 7.03 (t, J = 7.2 Hz, 2H), 6.94 (t, J = 7.6 Hz, 1H), 6.72 (s, 2H), 6.62 (d, J = 8.0 Hz, 1H), 5.46-4.46 (m, 2H), 4.26 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.36 (s, 9H), 1.22 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.4, 173.2, 169.1, 153.8, 142.8, 138.4, 135.5, 135.2, 132.3, 130.8, 129.9, 129.0, 128.8, 128.6, 128.4, 128.3, 128.0, 127.1, 127.0, 126.8, 123.6, 122.2, 108.8, 79.9, 68.5, 64.2, 61.5, 43.9, 28.1, 13.9; IR (KBr, cm-1): ν 3462, 2926, 1725, 1616, 1487, 1372, 1257, 1175, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C37H38N3O5 604.2806, found 604.2802; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 9.6 min (syn-major), 23.0 min (anti-minor), 25.9 min (syn-minor), 123.2 min (anti-major). benzyl


((diphenylmethylene)amino)acetate (3cb). White solid, 91% yield (181.8 mg), mp 93.3146.8 oC, 96:4 syn/anti, 98% ee for syn-isomer, [α]D25 +85.8 (c 1.36, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.34-7.25 (m, 7H), 7.23 (d, J = 6.8 Hz, 1H), 7.19-7.03 (m, 7H), 6.97 (d, J = 6.8 Hz, 2H), 6.89 (t, J = 7.6 Hz, 2H), 6.61 (d, J = 7.6 Hz, 3H), 5.22 (d, J = 12.4 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 5.18-4.45 (m, 2H), 4.28 (s, 1H), 1.36 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.3, 173.5, 168.8, 153.8, 142.8, 138.3, 135.5, 135.1, 135.0, 132.3, 130.9, 129.9, 129.0, 128.8, 128.5, 128.4, 128.4, 128.3, 128.1, 127.0, 126.8, 123.6, 122.2 108.8, 79.9, 68.5, 67.1, 64.1, 44.0, 28.1; IR (KBr, cm-1): ν 3422, 2926, 1725, 1616, 1487, 1364, 1263, 1168, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C42H40N3O5 666.2963, found 666.2952; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 80/20, flow rate: 0.9 mL/min): tR = 8.7 min (syn-major), 13.7 min (anti-minor), 21.8 min (syn-minor), 37.4 min (anti-major).


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methyl (R)-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-5-chloro-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3aq). White solid, 99% yield (186.5 mg), mp 88.295.5 oC, 90:10 syn/anti, 95% ee for syn-isomer, [α]D25 +85.0 (c 1.07, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 7.6 Hz, 2H, major and minor), 7.40 (t, J = 8.0 Hz, 1H, major and minor), 7.38-7.31 (m, 3H, major and minor), 7.28 (t, J = 8.0 Hz, 2H, major and minor), 7.23 (s, 1H, major and minor), 7.21-7.08 (m, 4H, major and minor), 7.06-6.98 (m, 2H, major and minor), 6.97-6.86 (m, 2H, major and minor), 6.77 (s, 0.84H, major), 6.54 (d, J = 8.4 Hz, 1H, major and minor), 4.95 (s, 1H), 4.80 (s, 1H), 4.42 (s, 0.90H, major), 4.22 (s, 0.10H, minor), 3.74 (s, 2.70H, major), 3.69 (s, 0.30H, minor), 1.36 (s, 9H, major and minor); 13C{1H} NMR (100 MHz, CDCl3): δ 174.1, 173.9, 169.7, 153.6, 141.9, 138.3, 135.3, 135.1, 135.0, 130.9, 129.0, 128.8, 128.7, 128.6, 128.4, 128.1, 127.6, 127.2, 126.8, 124.0, 109.8, 80.3, 68.2, 64.0, 63.3, 52.6, 44.2, 28.1; IR (KBr, cm-1): ν 3422, 2926, 1725, 1616, 1487, 1364, 1257, 1168, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C36H3535ClN3O5 624.2260, found 624.2269; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 9.9 min (syn-major), 25.7 min (syn-minor), 28.2 min (anti-minor), 55.0 min (anti-major). methyl (R)-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-5-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3ar). White solid, 99% yield (180.9 mg), mp 170.3-180.4 oC, 97:3 syn/anti, 99% ee for syn-isomer, [α]D25 +111.8 (c 3.06, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.33 (q, J = 7.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 4H), 7.24 (s, 1H), 7.20-7.02 (m, 4H), 6.96 (d, J = 8.0 Hz, 2H), 6.84 (s, 1H), 6.73 (s, 2H), 6.51 (d, J = 8.0 Hz, 1H), 4.93 (s, 1H), 4.78 (s, 1H), 4.32 (s, 1H), 3.73 (s, 3H), 2.18 (s, 3H), 1.36 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ174.3, 173.4, 169.9, 153.7, 140.7, 138.4, 135.6, 135.3, 131.5, 130.8, 129.1, 129.0, 128.6, 128.4, 128.0, 127.1, 127.0, 126.8, 124.5, 108.6, 79.9, 68.5, 64.2, 52.4, 44.1, 28.1, 21.0; IR (KBr, cm-1): ν 3415, 2926, 1725, 1623, 1494, 1372, 1269, 1168, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C37H38N3O5 604.2806, found 604.2822; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 80/20, flow rate: 0.9 mL/min): tR = 6.8 min (syn-major), 14.6 min (syn-minor), 17.9 min (anti-minor), 24.8 min (anti-major). methyl (R)-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-6-chloro-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3as). White solid, 99% yield (187.1 mg), mp 181.3-182.8 oC, 94:6 syn/anti, 96% ee for syn-isomer, [α]D25 +91.3 (c 1.65, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.39-7.26 (m, 5H), 7.24 (s, 1H), 7.14 (t, J = 7.2 Hz, 2H), 7.11-7.01 (m, 3H), 6.96 (dd, J = 8.0, 1.6



Hz, 1H), 6.86-6.78 (m, 3H), 6.63 (d, J = 1.2 Hz, 1H), 4.96 (s, 1H), 4.75 (s, 1H), 4.41 (s, 0.06H, minor), 4.37 (s, 0.94H, major), 3.73 (s, 2.82H, major), 3.62 (s, 0.18H, minor), 1.35 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.5, 173.8, 169.8, 153.7, 144.6, 138.3, 135.2, 135.0, 134.6, 131.0, 129.0, 128.8, 128.5, 128.5, 128.1, 127.3, 127.1, 126.8, 124.4, 122.2, 109.5, 80.2, 68.2, 63.7, 52.6, 44.3, 28.1; IR (KBr, cm-1): ν 3422, 2980, 1725, 1616, 1494, 1372, 1269, 1168, 740, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C36H3535ClN3O5 624.2260, found 624.2267; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.9 mL/min): tR = 9.0 min (syn-major), 13.0 min (anti-minor), 25.0 min (syn-minor), 77.2 min (anti-major). methyl

(R)-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-6-methoxy-2-oxoindolin-3-

yl)-2-((diphenylmethylene)amino)acetate (3at). White solid, 97% yield (180.4 mg), mp 106.1-134.1 oC, 95:5 syn/anti, 99% ee for syn-isomer, [α]D25 +87.8 (c 1.94, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.36-7.26 (m, 5H), 7.24 (s, 1H), 7.21-7.09 (m, 3H), 7.09-7.00 (m, 3H), 6.79 (d, J = 4.0 Hz, 2H), 6.45 (dd, J = 8.0, 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 4.95 (s, 1H), 4.74 (s, 1H), 4.32 (s, 1H), 3.72 (s, 3H), 3.69 (s, 3H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.8, 173.3, 169.9, 160.5, 153.7, 144.4, 138.4, 135.4, 135.3, 130.8, 129.0, 128.6, 128.6, 128.4, 128.0, 127.1, 126.8, 124.1, 120.5, 105.6, 97.2, 79.8, 68.6, 63.8, 55.2, 52.4, 44.1, 28.1; IR (KBr, cm-1): ν 3442, 2926, 1725, 1650, 1494, 1378, 1269, 1162, 754, 700; HRMS (ESITOF) m/z: [M + H]+ calcd for C37H38N3O6 620.2755, found 620.2753; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 80/20, flow rate: 0.9 mL/min): tR = 7.7 min (syn-major), 12.3 min (anti-minor), 20.0 min (syn-minor), 52.8 min (antimajor). methyl (R)-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-7-chloro-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3au). White solid, 99% yield (187.1 mg), mp 188.5-191.0 oC, 97:3 syn/anti, 97% ee for syn-isomer, [α]D25 +148.3 (c 1.16, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.39-7.27 (m, 5H), 7.23 (s, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.12-7.05 (m, 2H), 7.01 (s, 2H), 6.90 (t, J = 8.0 Hz, 2H), 6.74 (d, J = 5.2 Hz, 1H), 5.28 (s, 2H), 4.31 (s, 1H), 3.70 (s, 3H), 1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.0, 173.7, 169.6, 153.7, 139.2, 138.2, 137.4, 135.0, 131.4, 131.0, 129.0, 128.8, 128.4, 128.1, 128.1, 126.9, 126.5, 126.1, 123.1, 121.9, 115.2, 80.2, 68.3, 63.7, 52.5, 45.2, 28.1; IR (KBr, cm-1): ν 3455, 2926, 1725, 1643, 1487, 1358, 1277, 1162, 760, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C36H3535ClN3O5 624.2260, found 624.2258; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2propanol = 90/10, flow rate: 0.9 mL/min): tR = 9.3 min (syn-major), 21.1 min (anti-minor),


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Page 23 of 29 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


35.5 min (syn-minor), 48.9 min (anti-major). methyl (R)-2-((S)-1-benzyl-7-bromo-3-((tert-butoxycarbonyl)amino)-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3av). White solid, 99% yield (200.3 mg), mp 84.099.3 oC, 98:2 syn/anti, 98% ee for syn-isomer, [α]D25 +143.4 (c 3.26, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.40-7.28 (m, 6H), 7.24 (s, 1H), 7.13 (d, J = 7.2 Hz, 2H), 7.08 (d, J = 7.2 Hz, 1H), 7.02 (s, 2H), 6.85 (t, J = 8.0 Hz, 2H), 6.74 (d, J = 5.2 Hz, 2H), 5.31 (s, 2H), 4.32 (s, 1H), 3.69 (s, 3H), 1.36 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.3, 173.7, 169.7, 153.7, 140.7, 138.2, 137.4, 135.1, 134.8, 131.1, 129.1, 128.9, 128.5, 128.2, 128.1, 127.0, 126.4, 126.2, 123.6, 122.5, 102.3, 80.3, 68.3, 63.7, 52.5, 45.0, 28.1; IR (KBr, cm-1): ν 3442, 2926, 1725, 1643, 1487, 1351, 1269, 1162, 748, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C36H3579BrN3O5 668.1755, found 668.1769; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2propanol = 80/20, flow rate: 0.9 mL/min): tR = 6.9 min (syn-major), 12.1 min (anti-minor), 18.0 min (syn-minor), 22.4 min (anti-major). methyl (R)-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-7-methyl-2-oxoindolin-3-yl)2-((diphenylmethylene)amino)acetate (3aw). White solid, 99% yield (181.0 mg), mp 209.9-212.4 oC, 98:2 syn/anti, 99% ee for syn-isomer, [α]D25 +155.0 (c 2.26, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.39-7.27 (m, 5H), 7.24 (s, 1H), 7.11 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 7.2 Hz, 3H), 6.96 (d, J = 7.6 Hz, 2H), 6.87 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 5.6 Hz, 2H), 5.66-4.51 (m, 2H), 4.28 (s, 1H), 3.70 (s, 3H), 2.21 (s, 3H), 1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.4, 173.3, 169.8, 153.8, 141.0 , 138.4, 137.6, 135.3, 132.9, 130.9, 129.1, 128.7, 128.5, 128.4, 128.1, 127.1, 126.6, 125.6, 122.3, 121.5, 119.4, 79.9, 68.7, 63.6, 52.4, 45.4, 28.2, 18.7; IR (KBr, cm-1): ν 3415, 2926, 1725, 1603, 1487, 1358, 1269, 1162, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C37H38N3O5 604.2806, found 604.2810; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 80/20, flow rate: 0.9 mL/min): tR = 7.9 min (syn-major), 12.2 min (anti-minor), 21.0 min (syn-minor), 27.8 min (anti-major). Procedure for Hydrolysis of Mannich adduct 3ab. Mannich adduct 3ab (0.1 mmol, 59.0 mg) was dissolved in 1.0 M HCl/MeOH solution (1 mL) and stirred at room temperature. After 30 min, the mixture was neutralized by adding saturated aqueous NaHCO3 solution and then extracted by ethyl acetate. The organic phase was separated, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica-gel column chromatography (3:1 petroleum ether/ethyl acetate) to afford compound 4.



methyl

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(R)-2-amino-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-2-oxoindolin-3-

yl)acetate (4). White solid, 99% yield (42.4 mg), mp 146.1-150.8 oC, [α]D25 +11.1 (c 1.31, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.17 (dd, J = 7.6, 0.8 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.00 (dd, J = 7.2, 0.4 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.31 (s, 1H), 5.13 (s, 1H), 4.76 (s, 1H), 3.94 (s, 1H), 3.68 (s, 3H), 1.62 (s, 2H), 1.26 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.3, 172.3, 153.7, 143.9, 135.7, 129.4, 128.6, 127.5, 127.4, 126.7, 123.2, 122.4, 109.1, 80.3, 63.2, 58.9, 52.5, 44.3, 28.0; IR (KBr, cm-1): ν 3395, 2926, 1725, 1609, 1474, 1372, 1269, 1175, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H28N3O5 426.2024, found 426.2035. Procedure for Hydrolysis and Deprotection of Mannich adduct 3ab. Mannich adduct 3ab (0.1 mmol, 59.0 mg) was dissolved in 4.0 M HCl/MeOH solution (1 mL) and stirred at room temperature. After 2 hours, the mixture was neutralized by adding saturated aqueous NaHCO3 solution and then extracted by ethyl acetate. The organic phase was separated, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica-gel column chromatography (100:10:1 CH2Cl2/MeOH/NH4OH) to afford compound 5. methyl (R)-2-amino-2-((S)-3-amino-1-benzyl-2-oxoindolin-3-yl)acetate (5). Colorless oil, 99% yield (32.5 mg), [α]D25 +15.6 (c 0.96, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 7.6 Hz, 3H), 7.30 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.07 (d, J = 16.0 Hz, 1H), 4.73 (d, J = 16.0 Hz, 1H), 3.91 (s, 1H), 3.68 (s, 3H), 1.86 (s, 4H);

13

C{1H} NMR (100 MHz,

CDCl3): δ 178.8, 143.2, 135.5, 129.9, 129.5, 128.6, 127.7, 127.5, 127.2, 124.7, 122.6, 109.2, 52.0, 43.8; IR (KBr, cm-1): ν 3381, 3306, 2920, 1725, 1616, 1474, 1364, 1269, 1175, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H20N3O3 326.1499, found 326.1493. Procedure for Hydrogenation of Mannich adduct 3ab. Mannich adduct 3ab (0.2 mmol, 117.9 mg), Pd/C (0.02 mmol, 20% weight, 10.6 mg) and MeOH (2 mL) were added to a flame-dried Schlenk tube equipped a stir bar and the resulting mixture was alternately evacuated and charged with hydrogen (1 atm). After stirring at room temperature for 12 hours, the mixture was diluted with EtOAc and filtered through a Celite pad. The solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography (8:1 petroleum ether/ethyl acetate) to afford compound 6. methyl

(R)-2-(benzhydrylamino)-2-((S)-1-benzyl-3-((tert-butoxycarbonyl)amino)-2-

oxoindolin-3-yl)acetate (6). White solid, 96% yield (113.6 mg), mp 206.4-209.3 oC,


Page 25 of 29 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


[α]D25 +11.2 (c 2.10, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.45 (dd, J = 7.2, 2.0 Hz, 2H), 7.29 (d, J = 4.4 Hz, 4H), 7.27-7.19 (m, 8H), 7.19-7.13 (m, 2H), 7.09 (d, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 5.10 (d, J = 15.2 Hz, 1H), 4.81 (s, 1H), 4.64 (d, J = 2.0 Hz, 1H), 3.69 (d, J = 12.8 Hz, 1H), 3.56 (s, 3H), 2.62 (d, J = 11.6 Hz, 1H), 1.23 (s, 9H);

13

C{1H} NMR (100 MHz, CDCl3): δ 175.1, 171.4,

153.7, 143.7, 143.2, 141.1, 135.7, 129.4, 128.6, 128.5, 127.7, 127.6, 127.4, 127.3, 127.1, 123.7, 122.3, 109.0, 80.4, 65.3, 63.4, 62.2, 52.2, 44.5, 28.0; IR (KBr, cm-1): ν 3415, 2926, 1725, 1616, 1487, 1372, 1269, 1168, 754, 700; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C36H38N3O5 592.2806, found 592.2822; HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 70/30, flow rate: 0.9 mL/min): tR = 10.0 min (major), 22.9 min (minor). Procedure for Debenzylation of Mannich adduct 3ab. Under a nitrogen atmosphere, a solution of compound 3ab (0.1 mmol, 59.0 mg) in chlorobenzene (3 mL) containing NBS (0.14 mmol, 24.9 mg) and AIBN (0.03 mmol, 4.9 mg) was heated to reflux for 1 hour. The resulting solution was cooled to room temperature. Diethyl ether (2 mL) and water (4 mL) were added and stirred for 4 hours, and then the organic layer was separated, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica-gel column chromatography (2:1 petroleum ether/ethyl acetate) to afford Mannich adduct 3ad in 68% yield (34.2 mg).

ASSOCIATED CONTENT Supporting Information NMR spectra of new chiral ligands L11-L13; NMR spectra of chiral products 3-6 and HPLC chromatograms of products 3 and 6; X-ray structure of product 3ab; CIF file of enantiopure 3ab. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Tel: +86-21-64252011. ORCID Xin-Yan Wu: 0000-0002-6942-7067 Notes The authors declare no competing financial interest.



ACKNOWLEDGMENT We are grateful for the financial support by Shanghai Pujiang Program (18PJD010) and the Fundamental Research Funds for the Central Universities (222201814019). REFERENCES (1) For reviews, see: (a) Córdova, A. The Direct Catalytic Asymmetric Mannich Reaction. Acc. Chem. Res. 2004, 37, 102-112. (b) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Organocatalysed Asymmetric Mannich Reactions. Chem. Soc. Rev. 2008, 37, 29-41. (c) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Catalytic Enantioselective Formation of C-C Bonds by Addition to Imines and Hydrazones: A Ten-Year Update. Chem. Rev. 2011, 111, 2626-2704. (d) Karimi, B.; Enders, D.; Jafari, E. Recent Advances in Metal-Catalyzed Asymmetric Mannich Reactions. Synthesis 2013, 45, 2769-2812; (e) Saranya, S.; Harry, N. A.; Krishnan, K. K.; Anilkumar, G. Recent Developments and Perspectives in the Asymmetric Mannich Reaction. Asian J. Org. Chem. 2018, 7, 613-633. (2) For reviews, see: (a) Arrayás, R. G.; Carretero, J. C. Catalytic Asymmetric Direct Mannich Reaction: A Powerful Tool for the Synthesis of α,β-Diamino Acids. Chem. Soc. Rev. 2009, 38, 1940-1948. (b) Viso, A.; Fernández de la Pradilla, R.; Tortosa, M.; García, A.; Flores, A. Update 1 of: α,β-Diamino Acids: Biological Significance and Synthetic Approaches. Chem. Rev. 2011, 111, PR1-PR42. (3) For examples, see: (a) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. Catalytic Asymmetric Mannich Reactions of Glycine Derivatives with Imines. A New Approach to Optically Active α,β-Diamino Acid Derivatives. J. Org. Chem. 2003, 68, 2583-2591. (b) Yan, X.-X.; Peng, Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X.-L.; Wu, Y.-D. Highly Diastereoselective Switchable Enantioselective Mannich Reaction of Glycine Derivatives with Imines. J. Am. Chem. Soc. 2008, 130, 14362-14363. (c) Shang, D.; Liu, Y.; Zhou, X.; Liu, X.; Feng, X. A N,N’-DioxideCopper(II) Complex as an Efficient Catalyst for the Enantioselective and Diastereoselective Mannich-Type Reaction of Glycine Schiff Bases with Aldimines. Chem.-Eur. J. 2009, 15, 36783681. (d) Liang, G.; Tong, M.-C.; Tao, H.; Wang, C.-J. Catalytic Asymmetric Mannich Reaction of Glycine Derivatives with N-Tosylimines using Copper(I)/TF-BiphamPhos Complex. Adv. Synth. Catal. 2010, 352, 1851-1855. (e) Hernández-Toribio, J.; Gómez Arrayás, R.; Carretero, J. C. Substrate-Controlled Diastereoselectivity Switch in Catalytic Asymmetric Direct Mannich Reaction of Glycine Derivatives with Imines: From anti- to syn-α,β-Diamino Acids. Chem.-Eur. J. 2010, 16, 1153-1157. (f) Imae, K.; Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Ag/ThioClickFerrophos-Catalyzed Enantioselective Mannich Reaction and Amination of Glycine Schiff Base. J. Org. Chem. 2011, 76, 3604-3608. (g) Arai, T.; Mishiro, A.; Matsumura,


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