Asymmetric Synthesis of Spirocyclic Oxindole Î´-Lactams via NHC

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Asymmetric Synthesis of Spirocyclic Oxindole #-Lactams via NHC-Catalyzed Formal [2+4] Annulation of Aliphatic Aldehydes with Oxindole-derived #,#-Unsaturated Ketimines he chonglong, Zhanhuan Li, Jianfeng Xu, and HONGJUN REN J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01760 • Publication Date (Web): 22 Aug 2019 Downloaded from pubs.acs.org on August 25, 2019

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The Journal of Organic Chemistry

Asymmetric Synthesis of Spirocyclic Oxindole δ-Lactams via NHC-Catalyzed Formal [2+4] Annulation of Aliphatic Aldehydes with Oxindole-derived α,β-Unsaturated Ketimines Chonglong He,† Zhanhuan Li,† Jianfeng Xu,†,* and Hongjun Ren‡,* †

Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China

‡Advanced Research Institute and Department of Chemistry, Taizhou University, 1139 Shifu Avenue, Taizhou 318000, P. R. China.

ABSTRACT: An N-heterocyclic carbene (NHC) catalyzed formal [2+4] annulation reaction of aliphatic aldehydes with oxindole-derived α,β-unsaturated ketimines under oxidative condition is reported, affording spirocyclic oxindole δ-lactams with good yields, moderate diastereoselectivies, and good to excellent enantioselectivies. This reaction can be readily carried out on gram scale, and the products could be further transformed to other synthetically useful compounds.

Oxindoles bearing a spiro-ring fused at the C3-position represent a class of privileged structures that widely encounter in a variety of biologically active natural products and pharmaceutical compounds.1 In particular, spirocyclic oxindole -lactams are distributed as the core skeletons in a number of molecules which show diverse captivating biological and medicinal properties.2 For example, Surugatoxin is found in the Japanese ivory mollusk Babylonia japonica that functions as a ganglionic blocker of nicotinic acetylcholine receptors,2a and Lapatin B is isolated from the fungus Penicillium lapatayae which exhibits potent inhibitory activity against the aqua-bacterial V (Figure 1).2b,c

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Figure 1. Representative Examples of Natural Products Containing The Spirocyclic Oxindole -Lactam Motif.

However, despite their intriguing activities and potential uses in medicinal chemistry, to date the direct preparation of spirocyclic oxindole -lactams in a catalytic and asymmetric manner remains very limited.3 In 2015, Zhong and co-workers disclosed an NHC-catalyzed highly enantioselective [3+3] annulation reaction of oxindole-derived enals with N-sulfonyl ketimines under oxidative conditions (Scheme 1a).3a Very recently, Enders and co-workers modified this strategy by employing cyclic N-sulfonyl ketimines to construct enantioenriched pentacyclic spirooxindoles.3c In 2017, Kumar and coworkers discovered a Lewis acid promoted [4+2] annulation reaction of 2-aza-3-silyloxybutadienes with alkylidene oxindoles to afford chiral spirocyclic oxindole -lactams in high yields and good enantioselectivies (Scheme 1b).3b Nevertheless, the development of efficient asymmetric protocols to rapidly synthesize these precious molecules is still in high demand. Scheme 1. Catalytic Asymmetric Synthesis of Spirocyclic Oxindole -Lactams.

N-Heterocyclic carbenes (NHCs) are well known as an organocatalyst which can react with aldehydes to turn the electrophilic carbonyl carbon to a nucleophilic carbon.4


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Recently, the NHC-catalyzed direct asymmetric -carbon functionalization of saturated aldehydes has also been achieved by employing an oxidant to convert the key Breslow intermediate to an acyl azolium intermediate.5 Our group is interested in establishing new protocols to create structurally complex molecules through exploiting NHC as an intriguing catalyst.5f-g,6 Herein, as a continuous effort in constructing synthetically useful heterocyclic compounds via NHC catalyzed direct -functionalization of saturated aldehydes, we wish to report our recent progress on developing an NHC catalyzed asymmetric oxidative [2+4] annulation reaction of aliphatic aldehydes with oxindolederived ,-unsaturated ketimines (Scheme 1c). This reaction started by generation of Breslow intermediate I from addition of NHC catalyst to aliphatic aldehydes. Under an oxidative reaction condition, intermediate I was then oxidized and deprotonated to form enolate intermediate II, which next undergo a Michael addition reaction with oxindolederived ,-unsaturated ketimines to provide intermediate III. Intramolecular lactamization of intermediate III finally afforded spirocyclic oxindole -lactams in good yields, moderate diastereoselectivies, and good to excellent enantioselectivies and regenerated NHC catalyst.

Experimentally, we first set out to investigate this formal [2+4] annulation reaction by using hydrocinnamaldehyde 1a and oxindole-derived N-Ts ketimine 2a as the model substrates, and the key results are briefed in Table 1. When aminoindanol-derived NHC pre-catalyst A7 was employed, the anticipated spirocyclic oxindole -lactam 3a and 3a’ were successfully generated in 52% combined yield, 74:26 dr, 78% and 50% ee (Table 1, entry 1). L-phenylalanine derived NHC pre-catalyst B8 provided 3a and 3a’ with a slightly better yield and ee value (entry 2), while L-Leucine derived NHC pre-catalyst C9 resulted in a decrease in enantioselectivity (entry 3). So we chose NHC B as the optimal pre-catalyst, and then tested a series of solvents. Polar solvents such as 1,4-dixoane and ethyl acetate proceeded this reaction smoothly (entries 4-5). 1,2-Dichloroethane (DCE), to our surprise, showed the highest efficiency by delivering 3a and 3a’ in 82% combined yield, 70:30 dr, 90% and 84% ee (entry 6). Non-polar solvent such as toluene was not effective possibly due to the poor solubility (entry 7). With DCE as the optimal solvent, we next examined the base effect. Strong organic base such as 1,8diazabicyclo(5.4.0)undec-7-ene (DBU) exhibited poorer reactivity than Cs2CO3 (entry 8). Weaker bases such as N,N-diisopropylethylamine (DIPEA) and K2CO3 could furnish 3a with slightly higher diastereoselecitvites and enantioselectivies, but the yields were less satisfactory (entries 9-10). Reducing the reaction time to 24 h caused a drop in yields as substrate 2a was not completely consumed (entries 11-12). In the absence of 4 Å MS, the reaction became rather messy (entry 13). Further experiment revealed that using catalytic amount of 4 and stoichiometric amount of activated MnO2 as the oxidant was possible, albeit a slight drop in yield and diastereoselectivity was observed (entry 14).



Table 1. Optimization of Reaction Conditionsa

base

yield (%)b

drc

ee of 3a (%)d

ee of 3a’ (%)d

Cs2CO3 Cs2CO3 Cs2CO3

52 73 59

74:26 75:25 68:32

78 82 60

50 77 61

B B

1,4-dioxane Cs2CO3 EtOAc Cs2CO3

68 62

75:25 69:31

80 88

74 33

6 7

B B

DCE toluene

Cs2CO3 Cs2CO3

82 27

70:30 77:23

90 82

84 n.d.

8 9

B B

DCE DCE

DBU DIPEA

55 23

65:35 80:20

70 92

61 n.d.

10 11 e

B B

DCE DCE

K2CO3 Cs2CO3

37 44

87:13 70:30

90 90

n.d. 84

12e,f 13g

B B

DCE DCE

Cs2CO3 Cs2CO3

64 n.d.

74:26 n.d.

90 n.d.

68 n.d.

14h

B

DCE

Cs2CO3

75

66:34

90

84

entry

cat. solvent

1 2 3

A B C

THF THF THF

4 5

a

Reaction conditions unless otherwise specified: 1a (0.2 mmol), 2a (0.1 mmol), NHC (20 mol %), base (0.15 mmol), oxidant 4 (0.12 mmol), solvent (1 mL), and 4 Å MS (100 mg, powder) under a nitrogen atmosphere at 25 oC for 72 h. b Combined isolated yields of both diastereomers based on 2a. c Diastereomeric ratio of 3a and 3a’, determined via 1H NMR analysis of crude reaction mixtures. d Enantiomeric excess of 3a and 3a’, determined via chiral phase HPLC analysis. e 24 h. f 40 oC. g No 4 Å MS was used. h 4 (0.02 mmol) and activated MnO2 (0.1 mmol) was used as the oxidant. n.d. = not determined.

Having found the optimized reaction conditions (Table 1, entry 6), we next studied the scope of this formal [2+4] annulation reaction. As illustrated in Scheme 2, a variety of aliphatic aldehydes were first explored. Hydrocinnamaldehydes with an electron-rich substituent (4-OMe) or an electron-deficient substituent (4-Br) on the β-phenyl ring all reacted with 2a smoothly, affording the corresponding products 3b and 3c in 90% yield, 71:29 dr, 90% ee, and 84% yield, 69:31 dr, 92% ee, respectively. Linear aliphatic aldehydes with short (propanal) or long side chains (decanal) were also well tolerated,


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Scheme 2. Scope of Reactionsa

a

Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), NHC B (20 mol %), Cs2CO3 (0.15 mmol), DCE (1 mL), oxidant 4 (0.12 mmol), 4Å MS (100 mg, powder) under a nitrogen atmosphere at 25 oC for 72 h; Combined isolated yields of both diastereomers based on 2; The drs were determined via 1H NMR analysis; The ees were determined via chiral phase HPLC analysis.

leading to the desired products 3d-f in similar results. Notably, when an aldehyde with a carbon-carbon double bond on the side chain was utilized, this double bond can be directly maintained to the product 3g, which was possible for further transformations. A broad range of oxindole-derived ,-unsaturated ketimines with diverse electronic and steric properties were next evaluated. The installation of electron-donating groups (5-Me and 5-OMe) or electron-withdrawing groups (5-F, 5-Cl, and 5-Br) on the oxindole phenyl ring had little impact, as these substrates all delivered the corresponding products 3h-l successfully, and the absolute configuration of the major enantiomer was assigned based on X-ray crystallographic analysis of 3i (see supporting information for details). The replacement of the methyl group on the oxindole lactam ring with a benzyl or an allyl group caused a decrease in yield, but the diastereoselectivies and enantioselectivies were



generally the same (3m and 3n). Unfortunately, N-Boc and N-Ac protected ketimines were not accommodated in this reaction. The introduction of substituents to the ,unsaturated ketimine phenyl ring could further improve the enantioselectivities of the products (3o-s), and 4-methylphenyl substituted ketimine gave the best result by furnishing 3o in 72% yield, 71:29 dr, and 97% ee. Finally, the substitution patterns on the sulfonyl phenyl ring were investigated. Both 4-OMe and 4-NO2 substituted ketimines were proven to be compatible under the optimal reaction conditions, although a slight drop in diastereoselectivies was observed (3t and 3u).

Since the diastereoselectivities of the reactions shown in Scheme 2 were not satisfactory,10 we carried out two additional experiments to see if this phenomenon was attributed to the use of (Z)- and (E)-mixture of substrates 2. As depicted in Scheme 3, both (Z)-2j and (E)-2j gave the corresponding product 3p with similar results, suggesting that the configurations of the double bond on 2 almost had no effect on the diastereoselectivities of products 3. Scheme 3. Effect of (Z) and (E) Isomers.

Furthermore, we also tried to demonstrate the synthetic utility of this formal [2+4] annulation reaction by expanding the reaction scale and transforming the products to other useful molecules (Scheme 4). Under the optimal reaction conditions, this reaction can be readily performed on 3 mmol scale to directly give more than 1 gram of 3a. Treatment of 3a with sodium and naphthalene at -78 oC successfully removed the tosyl group to provide product 5 without loss of enantioselectivity, and hydrogenation of 3a stereoselectively reduced the double bond to afford saturated -lactam 6.


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Scheme 4. Gram-scale Preparation and Synthetic Transformation of 3a

In summary, we have developed an NHC-catalyzed oxidative [2+4] annulation reaction of aliphatic aldehydes with oxindole-derived ,-unsaturated ketimines to furnish spirocyclic oxindole -lactams in good yields, moderate diastereoselectivities, and good to excellent enantioselectivies. This reaction can be easily scaled up, the tosyl group could be readily removed, and the double bond can be straightforwardly reduced. Further controlled experiments show the configurations of the double bond on ketimines do not affect the outcomes.

EXPERIMENTAL SECTION General Information Commercially available materials were used as received. 1H and 13 CNMR spectra were recorded at 400 and 100 MHz, respectively. Chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethylsilane (δ = 0.00) or chloroform ( = 7.26). High-resolution mass spectra were obtained on a HRMS/LC-MS instrument with ESI as the ionization method. The determination of ee was performed via chiral HPLC analysis using IA, IC, ID, ADH and ASH columns (25 × 0.46 cm) on an HPLC instrument. Optical rotations were measured using a 1 mL cell with a 1 dm path length and are reported as follows: [α]rtD (c in g per 100 mL solvent). All reactions were monitored by TLC with GF 254 silica gel coated plates. Flash column chromatography was carried out using 200−300 mesh silica gel. All of the ketimine substrates 2 in this work were synthesized according to reported method.10,11 General Procedure for the Catalytic Synthesis of Spirocyclic Oxindole -lactams 3. To a dry 10 mL Schlenk tube equipped with a magnetic stir bar, was added 2 (0.1 mmol), chiral NHC pre-catalyst B (8.4 mg, 0.02 mmol), oxidant 4 (49.0 mg, 0.12 mmol), 4Å MS (100 mg), and Cs2CO3 (48.8 mg, 0.15 mmol). The tube was sealed with a septum, evacuated and refilled with nitrogen (3 cycles). DCE (1 mL) and 1 (0.2 mmol) were then added and the reaction mixture was allowed to stir for 72 hours at 25 oC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography using petroleum ether/EtOAc = 5/1 as eluent to afford the desired spirocyclic oxindole -lactams 3. Note: The racemic



catalyst that used for the preparation of the corresponding racemic products for HPLC analysis was synthesized by mixing chiral pre-catalyst A and ent-A in a 1:1 ratio. 3'-Benzyl-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (3a + 3a’): 44.9 mg, 82% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2a (41.6 mg, 0.1 mmol), 70:30 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H29N2O4S+ 549.1843; found 549.1857. (3R,3'S)-3'-Benzyl-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H) -dione (3a): yellow solid, 108-110 oC. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.33-7.28 (m, 5H), 7.18-7.12 (m, 6H), 6.99 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 7.6 Hz, 1H), 5.54 (s, 1H), 3.68 (t, J = 6.4 Hz, 1H), 3.13 (dd, J1 = 14.4 Hz, J2 = 6.4 Hz, 1H), 2.96 (s, 3H), 2.47 (s, 3H), 2.07 (dd, J1 = 14.4 Hz, J2 = 6.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.5, 172.2, 145.4, 143.3, 141.2, 138.2, 136.8, 135.8, 129.8, 129.4, 129.3, 129.2, 128.4, 128.1, 128.0, 126.4, 126.3, 126.3, 124.7, 123.8, 119.5, 108.4, 51.5, 51.4, 32.8, 26.3, 21.7. [α]13D = +74.0 (c = 0.3 in CH2Cl2); HPLC analysis: 90% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 10:90; retention times: 14.7 min (minor), 18.8 min (major)]. (3R,3'R)-3'-Benzyl-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H) -dione (3a’): yellow solid, 87-89 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 2H), 7.35-7.27 (m, 8H), 7.07-7.06 (m, 4H), 6.99 (t, J = 7.2 Hz, 1H), 6.87-6.82 (m, 3H), 5.38 (s, 1H), 3.33-3.00 (m, 1H), 3.17 (s, 3H), 3.10 (dd, J1 = 14.0 Hz, J2 = 7.2 Hz, 1H), 2.43 (s, 3H), 2.06 (dd, J1 = 14.0 Hz, J2 = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.8, 170.8, 144.5, 143.8, 142.7, 139.5, 137.3, 136.0, 130.0, 129.9, 129.2, 128.7, 128.6, 128.3, 128.0, 127.9, 126.0, 125.9, 123.2, 123.1, 118.1, 108.4, 52.8, 51.4, 31.5, 26.4, 21.6. [α]22D = -161.8 (c = 1.0 in CH2Cl2); HPLC analysis: 84% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 14.8 min (major), 22.4 min (minor)]. 3'-(4-Methoxybenzyl)-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3b + 3b’): 52.0 mg, 90% yield from aldehyde 1b (32.8 mg, 0.2 mmol) and ketimine 2a (41.6 mg, 0.1 mmol), 71:29 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C34H31N2O5S+ 579.1948; found 579.1957. (3R,3'S)-3'-(4-Methoxybenzyl)-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3b): yellow solid, 112-114 oC. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.32-7.28 (m, 5H), 7.17 (d, J= 6.8 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 7.6Hz, 1H), 6.71 (d, J = 8.4Hz, 2H), 5.53 (s, 1H), 3.74 (s, 3H), 3.62 (t, J = 6.8 Hz, 1H), 3.06 (dd, J1 = 14.8 Hz, J2 = 6.8 Hz, 1H), 2.98 (s, 3H), 2.47 (s, 3H), 2.04 (dd, J1 = 14.4 Hz, J2 = 6.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 172.3, 158.2, 145.3, 143.4, 141.2, 136.8, 135.9, 130.4, 130.1, 129.8, 129.4, 129.2, 128.4, 128.1, 126.5, 126.3, 124.7, 123.8, 119.6, 113.4, 108.4, 55.2, 51.6, 51.5, 32.0, 26.4, 21.7. [α]13D = +174.3 (c = 0.3 in CH2Cl2); HPLC analysis: 90% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 12.8 min (minor), 14.7 min (major)].


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3'-(4-Bromobenzyl)-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] (3c + 3c’): 52.7 mg, 84% yield from aldehyde 1c (42.6 mg, 0.2 mmol) and ketimine 2a (41.6 mg, 0.1 mmol), 69:31 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H28BrN2O4S+ 627.0948; found 627.0955. (3R,3'S)-3'-(4-Bromobenzyl)-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] -2,2'(3'H)-dione (3c): yellow solid, 135-137 oC. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.33-7.26 (m, 7H), 7.16 (d, J= 6.8 Hz, 2H), 7.12 (t, J = 6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 7.6Hz, 1H), 5.54 (s, 1H), 3.62 (t, J = 6 Hz, 1H), 3.05-2.99 (m, 4H), 2.47 (s, 3H), 2.04 (dd, J1 = 14.4 Hz, J2 = 5.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.5, 172.0, 145.5, 143.2, 141.3, 137.2, 136.7, 135.8, 131.1, 130.0, 129.7, 129.5, 129.2, 128.5, 128.1, 126.3, 126.2, 124.7, 124.0, 120.3, 119.3, 108.5, 51.5, 51.3, 32.4, 26.4, 21.7. [α]14D = +110.0 (c = 0.3 in CH2Cl2); HPLC analysis: 92% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 12.0 min (minor), 13.4 min (major)]. (3R,3'R)-3'-(4-Bromobenzyl)-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3c’): orange solid, 86-88 oC. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.34-7.29 (m, 8H), 7.18 (d, J= 8.4Hz, 2H), 7.07-7.00 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.4 Hz, 2H), 5.38 (s, 1H), 3.27-3.25 (m, 1H), 3.17 (s, 3H), 3.02 (dd, J1 = 14.4 Hz, J2 = 7.6 Hz, 1H), 2.46 (s, 3H), 2.07 (dd, J1 = 14.0 Hz, J2 = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.8, 170.8, 144.7, 144.0, 142.9, 138.4, 137.3, 136.1, 131.1, 130.7, 130.2, 129.9, 129.4, 128.7, 128.5, 128.2, 126.1, 123.3, 52.7, 51.4, 31.2, 26.5, 21.8. [α]22D = -36.3 (c = 0.3 in CH2Cl2); HPLC analysis: 92% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 24.7 min (major), 28.3 min (minor)]. 1,3'-Dimethyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (3d + 3d’): 31.2 mg, 66% yield from aldehyde 1d (11.6 mg, 0.2 mmol) and ketimine 2a (41.6 mg, 0.1 mmol), 69:31 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H25N2O4S+ 473.1530; found 473.1536. (3R,3'S)-1,3'-Dimethyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3d): red solid, 107-109 oC. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.2 Hz, 1H), 7.37-7.28 (m, 6H), 7.20 (d, J= 6.4 Hz, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.63 (s, 1H), 3.34 (q, J = 6.8 Hz, 1H), 3.25 (s, 3H), 2.48 (s, 3H), 0.83 (d, J= 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.9, 172.8, 145.4, 143.3, 141.6, 137.0, 136.0, 129.8, 129.3, 129.2, 128.4, 128.1, 126.3, 124.6, 124.0, 119.4, 108.3, 51.8, 45.6, 26.6, 21.7, 9.9. [α]13D = +72.0 (c = 0.3 in CH2Cl2); HPLC analysis: 94% ee , [CHIRALPAK ID column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 29.2 min (minor), 33.8 min (major)]. (3R,3'R)-1,3'-Dimethyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3d’): yellow solid, 122-124oC. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.38-7.28 (m, 8H), 7.17 (d, J= 7.2 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 5.40 (s, 1H), 3.20 (s, 3H), 3.12 (q, J = 6.8 Hz, 1H), 2.44 (s, 3H), 0.83 (d, J= 6.8 Hz, 3H); 13C NMR{1H} (100 MHz, CDCl3) δ 174.0, 171.8, 144.6, 144.0, 143.0, 137.6,



136.3, 130.4, 130.0, 129.2, 128.7, 128.4, 128.2, 126.2, 123.2, 122.8, 117.9, 108.4, 51.6, 45.9, 26.4, 21.8, 10.0. [α]22D = -111.3 (c = 0.3 in CH2Cl2); HPLC analysis: 65% ee, [CHIRALPAK AS-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 18.7 min (minor), 23.0 min (major)]. 3'-Butyl-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (3e + 3e’): 46.8 mg, 91% yield from aldehyde 1e (20.0 mg, 0.2 mmol) and ketimine 2a (41.6 mg, 0.1 mmol), 73:27 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C30H31N2O4S+ 515.1999; found 515.2007. (3R,3'S)-3'-Butyl-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3e): yellow solid, 110-112 oC. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 2H), 7.35-7.31 (m, 7H), 7.23 (d, J= 6.4 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 5.57 (s, 1H), 3.24 (s, 3H), 3.18-3.15 (m, 1H), 2.48 (s, 3H), 1.58-1.50 (m, 2H), 1.21-1.15 (m, 4H), 0.78 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.1, 172.6, 145.3, 143.2, 141.4, 137.1, 135.9, 129.8, 129.1, 128.4, 128.1, 126.8, 126.2, 124.6, 123.8, 119.5, 108.4, 51.9, 50.1, 30.7, 26.6, 26.3, 22.6, 21.7, 13.7. [α]14D = +58.0 (c = 0.3 in CH2Cl2); HPLC analysis: 91% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 6.3 min (minor), 12.5 min (major)]. (3R,3'R)-3'-Butyl-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3e’): red solid, 71-73 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.40-7.29 (m, 8H), 7.16 (d, J= 7.6 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.37 (s, 1H), 3.18 (s, 3H), 2.92-2.89 (m, 1H), 2.45 (s, 3H), 1.68-1.61 (m, 2H), 1.091.02 (m, 4H), 0.78 (t, J = 6.8 Hz, 3H); 13C NMR{1H} (100 MHz, CDCl3) δ 174.2, 171.5, 144.6, 144.0, 142.8, 137.7, 136.3, 130.1, 129.1, 128.8, 128.7, 128.3, 128.2, 126.1, 123.1, 123.0, 118.2, 108.3, 51.5, 50.3, 31.0, 26.5, 25.4, 22.2, 21.8, 13.6. [α]22D = -57.0 (c = 0.3 in CH2Cl2); HPLC analysis: 82% ee, [CHIRALPAK AS-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 20.0 min (major), 23.5 min (minor)]. 1-Methyl-3'-octyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (3f + 3f’): 45.6 mg, 80% yield from aldehyde 1f (31.2 mg, 0.2 mmol) and ketimine 2a (41.6 mg, 0.1 mmol), 69:31 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C34H39N2O4S+ 571.2625; found 571.2635. (3R,3'S)-1-Methyl-3'-octyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3f): yellow solid, 63-65 oC. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 2H), 7.35-7.30 (m, 7H), 7.23 (d, J= 6.4 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 5.57 (s, 1H), 3.24 (s, 3H), 3.17-3.15 (m, 1H), 2.48 (s, 3H), 1.62-1.51 (m, 2H), 1.26-1.14 (m, 12H), 0.85 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.1, 172.6, 145.3, 143.2, 141.4, 137.1, 135.9, 129.9, 129.1, 128.4, 128.1, 126.9, 126.2, 124.6, 123.8, 119.5, 108.3, 51.9, 50.2, 31.8, 29.5, 29.2, 29.1, 28.5, 26.6, 26.5, 22.6, 21.7, 14.0. [α]14D = +154.0 (c = 0.3 in CH2Cl2); HPLC analysis: 88% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 5.8 min (minor), 11.5 min (major)].


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(3R,3'R)-1-Methyl-3'-octyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3f’): yellow solid, 65-67 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.39-7.38 (m, 2H), 7.334-7.29 (m, 6H), 7.16 (d, J= 7.2 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.37 (s, 1H), 3.18 (s, 3H), 2.91-2.89 (m, 1H), 2.45 (s, 3H), 1.64-1.61 (m, 2H), 1.29-1.19 (m, 4H), 1.12-1.02 (m, 8H), 0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 171.5, 144.6, 144.0, 142.8, 137.7, 136.3, 130.6, 130.1, 129.1, 128.7, 128.3, 128.2, 126.1, 123.1, 123.0, 118.2, 108.3, 51.5, 50.3, 31.8, 29.7, 29.1, 29.0, 28.8, 26.5, 25.7, 22.6, 21.8, 14.0. [α]22D = -86.7 (c = 0.3 in CH2Cl2); HPLC analysis: 89% ee, [CHIRALPAK AS-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 7.6 min (major), 9.6 min (minor)]. 1-Methyl-3'-(non-8-en-1-yl)-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine-2,2'(3'H)dione (3g + 3g’): 47.2 mg, 81% yield from aldehyde 1g (33.6 mg, 0.2 mmol) and ketimine 2a (41.6 mg, 0.1 mmol), 69:31 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C35H39N2O4S+ 583.2625; found 583.2637. (3R,3'S)-1-Methyl-3'-(non-8-en-1-yl)-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine2,2'(3'H)-dione (3g): yellow solid, 80-81 oC. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 2H), 7.35-7.30 (m, 7H), 7.23 (d, J= 6.0 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 5.83-5.73 (m, 1H), 5.57 (s, 1H), 4.99-4.90 (m, 2H), 3.24 (s, 3H), 3.183.15 (m, 1H), 2.48 (s, 3H), 2.01-1.96 (m, 2H), 1.58-1.47 (m, 2H), 1.32-1.15 (m, 10H); 13 C{1H} NMR (100 MHz, CDCl3) δ 177.1, 172.6, 145.3, 143.2, 141.4, 139.2, 137.1, 135.9, 129.9, 129.1, 128.4, 128.1, 126.9, 126.2, 124.6, 123.8, 119.5, 114.1, 108.4, 51.9, 50.1, 33.7, 29.5, 29.1, 28.9, 28.8, 28.5, 26.6, 26.5, 21.7. [α]14D = +64.0 (c = 0.3 in CH2Cl2); HPLC analysis: 88% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 5.6 min (minor), 10.4 min (major)]. (3R,3'R)-1-Methyl-3'-(non-8-en-1-yl)-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3g’): yellow solid, 67-69 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 2H), 7.39-7.29 (m, 8H), 7.16 (d, J= 7.2 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.82-5.71 (m, 1H), 5.37 (s, 1H), 4.98-4.90 (m, 2H), 3.18 (s, 3H), 2.91-2.89 (m, 1H), 2.45 (s, 3H), 1.99-1.93 (m, 2H), 1.26-1.24 (m, 2H), 1.12-1.03 (m, 8H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 171.5, 144.6, 144.0, 142.8, 139.1, 137.6, 136.3, 130.6, 130.1, 129.1, 128.7, 128.3, 128.2, 126.1, 123.1, 123.0, 118.2, 114.1, 108.3, 51.5, 50.3, 33.7, 29.7, 29.1, 28.9, 28.9, 28.8, 26.5, 25.6, 21.8. [α]22D = -71.3 (c = 0.3 in CH2Cl2); HPLC analysis: 89% ee, [CHIRALPAK AS-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 8.3 min (major), 10.6 min (minor)]. 3'-Benzyl-1,5-dimethyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3h + 3h’): 51.8 mg, 92% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2b (43.1 mg, 0.1 mmol), 62:38 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C34H31N2O4S+ 563.1999; found 563.2010. (3R,3'S)-3'-Benzyl-1,5-dimethyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3h): yellow solid, 120-122 oC. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.31-7.27 (m, 5H), 7.20-7.12 (m, 6H), 7.01 (d, J = 7.2 Hz,



2H), 6.74 (d, J = 8.0 Hz, 1H), 5.54 (s, 1H), 3.66 (t, J = 6.4 Hz, 1H), 3.14 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H), 2.94 (s, 3H), 2.45 (s, 3H), 2.36 (s, 3H), 2.08 (dd, J1 = 14.4 Hz, J2 = 6.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.4, 172.3, 145.3, 141.1, 140.9, 138.3, 136.8, 136.0, 133.7, 129.7, 129.6, 129.3, 129.1.128.4, 128.1, 127.9, 126.4, 126.3, 125.5, 119.7, 108.2, 51.6, 51.5, 32.8, 26.4, 21.7, 21.2. [α]13D = +104.0 (c = 0.3 in CH2Cl2); HPLC analysis: 92% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: iPrOH/hexane = 20:80; retention times: 6.1 min (minor), 8.1 min (major)]. (3R,3'R)-3'-Benzyl-1,5-dimethyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3h’): yellow solid, 215-217 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.35-7.29 (m, 7H), 7.07-7.05 (m, 4H), 6.83-6.80 (m, 3H), 6.71 (d, J = 8.0 Hz, 1H), 5.37 (s, 1H), 3.32-3.29 (m, 1H), 3.19-3.14 (m, 4H), 2.45 (s, 3H), 2.19 (s, 3H), 2.02 (dd, J1 = 14.4 Hz, J2 = 4.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.9, 171.0, 144.6, 142.7, 141.5, 139.8, 137.5, 136.2, 132.8, 130.1, 130.0, 129.4, 128.7, 128.7, 128.3, 128.2, 128.0, 126.1, 126.0, 124.3, 118.5, 108.1, 52.9, 51.6, 31.6, 26.5, 21.7, 20.9. [α]22D = -147.0 (c = 0.3 in CH2Cl2); HPLC analysis: 90% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 11.6 min (major), 14.5 min (minor)]. 3'-Benzyl-5-methoxy-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3i + 3i’): 49.8 mg, 86% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2c (44.6 mg, 0.1 mmol), 73:27 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C34H31N2O5S+ 579.1948; found 579.1960. (3R,3'S)-3'-Benzyl-5-methoxy-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3i): red solid, 161-163 oC. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.46-7.26 (m, 5H), 7.21-7.03 (m, 5H), 6.96 (d, J = 2.4 Hz, 2H), 6.94 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.60 (s, 1H), 3.88 (s, 3H), 3.68 (t, J = 6.4 Hz, 1H), 3.16 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H), 2.95 (s, 3H), 2.45 (s, 3H), 2.13 (dd, J1 = 14.8 Hz, J2 = 6.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.2, 172.4, 157.1, 145.4, 141.1, 138.3, 136.6, 136.5, 136.0, 129.5, 129.3, 129.2, 128.5, 128.1, 128.0, 127.3, 126.4, 126.3, 120.0, 115.9, 110.2, 109.1, 56.3, 52.0, 51.8, 33.0, 26.4, 21.7. [α]15D = +98.3 (c = 0.3 in CH2Cl2); HPLC analysis: 91% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 7.1 min (minor), 8.0 min (major)]. (3R,3'R)-3'-Benzyl-5-methoxy-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3i’): red solid, 85-87 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 2H), 7.35-7.29 (m, 7H), 7.08-7.06 (m, 3H), 6.85-6.75 (m, 3H), 6.67 (d, J = 47.2 Hz, 1H), 6.60 (s, 1H), 5.37 (s, 1H), 3.66 (s, 3H), 3.30-3.27 (m, 1H), 3.20-3.15 (m, 4H), 2.45 (s, 3H), 2.08 (dd, J1 = 14.4 Hz, J2 = 4.4 Hz, 1H); 13C NMR{1H} (100 MHz, CDCl3) δ 173.7, 170.8, 156.5, 144.6, 142.8, 139.7, 137.4, 137.3 136.2, 131.1, 130.1, 128.8, 128.7, 128.4, 128.2, 128.1, 126.1, 126.0, 118.2, 114.2, 110.3, 108.9, 55.8, 53.0, 52.0, 31.7, 26.6, 21.8. [α]22D = -76.7 (c = 0.3 in CH2Cl2); HPLC analysis: 89% ee,


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[CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 28.0 min (major), 33.2 min (minor)]. 3'-Benzyl-5-fluoro-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] 2,2'(3'H)-dione (3j + 3j’): 46.5 mg, 82% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2d (43.4 mg, 0.1 mmol), 70:30 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H28FN2O4S+ 567.1748; found 567.1750. (3R,3'S)-3'-Benzyl-5-fluoro-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] -2,2'(3'H)-dione (3j): yellow solid, 125-127 oC. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.34-7.28 (m, 5H), 7.22-7.07 (m, 7H), 6.98 (d, J = 7.2 Hz, 2H), 6.77-6.74 (m, 1H), 5.50 (s, 1H), 3.68 (t, J = 6.4 Hz, 1H), 3.13 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H), 2.93 (s, 3H), 2.47 (s, 3H), 2.05 (dd, J1 = 14.4 Hz, J2 = 6.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.2, 171.1, 159.7 (d, JC-F = 241.2 Hz), 145.7, 141.7, 139.4, 127.5 (d, JC-F = 108.3 Hz), 135.5, 129.8, 129.3, 128.5, 128.1, 128.0, 127.8 (d, JC-F = 7.4 Hz), 126.5, 126.2, 118.7, 115.8 (d, JC-F = 23.6 Hz), 112.9 (d, JC-F = 25.4 Hz), 108.9 (d, JC-F = 8.2 Hz), 51.9, 51.1, 32.7, 26.5, 21.7. [α]13D = +193.7 (c = 0.3 in CH2Cl2); HPLC analysis: 91% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 8.7 min (minor), 12.6 min (major)]. (3R,3'R)-3'-Benzyl-5-fluoro-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3j’): yellow solid, 83-85 oC. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.33-7.29 (m, 6H), 7.09-7.07 (m, 3H), 6.99-6.95 (m, 1H), 6.83 (d, J = 5.2 Hz, 2H), 6.77-6.73 (m, 2H), 5.32 (s, 1H), 3.31-3.29 (m, 1H), 3.22-3.18 (m, 4H), 2.46 (s, 3H), 2.09 (dd, J1 = 14.0 Hz, J2 = 4.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.7, 170.6, 159.4 (d, JC-F = 241.1 Hz), 144.0 (d, JC-F = 155.5 Hz), 139.9, 139.2, 137.2, 136.1, 131.5 (d, JC-F = 7.7 Hz), 130.1, 128.7, 128.5, 128.2, 128.1, 126.2, 126.1, 117.3, 115.5 (d, JC-F = 23.5 Hz), 111.6 (d, JC-F = 25.1 Hz), 108.9 (d, JC-F = 7.7 Hz), 52.7, 51.9 31.8, 26.7, 21.7. [α]22D = -20.7 (c = 0.3 in CH2Cl2); HPLC analysis: 91% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 13.0 min (major), 21.9 min (minor)]. 3'-Benzyl-5-chloro-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] 2,2'(3'H)-dione (3k + 3k’): 42.0 mg, 72% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2e (45.1 mg, 0.1 mmol), 70:30 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H28ClN2O4S+ 583.1453; found 583.1461. (3R,3'S)-3'-Benzyl-5-chloro-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] -2,2'(3'H)-dione (3k): yellow solid, 116-118 oC. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.37-7.31 (m, 6H), 7.23-7.15 (m, 5H), 6.97 (d, J = 7.2 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 5.47 (s, 1H), 3.69 (t, J = 6.4 Hz, 1H), 3.17 (dd, J1 = 14.4 Hz, J2 = 7.6 Hz, 1H), 2.91 (s, 3H), 2.46 (s, 3H), 2.07 (dd, J1 = 14.8 Hz, J2 = 6.8 Hz, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ 176.0, 171.7, 145.6, 141.9, 141.7, 137.7, 136.7, 135.6, 129.7, 129.6, 129.4, 129.3, 128.6, 128.1, 128.0, 126.6, 126.2, 125.1, 118.4, 109.3, 51.6, 51.0, 32.8, 26.5, 21.8. [α]14D = +105.3 (c = 0.3 in CH2Cl2); HPLC analysis: 89% ee,



[CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 8.5 min (minor), 16.1 min (major)]. 3'-Benzyl-5-bromo-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] 2,2'(3'H)-dione (3l + 3l’): 41.4 mg, 66% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2f (49.5 mg, 0.1 mmol), 67:33 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H28BrN2O4S+ 627.0948; found 627.0958. (3R,3'S)-3'-Benzyl-5-bromo-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] -2,2'(3'H)-dione (3l): yellow solid, 117-119 oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.54-7.51 (m, 1H), 7.35-7.30 (m, 5H), 7.22-7.15 (m, 5H), 6.97 (d, J = 6.8 Hz, 2H), 6.72 (d, J = 8.4 Hz, 1H), 5.47 (s, 1H), 3.68 (t, J = 6.8 Hz, 1H), 3.19 (dd, J1 = 14.8 Hz, J2 = 6.4 Hz, 1H), 2.90 (s, 3H), 2.46 (s, 3H), 2.09 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.9, 171.7, 145.5, 142.4, 141.7, 137.7, 136.7, 135.8, 132.5, 129.7, 129.3, 129.2, 128.6, 128.4, 128.1, 128.0, 127.8, 126.6, 126.2, 118.4, 116.5, 109.8, 51.5, 51.0, 32.9, 26.4, 21.8. [α]15D = +146.7 (c = 0.3 in CH2Cl2); HPLC analysis: 88% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 8.7 min (minor), 16.2 min (major)]. (3R,3'R)-3'-Benzyl-5-bromo-1-methyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3l’): yellow solid, 182-184 oC. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.38-7.29 (m, 8H), 7.08-7.04 (m, 4H), 6.80-6.78 (m, 2H), 6.68 (d, J = 8.0 Hz, 1H), 5.31 (s, 1H), 3.32 (t, J = 6.4 Hz, 1H), 3.24 (dd, J1 = 14.4 Hz, J2 = 6.4 Hz, 1H), 3.17 (s, 3H), 2.46 (s, 3H), 2.13 (dd, J1 = 14.4 Hz, J2 = 4.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.4, 170.5, 144.8, 143.2, 142.9, 139.0, 137.2, 136.1, 132.0, 131.9, 130.1, 129.8, 128.7, 128.6, 128.2, 128.1, 126.8, 126.3, 126.1, 117.4, 115.8, 109.7, 52.6, 51.6, 31.9, 26.6, 21.8. [α]22D = +36.3 (c = 0.3 in CH2Cl2); HPLC analysis: 87% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 16.4 min (major), 25.6 min (minor)]. 1,3'-Dibenzyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (3m + 3m’): 41.2 mg, 66% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2g (49.3 mg, 0.1 mmol), 70:30 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C39H33N2O4S+ 625.2156; found 625.2166. (3R,3'S)-1,3'-Dibenzyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3m): yellow solid, 109-111 oC. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.31-7.20 (m, 17H), 7.10-7.07 (m, 3H), 6.79 (d, J = 8.0 Hz, 1H), 5.59 (s, 1H), 4.77 (d, J = 15.6 Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 3.72-3.69 (m, 1H), 3.04 (dd, J1 = 14.4 Hz, J2 = 7.6 Hz, 1H), 2.46 (s, 3H), 2.09 (dd, J1 = 14.4 Hz, J2 = 4.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.9, 172.0, 145.4, 142.5, 141.4, 138.6, 136.8, 135.8, 135.4, 129.7, 129.4, 129.3, 129.2, 128.9, 128.4, 128.0, 128.0, 127.8, 127.4, 126.4, 124.8, 123.9, 119.4, 109.5, 51.8, 44.1, 32.8, 21.7. [α]14D = +95.0 (c = 0.3 in CH2Cl2); HPLC analysis: 87% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: iPrOH/hexane = 20:80; retention times: 12.6 min (minor), 22.0 min (major)].


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(3R,3'R)-1,3'-Dibenzyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3m’): yellow solid, 72-74 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 2H), 7.35-7.28 (m, 12H), 7.17 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 6.4 Hz, 4H), 6.94 (t, J = 7.6 Hz, 1H), 6.88-6.86 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 5.43 (s, 1H), 4.98 (d, J = 15.2 Hz, 1H), 4.81 (d, J = 15.2 Hz, 1H), 3.35-3.32 (m, 1H), 3.19 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 1H), 2.45 (s, 3H), 2.07 (dd, J1 = 14.0 Hz, J2 = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.0, 171.0, 144.7, 143.1, 143.0, 139.9, 137.4, 136.2, 135.6, 130.1, 130.0, 129.1, 128.9, 128.7, 128.4, 128.2, 128.1, 127.8, 127.5, 126.2, 126.1, 123.4, 123.2, 118.2, 109.5, 53.3, 51.6, 44.2, 31.8, 21.8. [α]22D = -24.7 (c = 0.3 in CH2Cl2); HPLC analysis: 62% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 20.2 min (minor), 24.8 min (major)]. 1-Allyl-3'-benzyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (3n + 3n’): 29.9 mg, 52% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2h (44.3 mg, 0.1 mmol), 77:23 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C35H31N2O4S+ 575.1999; found 575.2009. (3R,3'S)-1-Allyl-3'-benzyl-6'-phenyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)dione (3n): yellow solid, 89-91 oC. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.2 Hz, 1H), 7.34-7.28 (m, 5H), 7.20-7.07 (m, 9H), 6.86 (d, J = 8.0 Hz, 1H), 5.81-5.71 (m, 1H), 5.56 (s, 1H), 5.25-5.20 (m, 2H), 4.19-4.05 (m, 2H), 3.68-3.65 (m, 1H), 3.04 (dd, J1 = 14.4 Hz, J2 = 7.6 Hz, 1H), 2.47 (s, 3H), 2.08 (dd, J1 = 14.4 Hz, J2 = 4.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.4, 172.1, 145.4, 142.5, 141.4, 138.6, 136.8, 135.8, 131.0, 129.8, 129.4, 129.3, 129.2, 128.4, 128.1, 126.4, 126.3, 124.8, 123.8, 119.4, 118.2, 109.3, 51.7, 51.7, 42.7, 32.8, 21.7. [α]14D = +56.7 (c = 0.3 in CH2Cl2); HPLC analysis: 91% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: iPrOH/hexane = 20:80; retention times: 7.0 min (minor), 8.0 min (major)]. 3'-Benzyl-1-methyl-6'-(p-tolyl)-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (3o + 3o’): 40.5 mg, 72% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2i (43.1 mg, 0.1 mmol), 71:29 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C34H31N2O4S+ 563.1999; found 563.2009. (3R,3'S)-3'-Benzyl-1-methyl-6'-(p-tolyl)-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3o): red solid, 93-95 oC. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 6.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.18 (t, J = 6.8 Hz, 2H), 7.14-7.08 (m, 6H), 6.98 (d, J = 6.8 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 5.50 (s, 1H), 3.66 (t, J = 6.8 Hz, 1H), 3.12 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H), 2.95 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H), 2.06 (dd, J1 = 14.8 Hz, J2 = 6.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 172.2, 145.3, 143.4, 141.3, 138.3, 138.2, 135.9, 134.1, 129.8, 129.4, 129.3, 129.1, 128.8, 128.0, 126.5, 126.4, 126.2, 124.7, 123.8, 118.9, 108.4, 51.5, 51.4, 32.9, 26.3, 21.7, 21.3. [α]14D = +49.0 (c = 0.3 in CH2Cl2); HPLC analysis: 97% ee, [CHIRALPAK AS-H column; 1 mL/min; solvent system: i-PrOH/hexane = 10:90; retention times: 17.4 min (major), 25.5 min (minor)].



(3R,3'R)-3'-Benzyl-1-methyl-6'-(p-tolyl)-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3o’): orange solid, 76-78 oC. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.31-7.29 (m, 3H), 7.27-7.25 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.08-7.06 (m, 4H), 7.00 (t, J = 7.6 Hz, 1H), 6.87-6.83 (m, 3H), 5.35 (s, 1H), 3.31-3.29 (m, 1H), 3.18 (s, 3H), 3.09 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 1H), 2.46 (s, 3H), 2.35 (s, 3H), 2.04 (dd, J1 = 14.0 Hz, J2 = 3.2 Hz, 1H); 13C NMR{1H} (100 MHz, CDCl3) δ 174.0, 171.0, 144.6, 144.0, 142.9, 139.7, 138.3, 136.2, 134.7, 130.2, 129.2, 128.9, 128.6, 128.1, 126.1, 126.0, 123.3, 123.2, 117.5, 108.4, 52.9, 51.5, 31.6, 26.5, 21.8, 21.3. [α]22D = -67.0 (c = 0.3 in CH2Cl2); HPLC analysis: 87% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: iPrOH/hexane = 20:80; retention times: 15.0 min (major), 30.3 min (minor)]. 3'-Benzyl-6'-(4-bromophenyl)-1-methyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] 2,2'(3'H)-dione (3p + 3p’): 55.9 mg, 89% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2j (49.5 mg, 0.1 mmol), 70:30 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H28BrN2O4S+ 627.0948; found 627.0950. (3R,3'S)-3'-Benzyl-6'-(4-bromophenyl)-1-methyl-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine] -2,2'(3'H)-dione (3p): yellow solid, 105-107 oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 2H), 7.44-7.33 (m, 6H), 7.20-7.15 (m, 6H), 6.98 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 5.53 (s, 1H), 3.66 (t, J = 6.4 Hz, 1H), 3.11 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H), 2.95 (s, 3H), 2.48 (s, 3H), 2.06 (dd, J1 = 14.8 Hz, J2 = 6.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.3, 171.9, 145.6, 143.3, 140.3, 138.0, 135.9, 135.6, 131.3, 129.7, 129.5, 129.3, 128.0, 127.8, 126.5, 126.1, 124.6, 123.8, 122.4, 120.0, 108.5, 51.5, 51.3, 32.8, 26.4, 21.7. [α]14D = +89.0 (c = 0.3 in CH2Cl2); HPLC analysis: 94% ee , [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 10.0 min (minor), 11.5 min (major)]. (3R,3'R)-3'-Benzyl-6'-(4-bromophenyl)-1-methyl-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3p’): orange solid, 83-85 oC. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.33-7.31 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 7.08-7.07 (m, 4H), 7.01 (t, J = 7.6 Hz, 1H), 6.86-6.84 (m, 3H), 5.37 (s, 1H), 3.313.28 (m, 1H), 3.17 (s, 3H), 3.07 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 1H), 2.46 (s, 3H), 2.04 (dd, J1 = 14.0 Hz, J2 = 3.2 Hz, 1H); 13C NMR{1H} (100 MHz, CDCl3) δ 173.7, 170.7, 144.9, 144.0, 141.9, 139.5, 136.5, 135.9, 131.4, 130.2, 129.9, 129.4, 128.9, 128.8, 128.1, 127.7, 126.1, 123.3, 122.4, 118.5, 108.5, 52.8, 51.6, 31.6, 26.5, 21.8. [α]22D = +16.0 (c = 0.3 in CH2Cl2); HPLC analysis: 92% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 16.1 min (major), 32.2 min (minor)]. 4-(3'-Benzyl-1-methyl-2,2'-dioxo-1'-tosyl-2',3'-dihydro-1'H-spiro[indoline-3,4'-pyridin]6'-yl)benzonitrile (3q + 3q’): 53.9 mg, 94% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2k (44.2 mg, 0.1 mmol), 69:31 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C34H28N3O4S+ 574.1795; found 574.1799. 4-((3R,3'S)-3'-Benzyl-1-methyl-2,2'-dioxo-1'-tosyl-2',3'-dihydro-1'H-spiro[indoline-3,4'pyridin]-6'-yl)benzonitrile (3q): yellow solid, 103-105 oC. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.40-7.28 (m, 6H), 7.21-7.14 (m, 3H), 7.08 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 7.2 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H), 5.62 (s, 1H),


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3.66 (t, J = 6.0 Hz, 1H), 3.09 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H), 2.97 (s, 3H), 2.51 (s, 3H), 2.05 (dd, J1 = 14.4 Hz, J2 = 6.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.1, 171.6, 146.0, 143.4, 141.6, 139.7, 137.8, 135.2, 132.1, 129.7, 129.4, 129.3, 128.0, 126.7, 126.6, 125.6, 124.5, 123.8, 121.6, 118.4, 112.0, 108.6, 51.6, 51.0, 32.6, 26.4, 21.8. [α]14D = -11.3 (c = 0.3 in CH2Cl2); HPLC analysis: 95% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 16.5 min (minor), 26.7 min (major)]. 3'-Benzyl-1-methyl-6'-(4-nitrophenyl)-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3r + 3r’): 45.7 mg, 77% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2l (49.5 mg, 0.1 mmol), 70:30 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H28N3O6S+ 594.1693; found 594.1696. (3R,3'S)-3'-Benzyl-1-methyl-6'-(4-nitrophenyl)-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3r): yellow solid, 91-93 oC. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.42-7.37 (m, 5H), 7.29 (d, J = 7.2 Hz, 1H), 7.217.14 (m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 6.8 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 3.67 (t, J = 6.4 Hz, 1H), 3.10 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H), 2.97 (s, 3H), 2.51 (s, 3H), 2.05 (dd, J1 = 14.4 Hz, J2 = 6.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.0, 171.6, 147.6, 146.1, 143.5, 143.4, 139.5, 137.8, 135.3, 129.8, 129.5, 129.3, 128.1, 126.8, 126.6, 125.6, 124.6, 123.9, 123.6, 121.9, 108.7, 51.6, 51.0, 32.6, 26.4, 21.8. [α]14D = +18.0 (c = 0.3 in CH2Cl2); HPLC analysis: 94% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 17.7 min (minor), 23.6 min (major)]. (3R,3'R)-3'-Benzyl-1-methyl-6'-(4-nitrophenyl)-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3r’): orange solid, 78-80 oC. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.0 Hz, 3H), 7.11-7.02 (m, 5H), 6.88-6.84 (m, 3H), 5.50 (s, 1H), 3.33-3.30 (m, 1H), 3.18 (s, 3H), 3.07 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 1H), 2.48 (s, 3H), 2.03 (dd, J1 = 14.0 Hz, J2 = 3.2 Hz, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ 173.3 170.4, 147.5, 145.2, 144.1, 144.0, 141.1, 139.3, 135.4, 130.3, 129.6, 129.5, 128.9, 128.2, 126.8, 126.2, 123.7, 123.4, 123.3, 120.5, 108.7, 52.5, 51.8, 31.4, 26.6, 21.8. [α]22D = -39.3 (c = 0.3 in CH2Cl2); HPLC analysis: 78% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 37.2 min (major), 77.2 min (minor)]. 3'-Benzyl-1-methyl-6'-(naphthalen-2-yl)-1'-tosyl-1'H-spiro[indoline-3,4'-pyridine]2,2'(3'H)-dione (3s + 3s’): 41.9 mg, 70% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2m (46.7 mg, 0.1 mmol), 83:17 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C37H31N2O4S+ 599.1999; found 599.2008. (3R,3'S)-3'-Benzyl-1-methyl-6'-(naphthalen-2-yl)-1'-tosyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3s): yellow solid, 91-93 oC. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 3H), 7.78 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 7.2 Hz, 2H), 7.55 (s, 1H), 7.47 (t, J = 4.4 Hz, 2H), 7.40 (t, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.21-7.13 (m, 4H), 7.02 (d, J = 7.2 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H), 5.68 (s, 1H), 3.73 (t, J = 6.4 Hz, 1H), 3.17 (dd, J1 = 14.4 Hz, J2 = 8.0 Hz, 1H), 2.97 (s, 3H), 2.47 (s, 3H), 2.11 (dd, J1 = 14.4 Hz, J2 = 6.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.5, 172.3, 145.4, 143.4, 141.3, 138.2, 135.9, 134.2, 133.2, 132.7, 129.8, 129.5, 129.3,



129.2, 128.0, 127.9, 127.8, 126.5, 126.4, 126.3, 125.0, 124.8, 124.4, 123.9, 120.0, 108.4, 51.6, 51.5, 32.9, 26.4, 21.7. [α]14D = +46.3 (c = 0.3 in CH2Cl2); HPLC analysis: 94% ee , [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 10:90; retention times: 23.6 min (major), 29.2 min (minor)]. 3'-Benzyl-1'-((4-methoxyphenyl)sulfonyl)-1-methyl-6'-phenyl-1'H-spiro[indoline -3,4'pyridine]-2,2'(3'H)-dione (3t + 3t’): 43.5 mg, 77% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2n (43.2 mg, 0.1 mmol), 65:35 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H29N2O5S+ 565.1792; found 565.1797. (3R,3'S)-3'-Benzyl-1'-((4-methoxyphenyl)sulfonyl)-1-methyl-6'-phenyl-1'H-spiro[indoline -3,4'-pyridine]-2,2'(3'H)-dione (3t): yellow solid, 121-123 oC. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.32-7.27(m, 3H), 7.20-7.11 (m, 6H), 6.98 (t, J = 9.2 Hz, 4H), 6.85 (d, J = 7.6 Hz, 1H), 5.54 (s, 1H), 3.90 (s, 3H), 3.68 (t, J = 6.4 Hz, 1H), 3.13 (dd, J1 = 14.4 Hz, J2 = 7.6 Hz, 1H), 2.95 (s, 3H), 2.07 (dd, J1 = 14.4 Hz, J2 = 8.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.5, 172.2, 164.1, 143.3, 141.3, 138.2, 136.9, 132.1, 130.1, 129.4, 129.3, 128.4, 128.1, 128.0, 126.4, 126.2, 124.7, 123.8, 119.4, 113.7, 108.4, 55.7, 51.5, 51.4, 32.8, 26.3. [α]14D = +198.3 (c = 0.3 in CH2Cl2); HPLC analysis: 91% ee, [CHIRALPAK ID column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 11.1 min (minor), 14.6 min (major)]. (3R,3'R)-3'-Benzyl-1'-((4-methoxyphenyl)sulfonyl)-1-methyl-6'-phenyl-1'Hspiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (3t’): yellow solid, 101-103 oC. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz, 2H), 3.37-7.31 (m, 6H), 7.09-7.07 (m, 4H), 7.00-6.87(m, 3H), 6.85 (t, J = 7.2 Hz, 3H), 5.38 (s, 1H), 3.90 (s, 3H), 3.32-3.29 (m, 1H), 3.18 (s, 3H), 3.09 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 1H), 2.06 (dd, J1 = 14.0 Hz, J2 = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.0 170.9, 163.8, 144.0, 142.9, 139.7, 137.6, 132.6, 130.5, 130.1, 129.3, 128.9, 128.4, 128.2, 128.1, 126.1, 123.4, 123.2, 118.0, 113.2, 108.4, 55.6, 52.9, 51.6, 31.7, 26.5. [α]22D = -85.3 (c = 0.3 in CH2Cl2); HPLC analysis: 88% ee, [CHIRALPAK AD-H column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 11.0 min (minor), 12.6 min (major)]. 3'-Benzyl-1-methyl-1'-((4-nitrophenyl)sulfonyl)-6'-phenyl-1'H-spiro[indoline-3,4'pyridine]-2,2'(3'H)-dione (3u + 3u’): 44.1 mg, 76% yield from aldehyde 1a (26.8 mg, 0.2 mmol) and ketimine 2o (44.7 mg, 0.1 mmol), 50:50 dr. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C32H26N3O6S+ 580.1537; found 580.1544. (3R,3'S)-3'-Benzyl-1-methyl-1'-((4-nitrophenyl)sulfonyl)-6'-phenyl-1'H-spiro[indoline3,4'-pyridine]-2,2'(3'H)-dione (3u): yellow solid, 88-90 oC. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.8 Hz, 2H), 8.30 (d, J = 7.6 Hz, 2H), 7.42 (s, 2H), 7.37-7.31 (m, 4H), 7.127.02 (m, 5H), 6.87-6.83 (m, 3H), 5.45 (s, 1H), 3.36 (t, J = 2.4 Hz, 1H), 3.14 (s, 3H), 2.94 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 1H), 1.98 (d, J = 18.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.6, 171.0, 150.7, 144.0, 143.8, 142.6, 139.2, 137.1, 131.9, 129.7, 129.5, 128.8, 128.4, 128.2, 126.3, 125.9, 123.4, 123.3, 123.1, 118.6, 108.6, 55.5, 51.7, 31.3 26.5. [α]14D = -39.3 (c = 0.3 in CH2Cl2); HPLC analysis: 90% ee, [CHIRALPAK ID column; 1 mL/min; solvent system: i-PrOH/hexane = 30:70; retention times: 26.8 min (minor), 39.0 min (major)].


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Page 19 of 23 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


(3R,3'R)-3'-Benzyl-1-methyl-1'-((4-nitrophenyl)sulfonyl)-6'-phenyl-1'H-spiro[indoline3,4'-pyridine]-2,2'(3'H)-dione (3u’): yellow solid, 76-78 oC. 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 9.2 Hz, 2H), 8.13(d, J = 8.8 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 10.0 Hz, 2H), 7.20-7.13 (m, 6H), 7.01 (d, J = 7.2 Hz, 2H), 6.88 (d, J = 8.0 Hz, 1H), 5.61 (s, 1H), 3.67 (t, J = 6.8 Hz, 1H), 3.10 (dd, J1 = 14.4 Hz, J2 = 7.2 Hz, 1H), 2.99 (s, 3H), 2.18 (dd, J1 = 14.4 Hz, J2 = 5.2 Hz, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ 176.2, 172.4, 150.8, 144.0, 143.4, 140.6, 137.8, 136.2, 131.0, 129.7, 129.2, 128.9, 128.3, 128.1, 126.6, 126.4, 126.2, 124.5, 123.9, 123.7, 120.3, 108.7, 51.7, 51.5, 33.0, 26.4. [α]22D = +30.0 (c = 0.3 in CH2Cl2); HPLC analysis: 96% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 10.2 min (minor), 11.5 min (major)]. Conversion of 3a to a mixture of 3a and 3a’. To a dry 10 mL Schlenk tube equipped with a magnetic stir bar, was added 3a (54.9 mg, 0.1 mmol), 4Å MS (100 mg), and Cs2CO3 (48.8 mg, 0.15 mmol). The tube was sealed with a septum, evacuated and refilled with nitrogen (3 cycles). DCE (1 mL) was then added and the reaction mixture was allowed to stir for 24 hours at 25 oC. After that, the reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography using petroleum ether/EtOAc = 5/1 as eluent to afford a mixture of 3a and 3a’ (52.1 mg, 95% combined yield, 71:29 dr). Transformation of 3a to 5. Under a nitrogen atmosphere, to a fresh prepared solution of Na (23 mg, 1 mmol, 10 equiv.) and naphthalene (128 mg, 1 mmol, 10 equiv.) in anhydrous THF (7 mL) at -78 oC, was added a solution of 3a (54.9 mg, 0.1 mmol, 90% ee) in THF (3 mL). This reaction mixture was stirred at that temperature for 5 minutes and then quenched with saturated NH4Cl aq. (10 mL). The aqueous phase was extracted with DCM, and the combined organic phase was washed with brine, dried over Na2SO4. Filtration and removal of solvent under reduced pressure afforded a residue, which was purified by column chromatography using petroleum ether/EtOAc = 5/1 as eluent to afford the desired product 5. (3R,3'S)-3'-Benzyl-1-methyl-6'-phenyl-1'H-spiro[indoline-3,4'-pyridine]-2,2'(3'H)-dione (5): 27.2 mg, 69% yield, single diastereomer; yellow solid, 79-81 oC. 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.41-7.31 (m, 7H), 7.20-7.06 (m, 4H), 6.96 (d, J = 7.6 Hz, 2H), 6.82 (d, J = 8.0 Hz, 1H), 5.18 (s, 1H), 3.77 (t, J = 6.8Hz, 1H), 3.26-3.18 (m, 1H), 2.93 (s, 3H), 2.10 (dd, J1 = 14.4 Hz, J2 = 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.4, 171.6, 143.0, 138.7, 138.5, 134.0, 129.3, 129.2, 129.1, 129.0, 128.8, 127.8, 126.2, 125.2, 123.9, 123.2, 108.4, 103.6, 52.7, 46.3, 31.7, 26.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H23N2O2+ 395.1754; found 395.1762. [α]24D = +191.7 (c = 0.3 in CH2Cl2); HPLC analysis: 90% ee, [CHIRALPAK IA column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 11.0 min (minor), 18.5 min (major)]. Transformation of 3a to 6. To a 25 mL round bottom flask equipped with a magnetic stir bar, was added 3a (54.9 mg, 0.1 mmol, 90% ee), Pd(OH)2 (28.1 mg, 10% on carbon, wetted with ca. 50% water), EtOAc (1 mL), and EtOH (1 mL). The flask was evacuated



and refilled with hydrogen (3 cycles) then sealed with a H2 balloon. The reaction mixture was stirred at room temperature for 24 hours, then diluted with ethyl acetate, and passed through a short pad of celite. The filtrate was removed under reduced pressure, and the residue was subjected to column chromatography using petroleum ether/EtOAc = 5/1 as eluent to afford the desired product 6. The relative configuration was determined by NOE spectra of 6. (3R,3'S)-3'-Benzyl-1-methyl-6'-phenyl-1'-tosylspiro[indoline-3,4'-piperidine]-2,2'-dione (3v): 30.3 mg, 55% yield, >20:1 dr; white solid, 174-176 oC. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 8.0 Hz, 3H), 7.26-7.23 (m, 4H), 7.16-7.07 (m, 7H), 6.78 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 3.6 Hz, 2H), 5.57-5.52 (m, 1H), 3.60-3.56 (m, 1H), 3.38 (dd, J1 = 14.0 Hz, J2 = 4.8 Hz, 1H), 2.67 (s, 3H), 2.43-2.37 (m, 4H), 2.23 (dd, J1 = 14.4 Hz, J2 = 10.0 Hz, 1H), 2.06 (dd, J1 = 14.8 Hz, J2 = 6.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.4, 172.6, 144.7, 143.8, 139.9, 136.9, 135.8, 129.4, 129.2, 128.8, 128.6, 128.0, 127.7, 127.5, 127.3, 126.5, 124.9, 123.2, 108.6, 59.0, 50.4, 49.7, 41.7, 35.1, 26.0, 21.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C33H31N2O4S+ 551.1999; found 551.1999. [α]24D = 65.0 (c = 0.3 in CH2Cl2); HPLC analysis: 94% ee, [CHIRALPAK IC column; 1 mL/min; solvent system: i-PrOH/hexane = 20:80; retention times: 24.8 min (minor), 27.6 min (major)]. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: NMR and HPLC spectra for all new compounds (PDF) X-ray data for 3i (CCDC 1935305) (CIF) AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected] and [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (Grant No. 21602203) for financial support. We also thank Dr Houting Liu from Liaocheng University for X-ray crystallographic analysis. REFERENCES (1) (a) Yu, B.; Yu, D. Q.; Liu, H. M. Spirooxindoles: Promising scaffolds for anticancer agents. Eur. J. Med. Chem. 2015, 97, 673-698. (b) Ye, N.; Chen, H. Y.; Wold, E. A.; Shi, P. Y.; Zhou, J. Therapeutic Potential of Spirooxindoles as Antiviral Agents. ACS Infect.


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pyrrol]-2’-yl)acrylates through phosphine-catalyzed [4+1] annulation of Morita-BaylisHillman carbonates with oxindole-derived α,β-unsaturated imines. RSC Adv. 2015, 5, 49657-49661. (11) Zhang, X. N.; Chen, G. Q.; Dong, X.; Wei, Y.; Shi, M. Phosphine‐Catalyzed Asymmetric [4+2] Annulation of Vinyl Ketones with Oxindole‐Derived α,β‐Unsaturated Imines: Enantioselective Syntheses of 2′,3′‐Dihydro‐1′H‐spiro[indoline‐3,4′‐pyridin]‐2‐ ones. Adv. Synth. Catal. 2013, 355, 3351-3357.


Asymmetric Synthesis of Spirocyclic Oxindole Î´-Lactams via NHC

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