and Enantioselective Synthesis of Spirooxindoles ... - ACS Publications

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Diastereo- and Enantioselective Synthesis of Spirooxindoles with Contiguous Tetrasubstituted Stereocenters via Catalytic Coupling of Two Tertiary Radicals Zhi-Yong Song, Kun-Quan Chen, Xiang-Yu Chen, and Song Ye J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03161 • Publication Date (Web): 06 Feb 2018 Downloaded from http://pubs.acs.org on February 6, 2018

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The Journal of Organic Chemistry

Diastereo- and Enantioselective Synthesis of Spirooxindoles with Contiguous Tetrasubstituted Stereocenters via Catalytic Coupling of Two Tertiary Radicals Zhi-Yong Song,a,b Kun-Quan Chen,a,b Xiang-Yu Chena and Song Yea,b * a

Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular

Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. b

University of Chinese Academy of Sciences, Beijing 100049, China.

TOC Graphic

ABSTRACT: The oxidative N-heterocyclic carbene-catalyzed [3 + 2] annulation of β,βdisubstituted enals and dioxindoles was developed, giving the spirocyclic oxindole-γlactones bearing two contiguous tetrasubstituted stereocenters in good yields with excellent diastereo- and good enantioselectivities.

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The asymmetric synthesis of chiral compounds is of great importance for their wide applications in medicinal and material science.1 Among the tremendous progress in this field, the enantioselective construction of tetrasubstituted stereocenters remains a remarkable challenge.2 Since the seminal report of Breslow intermediate in carbene catalysis,3 N-heterocyclic carbenes (NHCs) have been well established as the catalysts for various reactions.4 However, the NHC-catalyzed construction of tetrasubstituted stereocenters is still limited.5

Scheme 1. NHC-catalyzed synthesis of contiguous tetrasubstituted stereocenters 2


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Being a privileged structure in bioactive compounds,6 indole and its derivatives are of high interest in organic synthesis.7 Particularly, the spirocyclic oxindole is widely present in various bioactive compounds.8 Due to the steric congestion imposed by the four substituents, the construction of C-C bond bearing contiguous tetrasubstituted stereocenters is even more challenging. In 2014, Glorius et al. reported a Brønsted acidassisted NHC-catalyzed [3 + 2] annulation of β,β-disubstituted enals with isatins, giving the spirocyclic oxindoles with contiguous tetrasubstituted stereocenters (Scheme 1, reaction a).5c Recently, the NHC-catalyzed reaction via radical intermediate emerged as a powerful strategy.9 Our group developed the NHC-catalyzed oxidative annulation of enals and dioxindoles via the cross coupling of homoenolate and enolate radicals (Scheme 1, reaction b, R = H).10 We envisioned that the reactive radical intermediates could make the formation of quaternary centers possible (Scheme 1, reaction b, R = aryl, alkyl). In this communication, we report the NHC-catalyzed oxidative cross coupling of β,β-disubstituted homoenolate and enolate to give spirocyclic oxindoles with contiguous tetrasubstituted stereocenters.

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Table 1. Optimization of Reaction Conditions.a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16f 17g a

preNHC A1 A2 A3 A4 B1 B2 B1 B1 B1 B1 B1 B1 B1 B1 B1 B1 B1

base DABCO DABCO DABCO DABCO DABCO DABCO NaOAc KOtBu Cs2CO3 DBU/DABCOe DBU/DABCOe DBU/DABCOe DBU/DABCOe DBU/DABCOe DBU/DABCOe DBU/DABCOe DBU/DABCOe

solvent PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe DCM CHCl3 THF Et2O dioxane dioxane dioxane

yield[%]b trace 17 50 21 63 61 trace trace 14 39 60 27 84 31 89(87)h 79 60

drc >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

ee[%]d 65 75 -75 72 42 66 75 79 71 78 52 81 81 78

Unless otherwise specified, 1a (0.4 mmol), 2a (0.2 mmol), preNHC (20 mol%),

PhNO2 (0.4 mmol), base (0.24 mmol), solvent (2 ml), rt, 12h. b The yield was determined by 1H NMR (400 MHz) spectroscopy with 1,3,5-trimethoxybenzene as the internal standard. c Determined by 1H NMR (400 MHz) spectroscopy of the reaction 4


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mixture. d Determined by HPLC analysis on a chiral stationary phase. e DBU (0.2 equiv.) and DABCO (1.0 equiv.). f LiCl (10.2 mg, 1.2 equiv.) was added. g the experiment was conducted at 0 oC. h Isolated yield in parathesis. TMS = trimethylsilyl, Mes = mesityl. Initially, the reaction of β,β-disubstituted enal 1a with dioxindole 2a was investigated under NHC catalysis in the presence of nitrobenzene as the single electron oxidant (Table 1). It was disappointing that the reaction under our previous optimized conditions using the L-pyroglutamic acid-derived preNHC A1 as the catalyst for cinnamic aldehyde10 gave only trace of the desired cycloadduct 3a (entry 1). Interestingly, the preNHC A2 and A3 with less bulky N-aryl group led to much better yield (entries 2 & 3).11 The preNHC A4 with a silyl ether could also catalyze the reaction with opposite enantioselectivity (entry 4). The reaction catalyzed by tetracyclic preNHC B1 and B2

12

afforded the product in

good yield with moderate to good enantioselectivities (entries 5 and 6). Screening of bases revealed that low yields were observed when NaOAc, KOtBu and Cs2CO3 were used as the base (entries 7-9), while slight better enantioselectivity was obseved when the mixture base of DBU/DABCO was used (entry 10). The reaction worked best in 1,4-dioxane than other solvents (entries 10-15). The addition of LiCl made no apparent effect for the reaction (entry 16). The yield and enantioselectivity decreased somewhat when the reaction was carried out at 0oC instead of room temperature (entry 15 vs 17).

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Scheme 2. Substrate Scope.a

6


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a

Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), B1 (20 mol%), PhNO2 (0.4

mmol), DBU (0.04 mmol) and DABCO (0.2 mmol), dioxane (2ml), rt, 12h. b Yield and ee after recrystallization given in parenthesis. With the optimized conditions in hand, the scope of the reaction was then explored (Scheme 2). Arylenals with electron-donating group (Ar = 4-MeC6H4) or electronwithdrawing group (Ar = 4-ClC6H4) worked well to give the desired product in good yields with good enantioselectivities (3b-3c). meta-Substitutent (Ar = 3-MeOC6H4, 3MeC6H4, 3-BrC6H4) and -naphthyl were tolerable but led to somewhat decreased enantioselectvities (3d-3g), which could be improved by recrystallization (3g). The reaction of enals with 2-furyl provided the product in 83% yield but with 53% ee (3h). The β,β-disubstituted dienal could also give the desired -lactone 3i in 93% yield with 55% ee. Dioxindoles with different substituent at 5- or 6-position (5-Me, 5-MeO, 5-F, 5Cl, 6-Br) all worked well (3j-3n). The reaction of N-methyl dioxindole afforded the product with decreased diastereoselectivity and enantioselectivity (3o). The absolute and relative configurations of -lactone 3f was established by the analysis of its single crystal (ESI, Figure S1). The plausible catalytic cycle was depicted in Figure 1. The addition of NHC to aldehyde 1 gives homoenol I, which is oxidized by nitrobenzene via single electron transfer to afford homoenol radical II. At the meantime, the enol radical III is generated from dioxindole 2. The cross coupling of the two radicals affords adduct IV, which goes

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lactonization under base condition to furnishes the final product 3 and regenerates the NHC catalyst.

Figure 1 Plausible catalytic cycle.

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The homoenol and enol radicals were observed by EPR in our previous publication.10 The controlled experiment with the addition of TEMPO to quench the radical gave only trace of the desired cycloadduct (eq. 1).

In summary, the NHC-catalyzed oxidative [3 + 2] annulation reaction of dioxindoles and β,β-disubstituted enals was developed. This strategy provides an efficient access to spirocyclic oxindole-γ-lactones bearing two contiguous tetrasubstituted carbons in good yields with high diastereo- and good enantioselectivities. Further exploration of the NHCcatalyzed reaction via radicals is underway in our laboratory. 

EXPERIMENTAL SECTION

General Information. Unless otherwise indicated, all reactions were carried out under N2 with magnetic stirring. Anhydrous THF and toluene were distilled from sodium and benzophenone. Anhydrous CH2Cl2 was distilled from CaH2. Chiral triazolium salts11-12 and dioxindoles13 were synthesized according to literature. The mass spectra were collected with an ion trap analyzer. General Procedure of NHC-catalyzed oxidative [3 + 2] annulation of dioxindoles and β,β-disubstituted enals. To a solution of β,β-disubstituted enal 1 (0.4 mmol, 2.0 equiv.) in 1,4-dioxane (2.0 mL) was added dioxindole 2 (0.2 mmol, 1.0 equiv.), NHC 9



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precursor B1 (0.04 mmol, 16.8 mg, 0.2 equiv.), DABCO (0.20 mmol, 27 mg, 1.0 equiv.), DBU (0.04 mmol, 6 μl, 0.2 equiv.) and nitrobenzene (0.4 mmol, 49.2 mg, 2.0 equiv.) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature until the full consumption of the dioxindole (1 h-12 h). The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc as the eluent, typically 20:1-5:1) to furnish the corresponding products 3a-3o. Racemic samples for the chiral phase HPLC analysis were prepared using racemic NHC precursor rac-B1 under the same condition. (2R,3S)-3-methyl-3-phenyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione 3a, Yield: 50.8 mg, 87%; dr >20:1. white solid; mp 177-179 °C; 81% ee determined by HPLC (AD-H, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 21.6 min, tr min = 15.8 min; 1H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 7.5 Hz, 1H), 7.42 (td, J = 7.8, 1.2 Hz, 1H), 7.30 (s, 1H), 7.18 (d, J = 7.3 Hz, 4H), 6.88 – 6.87 (m, 2H), 6.82 (d, J = 7.8 Hz, 1H), 4.26 (d, J = 16.1 Hz, 1H), 2.64 (d, J = 16.2 Hz, 1H), 1.67 (s, 3H); 13C{1H}NMR (126 MHz, CDCl3) δ 175.23, 175.20, 142.2, 139.6, 131.6, 128.9, 128.0, 127.4, 125.5, 123.5, 123.1, 110.8, 88.1, 50.9, 39.2, 27.3; IR (KBr) 3286, 1793, 1735, 1472, 1199, 756, 700; HRMS (ESI) calcd for C18H14O3N [M-H]- 292.0979, found 292.0976. (2R,3S)-3-methyl-3-(p-tolyl)-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione 3b, Yield: 44.2 mg, 72%; dr >20:1. white solid, mp 223-225 °C; []25 D +31.1 (c 1.0, CHCl3); 79% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 17.8 min, tr min

= 11.8 min; 1H NMR (500 MHz, Chloroform-d) δ 7.55 – 7.51 (m, 2H), 7.40 (t, J = 7.6

Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.9 Hz, 2H), 6.82 (d, J = 7.8 Hz, 1H), 6.75 10


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(d, J = 7.9 Hz, 2H), 4.23 (d, J = 16.1 Hz, 1H), 2.61 (d, J = 16.2 Hz, 1H), 2.25 (s, 3H), 1.64 (s, 3H); 13C{1H}NMR (126 MHz, CDCl3) δ 176.0, 175.5, 142.2, 137.6, 136.6, 131.5, 129.5, 127.3, 125.4, 123.5, 123.0, 110.9, 88.2, 50.5, 39.3, 27.3, 21.1; IR (KBr) 3279, 1793, 1731, 1471, 1196, 755; HRMS (ESI) calcd for C19H18O3N [M+H]+ 308.1281, found 308.1278. (2R,3S)-3-(4-chlorophenyl)-3-methyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5dione 3c, Yield: 47.8 mg, 73%; dr = 8:1. white solid, mp 205-207 °C; []25 D +9.45 (c 1.0, CHCl3); 83% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 22.6 min, tr min = 13.3 min; 1H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.36 (s, 1H), 7.19 – 7.15 (m, 3H), 6.84 – 6.80 (m, 3H), 4.21 (d, J = 16.1 Hz, 1H), 2.63 (d, J = 16.1 Hz, 1H), 1.65 (s, 3H); 13C{1H}NMR (126 MHz, CDCl3) δ 175.0, 174.8, 142.1, 138.1, 134.0, 131.8, 129.0, 127.4, 127.0, 123.2, 123.0, 110.9, 87.9, 50.4, 39.1, 27.1; IR (KBr) 3280, 1793, 1731, 1496, 1471, 1198, 751; HRMS (ESI) calcd for C18H15O3NCl [M+H]+ 328.0735, found 328.0729. (2R,3S)-3-(3-methoxyphenyl)-3-methyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]2',5-dione 3d, Yield: 51.7 mg, 80%; dr > 20:1. white solid, mp 189-190 °C; []25D +3.6 (c 1.0, CHCl3); 63% ee determined by HPLC (AD-H, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj

= 26.8 min, tr min = 20.5 min; 1H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 7.6 Hz,

1H), 7.41 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.75 (dd, J = 8.3, 2.3 Hz, 1H), 6.51 – 6.49 (m, 1H), 6.36 (t, J = 2.1 Hz, 1H), 4.22 (d, J = 16.1 Hz, 1H), 3.59 (s, 3H), 2.64 (d, J = 16.1 Hz, 1H), 1.67 (s, 3H); 13C{1H}NMR (126 MHz, CDCl3) δ 175.1, 175.0, 159.7, 142.2, 141.4, 131.6, 129.9, 11



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127.4, 123.6, 123.1, 117.8, 113.3, 111.5, 110.7, 87.9, 55.1, 50.9, 39.3, 27.4; IR (KBr) 3297, 1793, 1735, 1471, 1197, 755, 703; HRMS (ESI) calcd for C19H18O4N [M+H]+ 324.1230, found 324.1225. (2R,3S)-3-methyl-3-(m-tolyl)-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione 3e, Yield: 32.0 mg, 52%; dr >20:1. white solid, mp 211-213 °C; []25 D +11.3 (c 1.0, CHCl3); 63% ee determined by HPLC(IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 13.4 min, tr min

= 10.4 min; 1H NMR (400 MHz, Chloroform-d) δ 7.56 – 7.52 (m, 2H), 7.41 (td, J =

7.8, 1.3 Hz, 1H), 7.19 – 7.15 (m, 1H), 7.05 – 6.98 (m, 2H), 6.82 (d, J = 7.8 Hz, 1H), 6.66 – 6.61 (m, 2H), 4.22 (d, J = 16.2 Hz, 1H), 2.63 (d, J = 16.2 Hz, 1H), 2.18 (s, 3H), 1.65 (s, 3H);

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C{1H}NMR (101 MHz, CDCl3) δ 175.40, 175.35, 142.3, 139.7, 138.4, 131.6,

128.70, 128.65, 127.3, 126.3, 123.6, 123.0, 122.5, 110.7, 88.2, 50.8, 39.3, 27.4, 21.6; IR (KBr) 3279, 1794, 1731, 1471, 1198, 755, 707; HRMS (ESI) calcd for C19H16O3N [MH]- 306.1136, found 306.1130. (2R,3S)-3-(3-bromophenyl)-3-methyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5dione 3f, Yield: 55.8 mg, 75%; dr >20:1. white solid, mp 194-195 °C; []25D +19.2 (c 1.0, CHCl3); 77% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 18.1 min, tr min = 12.9 min; 1H NMR (500 MHz, Chloroform-d) δ 7.56 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 4.1 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 4.19 (d, J = 16.1 Hz, 1H), 2.65 (d, J = 16.1 Hz, 1H), 1.66 (s, 3H); 13

C{1H}NMR (126 MHz, CDCl3) δ 174.8, 174.6, 142.2, 142.0, 131.9, 131.1, 130.4,

129.0, 127.4, 124.2, 123.3, 123.1, 123.0, 110.9, 87.7, 50.6, 39.1, 27.3; IR (KBr) 3265, 12


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1793, 1731, 1471, 1196, 754, 695; HRMS (ESI) calcd for C18H15O3NBr [M+H]+ 372.0230, found 372.0223. (2R,3S)-3-methyl-3-(naphthalen-2-yl)-3,4-dihydro-5H-spiro[furan-2,3'-indoline]2',5-dione 3g, Yield: 44.6 mg, 65% (27 mg, 40% after recrystallization); dr >20:1. white solid, mp 227-229 °C; []25D +102.3 (c 1.0, CHCl3); 97% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 24.6 min, tr min = 13.7 min; 1H NMR (500 MHz, Chloroform-d) δ7.75 – 7.73 (m, 1H), 7.68 – 7.64 (m, 1H), 7.63 (dd, J = 8.1, 3.8 Hz, 2H), 7.46 – 7.43 (m, 4H), 7.22 (td, J = 7.7, 1.1 Hz, 1H), 6.89 – 6.85 (m, 2H), 6.81 (d, J = 7.8 Hz, 1H), 4.41 (d, J = 16.1 Hz, 1H), 2.75 (d, J = 16.1 Hz, 1H), 1.75 (s, 3H); 13

C{1H}NMR (126 MHz, CDCl3) δ 175.2, 175.0, 142.2, 137.0, 133.2, 132.7, 131.7,

128.6, 128.3, 127.5, 127.4, 126.6, 126.5, 124.8, 123.5, 123.3, 123.1, 110.8, 88.1, 51.1, 39.3, 27.2; IR (KBr) 3283, 1798, 1737, 1471, 1197, 752; HRMS (ESI) calcd for C22H18O3N [M+H]+ 344.1281, found 344.1277. (2S,3S)-3-(furan-2-yl)-3-methyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione +40.0 (c 1.0, 3h, Yield: 52.6 mg, 83%; dr >20:1. white solid, mp 199-201 °C; []25 D CHCl3); 53% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 17.1 min, tr min = 13.1 min; 1H NMR (500 MHz, Chloroform-d) δ 7.46 (d, J = 7.5 Hz, 1H), 7.36 (td, J = 7.8, 1.2 Hz, 1H), 7.22 – 7.20 (m, 1H), 7.14 – 7.11 (m, 2H), 6.81 (d, J = 7.8 Hz, 1H), 6.25 (dd, J = 3.3, 1.8 Hz, 1H), 6.04 – 6.03 (m, 1H), 4.08 (d, J = 16.6 Hz, 1H), 2.64 (d, J = 16.7 Hz, 1H), 1.65 (s, 3H); 13C{1H}NMR (126 MHz, CDCl3) δ 175.6, 174.7, 152.3, 142.7, 142.0, 131.4, 127.3, 122.84, 122.76, 110.73, 110.70, 107.1, 87.8, 47.2, 39.2,

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24.1; IR (KBr) 3273, 1801, 1731, 1472, 1196, 753; HRMS (ESI) calcd for C16H12O4N [M-H]- 282.0772, found 282.0767. (2R,3S)-3-methyl-3-((E)-styryl)-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione 3i, Yield: 59 mg, 92.5%; dr >20:1. white solid, mp 154-155 °C; []25 D +3.0 (c 1.0, CHCl3); 55% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 18.3 min, tr min

= 12.6 min; 1H NMR (500 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.41 – 7.39 (m, 1H),

7.33 (td, J = 7.8, 1.3 Hz, 1H), 7.25 – 7.20 (m, 5H), 7.10 (td, J = 7.6, 1.0 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.34 – 6.06 (dd, J = 122.0, 16.1 Hz, 2H), 3.75 (d, J = 16.6 Hz, 1H), 2.50 (d, J = 16.6 Hz, 1H), 1.50 (s, 3H);

13

C{1H}NMR (126 MHz, CDCl3) δ 176.2, 175.5,

141.9, 136.2, 132.4, 131.3, 128.7, 128.3, 127.9, 127.4, 126.6, 122.8, 122.4, 111.0, 88.4, 48.6, 40.3, 23.5; IR (KBr) 3278, 1798, 1735, 1472, 1196, 753; HRMS (ESI) calcd for C20H16NO3 [M-H]- 318.1136, found 318.1129. (2R,3S)-3,5'-dimethyl-3-phenyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione 3j, Yield: 52.2 mg, 85%, dr >20:1. white solid; mp 68-70 °C; []25 D +24.0 (c 1.0, CHCl3); 78% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 14.3 min, tr min

= 10.1 min; 1H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J = 1.8 Hz, 1H), 7.28 –

7.22 (m, 4H), 7.12 (s, 1H), 6.93 – 6.91 (m, 2H), 6.73 (d, J = 7.9 Hz, 1H), 4.30 – 4.27 (m, 1H), 2.66 (d, J = 16.2 Hz, 1H), 2.43 (s, 3H), 1.70 (d, J = 0.9 Hz, 3H); 13C{1H}NMR (126 MHz, CDCl3) δ 175.3, 175.1, 139.8, 139.6, 132.7, 131.9, 128.8, 128.1, 127.9, 125.6, 123.5, 110.5, 88.2, 50.8, 39.2, 27.4, 21.4; IR (KBr) 3289, 1796, 1727, 1492, 1205, 763, 698; HRMS (ESI) calcd for C19H16O3N [M-H]- 306.1136, found 306.1130.

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(2R,3S)-5'-methoxy-3-methyl-3-phenyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]2',5-dione 3k, Yield: 60 mg, 93%, dr >20:1. white solid; mp 178-180 °C; []25 D +53.8 (c 1.0, CHCl3); 77% ee determined by HPLC (IA, 92:8 hexanes/i-PrOH, 1.0 ml/min), tr maj = 29.3 min, tr min = 19.0 min; 1H NMR (500 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.17 – 7.13 (m, 4H), 6.92 (dd, J = 8.5, 2.6 Hz, 1H), 6.87 – 6.86 (m, 2H), 6.74 (d, J = 8.4 Hz, 1H), 4.23 (d, J = 16.2 Hz, 1H), 3.84 (d, J = 4.5 Hz, 3H), 2.62 (d, J = 16.2 Hz, 1H), 1.65 (s, 3H); 13

C{1H}NMR (126 MHz, CDCl3) δ 175.6, 175.4, 155.8, 139.6, 135.5, 128.8, 127.9, 125.5,

124.5, 116.1, 114.4, 111.5, 88.5, 56.0, 50.8, 39.2, 27.3; IR (KBr) 3288, 1797, 1732, 1489, 1204, 763, 698; HRMS (ESI) calcd for C19H16O4N [M-H]- 322.1085, found 322.1079. (2R,3S)-5'-fluoro-3-methyl-3-phenyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5dione 3l, Yield: 48 mg, 77%, dr >20:1. white solid; mp 194-196 °C; []25D +35.7 (c 1.0, CHCl3); 71% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 16.5 min, tr min = 11.0 min; 1H NMR (500 MHz, Chloroform-d) δ 7.32 (dd, J = 7.9, 2.6 Hz, 1H), 7.25 – 7.17 (m, 4H), 7.14 (td, J = 8.7, 2.6 Hz, 1H), 6.92 – 6.84 (m, 2H), 6.78 (dd, J = 8.6, 4.1 Hz, 1H), 4.25 (d, J = 16.2 Hz, 1H), 2.65 (d, J = 16.2 Hz, 1H), 1.67 (s, 3H); 13

C{1H}NMR (126 MHz, CDCl3) δ 175.1, 174.8, 158.9 (d, J = 243.2 Hz), 139.3, 138.1,

129.0, 128.1, 125.5 (d, J = 7.6 Hz), 124.97 (d, J = 8.75), 118.2 (d, J = 23.9 Hz), 115.4 (d, J = 26.5 Hz), 111.5 (d, J = 7.6 Hz), 88.0, 51.0, 39.0, 27.1; IR (KBr) 3358, 1798, 1735, 1487, 1190, 698; HRMS (ESI) calcd for C18H13O3NF [M-H]- 310.0885, found 310.0880. (2R,3S)-5'-chloro-3-methyl-3-phenyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5dione 3m, Yield: 51.2 mg, 78%, dr >20:1. white solid; mp 66-70 °C; []25D +74.48 (c 1.0, CHCl3); 72% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 15



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16.0 min, tr min = 10.6 min; 1H NMR (500 MHz, Chloroform-d) δ 7.72 (s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 8.3, 2.1 Hz, 1H), 7.19 (td, J = 5.9, 2.8 Hz, 3H), 6.87 – 6.86 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 4.21 (d, J = 16.2 Hz, 1H), 2.64 (d, J = 16.2 Hz, 1H), 1.67 (s, 3H); 13C{1H}NMR (126 MHz, CDCl3) δ 175.2, 174.8, 140.7, 139.2, 131.6, 129.0, 128.5, 128.2, 127.6, 125.4, 125.1, 112.0, 87.9, 51.0, 39.0, 27.2; IR (KBr) 3289, 1797, 1739, 1475, 1195, 699; HRMS (ESI) calcd for C18H13O3NCl [M-H]- 326.0589, found 326.0584. (2R,3S)-6'-bromo-3-methyl-3-phenyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5dione 3n, Yield: 58.7 mg, 79%, dr >20:1. white solid; mp 257-259 °C; []25D +74.51 (c 1.0, CHCl3); 90% ee determined by HPLC (IA, 90:10 hexanes/i-PrOH, 1.0 ml/min), tr maj = 19.5 min, tr min = 14.0 min; 1H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J = 8.1 Hz, 1H), 7.33 (dd, J = 8.1, 1.7 Hz, 1H), 7.23 (dd, J = 5.2, 2.0 Hz, 4H), 7.01 (d, J = 1.7 Hz, 1H), 6.90 – 6.88 (m, 2H), 4.23 (d, J = 16.2 Hz, 1H), 2.64 (d, J = 16.2 Hz, 1H), 1.65 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ 174.8, 143.3, 139.3, 129.0, 128.5, 128.1, 126.1, 125.5, 122.4, 114.3, 87.6, 50.9, 39.0, 27.2; IR (KBr) 3273, 1794, 1741, 1615, 1200, 1047, 699, 635; HRMS (ESI) calcd for C18H13O3NBr [M-H]- 370.0084, found 370.0079. (2R,3S)-1',3-dimethyl-3-phenyl-3,4-dihydro-5H-spiro[furan-2,3'-indoline]-2',5-dione 3o, Yield: 41.4 mg, 67% (29 mg, 47% after recrystallization), dr = 10/1. white solid; mp 223-225 °C; [] 25 -11.2 (c 1.0, CHCl3); >99% ee determined by HPLC (IA, 90:10 D hexanes/i-PrOH, 1.0 ml/min), tr min= 16.4 min; tr maj = 118.0 min; 1H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J = 7.5, 1.2 Hz, 1H), 7.47 (td, J = 7.8, 1.2 Hz, 1H), 7.21 – 7.15 (m, 4H), 6.83 – 6.79 (m, 3H), 4.31 (d, J = 16.1 Hz, 1H), 2.76 (s, 3H), 2.65 (d, J = 16.1 Hz, 16


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1H), 1.66 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 175.3, 173.6, 145.2, 139.7, 131.6, 128.6, 127.9, 126.9, 125.5, 123.1, 122.9, 108.9, 88.1, 50.9, 39.2, 27.2, 25.8; IR (KBr) 1792, 1727, 1471, 1199, 768, 754; HRMS (ESI) calcd for C19H17O3NNa [M+Na]+ 330.1101, found 330.1098.

ASSOCIATED CONTENT

AUTHOR INFORMATION

Corresponding Author

*Email: [email protected]

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT

Financial support from the National Natural Science Foundation of China (Nos: , 21672216, 21521002, 21425207, ) is gratefully acknowledged.

Supporting Information

The NMR and HPLC spectra for obtained compounds (PDF). X‐ray data for 3f (CIF). This material is available free of charge via the Internet at http://pubs.acs.org. 17



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