Ag(I)/CAAA-Amidphos Complex Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Acrylates for the Formal Synthesis of (+)-Ibophyllidine

Abstract

In this work, we introduced a multifunctional Ag(I)/CAAA-amidphos complex catalyzed asymmetric 1,3-dipolar cycloaddition of acrylates with α-imino esters, affording a series of 2,4,5-trisubstituted endo-pyrrolidines in good yields (up to 97%) with high enantioselectivities (up to 98% ee). Meanwhile, the catalytic system was also applied in the three-component one-pot reaction of α-imino esters formed in situ under the action of N,N′-diisopropylcarbodiimide. In addition, the gram-scale reaction was realized for the formal synthesis of (+)-ibophyllidine in eight steps.

Key words

1,3-dipolar cycloaddition - α-imino esters - acrylates - three-component - one-pot reaction - (+)-ibophyllidine

Publication History

Received: 24 April 2021

Accepted after revision: 23 June 2021

Article published online:
06 July 2021

• References and Notes

• 1a Stylianakis I, Kolocouris A, Kolocouris N, Fytas G, Foscolos GB, Padalko E, Neyts J, De Clercq E. Bioorg. Med. Chem. Lett. 2003; 13. 1699
• 1b Michael JP. Nat. Prod. Rep. 2008; 25: 139
• 1c Arun Y, Bhaskar G, Balachandran C, Ignacimuthu S, Perumal PT. Bioorg. Med. Chem. Lett. 2013; 23: 1839
• 1d Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 2 Xiong Y, Du Z, Chen H, Yang Z, Tan Q, Zhang C, Zhu L, Lan Y, Zhang M. J. Am. Chem. Soc. 2019; 141: 961
• 3a Khuong-Huu F, Cesario M, Guilhem J, Goutarel R. Tetrahedron 1976; 32: 2539
• 3b Andrews IP, Kwon O. Chem. Sci. 2012; 3: 2510
• 4a Onodera H, Hasegawa A, Tsumagari N, Nakai R, Ogawa T, Kanda Y. Org. Lett. 2004; 6: 4101
• 4b Sumagari N, Nakai R, Onodera H, Hasegawa A, Rahayu ES, Ando K, Yamashita Y. J. Antibiot. 2004; 57: 532
• 4c Codelli JA, Puchlopek AL. A, Reisman SE. J. Am. Chem. Soc. 2012; 134: 1930
• 5a Naodovic M, Yamamoto H. Chem. Rev. 2008; 108: 3132
• 5b Stanley LM, Sibi MP. Chem. Rev. 2008; 108: 2887
• 5c Adrio J, Carretero JC. Chem. Commun. 2011; 47: 6784
• 5d Moyano A, Rios R. Chem. Rev. 2011; 111: 4703
• 5e Albrecht Ł, Jiang H, Jørgensen KA. Angew. Chem. Int. Ed. 2011; 50: 8492
• 5f Adrio J, Carretero JC. Chem. Commun. 2014; 50: 12434
• 5g Hashimoto T, Maruoka K. Chem. Rev. 2015; 115: 5366
• 5h Bdiri B, Zhao B.-J, Zhou Z.-M. Tetrahedron: Asymmetry 2017; 28: 876
• 5i Pellissier H. Chem. Rev. 2016; 116: 14868
• 6a Chen C, Li X, Schreiber SL. J. Am. Chem. Soc. 2003; 125: 10174
• 6b Nájera C, de Gracia Retamosa M, Martín-Rodríguez M, Sansano JM, de Cózar A, Cossío FP. Eur. J. Org. Chem. 2009; 5622
• 6c Nájera C, Retamosa M. d.G, Sansano JM. Angew. Chem. Int. Ed. 2008; 47: 6055
• 6d Dogan Ö, Koyuncu H, Garner P, Bulut A, Youngs WJ. Org. Lett. 2006; 8: 4687
• 6e Tsubogo T, Saito S, Seki K, Yamashita Y, Kobayashi S. J. Am. Chem. Soc. 2008; 130: 13321
• 6f Wang C.-J, Liang G, Xue Z.-Y, Gao F. J. Am. Chem. Soc. 2008; 130: 17250
• 6g Kim HY, Shih H.-J, Knabe WE, Oh K. Angew. Chem. Int. Ed. 2009; 48: 7420
• 7a Caleffi GS, Larrañaga O, Ferrándiz-Saperas M, Costa PR. R, Nájera C, de Cózar A, Cossío FP, Sansano JM. J. Org. Chem. 2019; 84: 10593
• 7b Fukuzawa S, Oki H. Org. Lett. 2008; 10: 1747
• 7c Yamashita Y, Imaizumi T, Kobayashi S. Angew. Chem. Int. Ed. 2011; 50: 4893
• 7d Yamashita Y, Imaizumi T, Guo X.-X, Kobayashi S. Chem. Asian J. 2011; 6: 2550
• 8a Wang H, Deng Q, Zhou Z, Hu S, Liu Z, Zhou L.-Y. Org. Lett. 2016; 18: 404
• 8b Hou Y, Zhou Z, Liu P, Wang J, Hou Q, Wen P, Wang H. Tetrahedron: Asymmetry 2017; 28: 930
• 8c Zhou Z, Zheng X, Liu J, Li J, Wen P, Wang H. Synlett 2017; 28: 999
• 8d Hou Q, You Y, Song X, Wang Y, Chen K, Wang H. Catalysts 2020; 10: 28
• 8e Zhang K.-Q, Deng QF, Luo J, Gong C.-L, Chen ZG, Zhong W, Hu S.-Q, Wang H.-F. ACS Catal. 2021; 11: 5100
• 9 The absolute configurations of the known products endo-4aa, endo-4ac, endo-4pa, and endo-4pb were assigned by HPLC and optical rotation comparisons with the reported data (see ref. 6a,c,e and the Supporting Information), and those of other adducts were deduced on the basis of these results.
• 10 For the 1,3-dipolar cycloaddition reaction of the methyl cinnamate, see the Supporting Information.
• 11 Melting points are uncorrected. ¹H NMR and ¹³C NMR spectra were recorded on Bruker AV-400 spectrometers in CDCl₃ unless otherwise noted. CDCl₃ served as internal standard (δ = 7.26) for ¹H NMR and (δ = 77.0) for ¹³C NMR. IR spectra were recorded on a Bruker Alpha FT-IR spectrophotometer. High-performance liquid chromatography was carried out using an Agilent 1260 apparatus which was equipped with a spectrophotometric detector (monitoring at 205–230 nm) using a Daicel chiral AS-H column, OD-H column, and AD-H column. High-resolution mass spectrometry was recorded with a Micromass LCMS-IT-TOF instrument. Optical rotations were measured on a Insmark IP-digi300/2. X-ray diffraction analysis was measured on a Bruker Apex-II CCD diffractometer with monochromatic Mo Kα radiation. Most chemical reagents were purchased from Adamas-beta® Co., Ltd. (Shanghai, China), aladdin® Co., Ltd. (Shanghai, China), and Sigma-Aldrich Co. (St. Louis, Missouri, USA) and were used as received without further purification. All reactions were carried out under argon atmosphere in oven-dried glassware with magnetic stirring. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. Reactions were monitored by thin-layer chromatography (TLC) on silica gel precoated glass plates (qingdaohaiyang, GF254). Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or potassium permanganate stains. Flash column chromatography was performed using silica gel 200-300 (particle size 0.0040–0.0750 mm) from Qingdaohaiyang. N-((R)-1-{(S)-[(2S)-8-ethylquinuclidin-2-yl](quinolin-4-yl)methylcarbamoyl}-2,2-dimethylpropyl)-2-(diphenylphosphino)benzamide (1e) Precatalyst 1e was prepared according to our previous reported procedure^8a on a 1.0 mmol scale. White solid (529 mg, 76%); mp 123–124 °C; [α]_D ²⁵ +21.9 (c 0.60, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.86 (d, J = 4.4 Hz, 1 H), 8.40 (d, J = 8.0 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.56–7.52 (m, 3 H), 7.42 (d, J = 4.8 Hz, 1 H), 7.31–7.21 (m, 12 H), 7.00 (dd, J = 6.4, 3.2 Hz, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 5.41 (br s, 1 H), 4.41 (d, J = 8.8 Hz, 1 H), 3.18 (dd, J = 13.6, 10.0 Hz, 1 H), 2.99 (br s, 2 H), 2.64 (s, 3 H), 2.37 (dd, J = 13.6, 3.3 Hz, 1 H), 1.64–1.57 (m, 2 H), 1.48–1.41 (m, 2 H), 0.84 (s, 9 H), 0.76 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.8, 149.9, 141.5, 141.2, 137.6, 137.5, 137.3, 137.2, 136.2, 136.0, 134.5, 133.8, 133.8, 133.6, 133.6, 130.3, 130.3, 129.1, 128.8, 128.6, 128.5, 128.4, 128.4, 127.5, 127.4, 60.9, 60.3, 57.3, 40.8, 37.1, 34.9, 28.3, 27.3, 26.7, 25.1, 21.0, 14.1, 11.9. ³¹P NMR (162 MHz, CDCl₃): δ = –10.2. HRMS (ESI): m/z calcd for C₄₄H₅₀N₄O₂P [M + H]⁺: 697.3666; found: 697.3658. N-((S)-1-{(S)-[(2S)-3-ethylquinuclidin-2-yl](quinolin-4-yl)methylcarbamoyl}-2,2-dimethylpropyl)-2-(diphenylphosphino)benzamide (1f) Catalyst 1f was prepared according to the procedure used to synthesize catalyst 1e. White solid (592 mg, 85%); mp 210–211 °C; [α]_D ³⁰ –34.4 (c 0.55, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.87 (d, J = 3.2 Hz, 1 H), 8.34 (d, J = 6.8 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.72–7.70 (m, 1 H), 7.62–7.59 (m, 3 H), 7.41–7.11 (m, 13 H), 6.99–6.97 (m, 1 H), 6.68–6.16 (m, 1 H), 5.90–5.84 (m, 1 H), 5.29 (br s, 1 H), 5.14–5.07 (m, 1 H), 4.43 (d, J = 8.8 Hz, 1 H), 3.48 (dd, J = 6.8 , 13.6 Hz, 1 H), 2.97–2.91 (m, 3 H), 2.43–2.28 (m, 2 H), 1.62–1.43 (m, 4 H), 1.21 (t, J = 7.2 Hz, 3 H), 0.99–0.85 (m, 3 H), 0.85 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.8, 168.7, 149.8, 148.4, 140.2, 137.3, 134.6, 133.8, 133.6, 130.3, 129.2, 128.8, 128.6, 128.4, 127.5, 114.9, 65.8, 60.9, 49.1, 47.0, 39.2, 37.3, 35.1, 27.2, 27.0, 26.9, 26.7, 25.9, 25.7, 15.2, 12.1. ³¹P NMR (162 MHz, CDCl₃): δ = –10.3. HRMS (ESI): m/z calcd for C₄₄H₄₉N₄O₂P₁ [M + H]⁺: 697.3666; found: 697.3669. General Procedure A of the Ag₂CO₃/1g-Catalyzed Cycloaddition of Various Imino Esters 3 Under N₂ atmosphere, a solution of precatalyst 1e (0.008 mmol) and Ag₂O (0.004 mmol) in toluene (1.4 mL) in a flame-dried glass tube with aluminum foil was stirred for 1 h at room temperature, followed by the addition of the acrylate 2 (0.2 mmol) and imino ester 3 (0.3 mmol). Once starting material was consumed (monitored by TLC), the mixture was purified by column chromatography to give the corresponding cycloaddition product endo-4, which was then directly analyzed by chiral HPLC. General Procedure B of the Ag₂CO₃/1g-Catalyzed Three-Component Reaction of α-Imino Esters Generated in situ To a solution of tert-butyl glycine (31.5 mg, 0.24 mmol) in toluene (1 mL) was added the aldehyde 5 (0.24 mmol) and N,N′-diisopropylcarbodiimide (1.9 mg, 0.24 mmol), which was stirred for 2 h at room temperature. Then, a solution of precat. 1e or 1f (5.56 mg, 0.008 mmol) and Ag₂O (0.93 mg, 0.004 mmol) in toluene (0.2 mL), stirred for 1 h, was mixed with the above solution, followed by methyl acrylate 3a (17.2 mg, 0.2 mmol) dropwise at –5 °C. The reaction was monitored by TLC plate, and the residue was purified by silica gel column chromatography to afford the corresponding cycloaddition product 6, which was then directly analyzed by chiral HPLC. (2R,4R,5S)-Dimethyl 5-Phenylpyrrolidine-2,4-dicarboxylate (4aa) White solid, yield 48 mg (92%); mp 72–73 °C; [α]_D ³⁰ –30.4 (c 0.50, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.30–7.20 (m, 5 H), 4.51 (d, J = 7.6 Hz, 1 H), 3.96 (t, J = 8.0 Hz, 1 H), 3.79 (s, 3 H), 3.29 (q, J = 7.2 Hz, 1 H), 3.18 (s, 3 H), 2.92 (br s, 1 H), 2.39 (t, J = 7.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.6, 172.8, 138.9, 128.0, 127.4, 126.5, 65.6, 59.7, 52.0, 51.0, 49.5, 33.1. HRMS (ESI): m/z calcd for C₁₄H₁₇NO₄ [M + H]⁺ 264.1230; found: 264.1234. The ee value was 94%, t _R(minor) = 10.99 min, t _R(major) = 15.17 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2S,4S,5R)-Dimethyl 5-Phenylpyrrolidine-2,4-dicarboxylate (ent-endo-4aa) White solid, yield 47 mg (91%); mp 72–73 °C; [α]_D ³⁰ +28.0 (c 1.12, CH₂Cl₂). The ee value was 92%, t _R(major) = 9.07min, t _R(minor) = 12.69 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 20:80, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(p-Tolyl)pyrrolidine-2,4-dicarboxylate (4ba) Colorless oil, yield 49 mg (89%); [α]_D ³⁰ –35.5 (c 0.76, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.17 (d, J = 7.6 Hz, 2 H), 7.09 (d, J = 7.6 Hz, 2 H), 4.48 (d, J = 7.6, 1 H), 3.95 (t, J = 8.0 Hz, 1 H), 3.80 (s, 3 H), 3.29–3.26 (m, 1 H), 3.23 (s, 3 H), 2.84 (br s, 1 H), 2.38 (dd, J = 7.6, 7.2 Hz, 2 H), 2.29 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.7, 173.0, 137.1, 135.9, 128.8, 126.5, 65.6, 59.8, 52.1, 51.1, 49.6, 33.3, 21.0. HRMS (ESI): m/z calcd for C₁₅H₁₉NO₄ [M + H]⁺: 278.1387; found: 278.1390. The ee value was 92%, t _R (minor) = 10.05 min, t _R (major) = 16.42 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(4-Methoxyphenyl)pyrrolidine-2,4-dicarboxylate (4ca) White solid, yield 50 mg (85%); mp 56–59 °C; [α]_D ³⁰ –35.8 (c 0.86, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.22 (d, J = 8.0 Hz, 2 H), 6.83 (d, J = 8.0 Hz, 2 H), 4.48 (d, J = 8.0 Hz, 1 H), 3.95 (t, J = 8.0 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.29–3.24 (m, 1 H), 3.24 (s, 3 H), 2.67 (s, 1 H), 2.38 (t, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.8, 173.0, 158.9, 131.1, 127.8, 113.5, 65.3, 59.8, 55.1, 52.2, 51.2, 49.6, 33.2. HRMS (ESI): m/z calcd for C₁₅H₁₉NO₅ [M + H]⁺: 294.1336; found: 294.1338. The ee value was 93%, t _R (minor) = 12.70 min, t _R (major) = 16.68 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 20:80, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(4-Fluorophenyl)pyrrolidine-2,4-dicarboxylate (4da) Colorless oil, yield 52 mg (92%); [α]_D ³⁰ –29.5 (c 0.67, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.31 (t, J = 7.2 Hz, 2 H), 7.00 (t, J = 8.4 Hz, 2 H), 4.54 (d, J = 8.0 Hz, 1 H), 3.98 (dd, J = 8.4, 8.0 Hz, 1 H), 3.82 (s, 3 H), 3.33–3.29 (m, 1 H), 3.25 (s, 3 H), 2.72 (br s, 1 H), 2.41 (t, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.7, 172.7, 163.3, 160.9, 135.0, 128.4, 115.0, 114.8, 64.8, 59.7, 52.2, 51.2, 49.5, 32.9. HRMS (ESI): m/z calcd for C₁₄H₁₆FNO₄ [M + H]⁺: 282.1136; found: 282.1138. The ee value was 94%, t _R (minor) = 12.69 min, t _R (major) = 16.09 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(4-Chlorophenyl)pyrrolidine-2,4-dicarboxylate (4ea) Colorless oil, yield 58 mg (97%); [α]_D ³⁰ –24.9 (c 0.92, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.28 (s, 4 H), 4.52 (d, J = 7.6 Hz, 1 H), 3.98 (t, J = 8.0 Hz, 1 H), 3.82 (s, 3 H), 3.33–3.30 (m, 1 H), 3.27 (s, 3 H), 2.67 (br s, 1 H), 2.43–2.40 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.6, 172.6, 137.8, 133.2, 128.2, 128.2, 64.9, 59.7, 52.2, 51.3, 49.4, 32.9. HRMS (ESI): m/z calcd for C₁₄H₁₆ClNO₄ [M + H]⁺: 298.0841; found: 298.0844. The ee value was 90%, t _R (minor) = 9.61 min, t _R (major) = 16.81 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(4-Bromophenyl)pyrrolidine-2,4-dicarboxylate (4fa) Colorless oil, yield 59 mg (86%); [α]_D ³⁰ –56.2 (c 1.30, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.41 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 7.6 Hz, 2 H), 4.48 (d, J = 8.0 Hz, 1 H), 3.95 (dd, J = 8.4, 8.0 Hz, 1 H), 3.79 (s, 3 H), 3.31–3.28 (m, 1 H), 3.24 (s, 3 H), 2.65 (br s, 1 H), 2.38 (t, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.6, 172.6, 138.4, 131.2, 128.5, 121.4, 64.9, 59.7, 52.2, 51.3, 49.4, 33.0. HRMS (ESI): m/z calcd for C₁₄H₁₆BrNO₄ [M + H]⁺: 342.0335; found: 342.0338. The ee value was 94%, t _R (minor) = 12.69 min, t _R (major) = 16.09 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-[4-(tert-Butyl)phenyl]pyrrolidine-2,4-dicarboxylate (4ga) Colorless oil, yield 50 mg (78%); [α]_D ³⁰ –26.6 (c 0.80, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.32 (d, J = 7.6 Hz, 2 H), 7.23 (d, J = 7.6 Hz, 2 H), 4.51 (d, J = 7.6 Hz, 1 H), 3.95 (t, J = 8.0 Hz, 1 H), 3.81 (s, 3 H), 3.31–3.25 (m, 1 H), 3.18 (s, 3 H), 2.74 (br s, 1 H), 2.40 (t, J = 7.2 Hz, 2 H), 1.28 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.8, 173.1, 150.5, 135.9, 126.4, 125.0, 65.6, 60.0, 52.2, 51.1, 49.7, 34.4, 33.3, 31.2. HRMS (ESI): m/z calcd for C₁₈H₂₅NO₄ [M + H]⁺: 320.1856; found: 320.1857. The ee value was 93%, t _R (minor) = 6.80 min, t _R (major) = 12.39 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(2-Chlorophenyl)pyrrolidine-2,4-dicarboxylate (4ha) Colorless oil, yield 46 mg (78%); [α]_D ³⁰ –78.6 (c 0.55, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.51 (d, J = 7.2 Hz, 1 H), 7.35–7.17 (m, 3 H), 4.82 (d, J = 7.2 Hz, 1 H), 3.97 (t, J = 8.0 Hz, 1 H), 3.82 (s, 3 H), 3.51 (dd, J = 13.2, 6.4 Hz, 1 H), 3.13 (s, 3 H), 2.73 (br s, 1 H), 2.47 (dd, J = 7.2, 6.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 173.0, 136.1, 133.2, 129.0, 128.5, 127.0, 126.5, 62.3, 59.2, 52.1, 51.0, 46.7, 32.9. HRMS (ESI): m/z calcd for C₁₄H₁₆ClNO₄ [M + H]⁺: 298.0841; found: 298.0846. The ee value was 87%, t _R (minor) = 11.48 min, t _R (major) = 20.99 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(3-Chlorophenyl)pyrrolidine-2,4-dicarboxylate (4ia) Colorless oil, yield 51 mg (86%); [α]_D ³⁰ –31.8 (c 0.64, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.24 (m, 4 H), 4.51 (d, J = 7.6, 1 H), 3.98 (dd, J = 8.4, 8.0 Hz, 1 H), 3.83 (s, 3 H), 3.34–3.31 (m, 1 H), 3.29 (s, 3 H), 2.67 (br s, 1 H), 2.41 (dd, J = 7.6, 7.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 172.5, 141.5, 134.0, 129.4, 127.6, 127.1, 124.9, 64.9, 59.6, 52.2, 51.3, 49.4, 32.8. HRMS (ESI): m/z calcd for C₁₄H₁₆ClNO₄ [M + H]⁺: 298.0841; found: 298.0846. The ee value was 91%, t _R (minor) = 13.82 min, t _R (major) = 22.21 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(Naphthalen-1-yl)pyrrolidine-2,4-dicarboxylate (4ja) Colorless oil, yield 59 mg (95%); [α]_D ³⁰ –62.8 (c 0.60, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 6.8 Hz, 1 H), 7.55–7.43 (m, 3 H), 5.28 (d, J = 7.6 Hz, 1 H), 4.07 (t, J = 8.0 Hz, 1 H), 3.85 (s, 3 H), 3.54 (dd, J = 13.2, 6.4 Hz, 1 H), 2.86 (s, 3 H), 2.69 (br s, 1 H), 2.53 (dd, J = 7.2, 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.6, 173.0, 134.2, 133.4, 131.1, 128.8, 128.1, 126.0, 125.4, 125.1, 122.8, 122.7, 61.7, 59.4, 52.2, 50.9, 48.6, 33.4. HRMS (ESI): m/z calcd for C₁₈H₁₉NO₄ [M + H]⁺: 314.1387; found: 314.1382. The ee value was 93%, t _R (minor) = 21.61 min, t _R (major) = 31.79 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(Naphthalen-2-yl)pyrrolidine-2,4-dicarboxylate (4ka) Colorless oil, yield 59 mg (95%); [α]_D ³⁰ –22.7 (c 0.68, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.81–7.78 (m, 4 H), 7.47–7.43 (m, 3 H), 4.68 (d, J = 7.6 Hz, 1 H), 4.04 (t, J = 8.0 Hz, 1 H), 3.85 (s, 3 H), 3.40 (dd, J = 13.6, 6.4 Hz, 1 H), 3.12 (s, 3 H), 2.84 (br s, 1 H), 2.47 (dd, J = 7.2, 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.7, 173.0, 136.4, 133.0, 132.8, 127.9, 127.7, 127.5, 126.0, 125.8, 125.3, 125.0, 65.9, 59.9, 52.3, 51.2, 49.5, 33.4. HRMS (ESI): m/z calcd for C₁₈H₁₉NO₄ [M + H]⁺: 314.1387; found: 314.1395. The ee value was 93%, t _R (minor) = 14.80 min, t _R (major) = 25.68 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(Thiophen-2-yl)pyrrolidine-2,4-dicarboxylate (4la) Colorless oil, yield 41 mg (88%); [α]_D ³⁰ –8.8 (c 0.74, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.19 (d, J = 4.8 Hz, 1 H), 6.97–6.92 (m, 2 H), 4.77 (d, J = 7.2 Hz, 1 H), 3.97 (t, J = 8.0 Hz, 1 H), 3.80 (s, 3 H), 3.42 (s, 3 H), 3.34 (dd, J = 7.6, 7.2 Hz, 1 H), 2.76 (br s, 1 H), 2.42 (t, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 172.3, 143.2, 126.6, 124.6, 124.5, 61.1, 59.5, 52.3, 51.5, 49.8, 32.4. HRMS (ESI): m/z calcd for C_{12 H15}NO₄S [M + H]⁺: 270.0795; found: 270.0798. The ee value was 81%, t _R (minor) = 8.80 min, t _R (major) = 11.79 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 30:70, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(Furan-2-yl)pyrrolidine-2,4-dicarboxylate (4ma) Colorless oil, yield 38 mg (76%); [α]_D ³⁰ –7.9 (c 0.83, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.33 (s, 1 H), 6.29 (d, J = 10.0 Hz, 2 H), 4.56 (d, J = 7.6 Hz, 1 H), 3.94 (t, J = 8.0 Hz, 1 H), 3.80 (s, 3 H), 3.48 (s, 3 H), 3.28 (dd, J = 7.6, 7.2 Hz, 1 H), 2.81 (br s, 1 H), 2.49–2.36 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.8, 172.4, 152.9, 142.0, 110.2, 107.0, 59.4, 52.3, 51.8, 48.4, 32.3. HRMS (ESI): m/z calcd for C₁₂H₁₅NO₅ [M + H]⁺: 254.1023; found: 254.1025. The ee value was 90%, t _R(minor) = 13.22 min, t _R (major) = 22.81 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(Pyridin-2-yl)pyrrolidine-2,4-dicarboxylate (4na) Colorless oil, yield 38 mg (72%); [α]_D ³⁰ –2.1 (c 0.78, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.52 (d, J = 4.0 Hz, 1 H), 7.64 (t, J = 7.6 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.17–7.14 (m, 1 H), 4.58 (d, J = 7.6 Hz, 1 H), 4.01 (t, J = 8.0 Hz, 1 H), 3.80 (s, 3 H), 3.34 (q, J = 6.8 Hz, 1 H), 3.26 (s, 3 H), 3.13 (br s, 1 H), 2.47–2.43 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 172.9, 158.1, 148.9, 136.3, 122.5, 122.2, 66.8, 60.2, 52.2, 51.3, 49.2, 33.6. HRMS (ESI): m/z calcd for C_{13 H16}N₂O₄ [M + H]⁺: 265.1183; found: 265.1180. The ee value was 90%, t _R (minor) = 6.41 min, t _R (major) = 7.33 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 50:50, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-Cyclohexylpyrrolidine-2,4-dicarboxylate (4oa) Colorless oil, yield 40 mg (74%); [α]_D ³⁰ +11.4 (c 0.72, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 3.81 (dd, J = 4.8, 5.2 Hz, 1 H), 3.73 (s, 3 H), 3.62 (s, 3 H), 2.93 (s, 1 H), 2.81–2.79 (m, 1 H), 2.32–2.30 (m, 2 H), 2.20–2.18 (m, 1 H), 1.94 (dd, J = 71.6, 11.6 Hz, 2 H), 1.69 (s, 2 H), 1.22–1.15 (m, 4 H), 0.99–0.93 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.7, 173.6, 69.7, 59.4, 52.0, 51.2, 45.4, 39.6, 34.6, 31.4, 30.9, 26.1, 25.8, 25.7. HRMS (ESI): m/z calcd for C₁₄H₂₃NO₄ [M + H]⁺: 270.1700; found: 270.1704. The ee value was 67%, t _R(minor) = 6.61 min, t _R (major) = 14.86 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-4-Ethyl 2-Methyl-5-phenylpyrrolidine-2,4-dicarboxylate (4ab) White solid, yield 50 mg (91%); mp 63–65 °C; [α]_D ³⁰ –32.3 (c 0.65, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.32–7.24 (m, 5 H), 4.53 (d, J = 7.6 Hz, 1 H), 3.98 (t, J = 8.0 Hz, 1 H), 3.82 (s, 3 H), 3.75–3.58 (m, 2 H), 3.29 (dd, J = 6.8, 14.0 Hz, 1 H), 2.71 (br s, 1 H), 2.42 (t, J = 8.0 Hz, 2 H), 0.81 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.7, 172.6, 139.0, 128.1, 127.5, 126.9, 65.9, 60.3, 60.0, 52.3, 49.7, 33.5, 13.6. HRMS (ESI): m/z calcd for C₁₅H₁₉NO₄ [M + H]⁺: 278.1387; found: 278.1391. The ee value was 94%, t _R(minor) = 9.43 min, t _R (major) = 15.95 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-4-tert-Butyl 2-Methyl-5-phenylpyrrolidine-2,4-dicarboxylate (4ac) White solid, yield 55 mg (90%); mp 69–72 °C; [α]_D ³⁰ –26.7 (c 0.58, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.22 (m, 5 H), 4.47 (d, J = 7.6 Hz, 1 H), 3.95 (t, J = 8.4 Hz, 1 H), 3.81 (s, 3 H), 3.26 (dd, J = 6.8, 14.4 Hz, 1 H), 2.86 (br s, 1 H), 2.48–2.40 (m, 1 H), 2.34–2.27 (m, 1 H), 1.02 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.6, 171.8, 139.3, 128.1, 127.2, 127.2, 80.5, 65.5, 59.9, 52.1, 50.2, 34.1, 27.4. HRMS (ESI): m/z calcd for C₁₇H₂₃NO₄ [M + H]⁺: 306.1700; found: 306.1702. The ee value was 78%, t _R(minor) = 6.63min, t _R (major) = 8.92 min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 2-Methyl-5-phenylpyrrolidine-2,4-dicarboxylate (4pa) Colorless oil, yield 43 mg (78%); [α]_D ³⁰ –20.8 (c 0.83, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.25 (m, 5 H), 4.66 (d, J = 7.2 Hz, 1 H), 3.84 (s, 3 H), 3.35 (dd, J = 12.8, 7.2 Hz, 1 H), 3.21 (s, 3 H), 3.16 (br s, 1 H), 2.72 (dd, J = 13.6, 4.8 Hz, 1 H), 2.06 (dd, J = 13.6, 7.6 Hz, 1 H), 1.51 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.6, 173.0, 139.0, 128.1, 127.5, 126.6, 65.7, 64.9, 52.5, 51.1, 50.5, 40.3, 27.6. HRMS (ESI): m/z calcd for C₁₅H₁₉NO₄ [M + H]⁺: 278.1387; found: 278.1392. The ee value was 88%, t _R(minor) = 11.22 min, t _R (major) = 20.72 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(4-Methoxyphenyl)-2-methylpyrrolidine-2,4-dicarboxylate (4qa) Colorless oil, yield 48 mg (78%); [α]_D ³⁰ –35.6 (c 0.54, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.19 (d, J = 6.8 Hz, 2 H), 6.83 (d, J = 6.8 Hz, 2 H), 4.61 (d, J = 6.4 Hz, 1 H), 3.82 (s, 3 H), 3.77 (s, 3 H), 3.33–3.29 (m, 1 H), 3.24 (s, 3 H), 2.95 (br s, 1 H), 2.72–2.67 (m, 1 H), 2.06–2.00 (m, 1 H), 1.48 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.6, 173.1, 158.9, 131.1, 127.8, 113.5, 65.6, 64.5, 55.1, 52.5, 51.2, 50.4, 40.2, 27.5. HRMS (ESI): m/z calcd for C₁₆H₂₁NO₅ [M + H]⁺: 308.1492; found: 308.1498. The ee value was 91%, t _R(minor) = 18.55 min, t _R (major) = 27.12 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(4-Fluorophenyl)-2-methylpyrrolidine-2,4-dicarboxylate (4ra) Colorless oil, yield 50 mg (85%); [α]_D ³⁰ 27.2 (c 1.10, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.27 (d, J = 7.6 Hz, 2 H), 6.99 (t, J = 8.0 Hz, 2 H), 4.65 (d, J = 7.6 Hz, 1 H), 3.83 (s, 3 H), 3.34 (dd, J = 12.8, 6.8 Hz, 1 H), 3.24 (s, 3 H), 2.93 (br s, 1 H), 2.72 (dd, J = 13.6, 5.2 Hz, 1 H), 2.05 (dd, J = 13.6, 7.6 Hz, 1 H), 1.50 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.4, 172.8, 163.3, 160.8, 135.0, 128.3, 115.0, 114.8, 65.5, 64.0, 52.4, 51.1, 50.2, 39.9, 27.3. HRMS (ESI): m/z calcd for C₁₅H₁₈FNO₄ [M + H]⁺: 296.1293; found: 296.1296. The ee value was 91%, t _R(minor) = 8.68 min, t _R (major) = 16.34 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(4-Chlorophenyl)-2-methylpyrrolidine-2,4-dicarboxylate (4sa) White solid, yield 45mg (72%); mp 49–52 °C; [α]_D ³⁰ –28.6 (c 0.45, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.29–7.23 (m, 4 H), 4.64 (d, J = 7.6 Hz, 1 H), 3.83 (s, 3 H), 3.35 (dd, J = 12.8, 6.0 Hz, 1 H), 3.25 (s, 3 H), 3.02 (br s, 1 H), 2.72 (dd, J = 13.2, 4.4 Hz, 1 H), 2.05 (dd, J = 13.2, 7.6 Hz, 1 H), 1.50 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.4, 172.7, 138.4, 131.2, 128.5, 121.3, 65.6, 64.1, 52.5, 51.2, 50.1, 40.0, 27.4. HRMS (ESI): m/z calcd for C₁₅H₁₈ClNO₄ [M + H]⁺: 312.0997; found: 312.0992. The ee value was 90%, t _R(minor) = 9.61 min, t _R (major) = 16.81 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 5-(4-Bromophenyl)-2-methylpyrrolidine-2,4-dicarboxylate (4ta) White solid, yield 54 mg (76%); mp 74–77 °C; [α]_D ³⁰ –15.5 (c 0.73, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.41 (d, J = 7.6 Hz, 2 H), 7.17 (t, J = 7.6 Hz, 2 H), 4.60 (d, J = 7.2 Hz, 1 H), 3.81 (s, 3 H), 3.33 (dd, J = 12.8, 6.0 Hz, 1 H), 3.24 (s, 3 H), 2.70 (dd, J = 13.6, 4.8 Hz, 1 H), 2.05 (dd, J = 13.6, 7.6 Hz, 1 H), 1.48 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.4, 172.7, 138.4, 131.2, 128.5, 121.3, 65.6, 64.1, 52.5, 51.2, 50.1, 40.0, 27.4. HRMS (ESI): m/z calcd for C₁₅H₁₈BrNO₄ [M + H]⁺: 356.0492; found: 356.0495. The ee value was 90%, t _R(minor) = 10.19 min, t _R (major) = 17.86 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 2-Methyl-5-(naphthalen-2-yl)pyrrolidine-2,4-dicarboxylate (4ua) White solid, yield 56 mg (85%); mp 84–87 °C; [α]_D ³⁰ –31.2 (c 0.28, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.80–7.77 (m, 4 H), 7.46– 7.38 (m, 3 H), 4.81 (d, J = 7.2 Hz, 1 H), 3.86 (s, 3 H), 3.47–3.42 (m, 1 H), 3.30 (br s, 1 H), 3.12 (s, 3 H), 2.79 (dd, J = 13.6, 4.4 Hz, 1 H), 2.11 (dd, J = 13.6, 7.6 Hz, 1 H), 1.55 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.5, 173.0, 136.4, 133.1, 132.7, 127.9, 127.7, 127.4, 125.9, 125.7, 125.2, 124.9, 65.7, 64.9, 52.4, 51.1, 50.3, 40.4, 27.6. HRMS (ESI): m/z calcd for C₁₉H₂₁NO₄ [M + H]⁺: 328.1543; found: 328.1545. The ee value was 87%, t _R(minor) = 20.78 min, t _R (major) = 29.80 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 2-Benzyl-5-phenylpyrrolidine-2,4-dicarboxylate (4va) White solid, yield 53 mg (75%); mp 77–79 °C; [α]_D ³⁰ –8.0 (c 0.40, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.27–7.23 (m, 10 H), 4.52 (d, J = 7.2 Hz, 1 H), 3.76 (s, 3 H), 3.21–3.16 (m, 1 H), 3.18 (s, 3 H), 3.12 (d, J = 13.2 Hz, 1 H), 3.04 (br s, 1 H), 2.95 (d, J = 13.2 Hz, 1 H), 2.76 (dd, J = 13.6, 4.8 Hz, 1 H), 2.20 (dd, J = 13.6, 7.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.7, 173.0, 139.6, 136.9, 130.1, 128.1, 128.0, 127.6, 126.7, 70.4, 65.1, 52.2, 51.1, 50.1, 45.9, 38.6. HRMS (ESI): m/z calcd for C_{21 H23}NO₄ [M + H]⁺: 354.1700; found: 354.1702. The ee value was 81%, t _R(minor) = 17.24 min, t _R (major) = 19.67 min (Chiralcel AD-H, λ = 205 nm, i-PrOH/hexanes = 3:97, flow rate = 1.0 mL/min). (2R,4R,5S)-Dimethyl 2,5-Diphenylpyrrolidine-2,4-dicarboxylate (4wa) White solid, yield 56 mg (82%); mp 110–113 °C; [α]_D ³⁰ –31.2 (c 0.63, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.73 (d, J = 8.0 Hz, 2 H), 7.38–7.26 (m, 8 H), 4.55 (d, J = 7.6 Hz, 1 H), 3.76 (s, 3 H), 3.48 (br s, 1 H), 3.27–3.22 (m, 1 H), 3.22 (s, 3 H), 3.16 (dd, J = 5.6, 13.2 Hz, 1 H), 2.62 (dd, J = 7.0, 13.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.5, 173.1, 143.0, 139.1, 128.3, 128.2, 127.6, 127.5, 126.7, 126.3, 71.8, 64.7, 52.8, 51.2, 50.3, 41.0. HRMS (ESI): m/z calcd for C₂₀H₂₁NO₄ [M + H]⁺: 340.1543; found: 340.1545. The ee value was 86%, t _R(major) = 15.80 min, t _R (minor) = 17.23 min (Chiralcel AD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-4-tert-Butyl 2-Methyl-2-methyl-5-phenylpyrrolidine-2,4-dicarboxylate (4pb) White solid, yield 48 mg (76%); mp 59–62 °C; [α]_D ³⁰ –15.5 (c 0.64, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.32–7.23 (m, 5 H), 4.61 (d, J = 7.6 Hz, 1 H), 3.81 (s, 3 H), 3.33 (dd, J = 7.2, 14.0 Hz, 1 H), 3.18 (br s, 1 H), 2.63 (dd, J = 6.0, 13.6 Hz, 1 H), 2.07 (dd, J = 7.6, 13.2 Hz, 1 H), 1.49 (s, 3 H), 1.01 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.2, 171.5, 139.4, 127.9, 127.1, 127.0, 80.2, 65.3, 64.2, 52.3, 50.6, 40.7, 27.3. HRMS (ESI): m/z calcd for C₁₈H₂₅NO₄ [M + H]⁺: 320.1856; found: 320.1859. The ee value was 80%, t _R(minor) = 10.01 min, t _R (major) = 13.04 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 1.0 mL/min). (2R,4R,5S)-2-tert-Butyl 4-Methyl 5-phenylpyrrolidine-2,4-dicarboxylate (endo-6aa) White solid, yield 33 mg (82%); mp 65–67 °C; [α]_D ³⁰ –24.3 (c 0.90, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.22 (m, 5 H), 4.53 (d, J = 7.6 Hz, 1 H), 3.86 (t, J = 8.4 Hz, 1 H), 3.32 (dd, J = 14.4, 7.6 Hz, 1 H), 3.22 (s, 3 H), 2.62 (br s, 1 H), 2.43–2.29 (m, 2 H), 1.53 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.0, 172.5, 139.4, 128.2, 127.5, 126.8, 81.5, 65.9, 60.8, 51.2, 50.0, 33.6, 28.1. HRMS (ESI): m/z calcd for C₁₇H₂₃NO₄ [M + H]⁺: 306.1700; found: 306.1702. The ee value was 94%, t _R(minor) = 12.40 min, t _R (major) = 15.38 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 5:95, flow rate = 0.9 mL/min). (2S,4S,5R)-2-tert-Butyl 4-Methyl-5-phenylpyrrolidine-2,4-dicarboxylate (ent-endo-6aa) White solid, yield 35 mg (85%); [α]_D ³⁰ +26.1 (c 0.57, CH₂Cl₂). The ee value was 94%, t _R(minor) = 12.38 min, t _R (major) = 15.58 min ( Chiralcel OD-H, λ = 205nm, i-PrOH/hexanes = 5:95, flow rate = 0.9 mL/min). (2R,4R,5S)-2-tert-Butyl 4-Methyl-5-(p-tolyl)pyrrolidine-2,4-dicarboxylate (endo-6ba) White solid, yield 38 mg (86%); mp 66–68 °C; [α]_D ³⁰ –21.6 (c 0.80, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.19 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 8.0 Hz, 2 H), 4.49 (d, J = 7.6 Hz, 1 H), 3.32 (t, J = 8.0 Hz, 1 H), 3.30 (t, J = 7.2 Hz, 1 H), 3.26 (s, 3 H), , 2.42–2.27 (m, 5 H), 1.52 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.0, 172.5, 137.1, 136.3, 128.9, 126.6, 81.5, 65.7, 60.8, 51.2, 50.0, 33.7, 28.1, 21.1. HRMS (ESI): m/z calcd for C₁₈H₂₅NO₄ [M + H]⁺: 320.1856; found: 320.1863. The ee value was 93%, t _R(minor) = 9.82 min, t _R (major) = 11.80 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 0.9 mL/min). (2S,4S,5R)-2-tert-Butyl 4-Methyl-5-(p-tolyl)pyrrolidine-2,4-dicarboxylate (ent-endo-6ba) White solid, yield 36 mg (82%); mp 66–68 °C; [α]_D ³⁰ +28.2 (c 0.59, CH₂Cl₂). The ee value was 92%, t _R(minor) = 9.76 min, t _R (major) = 11.99 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 0.9 mL/min). (2R,4R,5S)-2-tert-Butyl 4-Methyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate (endo-6ca) White solid, yield 43 mg (90%); mp 75–76 °C; [α]_D ³⁰ –9.0 (c 0.85, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.27 (d, J = 4.4 Hz, 4 H), 4.51 (d, J = 7.6 Hz, 1 H), 3.86 (t, J = 8.0 Hz, 1 H), 3.32 (t, J = 7.4 Hz, 1 H), 3.28 (s, 3 H), 2.68 (br s, 1 H), 2.42–2.29 (m, 2 H), 1.52 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.7, 172.5, 138.2, 133.3, 128.3, 128.3, 81.7, 65.0, 60.7, 51.3, 49.7, 33.4, 28.1. HRMS (ESI): m/z calcd for C₁₇H₂₂ClNO₄ [M + H]⁺: 340.1310; found: 340.1313. The ee value was 94%, t _R(minor) = 6.87 min, t _R (major) = 8.01 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2S,4S,5R)-2-tert-Butyl 4-Methyl-5-(4-chlorophenyl)pyrrolidine-2,4-dicarboxylate (ent-endo-6ca) White solid, yield 42 mg (87%); mp 75–76 °C; [α]_D ³⁰ +12.3 (c 0.59, CH₂Cl₂). The ee value was 93%, t _R(minor) = 6.85 min, t _R (major) = 8.04 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 1.0 mL/min). (2R,4R,5S)-2-tert-Butyl 4-Methyl-5-(4-bromophenyl)pyrrolidine-2,4-dicarboxylate (endo-6da) White solid, yield 45 mg (80%); mp 71–73 °C; [α]_D ³⁰ –19.7 (c 0.80, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.42 (d, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 2 H), 4.48 (d, J = 8.0 Hz, 1 H), 3.85 (t, J = 8.2 Hz, 1 H), 3.31 (dd, J = 7.2, 7.6 Hz, 1 H), 3.27 (s, 3 H), 2.51 (br s, 1 H), 2.42–2.27(m, 2 H), 1.51 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.7, 172.4, 138.7, 131.3, 128.6, 121.4, 81.7, 65.1, 60.6, 51.4, 49.7, 33.4, 28.1. HRMS (ESI): m/z calcd for C₁₇H₂₂BrNO₄ [M + H]⁺: 384.0805; found: 384.0808. The ee value was 94%, t _R(minor) = 7.95 min, t _R (major) = 9.42 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 0.9 mL/min). (2S,4S,5R)-2-tert-Butyl 4-Methyl-5-(4-bromophenyl)pyrrolidine-2,4-dicarboxylate (ent-endo-6da) White solid, yield 48 mg (84%); mp 71–73 °C; [α]_D ³⁰ +23.4 (c 0.80, CH₂Cl₂). The ee value was 93%, t _R(minor) = 7.94 min, t _R (major) = 9.50 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 0.9 mL/min). (2R,4R,5S)-2-tert-Butyl 4-Methyl-5-(1-benzyl-1H-indol-3-yl)pyrrolidine-2,4-dicarboxylate (endo-6ea) White solid, yield 61 mg (91%); mp 89–91 °C; [α]_D ³⁰ –55.6 (c 0.58, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.65 (d, J = 7.6 Hz, 1 H),7.29–7.05 (m, 8 H), 5.28 (dd, J = 20.0, 16.0 Hz, 2 H), 4.49 (d, J = 7.2 Hz, 1 H), 3.89 (t, J = 8.2 Hz, 1 H), 3.43 (dd, J = 7.2, 14.0 Hz, 1 H), 3.09 (s, 3 H), 2.79 (br s, 1 H), 2.49–2.33 (m, 2 H), 1.50 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.4, 172.8, 137.4, 136.4, 128.7, 127.5, 127.0, 126.6, 125.7, 121.19, 119.4, 119.2, 114.2, 109.7, 81.5, 60.3, 59.0, 51.0, 50.0, 49.2, 33.7, 28.0. HRMS (ESI): m/z calcd for C₂₆H₃₀N₂O₄ [M + H]⁺: 435.2278; found: 435.2283. The ee value was 93%, t _R(minor) = 14.37 min, t _R (major) = 16.67 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 50:50, flow rate = 1.0 mL/min). (2S,4S,5R)-2-tert-Butyl 4-Methyl-5-(1-benzyl-1H-indol-3-yl)pyrrolidine-2,4-dicarboxylate (ent-endo-6ea) White solid, yield 58 mg (87%); mp 89–91 °C; [α]_D ³⁰ +68.0 (c 0.43, CH₂Cl₂). The ee value was 93%, t _R(minor) = 14.21 min, t _R (major) = 17.00 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 50:50, flow rate = 1.0 mL/min). (2R,4R,5S)-2-tert-Butyl 4-Methyl-5-[1-(methylsulfonyl)-1H-indol-3-yl]pyrrolidine-2,4-dicarboxylate (endo-6fa) White solid, yield 71 mg (84%); mp 83–85 °C; [α]_D ³⁰ –28.5 (c 0.52, CH₂Cl₂).¹H NMR (400 MHz, CDCl₃): δ = 7.89 (d, J = 8.0 Hz, 1 H), 7.64 (dd, J = 7.2, 8.0 Hz, 1 H), 7.48 (d, J = 0.8 Hz, 1 H), 7.37–7.31 (m, 2 H), 4.79 (dd, J = 0.8, 7.2 Hz, 1 H), 3.92 (dd, J = 8.0, 8.4 Hz, 1 H), 3.44 (dd, J = 7.2, 14.0 Hz, 1 H), 3.19 (s, 3 H), 3.03 (s, 3 H), 2.50–2.37 (m, 2 H), 2.08 (br s, 1 H), 1.53 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.6, 172.3, 135.2, 129.4, 125.2, 123.5, 123.4, 121.8, 120.2, 113.2, 82.0, 60.2, 58.2, 51.3, 48.6, 40.4, 33.3, 28.1. HRMS (ESI): m/z calcd for C₂₀H₂₆N₂O₆S [M + H]⁺: 423.1584; found: 423.1585. The ee value was 96%, t _R(minor) = 7.93 min, t _R (major) = 9.59 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 40:60, flow rate = 1.0 mL/min). (2S,4S,5R)-2-tert-Butyl 4-Methyl-5-[1-(methylsulfonyl)-1H-indol-3-yl]pyrrolidine-2,4-dicarboxylate (ent-endo-6fa) White solid, yield 70 mg (83%); mp 83–85 °C; [α]_D ³⁰ +30.6 (c 0.41, CH₂Cl₂). The ee value was 98%, t _R(minor) = 9.76 min, t _R (major) = 11.99 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 40:60, flow rate = 1.0 mL/min). Gram-Level Synthesis of ent-endo-6fa To a solution of tert-butyl glycine (630 mg, 4.8 mmol) in toluene (20 mL) was added the aldehyde 5f (4.8 mmol) and N,N′-diisopropylcarbodiimide (37.8 mg, 4.8 mmol), which was stirred for 2 h at room temperature. Then, a solution of precat. 1f (111.46 mg, 0.16 mmol) and Ag₂O (18.54 mg, 0.08 mmol) in toluene (8 mL), stirred for 1 h, was mixed with the above solution, followed by methyl acrylate dropwise (344 mg, 4 mmol) at –5 °C. The reaction was monitored by TLC plate, and the residue was purified by silica gel column chromatography to afford the ent-endo-6fa as a white solid (1.20 g, 71%). Synthesis of (2S,4S,5R)-2-tert-Butyl 4-Methyl-5-[1-(methylsulfonyl)-1H-indol-3-yl]-1-tosylpyrrolidine-2,4-dicarboxylate (7) To a solution of p-toluenesulfonyl chloride (953.5 mg, 5 mmol) in dichloromethane (30 mL) was added the 6fa (2 mmol) and triethylamine (1.04 mL, 6 mmol), which was stirred for 2 h at room temperature. The reaction was monitored by TLC plate, removed excess dichloromethane from the system, and the residue was purified by silica gel column chromatography to afford compound 7 as a white solid (980 mg, 85%); mp 74–76 °C; [α]_D ³⁰ +114.9 (c 0.58, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.83–7.81 (m, 1 H), 7.77 (s, 1 H), 7.68 (d, J = 8.0 Hz, 2 H), 7.53 (dd, J = 6.8, 1.2 Hz, 1 H), 7.33–7.25 (m, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 5.47 (d, J = 8.4 Hz, 1 H), 4.27 (dd, J = 11.2, 6.8 Hz, 1 H), 3.19–3.12 (m, 1 H), 3.10 (s, 3 H), 2.94 (s, 3 H), 2.58–2.39 (m, 2 H), 2.33 (s, 3 H), 1.59 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.2, 168.9, 144.0, 135.0, 134.9, 129.5, 128.7, 127.9, 126.7, 124.9, 123.1, 119.5, 113.1, 82.8, 61.6, 57.0, 51.7, 48.2, 40.3, 28.0, 21.4. HRMS (ESI): m/z calcd for C₂₇H₃₂N₂O₈S₂ [M + H]⁺: 577.1673; found: 577.1678. The ee value was 98%, t _R(minor) = 11.50 min, t _R (major) = 13.76 min (Chiralcel OD-H, λ = 205nm, i-PrOH/hexanes = 20:80, flow rate = 1.0 mL/min). Synthesis of (2R,3S,5S)-Methyl 5-[Methoxy(methyl)carbamoyl]-2-[1-(methylsulfonyl)-1H-indol-3-yl]-1-tosylpyrrolidine-3-carboxylate (8) Compound 7 (980 mg,1.7 mmol) was dissolved in CH₂Cl₂ (21 mL) and trifluoroacetic acid (4.3 mL) was dropwise added at 0 °C. Then the reaction mixture was stirred for 3 h at room temperature. All volatile compounds were removed in vacuo, and the residue was dissolved in water and treated with the saturated monosodium citrate solution. The resulting mixture was extracted with CH₂Cl₂ (3 × 30 mL), and the combined organic layers were dried over Na₂SO₄. After filtration and then evaporation of the solvent, the crude free amine was obtained without purification for the next step. To the solution of the free carboxylic acid in CH₂Cl₂ (26 mL) was added N,N,N′,N′-tetramethylchloroformamidinium-hexafluorophosphate (TCFH, 573 mg, 2.02 mmol), followed by the addition of 1-methylimidazole (0.41mL, 5.1 mol) and N,O-dimethylhydroxylamine hydrochloride (332 mg, 3.4 mmol). The reaction mixture was then stirred for 5 h at room temperature. The mixture was combined with CH₂Cl₂ and water, and the organic layer was separated, washed with saturated ammonium chloride (2 × 30 mL), saturated sodium bicarbonate (2 × 30 mL) and saturated sodium chloride, and dried over Na₂SO₄. The solvent was removed in vacuo to afford the crude product as a colorless oil, which was purified by flash chromatography to afford compound 8 as a white solid (774 mg, 79%); mp 92–94 °C; [α]_D ³⁰ +81.7 (c 0.44, CH₂Cl₂).¹H NMR (400 MHz, CDCl₃): δ = 8.06 (s, 1 H), 7.76 (dd, J = 6.8, 0.8 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), 7.51 (dd, J = 6.8, 2.0 Hz, 1 H), 7.29–7.21 (m, 2 H), 7.02 (d, J = 8.0 Hz, 2 H), 5.62 (d, J = 8.4 Hz, 1 H), 5.08 (t, J = 8.8 Hz, 1 H), 3.85 (s, 3 H), 3.44 (dd, J = 18.0, 9.2 Hz, 1 H), 3.32 (s, 3 H), 3.11 (s, 3 H), 2.85 (s, 3 H), 2.52–2.47 (m, 2 H), 2.23 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.3, 168.9, 143.5, 136.1, 134.7, 129.0, 128.7, 128.0, 127.4, 124.5, 122.9, 119.3, 112.9, 61.5, 58.0, 56.2, 51.6, 48.6, 40.2, 32.6, 30.2, 21.3. HRMS (ESI): m/z calcd for C₂₅H₂₉N₃O₈S₂ [M + H]⁺: 564.1469; found: 564.1464. The ee value was 98%, t _R(minor) = 23.75 min, t _R (major) = 26.20 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 20:80, flow rate = 0.8 mL/min). Synthesis of {(2R,3S,5S)-2-[1-(Methylsulfonyl)-1H-indol-3-yl]-1-tosyl-5-vinylpyrrolidin-3-yl}methanol (9) To a well-stirred suspension of lithium aluminum hydride (197 mg, 5.2 mmol) in dry tetrahydrofuran (5.4 mL) at –45 °C under a nitrogen atmosphere was slowly added a solution of 8 (732 mg, 1.3 mmol) in dry tetrahydrofuran (5 mL). After the completion of addition, the mixture was allowed to warm to room temperature and was stirred until the reaction became complete. The reaction mixture was cooled to –35 °C, and the saturated sodium bicarbonate was slowly added to destroy the excess of the hydride. The mixture was diluted with diethyl ether, washed with saturated ammonium chloride (2 × 30 mL), saturated sodium bicarbonate (2 × 30 mL) and saturated sodium chloride, and dried over Na₂SO₄. The solvent was removed in vacuo to afford the crude product as a colorless oil. The next step followed without any processing. Preparation of ylide solution: KOt-Bu (346.6 mg, 2.86 mmol) was added to MePPh₃Br (1.025 g, 2.86 mmol) in dry tetrahydrofuran (8.6 mL). The resulting suspension was placed in a sonication bath until a homogenous bright yellow solution had formed (ca. 1 min). This solution was stirred for 1.5 h at room temperature. The crude product from the previous step was dissolved in dry tetrahydrofuran (7 mL) and the solution added rapidly to the above slowly prepared ylide solution under –56 °C, which was allowed to warm to room temperature and was stirred until the reaction became complete. After 2 h TLC analysis indicated complete consumption of starting material. Saturated ammonium chloride was added, and THF was removed under reduced pressure. Water and dichloromethane were added to the residue. The layers were separated, and the aqueous layer was further extracted with dichloromethane (3 × 30 mL). The combined organic extracts were washed with brine (35 mL), dried (Na₂SO₄), and concentrated. The crude residue was purified by column chromatography to afford compound 9 as a white solid (413 mg, 67%); mp 82–84 °C; [α]_D ³⁰ +45.7 (c 0.42, CH₂Cl₂).¹H NMR (400 MHz, CDCl₃): δ = 7.89 (d, J = 8.0 Hz, 1 H), 7.71 (dd, J = 11.6, 8.0 Hz, 3 H), 7.40–7.28 (m, 5 H), 6.20–6.11 (m, 1 H), 5.37–5.26 (m, 3 H), 4.15–4.09 (m, 1 H), 3.22 (d, J = 6.8 Hz, 2 H), 3.06 (s, 3 H), 2.42 (s, 3 H), 2.34–2.24 (m, 1 H), 2.13–2.07 (m, 1 H), 1.81–1.72 (m, 1 H), 1.81–1.72 (m, 1 H), 1.37 (t, J = 7.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.7, 138.7, 135.1, 134.8, 129.7, 129.3, 127.6, 125.2, 125.0, 123.5, 122.0, 119.9, 116.6, 113.2, 62.7, 61.8, 58.5, 45.0, 40.5, 33.9, 21.5. HRMS (ESI): m/z calcd for C_{23 H26}N₂O₅S₂ [M + H]⁺: 475.1356; found: 475.13569. The ee value was 98%, t _R(minor) = 10.13 min, t _R (major) = 15.18 min (Chiralcel AD-H, λ = 205nm, i-PrOH/hexanes = 40:60, flow rate = 1.0 mL/min). Synthesis of tert-Butyl 3-[(2R,3S,5S)-3-(Hydroxymethyl)-1-tosyl-5-vinylpyrrolidin-2-yl]-1H-indole-1-carboxylate (10) A mixture of 9 (408 mg, 0.86 mmol), TBAF 1.0 M solution in THF (0.86 mL, 0.86 mmol), and THF (18 mL) was refluxed for 2 h. After cooling, the reaction mixture was evaporated in vacuo, and H₂O was added to the residue. The mixture was extracted with dichloromethane, dried over Na₂SO₄, and evaporated in vacuo to afford the crude product as a colorless oil. The next step followed without any processing. To a solution of the crude product from the previous step in distilled acetonitrile were added di-tert-butyl dicarbonate and DMAP. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography to afford compound 10 as a white solid (218 mg, 51%); mp 70–72 °C; [α]_D ³⁰ +30.8 (c 0.25, CH₂Cl₂).¹H NMR (400 MHz, CDCl₃): δ = 8.12–8.11 (m, 1 H), 7.64 (dd, J = 12.4, 8.0 Hz, 3 H), 7.43 (s, 1 H), 7.33–7.20 (m, 4 H), 6.19–6.10 (m, 1 H), 5.35 (dd, J = 17.6, 8.4 Hz, 2 H), 5.26 (d, J = 10.4 Hz, 1 H), 4.20–4.14 (m, 1 H), 3.30–3.17 (m, 2 H), 2.40 (s, 3 H), 2.27–2.21 (m, 1 H), 2.13–2.07 (m, 1 H), 1.84–1.75 (m, 1 H), 1.67 (s, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.4, 143.4, 138.9, 135.2, 129.5, 128.9, 127.6, 125.0, 124.6, 122.6, 119.7, 118.9, 116.2, 115.3, 83.8, 62.4, 61.9, 58.4, 45.0, 33.7, 28.1, 21.5. HRMS (ESI): m/z calcd for C₂₇H₃₂N₂O₅S [M + H]⁺: 497.2105; found: 497.2113. The ee value was 98%, t _R(minor) = 15.22 min, t _R (major) = 16.73 min (Chiralcel AD-H, λ = 205nm, i-PrOH/hexanes = 20:80, flow rate = 0.8 mL/min). Synthesis of tert-Butyl 3-[(2R,3S,5R)-5-Ethyl-3-(hydroxymethyl)-1-tosylpyrrolidin-2-yl]-1H-indole-1-carboxylate (11) A solution of 10 (214 mg,0.43 mmol) in absolute methanol (5 mL) was hydrogenated in the presence of 10% Pd/C (64 mg) at room temperature for 4 h. The mixture was filtered (Celite) and washed with methanol. The solvent was removed under reduced pressure. The residue was purified by column chromatography to afford the 11 as a white solid (214 mg, 98%). The spectroscopic data of 11 were consistent with this reported in the literature^3b; mp 82–84 °C; [α]_D ²⁴ +123.8 (c 1.00, CHCl₃).¹H NMR (400 MHz, CDCl₃): δ = 8.09 (dd, J = 4.0, 2.0 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 7.6 Hz, 1 H), 7.49 (d, J = 1.2 Hz , 1 H), 7.32–7.20 (m, 4 H), 5.25 (d, J = 8.0 Hz, 1 H), 3.55–3.48 (m, 1 H), 3.31–3.25 (m, 1 H), 3.17 (dd, J = 10.4, 5.6 Hz, 1 H), 2.50–2.44 (m, 1 H), 2.41 (s, 3 H), 2.14–2.05 (m, 2 H), 1.77–1.71 (m, 1 H), 1.68 (s, 9 H), 1.59–1.49 (m, 1 H), 1.28–1.24 (m, 1 H), 1.00 (dd, J = 7.2, 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.5, 143.4, 134.8, 129.6, 129.2, 129.0, 127.6, 125.0, 124.5, 122.5, 120.0, 118.9, 115.3, 83.8, 62.5, 62.1, 58.5, 44.9, 33.0, 28.1, 21.5, 10.7. HRMS (ESI): m/z calcd for C₂₇H₃₄N₂O₅S [M + H]⁺: 499.2261; found: 499.2269. The ee value was 98%, t _R(minor) = 14.51 min, t _R (major) = 19.58 min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes = 10:90, flow rate = 0.8 mL/min).