Synlett 2021; 32(14): 1437-1446
DOI: 10.1055/s-0040-1706053
letter

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

a   College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, Hunan Province, P. R. of China
,
Chuliang Gong
a   College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, Hunan Province, P. R. of China
,
Chen Zhang
a   College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, Hunan Province, P. R. of China
,
Xiaojun Zheng
a   College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, Hunan Province, P. R. of China
,
Qinglin Hou
b   Fundamental Chemical Experiment Center, Hunan University of Technology, Zhuzhou 412007, Hunan Province, P. R. of China
,
Qingxia Zhou
a   College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, Hunan Province, P. R. of China
,
Guiyin Zhou
a   College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, Hunan Province, P. R. of China
,
Yao Chen
a   College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, Hunan Province, P. R. of China
› Author Affiliations
We thank the National Natural Science Foundation of China (Grant Numbers 21202042, 51374103, 51674114, and 52070078) and the Natural Science Foundation of Hunan Province (Grant Numbers 2017JJ2067, 2020JJ5125) for financial support of this work.


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.

Supporting Information

Primary Data



Publication History

Received: 24 April 2021

Accepted after revision: 23 June 2021

Article published online:
06 July 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References and Notes

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  • 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 procedure8a 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 C12 H15NO4S [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 C13 H16N2O4 [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 C21 H23NO4 [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 C23 H26N2O5S2 [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 literature3b; 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).