Asymmetric Synthesis of Chiral
Oxazolines by Organocatalytic Cyclization of α-Aryl Isocyanoesters
with Aldehydes

Meng-Xia Xue; Chang Guo; Liu-Zhu Gong

doi:10.1055/s-0029-1217549

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Synlett 2009(13): 2191-2197
DOI: 10.1055/s-0029-1217549

LETTER

Asymmetric Synthesis of Chiral Oxazolines by Organocatalytic Cyclization of α-Aryl Isocyanoesters with Aldehydes

Meng-Xia Xue^a,c, Chang Guo^b, Liu-Zhu Gong*^a,b
^a Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
^b Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. of China
Fax: +86(551)3606266; e-Mail: gonglz@ustc.edu.cn;
^c Graduate School of Chinese Academy of Sciences, Beijing 100049, P. R. of China

Further Information

Publication History

Received 9 April 2009
Publication Date:
15 July 2009 (online)

Abstract
Full Text
References
Supplementary Material

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Abstract

A cinchona alkaloid derivative catalyzed the asymmetric formal [3+2] cycloaddition of α-aryl isocyanoesters with aldehydes, affording highly substituted 2-oxazolines with good stereoselectivities of up to 18:1 dr and 90% ee.

Key words

cinchona alkaloid - formal [3+2] cycloaddition - α-aryl isocyanoester - aldehydes - chiral oxazolines

Supporting Information

References and Notes

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12

CCDC 720140.

13

General procedure for the cycloaddition reaction of isocyanoester to aldehyde catalyzed by 4g: To a solution of aldehyde 2 (0.2 mmol), catalyst 4g (0.02 mmol), 4 Å MS (100 mg) and NH₄Cl (0.01 mmol) in CH₂Cl₂ (1.0 mL), was added an isocyanoester 1 (0.4 mmol). The reaction mixture was stirred at r.t. until complete. After removal of the solvent, the residue was analyzed by ^¹H NMR to determine the dr and purified through column chromatography on silica to yield pure product. For spectroscopic data, see supporting information.

14

Methyl 4-Phenyl-5-(4-nitrophenyl)-2-oxazoline-4-carboxylate (3aa): Yield: 94%; dr 6:1; [α]_D ^²0 78.3 (c 0.572, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.83 (s, 3 H), 6.40 (s, 1 H), 6.89-6.91 (m, 2 H), 7.02-7.05 (m, 3 H), 7.18 (d, J = 8.7 Hz, 2 H), 7.41 (s, 1 H), 7.90 (d, J = 8.8 Hz, 2 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.22, 155.84, 147.34, 142.58, 135.03, 128.72, 128.06, 128.01, 127.70, 126.00, 122.75, 84.89, 83.82, 53.43; IR (KBr): 3068, 2960, 2918, 2852, 1734, 1677, 1625, 1602, 1522, 1451, 1343, 1253, 1116, 861, 838, 743, 701 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₅N₂O₅: 327.0981; found: 327.0972. The enantiomeric excess was 78%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 70: 30; flow rate: 1.0 mL/min): t _R = 10.955 min, 12.329 min.

15

Methyl 4-Phenyl-5-(4-cyanophenyl)-2-oxazoline-4-carboxylate (3ab): Yield: 94%; dr 6:1; [α]_D ^²0 93.9 (c 0.506, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.82 (s, 3 H), 6.34 (s, 1 H), 6.87-6.89 (m, 2 H), 7.05-7.06 (m, 3 H), 7.10 (d, J = 8.2 Hz, 2 H), 7.34 (dd, J ₁ = 4.8 Hz, J ₂ = 1.7 Hz, 2 H), 7.38 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.44, 155.93, 140.74, 135.23, 131.54, 128.80, 128.17, 128.12, 127.65, 127.49, 126.16, 118.44, 111.82, 85.28, 83.89, 53.59; IR (KBr): 3432, 2951, 2225, 1734, 1625, 1498, 1446, 1253, 1116, 851, 748, 701 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₈H₁₅N₂O₃: 307.1083; found: 307.1081. The enantiomeric excess was 84%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 70: 30; flow rate: 1.0 mL/min): t _R = 13.452 min, 15.280 min.

16

Methyl 4-Phenyl-5-[3,5-di(trifluoromethyl)phenyl]-2-oxazoline-4-carboxylate (3ac): Yield: 71%; dr 8:1; [α]_D ^²0 48.3 (c 0.544, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.86 (s, 3 H), 6.41 (s, 1 H), 6.83-6.85 (m, 2 H), 7.04-7.06 (m, 3 H), 7.40-7.41 (m, 3 H), 7.55 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.33, 155.96, 138.33, 134.99, 131.34, 131.00, 129.14, 128.40, 128.30, 127.15, 125.99, 124.33, 121.80, 121.80, 121.76, 121.72, 84.78, 84.17, 53.71; IR (KBr): 3059, 2951, 2847, 1734, 1630, 1493, 1385, 1343, 1286, 1173, 1125, 890, 842, 739 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₉H₁₄NO₃F₆: 418.0878; found: 418.0874. The enantiomeric excess was 83%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 94:6; flow rate: 1.0 mL/min): t _R = 17.179 min, 19.110 min.

17

Methyl 4-Phenyl-5-(3-nitrophenyl)-2-oxazoline-4-carboxylate (3ad): Yield: 92%; dr 6:1; [α]_D ^²0 82.9 (c 0.684, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.85 (s, 3 H), 6.42 (s, 1 H), 6.89-6.92 (m, 2 H), 7.03-7.05 (m, 3 H), 7.22-7.27 (m, 1 H), 7.34 (s, 1 H), 7.80 (s, 1 H), 7.81 (d, J = 1.8 Hz, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.41, 155.99, 147.68, 137.75, 135.27, 132.95, 128.76, 128.27, 128.11, 126.18, 122.97, 121.99, 84.98, 83.92, 53.63; IR (KBr): 3074, 956, 2356, 1970, 1889, 1729, 165, 1536, 1493, 1441, 1343, 1253, 1111, 729, 706 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₅N₂O₅: 327.0981; found: 327.0977. The enantiomeric excess was 84%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 98:2; flow rate: 1.0 mL/min): t _R = 5.75 min, 6.96 min.

18

Methyl 4-Phenyl-5-(2-nitrophenyl)-2-oxazoline-4-carboxylate (3ae): Yield: 95%; dr 3:1; [α]_D ^²0 63.9 (c 0.656, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.87 (s, 3 H), 6.99-7.04 (m, 6 H), 7.19 (s, 1 H), 7.27 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 171.46, 156.07, 135.90, 132.90, 132.37, 128.85, 128.62, 127.76, 127.70, 127.03, 124.31, 84.45, 82.03, 53.61; IR (KBr): 3399, 3342, 2923, 1734, 1677, 1531, 1352, 1239, 1187, 1059, 753 cm^-¹; HRMS: m/z [M + Na⁺] calcd for C₁₇H₁₄N₂NaO₅: 49.0795; found: 349.0790. The enantiomeric excess was 88%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 70:30; flow rate: 1.0 mL/min): t _R = 10.158 min, 17.690 min.

19

Methyl 4-Phenyl-5-(4-trifluoromethylphenyl)-2-oxazoline-4-carboxylate (3af): Yield: 78%; dr 4:1; [α]_D ^²0 64.4 (c 0.348, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.82 (s, 3 H), 6.37 (s, 1 H), 6.89-6.91 (m, 2 H), 7.03-7.05 (m, 3 H), 7.09 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.37 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.63, 156.06, 139.42, 135.50, 128.87, 128.18, 128.06, 127.97, 127.44, 126.55, 126.26, 124.72, 124.69, 85.58, 83.70, 53.55; IR (KBr): 3068, 2951, 2923, 2852, 1729, 1687, 1621, 1498, 147, 1318, 1258, 1158, 1116, 1064, 847 cm^-¹; HRMS:
m/z [M + Na⁺] calcd for C₁₈H₁₄F₃NaO₃: 372.0818; found: 372.0817. The enantiomeric excess was 78%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 85:15; flow rate: 1.0 mL/min): t _R = 10.996 min, 13.343 min.

20

Methyl 4-Phenyl-5-(2-trifluoromethylphenyl)-2-oxazoline-4-carboxylate (3ag): Yield: 62%; dr 2:1 unseperatable diastereomeric mixture; ^¹H NMR (CDCl₃, 400 MHz): δ = 3.2 (s, 1 H), 3.78 (s, 2 H), 6.24 (s, 0.3 H), 6.76 (d, J = 7.6 Hz, 0.7 H), 6.97 (s, 0.7 H), 7.02-7.04 (m, 2.3 H), 7.08-7.10 (m, 2.7 H), 7.15 (s, 0.3 H), 7.26-7.40 (m, 3.0 H),7.48 (d, J = 7.3 Hz, 0.7 H), 7.63 (d, J = 7.2 Hz, 0.3 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 171.96, 156.07, 155.34, 136.59, 134.79, 132.37, 131.19, 129.78, 129.14, 128.78, 128.58, 128.32, 127.87, 127.58, 127.26, 127.07, 126.16, 125.95, 125.40, 125.18, 125.13, 84.34, 83.75, 81.53, 53.61, 52.28; IR (KBr): 3068, 2956, 2927, 2856, 1739, 1621, 1493, 1455, 1309, 1253, 1163, 1121, 936, 762, 734, 706 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₈H₁₅NO₃F₃: 350.1004; found: 350.1008. The enantiomeric excess was 87%, determined by HPLC (Daicel Chiralpak AD-H; hexane-
i-PrOH, 97:3; flow rate: 1.0 mL/min): t _R (major) = 15.238 min, 26.670 min, t_R(minor) = 37.920 min, 41.071 min.

21

Methyl 4-Phenyl-5-(4-methoxycarbonylphenyl)-2-oxazoline-4-carboxylate (3ah): Yield: 82%; dr 4:1; [α]_D ^²0 79.0 (c 0.38, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.83 (s, 3 H), 3.85 (s, 3 H), 6.38 (s, 1 H), 6.91-6.93 (m, 2 H), 7.02-7.07 (m, 5 H), 7.71 (s, 1 H), 7.72 (d, J = 8.2 Hz, 2 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.38, 168.21, 156.08, 129.09, 128.06, 127.93, 127.11, 126.34, 85.79, 53.55, 52.15, 29.79; IR (KBr): 2960, 2918, 2852, 1720, 1630, 1493, 1437, 1281, 1106, 1017, 805, 739, 706 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₉H₁₈NO₅: 340.1185; found: 340.1183. The enantiomeric excess was 70%, determined by HPLC (Daicel Chiralpak OD-H, hexane-i-PrOH, 85:15; flow rate: 1.0 mL/min): t _R = 11.629 min, 13.239 min.

22

Methyl 4-Phenyl-5-(3-cyanophenyl)-2-oxazoline-4-carboxylate (3ai): Yield: 85%; dr 5:1 [α]_D ^²0 36.1 (c 0.488, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.84 (s, 3 H), 6.33 (s, 1 H), 6.88-6.89 (m, 2 H), 7.06-7.08 (m, 3 H), 7.16-7.18 (m, 1 H), 7.20-7.22 (m, 2 H), 7.33 (d, J = 7.1 Hz, 1 H), 7.38 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 171.40, 154.89, 136.10, 134.24, 130.57, 130.23, 129.48, 127.70, 127.54, 127.17, 127.05, 125.13, 117.23, 110.99, 84.01, 82.72, 52.55, 28.68; IR (KBr): 3064, 3031, 2951, 2852, 2229, 1734, 1630, 1578, 1493, 1432, 1253, 1111, 805, 753, 691 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₈H₁₅N₂O₃: 307.1083; found: 307.1085. The enantiomeric excess was 76%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 80:20; flow rate: 1.0 mL/min): t _R = 13.320 min, 15.267 min.

23

Methyl 4-Phenyl-5-(2,6-dichlorophenyl)-2-oxazoline-4-carboxylate (3ak): Yield: 83%; dr 18:1; [α]_D ^²0 13.7 (c 0.3, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.75 (s, 3 H), 6.90 (d, J = 8.0 Hz, 1 H), 6.99 (t, J ₁ = J ₂ = 8.0 Hz, 1 H), 7.06-7.07 (m, 3 H), 7.18 (s, 1 H), 7.23-7.26 (m, 3 H), 7.33 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.35, 156.10, 136.40, 136.14, 135.29, 131.46, 130.13, 129.94, 128.25, 127.74, 127.38, 126.68, 84.37, 82.56, 53.68, 29.77; IR (KBr): 3074, 2999, 2947, 2919, 1730, 1617, 1588, 1565, 1489, 1433, 1235, 1126, 772, 740 cm^-¹; HRMS: m/z calcd for C₁₇H₁₄NO₃Cl₂: 349.0272; found: 349.0281. The enantiomeric excess was 88%, determined by HPLC (Daicel Chiralpak AD-H; hexane-i-PrOH, 85:15; flow rate: 1.0 mL/min): t _R = 11.629 min, 13.239 min.

24

Methyl 4-Phenyl-5-(3,5-difluorophenyl)-2-oxazoline-4-carboxylate (3al): Yield: 75%; dr 6:1; [α]_D ^²0 69.2 (c 0.63, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.83 (s, 3 H), 6.27 (s, 1 H), 6.47-6.55 (m, 3 H), 6.93-6.95 (m, 2 H), 7.09-7.12 (m, 3 H), 7.35 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.48, 163.80, 163.677, 161.33, 155.88, 139.41, 135.23, 128.14, 126.17, 110.16, 110.09, 109.97, 109.90, 103.63, 103.38, 103.13, 84.97, 83.83, 53.58; IR (KBr): 3068, 2951, 1729, 1625, 1597, 1465, 1258, 1116, 1003, 951, 861, 697 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₄NO₃F₂: 318.0942; found: 318.0940. The enantiomeric excess was 79%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 80:20; flow rate: 1.0 mL/min): t _R = 11.150 min, 13.363 min.

25

Methyl 4-Phenyl-5-(3,5-dibromophenyl)-2-oxazoline-4-carboxylate (3am): Yield: 89%; dr 5:1; [α]_D ^²0 34.9 (c 0.624, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.83 (s, 3 H), 6.22 (s, 1 H), 6.90-6.93 (m, 2 H), 7.03 (d, J = 1.4 Hz, 2 H), 7.11-7.13 (m, 3 H), 7.33 (d, J = 1.9 Hz, 2 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.38, 155.88, 139.27, 135.18, 133.51, 128.80, 128.23, 128.13, 126.13, 122.29, 84.63, 83.90, 53.59; IR (KBr): 3068, 2951, 2842, 1734, 1635, 1588, 1559, 1437, 1253, 1111, 861, 800, 730, 691 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₄Br₂NO₃: 439.9320; found: 439.9315. The enantiomeric excess was 72%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 80:20; flow rate: 1.0 mL/min): t _R = 11.694 min, 13.552 min.

26

Methyl 4-Phenyl-5-(4-bromophenyl)-2-oxazoline-4-carboxylate (3an): Yield: 80%; dr 4:1; [α]_D ^²0 48.0 (c 0.198, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.81 (s, 3 H), 6.29 (s, 1 H), 6.83 (d, J = 6.8 Hz, 2 H), 6.85-6.94 (m, 2 H), 7.06-7.08 (m, 3 H), 7.18 (dd, J ₁ = 6.70 Hz, J ₂ = 1.8 Hz, 2 H), 7.34 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 72.76, 156.09, 135.77, 134.45, 130.98, 128.85, 128.09, 127.91, 126.38, 122.18, 85.78, 53.51; IR (KBr): 3059, 3031, 2923, 2847, 1734, 1630, 1493, 1428, 1262, 1111, 833, 743 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₅NO₃Br: 360.0235; found: 360.0231. The enantiomeric excess was 76%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 80:20; flow rate: 1.0 mL/min): t _R = 9.941 min, 11.893 min.

27

Methyl 4-Phenyl-5-(3,4-difluorophenyl)-2-oxazoline-4-carboxylate (3ao): Yield: 61%; dr 5:1; [α]_D ^²0 66.5 (c 0.49, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.82 (s, 3 H), 6.27 (s, 1 H), 6.75-6.78 (m, 2 H), 6.91-6.74 (m, 3 H), 7.09-7.10 (m, 3 H), 7.35 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.62, 155.95, 135.54, 128.15, 128.04, 126.24, 123.38, 123.34, 123.32, 123.28, 116.78, 116.61, 116.27, 116.08, 85.11, 83.47, 53.54; IR (KBr): 3068, 2956, 2847, 2352, 1729, 1625, 1517, 1432, 1262, 1111, 876 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₄NO₃F₂: 318.0942; found: 318.0940. The enantiomeric excess was 77%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 80:20; flow rate: 1.0 mL/min): t _R = 11.884 min, 13.881 min.

28

Methyl 4-Phenyl-5-(3,4,5-trifluorophenyl)-2-oxazoline-4-carboxylate (3ap): Yield: 90%; dr 7:1; [α]_D ^²0 87.2 (c 0.912, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.84 (s, 3 H), 6.21 (s, 1 H), 6.62-6.66 (dd, J ₁ = 7.9 Hz, J ₂ = 6.6 Hz, 2 H), 6.91-6.93 (m, 2 H), 7.12-7.14 (m, 3 H), 7.34 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.56, 155.81, 135.11, 128.33, 126.10, 111.40, 111.34, 111.12, 111.72, 84.64, 53.66, 29.79; IR (KBr): δ = 3064, 2956, 2847, 1729, 1696, 1621, 1536, 1488, 1461, 1376, 1253, 1116, 1040, 961, 866 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₃NO₃F₃: 336.0848; found: 336.0845. The enantiomeric excess was 85%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 80:20; flow rate: 1.0 mL/min): t _R = 9.928 min, 11.640 min.

29

Methyl 4,5-Diphenyl-2-oxazoline-4-carboxylate (3aq): Yield: 44%; dr 2:1; [α]_D ^²0 30.7 (c 0.044, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.81 (s, 3 H), 6.35 (s, 1 H), 6.95-6.6.97 (m, 4 H), 7.02-7.06 (m, 6 H), 7.36 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 156.24, 136.19, 135.36, 128.11, 127.82, 127.57, 127.24, 126.53, 86.44, 53.44, 29.78; IR (KBr): 3328, 3068, 2956, 1725, 1696, 1621, 1493, 1455, 1258, 1116, 739, 691 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₆NO₃: 282.1130; found: 282.1137. The enantiomeric excess was 74%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 93:7; flow rate: 1.0 mL/min): t _R = 11.211 min, 13.919 min.

30

Methyl 4-Phenyl-5-(thiophen-2-yl)-2-oxazoline-4-carboxylate (3ar): Yield: 18%; dr 4:1; [α]_D ^²0 40.4 (c 0.094, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.79 (s, 1 H), 6.66 (s, 1 H), 6.73-6.74 (m, 1 H), 6.84 (m, 1 H), 7.04 (d, J = 1.1 Hz, 1 H), 7.09-7.14 (m, 5 H), 7.29 (s, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.37, 155.82, 133.14, 133.04, 131.95, 128.83, 128.70, 128.02, 127.96, 127.48, 126.77, 126.51, 126.11, 83.08, 53.53; IR (KBr): 3059, 2956, 2923, 2861, 1734, 1625, 1488, 1432, 1258, 1116, 691 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₅H₁₄NO₃S: 288.0694; found: 288.0696. The enantiomeric excess was 70%, determined by HPLC (Daicel Chiralpak OD-H; hexane-i-PrOH, 98:2; flow rate: 1.0 mL/min): t _R = 5.75 min, 6.96 min.

31

Methyl 4-Phenyl-5-(propylbenzyl)-2-oxazoline-4-carboxylate (3as): Yield: 30%; dr 2:1; [α]_D ^²0 93.9 (c 0.334, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 1.15-1.17 (m, 1 H), 1.40-1.41 (m, 1 H), 2.60-2.69 (m, 2 H), 3.75 (s, 3 H), 5.27 (dd, J ₁ = 10.4 Hz, J ₂ = 3.5 Hz, 1 H), 7.02 (d, J = 6.8 Hz, 2 H), 7.03-7.34 (m, 10 H); ^¹³C NMR (CDCl₃, 100 MHz):
δ = 156.04, 140.58, 130.02, 129.72, 129.26, 128.55, 128.48, 128.45, 128.30, 128.06, 127.71, 127.55, 126.56, 126.10, 83.82, 63.72, 53.27, 51.56, 33.83, 32.36, 29.79; IR (KBr): 3064, 3026, 2951, 2852, 1725, 1691, 1621, 1488, 1437, 1370, 1262, 1135, 913, 734, 691 cm^-¹; HRMS: m/z calcd for C₁₉H₁₉NO₃: 309.1365; found: 309.1367. The enantiomeric excess of the major product was 89%, determined by HPLC (Daicel Chiralpak IA-H; hexane-i-PrOH, 90:10; flow rate: 1.0 mL/min): t _R = 7.486 min, 8.704 min.

32

Ethyl 4-Phenyl-5-(3-nitrophenyl)-2-oxazoline-4-carboxylate (3be): Yield: 95%; dr 3:1; [α]_D ^²0 59.6 (c 0.182, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 1.28-1.32 (t, J ₁ = J ₂ = 7.0 Hz, 3 H), 4.29-4.42 (m, 2 H), 6.98-7.05 (m, 6 H), 7.19-7.23 (m, 2 H), 7.28-7.32 (t, J ₁ = J ₂ = 7.7 Hz, 1 H), 7.39 (s, 1 H), 7.77-7.79 (dd, J ₁ = 8.2 Hz, J ₂ = 1.2 Hz, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 170.91, 155.97, 147.52, 136.03, 132.89, 132.55, 128.81, 128.65, 127.67, 127.63, 127.12, 124.32, 84.48, 82.08, 62.75, 29.75, 14.07; IR (KBr): 3437, 3074, 2983, 2946, 2856, 1720, 1625, 1578, 1522, 1446, 1347, 1243, 1116, 946, 876, 795, 734 cm^-¹; HRMS: m/z [M + Na⁺] calcd for C₁₈H₁₆N₂NaO₅: 363.0951; found: 363.0953. The enantiomeric excess of major product was 85%, determined by HPLC (Daicel Chiralpak AD-H; hexane-i-PrOH, 70:30; flow rate: 1.0 mL/min): t _R = 8.755 min, 11.798 min.

33

Benzyl 4-Phenyl-5-(2-nitrophenyl)-2-oxazoline-4-carboxylate (3ce): Yield: 95%; dr 4:1 unseperatable diastereomeric mixture; ^¹H NMR (CDCl₃, 400 MHz): δ = 4.66 (d, J = 12.2 Hz, 0.2 H), 4.79 (d, J = 12.1 Hz, 0.2 H), 5.27 (d, J = 12.4 Hz, 0.8 H), 5.38 (d, J = 12.4 Hz, 0.8 H), 6.69 (s, 0.2 H), 6.96-6.99 (m, 5.7 H), 7.18-7.38 (m, 8.7 H), 7.65 (d, J = 8.5 Hz, 0.4 H), 7.76 (d, J = 8.2 Hz, 0.8 H), 7.85 (d, J = 8.2 Hz, 0.2 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 170.68, 156.10, 155.00, 147.41, 135.79, 132.92, 129.57, 128.81, 128.74, 128.61, 128.54, 128.47, 128.40, 128.37, 128.24, 128.15, 127.88, 127.67, 27.57, 127.16, 126.34, 124.29, 84.49, 83.04, 82.12, 68.05, 67.23, 29.72; IR (KBr): 3068, 3031, 2918, 2856, 1729, 1630, 1522, 1484, 1451, 1343, 1239, 1116, 955, 857, 729, 701 cm^-¹; HRMS: m/z
[M + 1⁺] calcd for C₂₃H₁₉N₂O₅: 403.1294; found: 403.1290. The enantiomeric excess of the major product was 90%, determined by HPLC (Daicel Chiralpak IA-H; hexane- i-PrOH, 70:30; flow rate: 1.0 mL/min): t _R(major) = 9.633 min, 18.810 min, t _R(minor) = 13.676 min, 16.793 min.

34

Methyl 4-(2-Chlorophenyl)-5-(2-nitrophenyl)-2-oxazoline-4-carboxylate (3de): Yield: 27%; dr 5:1; ^¹H NMR (CDCl₃, 400 MHz): δ = 3.19 (s, 0.5 H), 3.76 (s, 2.5 H), 6.79 (d, J = 1.3 Hz, 0.8 H), 6.97 (d, J = 1.3 Hz, 0.8 H), 7.22-7.23 (m, 3.4 H), 7.34-7.77 (m, 4.8 H), 8.09 (d, J = 1.3 Hz, 0.2 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 170.71, 156.85, 155.27, 135.78, 133.45, 132.11, 131.58, 131.48, 130.86, 129.91, 129.79, 129.52, 129.43, 129.25, 129.13, 127.35, 127.19, 126.77, 125.13, 124.31, 79.40, 78.79, 53.90, 52.52, 29.77; IR (KBr): 3087, 2946, 2856, 1758, 1734, 1621, 1522, 1437, 1347, 1253, 1229, 1121, 1059, 965, 942, 851, 739,
691 cm^-¹; HRMS: m/z [M + H₂O + Na⁺] calcd for C₁₇H₁₅ClN₂NaO₅: 401.0511; found: 401.0499. The enantiomeric excess of the major product was 53%, determined by HPLC (Daicel Chiralpak IA-H; hexane-
i-PrOH, 70:30; flow rate: 1.0 mL/min): t _R(major) = 7.674 min, 9.116 min, t _R(minor) = 11.377 min, 14.367 min.

35

Methyl 4-(3-Chlorophenyl)-5-(2-nitrophenyl)-2-oxazoline-4-carboxylate (3ee): Yield: 69%; dr 4:1; [α]_D ^²0 59.6 (c 0.182, EtOAc); ^¹H NMR (CDCl₃, 400 MHz): δ = 3.90 (s, 3 H), 6.91-6.93 (m, 2 H), 6.97 (d, J = 2.1 Hz, 1 H), 7.04 (s, 1 H), 7.05 (s, 1 H), 7.07-7.12 (m, 1 H), 7.26-7.40 (m, 2 H), 7.84 (dd, J ₁ = 8.2 Hz, J ₂ = 1.4 Hz, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 170.96, 156.50, 138.12, 133.92, 133.14, 132.06, 129.24, 128.94, 128.50, 127.99, 127.56, 125.43, 124.44, 83.96, 82.30, 53.84, 29.78; IR (KBr): δ = 3068, 2927, 2847, 1734, 1625, 1583, 1517, 1446, 1361, 1338, 1253, 1135, 951, 791, 706 cm^-¹; HRMS: m/z [M + 1⁺] calcd for C₁₇H₁₄N₂O₅Cl: 361.0591; found: 361.0590. The enantiomeric excess was 87%, determined by HPLC (Daicel Chiralpak IA-H; hexane-i-PrOH, 80:20; flow rate: 1.0 mL/min): t _R = 8.794 min, 15.807 min.

36

Methyl 4-Benzyl-5-(2-nitrophenyl)-2-oxazoline-4-carboxylate (3fe): Yield: 31%; dr 1:1; ^¹H NMR (CDCl₃, 400 MHz): δ = 2.53 (d, J = 14.1 Hz, 1 H), 2.91 (d, J = 14.1 Hz, 1 H), 6.52 (s, 1 H), 6.96-6.98 (m, 2 H), 7.08-7.10 (m, 3 H), 7.21 (s, 1 H), 7.25 (s, 1 H), 7.41 (d, J = 1.1 Hz, 1 H), 7.50-7.52 (m, 2 H), 8.07 (d, J = 6.5 Hz, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 172.33, 154.80, 135.76, 133.32, 131.39, 130,37, 129.45, 128.86, 127.79, 126.53, 125.17, 82.25, 0.81, 52.99, 40.23, 29.78; IR (KBr): 3031, 2923, 2856, 1734, 1677, 1630, 1522, 1455, 1347, 1253, 1206, 1106, 1079, 955, 857, 729 cm^-¹; HRMS: m/z calcd for C₁₈H₁₆N₂O₅: 340.1059; found: 340.1066. The enantiomeric excess was 52%, determined by HPLC (Daicel Chiralpak AD-H; hexane-i-PrOH, 80:20; flow rate: 1.0 mL/min): t _R(major) = 9.501 min, 11.151 min, t _R(minor) = 8.903 min, 10.819 min.

37

Methyl 5-(2-Nitrophenyl)-2-oxazoline-4-carboxylate (3ge): Yield: 89%; dr 13:1; ^¹H NMR (CDCl₃, 400 MHz): δ = 3.88 (s, 3 H), 4.54 (dd, J ₁ = 6.4 Hz, J ₂ = 2.0 Hz, 1 H), 6.30 (d, J = 6.4 Hz, 1 H), 7.20 (d, J = 2.0 Hz, 1 H), 7.55-7.59 (m, 2 H), 7.70-7.72 (m, 1 H), 8.16 (dd, J ₁ = 8.2 Hz, J ₂ = 1.3 Hz, 1 H); ^¹³C NMR (CDCl₃, 100 MHz): δ = 170.76, 156.35, 146.31, 135.19, 134.51, 134.13, 129.44, 127.74, 126.74, 125.48, 125.05, 79.35, 79.20, 75.96, 71.48, 53.04, 29.71; IR (KBr): 3078, 3008, 2960, 2866, 1739, 1625, 1573, 1531, 1432, 1347, 1272, 1206, 1173, 1106, 946, 781, 734, 706
cm^-¹; HRMS: m/z [M + H₂O + Na⁺] calcd for C₁₁H₁₀N₂NaO₅: 273.0482; found: 273.0487. The enantiomeric excess of the major product was 31%, determined by HPLC (Daicel Chiralpak IA-H; hexane-i-PrOH, 90:10; flow rate: 1.0 mL/min): t _R(major) = 18.105 min, 26.731 min, t _R(minor) = 16.855 min, 20.105 min.

38

The general procedure for hydrolysis of 3: A few drops of concd HCl were added to a solution of compound 3 in methanol. The mixture was stirred at room temperature for 30 min, then the solvent was removed to give the product.

Supplementary Material

Supporting Information