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Synlett 2011(3): 420-424  
DOI: 10.1055/s-0030-1259319
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Organocatalytic Enantioselective Mannich-Type Reactions of Fluorinated Keto Esters with N-Boc-Aldimines

Sung Je Yoon, Young Ku Kang, Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Korea
Fax: +82(41)5301247; e-Mail: dyoung@sch.ac.kr;
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Publication History

Received 4 November 2010
Publication Date:
13 January 2011 (online)

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Abstract

The catalytic enantioselective Mannich reaction promoted by chiral bifunctional organocatalysts is described. The treatment of α-fluoro-β-keto esters with N-Boc aldimines under mild reaction conditions afforded the corresponding β-aminated α-fluoro-β-keto esters with excellent enantioselectivities (up to 98% ee).

Key words

Mannich reaction - asymmetric catalysis - bifunctional organocatalyst - α-fluoro-β-keto esters - aldimines

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Typical General Procedure for the Mannich-Type Reaction of α-Fluoro-β-keto Ester 1 with N -Boc Aldimine 2: To a solution of α-fluoro-β-keto ester 1 (0.3 mmol) and catalyst I (0.03 mmol, 20 mg) in Et2O (6 mL) was added N-Boc aldimine 2 (0.45 mmol). The reaction mixture was stirred for 24-36 h. The catalyst I was removed by short column chromatography (EtOAc-hexane, 1:5). The crude oil was purified by flash column chromatography (EtOAc-hexane, 1:7) to afford the Mannich adduct 3.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-(4-chlorophenyl)propanoate (3c): major diastereomer: [α]²6 D 7.0 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3): δ = 1.28 (t, J = 13.9 Hz, 3 H), 1.39 (s, 9 H), 4.18-4.41 (m, 2 H), 5.45 (d, J = 10.4 Hz, 1 H), 5.87 (dd, J = 28.8, 10.4 Hz, 1 H), 7.35-7.44 (m, 5 H), 7.54-7.58 (m, 2 H), 7.80-7.84 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.82, 28.15, 56.78 (d, J = 17.7 Hz), 63.32, 80.35, 102.01 (d, J = 204.4 Hz), 128.54, 129.56, 129.81, 130.24 (2), 134.01, 135.12, 154.30, 165.32 (d, J = 26.5 Hz), 190.33 (d, J = 25.7 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t R = 23.8 min (minor), t R = 28.1 min (major); 81% ee.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-propanoate (3d): major diastereomer: [α]²9 D 39.3 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3): δ = 1.26 (t, J = 13.6 Hz, 3 H), 1.38 (s, 9 H), 4.16-4.39 (m, 2 H), 5.57 (d, J = 10.5 Hz, 1 H), 6.02 (dd, J = 28.8, 10.5 Hz, 1 H), 7.19-7.33 (m, 4 H), 7.36-7.51 (m, 4 H), 7.80-7.83 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.75, 28.08, 57.38 (d, J = 18.5 Hz), 63.11, 79.97, 102.19 (d, J = 204.0 Hz), 128.01, 128.26, 128.34, 128.74, 129.28, 129.39, 133.69, 136.50, 154.31, 165.38 (d, J = 27.1 Hz), 190.80 (d, J = 25.6 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t R = 23.5 min (minor), t R = 31.0 min (major); 88% ee.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-(2-chlorophenyl)propanoate (3e): major diastereomer: [α]²8 D 55.5 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3): δ = 1.28 (t, J = 12.1 Hz, 3 H), 1.39 (s, 9 H), 4.23-4.35 (m, 2 H), 5.55 (d, J = 10.1 Hz, 1 H), 6.47 (dd, J = 26.1, 10.1 Hz, 1 H), 7.10-7.18 (m, 2 H), 7.33-7.55 (m, 5 H), 7.87-7.91 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.53, 27.88, 53.62 (d, J = 18.7 Hz), 63.02, 79.84, 101.30 (d, J = 205.4 Hz), 126.76, 128.30, 128.85, 129.09, 129.22, 129.85 (2), 133.71, 134.57, 134.97, 153.89, 165.15 (d, J = 26.7 Hz), 190.22 (d, J = 24.9 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t R = 30.4 min (minor), t R = 51.2 min (major); 86% ee.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-(furan)propanoate (3f): major diastereomer: [α]²8 D 35.3 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3):
δ = 1.28 (t, J = 14.0 Hz, 3 H), 1.43 (s, 9 H), 4.18-4.38 (m, 2 H), 5.35 (d, J = 10.7 Hz, 1 H), 6.17 (dd, J = 28.2, 10.7 Hz, 1 H), 6.24-6.26 (m, 2 H), 7.27-7.29 (m, 1 H), 7.38-7.46 (m, 2 H), 7.53-7.60 (m, 1 H), 7.90-7.94 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.79, 28.15, 52.07 (d, J = 19.7 Hz), 63.24, 80.33, 101.45 (d, J = 204.5 Hz), 108.84, 110.30, 128.51, 129.49, 129.61, 133.90, 142.37, 149.35, 154.32, 164.90 (d, J = 26.6 Hz), 190.39 (d, J = 25.2 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t R = 20.9 min (minor), t R = 34.5 min (major); 98% ee.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-(thiophene)propanoate (3g): major diastereomer: [α]²6 D 54.7 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3): δ = 1.27 (t, J = 13.9 Hz, 3 H), 1.41 (s, 9 H), 4.17-4.40 (m, 2 H), 5.36 (d, J = 10.4 Hz, 1 H), 6.31 (dd, J = 28.3, 10.4 Hz, 1 H), 6.86-6.90 (m, 1 H), 7.06-7.08 (m, 1 H), 7.16-7.18 (m, 1 H), 7.36-7.44 (m, 2 H), 7.51-7.59 (m, 1 H), 7.89-7.93 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.74, 28.10, 53.53 (d, J = 19.35 Hz), 63.12, 80.27, 101.92 (d, J = 204.2 Hz), 125.53, 126.56, 127.18, 128.46, 129.45, 129.56, 133.91, 138.75, 154.11, 164.96 (d, J = 26.9 Hz), 190.34 (d, J = 25.3 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 90:10; λ = 254 nm, flow rate: 0.5 mL/min); t R = 30.9 min (minor), t R = 44.4 min (major); 95% ee.
(2 S ,3 S )-Ethyl 2-(4-Nitrobenzoyl)-3-( tert -butoxy-carbonylamino)-2-fluoro-3-(furan)propanoate (3h): major diastereomer: [α]³¹ D 19.7 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3): δ = 1.31 (t, J = 14.4 Hz, 3 H), 1.44 (s, 9 H), 4.20-4.41 (m, 2 H), 5.36 (d, J = 10.2 Hz, 1 H), 6.15 (dd, J = 28.2, 10.2 Hz, 1 H), 6.27-6.31 (m, 2 H), 7.30 (m, 1 H), 8.01-8.06 (m, 2 H), 8.24-8.28 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.83, 28.16, 52.21 (d, J = 19.3 Hz), 63.69, 80.67, 101.58 (d, J = 204.4 Hz), 109.13, 110.48, 123.62, 130.64, 138.59, 142.66, 148.90, 150.51, 154.30, 164.15 (d, J = 26.7 Hz), 189.96 (d, J = 25.7 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t R = 26.8 min (minor), t R = 45.6 min (major); 98% ee.
(2 S ,3 S )-Ethyl 2-[4-(Trifluoromethyl)phenyl]-3-( tert -butoxycarbonylamino)-2-fluoro-3-(furan)propanoate (3i): major diastereomer: [α]³0 D 26.0 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3): δ = 1.30 (t, J = 14.5 Hz, 3 H), 1.44 (s, 9 H), 4.20-4.40 (m, 2 H), 5.35 (d, J = 10.5 Hz, 1 H), 6.17 (dd, J = 28.4, 10.5 Hz, 1 H), 6.25-6.27 (m, 2 H), 7.27-7.29 (m, 1 H), 7.67-7.71 (m, 2 H), 7.99-8.03 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.79, 28.14, 52.14 (d, J = 19.2 Hz), 63.51, 80.53, 101.54 (d, J = 204.5 Hz), 109.01, 110.39, 123.35 (q, J = 271.5 Hz), 125.55, 129.80, 134.94 (q, J = 32.5 Hz), 136.66, 142.55, 149.07, 154.31, 164.42 (d, J = 26.6 Hz), 189.56 (d, J = 29.0 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t R = 15.7 min (minor), t R = 28.5 min (major); 96% ee.
(2 S ,3 S )-Ethyl 2-(4-Methoxybenzoyl)-3-( tert -butoxy-carbonylamino)-2-fluoro-3-(furan)propanoate (3j): major diastereomer: [α]³0 D 19.1 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3): δ = 1.26 (t, J = 13.9 Hz, 3 H), 1.43 (s, 9 H), 3.84 (s, 3 H), 4.16-4.36 (m, 2 H), 5.36 (d, J = 10.5 Hz, 1 H), 6.16 (dd, J = 28.3, 10.5 Hz, 1 H), 6.23-6.25 (m, 2 H), 6.86-6.93 (m, 2 H), 7.79 (m, 1 H), 7.95-8.00 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.74, 28.10, 51.96 (d, J = 19.5 Hz), 55.42, 63.06, 80.19, 101.50 (d, J = 204.4 Hz), 108.70, 110.24, 113.79, 126.60, 132.25, 142.22, 149.57, 154.31, 164.18, 165.20 (d, J = 26.9 Hz), 188.24 (d, J = 24.3 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t R = 26.6 min (minor), t R = 49.6 min (major); 96% ee.
(2 S ,3 S )-Ethyl 2-(4-Bromobenzoyl)-3-( tert -butoxy-carbonylamino)-2-fluoro-3-(furan)propanoate (3k): major diastereomer: [α]³¹ D 21.1 (c = 1.0, CHCl3). ¹H NMR (200 MHz, CDCl3): δ = 1.28 (t, J = 14.0 Hz, 3 H), 1.43 (s, 9 H), 4.19-4.37 (m, 2 H), 5.32 (d, J = 10.1 Hz, 1 H), 6.14 (dd, J = 28.4, 10.1 Hz, 1 H), 6.23-6.31 (m, 2 H), 7.27-7.29 (m, 1 H), 7.54-7.59 (m, 2 H), 7.78-7.81 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 13.81, 28.16, 52.08 (d, J = 19.3 Hz), 63.40, 80.45, 101.51 (d, J = 204.1 Hz), 108.93, 110.36, 129.47, 131.00, 131.92, 132.48, 142.46, 149.22, 154.31, 164.68 (d, J = 27.9 Hz), 189.64 (d, J = 25.5 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 90:10; λ = 254 nm, flow rate: 0.5 mL/min); t R = 24.7 min (minor), t R = 55.2 min (major); 98% ee.