Efficient synthesis of 3-hydroxyprolines and 3-hydroxyprolinols from sugars

4.1. General

All non-aqueous reaction was carried out under an inert nitrogen atmosphere. THF was distilled from Na/benzophenone; 2,2-dimethoxypropane, DMF, and methylene chloride were distilled from CaH2. Column chromatography was carried out using 230–400 mesh silica gel. Final solution before evaporation was washed with brine and dried over anhydrous Na2SO4. Melting points are uncorrected. 1H and 13C NMR experiments were conducted on Brucker AW-500 spectrometer. HREIMS were obtained on a JEOLJMS-700 mass spectrometer. Optical rotations were measured on a JASCO DIP-1000 polarimeter and [α]D-values are given in units of 10?1 deg cm2 g?1.

4.1.1. Methyl 2-deoxy-3,4-O-isopropylidene-2-[(9-phenyl-9-fluorenyl)-amino]-d-mannonate 5

This was prepared from d-glucono-δ-lactone as described:16 mp 69–70°C (lit.,16 68–70°C).

4.1.2. Methyl 2-deoxy-3,4-O-isopropylidene-2-[(9-phenyl-9-fluorenyl)-amino]-d-lyxonate 6

To a solution of diol 5 (6.00 g, 12.26 mmol) in EtOH–H2O (80:40 mL) was NaIO4 (3.15 g, 14.70 mmol) at room temperature. After stirring for 3 h, the mixture was cooled to 0°C, and then NaBH4 (0.56 g, 14.70 mmol) was added and stirred for 10 min. After evaporation of EtOH, the mixture was poured into excess of H2O and extracted with EtOAc (100 mL×3). After concentration of combined extracts, the residue was chromatographed on silica gel [hexane–EtOAc (3:1)] to give compound 6 (5.52 g, 98%) as a solid, mp 64–66°C; [α]D20=?150 (c 1.16, CHCl3); IR (KBr): 3500, 3050, 1740 cm?1; δH (500 MHz; CDCl3) 1.09 (3H, s), 1.28 (3H, s), 2.63 (1H, d, J=8.8 Hz), 3.23 (3H, s), 3.35 (1H, s, OH), 3.76–3.92 (4H, m), 7.09–7.73 (13H, m, Pf); δC (125 MHz; CDCl3) 26.4, 26.8, 51.9, 58.6, 63.8, 72.6, 80.2, 80.3, 109.5, 120.2, 125.5, 125.7, 126.1, 127.4, 127.5, 128.4, 128.5, 128.6, 128.9, 140.4, 141.1, 143.1, 147.9, 174.7 (Found: C, 73.18; H, 6.39; N, 3.02. C28H29NO5 requires C, 73.18; H, 6.36; N, 3.05%).

4.1.3. Methyl 2-deoxy-3,4-O-isopropylidene-5-O-methanesulfonyl-2-[(9-phenyl-9-fluorenyl)-amino]-d-lyxonate 7

To a solution of alcohol 6 (5.40 g, 11.75 mmol) in THF (58 mL) were added triethylamine (3.26 mL, 23.50 mmol) and MsCl (1.36 mL, 17.63 mmol) at 0°C. The reaction mixture was stirred for 20 min at room temperature, then was quenched with saturated aqueous NaHCO3 (50 mL). The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (50 mL×3). After concentration of combined extracts, the resulting residue was chromatographed on silica gel [hexane–EtOAc (5:1)] to give compound 7 (6.20 g, 98%) as a solid, mp 155–158°C; [α]D20=?204 (c 1.00, CHCl3); IR (KBr): 3290, 3010, 1715 cm?1; δH (500 MHz; CDCl3) 1.10 (3H, s), 1.31 (3H, s), 2.62 (1H, dd, J=11.0, 9.0 Hz), 3.12 (3H, s), 3.24 (3H, s,), 3.82 (1H, dd, J=8.8, 7.3 Hz), 4.00 (1H, m), 4.46 (1H, dd, J=10.9, 6.1 Hz), 4.77 (1H, dd, J=11.0, 2.4 Hz), 7.11–7.74 (13H, m, Pf); δC (125 MHz; CDCl3) 26.6, 26.8, 51.9, 58.8, 70.3, 72.6, 78.0, 78.2, 110.6, 120.2, 120.3, 125.1, 125.9, 126.1, 127.5, 128.3, 128.5, 128.6, 128.8, 140.1, 141.3, 143.4, 147.9, 148.2, 174.4 (Found: C, 64.73; H, 5.80; N, 2.59. C29H31NO7S requires C, 64.79; H, 5.81; N, 2.61%).

4.1.4. Methyl 2,5-dideoxy-3,4-O-isopropylidene-5-iodo-2-[(9-phenyl-9-fluorenyl)-amino]-d-lyxonate 8

To a solution of mesylate 7 (6.10 g, 11.34 mmol) in dried DMF (38 mL) was added LiI (6.17 g, 46.12 mmol). After stirring of the mixture for overnight at 80°C, saturated aqueous NaHCO3 (50 mL) was added and the mixture was extracted with EtOAc (40 mL×3). The extract was evaporated and the remaining residue was chromatographed on silica gel [hexane–EtOAc (10:1)] to give compound 8 (6.14 g, 95%) as a solid, mp 60–65°C; [α]D20=?161.8 (c 1.2, CHCl3); IR (KBr): 3320, 3040, 1735 cm?1; δH (500 MHz; CDCl3) 1.07 (3H, s), 1.34 (3H, s), 2.63 (1H, m), 3.04 (1H, d, J=11 Hz), 3.23 (3H, s), 3.44 (1H, m), 3.67 (1H, dd, J=10.2, 3.2 Hz), 7.13–7.71 (13H, m, Pf); δC (125 MHz; CDCl3) 8.8, 27.5, 27.9, 52.2, 59.0, 73.0, 80.0, 82.6, 99.5, 110.6, 120.6, 125.5, 126.3, 126.5, 127.8, 127.9, 128.8, 128.9, 129.0, 129.1, 140.6, 141.6, 144.1, 148.6, 148.7, 174.9 (Found: C, 59.02; H, 4.97; N, 2.49. C28H28INO4 requires C, 59.06; H, 4.96; N, 2.46%).

4.1.5. Methyl (2S,3S)-3-hydroxy-2-[(9-phenyl-9-fluorenyl)-amino]-4-pentenoate 9

A solution of iodinated 8 (6.00 g, 10.54 mmol) in THF (53 mL) was cooled to ?40°C, 2.5 M n-BuLi (16.90 mL, 42.16 mmol, 400 mmol%) was added dropwise over 30 min via syring pump. The reaction mixture was stirred an additional 20 min at ?40°C, then quenched with saturated aqueous NH4Cl (40 mL). The mixture was extracted with EtOAc (40 mL×3) and combined extracts were concentrated. The resulting residue was chromatographed on silica gel [hexane–EtOAc (4:1)] to give compound 9 (3.45 g, 85%) as a solid, mp 120–122°C; [α]D20=?278.2 (c 1.00, CHCl3); IR (KBr): 3480, 3045, 1735 cm?1; δH (500 MHz; CDCl3) 2.77 (1H, d, J=5.5 Hz), 3.28 (3H, s), 4.01 (1H, t, J=5.5 Hz), 4.69 (1H, s, NH), 5.15 (1H, d, J=10.6 Hz), 5.25 (1H, d, J=14.7 Hz), 5.74 (1H, ddd, J=16.3, 10.5, 5.5 Hz), 7.20–7.67 (13H, m, Pf); δC (125 MHz; CDCl3) 50.4, 58.8, 71.4, 72.0, 115.2, 118.8, 118.9, 124.0, 124.8, 125.1, 126.2, 126.2, 127.0, 127.2, 127.3, 127.5, 135.6, 139.0, 139.9, 142.9, 146.9, 147.3, 172.7 (Found: C, 77.40; H, 6.05; N, 3.60. C25H23NO3 requires C, 77.90; H, 6.01; N, 3.63%).

4.1.6. Methyl (2S,3S)-3-(tert-butyldimethylsilyl)oxy-2-[(9-phenyl-9-fluorenyl)-amino]-4-pentenoate 10

To a solution of compound 9 (3.40 g, 8.82 mmol) in DMF (30 mL) were added imidazole (1.20 g, 17.64 mmol) and TBDMSCl (2.66 g, 17.64 mmol) at room temperature. After stirring of the mixture for 12 h, saturated aqueous NaHCO3 (40 mL) was added and the mixture was extracted with EtOAc (40 mL×3). After concentration of combined extracts, the remaining residue was chromatographed on silica gel [hexane–EtOAc (12:1)] to give compound 10 (4.32 g, 98%) as a solid, mp 95–98°C; [α]D20=?208.0 (c 1.46, CHCl3); IR (KBr): 3315, 3040, 1740 cm?1; δH (500 MHz; CDCl3) ?0.01 (3H, s), 0.03 (3H, s), 0.81 (9H, s), 2.66 (1H, d, J=7.9 Hz), 3.21 (3H, s), 4.13 (1H, t, J=7.3 Hz), 5.25 (2H, m), 5.74 (1H, ddd, J=17.3, 10.3, 7.1 Hz), 7.22–7.71 (13H, m, Pf); δC (125 MHz; CDCl3) ?5.2, ?4.3, 17.9, 25.6, 51.3, 61.2, 72.7, 76.9, 116.9, 119.9, 119.9, 125.8, 126.1, 126.1, 127.2, 127.3, 127.7, 128.2, 128.3, 128.3, 139.3, 140.2, 141.1, 144.8, 148.5, 148.6, 175.3 (Found: C, 74.54; H, 7.42; N, 2.78. C31H37NO3Si requires C, 74.51; H, 7.46; N, 2.80%).

4.1.7. Methyl (2S,3S)-3-(tert-butyldimethylsilyl)oxy-5-hydroxy-2-[(9-phenyl-9-fluorenyl)-amino] pentanoate 11

To a solution of pentenoate 10 (4.30 g, 8.60 mmol) in THF (43 mL) were added BH3(CH3)2S (12.90 mL, 25.80 mmol) at 0°C. After stirring of the mixture for 10 h at room temperature, the reaction mixture was quenched by sequential addition of water (2.6 mL), 3 M sodium hydroxide (3.25 mL), 30% hydrogen peroxide (5.85 mL). The mixture was extracted with EtOAc (40 mL×3) and combined extracts was concentrated. The residue was chromatographed on silica gel [hexane–EtOAc (4:1)] to give compound 11 (3.12 g, 70%) as a solid, mp 64–66°C; [α]D20=?81.6 (c 1.73, CHCl3); IR (KBr): 3530, 3060, 1745 cm?1; δH (500 MHz; CDCl3) 0.00 (3H, s), 0.07 (3H, s), 0.80 (9H, s), 1.85 (1H, m), 2.01 (1H, m), 2.72 (1H, d, J=7.7 Hz), 3.21 (3H, s), 3.45 (2H, m), 3.87 (1H, m), 7.15–7.73 (13H, m, Pf); δC (125 MHz; CDCl3) ?5.2, ?4.4, 17.7, 25.6, 36.6, 51.5, 59.3, 59.8, 72.7, 74.5, 120.1, 120.2, 125.7, 125.9, 126.1, 127.3, 127.5, 127.9, 128.4, 128.4, 128.7, 140.4, 141.1, 143.9, 148.3, 148.4, 175.6 (Found: C, 71.88; H, 7.59; N, 2.75. C31H39NO4Si requires C, 71.92; H, 7.59; N, 2.71%).

4.1.8. trans-3-O-(tert-Butyldimethylsilyl)-1-(9-phenyl-9-fluorenyl)-l-proline methyl ester 12

To a solution of alcohol 11 (3.00 g, 5.79 mmol) in THF (29 mL) were added triethylamine (1.57 mL, 11.30 mmol) and MsCl (0.66 mL, 8.46 mmol). The reaction mixture was stirred for 3 h at 0°C, then was quenched with saturated aqueous NaHCO3 (30 mL). The reaction mixture was extracted with EtOAc (20 mL×3). After concentration of combined extracts, the resulting residue was chromatographed on silica gel [hexane–EtOAc (15:1)] to give compound 12 (2.52 g, 87%) as a oil, [α]D20=+272.6 (c 2.5, CHCl3); IR (neat): 3030, 2910, 1725 cm?1; δH (500 MHz; CDCl3) ?0.11 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.73 (1H, m), 2.16 (1H, m), 2.97 (1H, d, J=1.0 Hz), 3.33 (1H, m), 3.40 (1H, m), 3.44 (3H, s), 4.17 (1H, m), 7.22–7.85 (13H, m, Pf); δC (125 MHz; CDCl3) ?5.1, 17.7, 25.6, 34.5, 47.0, 51.2, 69.7, 76.0, 119.7, 119.8, 126.9, 127.0, 127.0, 127.2, 127.6, 127.6, 128.1, 128.2, 128.4, 139.4, 141.7, 142.9, 145.9, 148.4, 175.3 (Found: C, 74.54; H, 7.49; N, 2.78. C31H37NO3Si requires C, 74.51; H, 7.46; N, 2.80%).

4.1.9. trans-3-Hydroxy-1-(9-phenyl-9-fluorenyl)-l-prolinol 13

To an ice-cooled solution of LAH (0.08 g, 2.10 mmol) in THF (7 mL) was added a solution of proline methyl ester 12 (0.70 g, 1.40 mmol) in THF (4 mL). The reaction mixture was warmed to room temperature, stirred for 7 h, then quenched by the sequential addition of water (0.8 mL), 15% aqueous NaOH (0.8 mL), and water (2.4 mL). The mixture was filtered and evaporated. The resulting residue was chromatographed on silica gel [hexane–EtOAc (2:1)] to give compound 13 (0.45 g, 89%) as a solid, mp 150–160°C; [α]D20=+18.6 (c 1.00, CHCl3); IR (KBr): 3480, 3040, 2890 cm?1; δH (500 MHz; CDCl3) 1.64 (1H, m), 1.92 (1H, m), 2.32 (1H, m), 2.51 (1H, dd, J=10.5, 5.6 Hz), 3.05 (1H, d, J=10.1 Hz), 3.27 (2H, m), 4.03 (1H, s), 7.18–7.74 (13H, m, Pf); δC (125 MHz; CDCl3) 31.7, 47.2, 61.5, 66.3, 75.1, 118.5, 118.7, 124.3, 125.0, 125.9, 125.9, 126.3, 126.4, 126.9, 127.1, 127.4, 137.4, 1405, 141.3, 145.0, 147.4 (Found: C, 80.61; H, 6.51; N, 3.90. C24H23NO2 requires C, 80.64; H, 6.49; N, 3.92%).

4.1.10. Methyl 2-deoxy-3,4-O-isopropylidene-2-[(9-phenyl-9-fluorenyl)-amino]-d-arabinonate 14

This was prepared from l-gulonic acid γ-lactone as described:17 mp 57–58°C (lit.,17 56–58°C).

4.1.11. Methyl 2-deoxy-3,4-O-isopropylidene-5-O-methanesulfonyl-2-[(9-phenyl-9-fluorenyl)-amino]-d-arabinonate 15

To a solution of alcohol 14 (5.40 g, 11.75 mmol) in THF (58 mL) were added triethylamine (3.26 mL, 23.50 mmol) and MsCl (1.42 mL, 17.63 mmol), at 0°C. After stirring of the mixture for 15 min at room temperature, saturated aqueous NaHCO3 (50 mL) was added and the mixture was extracted with CH2Cl2 (60 mL×3). After concentration of combined extracts, the residue was chromatographed on silica gel [hexane–EtOAc (5:1)] to give compound 15 (6.19 g, 98%) as a solid, mp 55–60°C; [α]D20=+230.2 (c 1.00, CHCl3); IR (KBr): 3310, 3030, 1730 cm?1; δH (500 MHz; CDCl3) 1.35 (3H, s), 1.46 (3H, s), 2.65 (1H, s), 2.99 (3H, s), 3.33 (3H, s), 3.75 (1H, m), 3.87 (1H, dd, J=11.5, 5.2 Hz), 4.20 (1H, dd, J=11.5, 2.7 Hz), 4.47 (1H, m), 7.20–7.67 (13H, m, Pf); δC (125 MHz; CDCl3) 27.0, 27.1, 37.7, 51.9, 55.2, 68.4, 72.9, 74.6, 77.6, 110.3, 120.0, 120.2, 125.3, 126.6, 126.7, 127.4, 127.5, 128.1, 128.5, 128.6, 128.8, 140.3, 141.0, 143.7, 147.8, 148.4, 173.5 (Found: C, 64.82; H, 5.80; N, 2.59. C29H31NO7S requires C, 64.79; H, 5.81; N, 2.61%).

4.1.12. Methyl 2,5-dideoxy-3,4-O-isopropylidene-5-iodo-2-[(9-phenyl-9-fluorenyl)-amino]-d-arabinonate 16

To a solution of mesylate 15 (6.00 g, 11.16 mmol) in DMF (40 mL) was added LiI (6.17 g, 46.12 mmol). After stirring of the mixture for overnight at 80°C, saturated aqueous NaHCO3 (50 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). After evaporation of combined extracts, the resulting residue was chromatographed on silica gel [hexane–EtOAc (10:1)] to give compound 16 (5.72 g, 90%) as a solid, mp 59–64°C; [α]D20=+200.7 (c 1.25, CHCl3); IR (KBr): 3340, 3020, 1730 cm?1; δH (500 MHz; CDCl3) 1.37 (3H, s), 1.50 (3H, s), 2.64 (1H, m), 2.89 (1H, dd, J=10.8, 5.8 Hz), 3.01 (1H, dd, J=10.8, 4.0 Hz), 3.33 (1H, s), 3.60 (1H, dd, J=7.6, 3.0 Hz), 4.13 (1H, m), 7.21–7.69 (13H, m, Pf); δC (125 MHz; CDCl3) 5.9, 27.2, 51.8, 55.3, 72.8, 75.4, 81.8, 109.7, 119.9, 120.1, 125.4, 126.1, 126.9, 127.3, 127.4, 128.1, 128.3, 128.4, 128.5, 128.7, 140.2, 141.1, 143.9, 147.8, 148.6, 173.6 (Found: C, 59.02; H, 4.99; N, 2.47. C28H28INO4 requires C, 59.06; H, 4.96; N, 2.46%).

4.1.13. Methyl (2R,3S)-3-hydroxy-2-[(9-phenyl-9-fluorenyl)-amino]-4-pentenoate 17

A solution of iodinated 16 (5.30 g, 9.31 mmol) in THF (50 mL) was cooled to ?40°C, 2.5 M n-BuLi (14.90 mL, 37.24 mmol, 400 mmol%) was added dropwise over 30 min via syring pump. The reaction mixture was stirred an additional 20 min at ?40°C, then quenched with saturated aqueous NH4Cl (40 mL). The mixture was extracted with EtOAc (50 mL×3) and combined extracts were concentrated. The remaining residue was chromatographed on silica gel [hexane–EtOAc (4:1)] to give compound 17 (3.23 g, 90%) as a solid, mp 117–120°C; [α]D20=+278.9 (c 1.25, CHCl3); IR (KBr): 3490, 3020, 1720 cm?1; δH (500 MHz; CDCl3) 2.51 (1H, d, J=7.8 Hz), 3.20 (3H, s), 3.89 (1H, dd, J=7.7, 6.9 Hz), 5.04 (1H, dt, J=10.4, 1.1 Hz), 5.16 (1H, dt, J=17.1, 1.3 Hz), 5.49 (1H, m), 7.23–7.39 (13H, m, Pf); δC (125 MHz; CDCl3) 51.5, 61.0, 72.5, 74.3, 117.7, 120.1, 120.1, 125.3, 125.9, 126.2, 127.4, 127.5, 128.4, 128.5, 128.6, 128.7, 136.1, 140.1, 141.2, 143.8, 148.1, 148.1, 174.3 (Found: C, 77.88; H, 6.03; N, 3.60. C25H23NO3 requires C, 77.90;H, 6.01; N, 3.63%).

4.1.14. Methyl (2R,3S)-3-(tert-butyldimethylsilyl)oxy-2-[(9-phenyl-9-fluorenyl)-amino]-4-pentenoate 18

To a solution of pentenoate 17 (3.20 g, 8.30 mmol) in DMF (28 mL) were added imidazole (1.13 g, 16.60 mmol) and TBDMSCl (2.50 g, 16.60 mmol) at room temperature. After stirring of the mixture for 12 h, saturated aqueous NaHCO3 (40 mL) was added and the mixture was extracted with EtOAc (50 mL×3). After concentration of combined extracts, the residue was chromatographed on silica gel [hexane–EtOAc (10:1)] to give compound 18 (4.06 g, 98%) as a oil, [α]D20=?109.2 (c 3.00, CHCl3); IR (neat): 3340, 3040, 1730 cm?1; δH (500 MHz; CDCl3) ?0.06 (3H, s), 0.00 (3H, s), 0.91 (9H, s), 2.84 (1H, s), 3.11 (1H, s), 3.32 (3H, s), 4.20 (1H, m), 5.25 (1H, dt, J=10.4, 1.3 Hz), 5.31 (1H, dt, J=17.2, 1.6 Hz), 6.03 (1H, ddd, J=17.0, 10.4, 6.4 Hz), 7.31–7.79 (13H, m, Pf); δC (125 MHz; CDCl3) ?4.8, ?4.5, 18.4, 26.1, 51.5, 61.1, 73.2, 76.5, 116.6, 120.2, 120.3, 125.8, 126.6, 126.8, 127.5, 127.7, 128.2, 128.6, 128.7, 137.9, 140.7, 141.4, 145.0, 149.2, 149.5, 174.4 (Found: C, 74.48; H, 7.49; N, 2.76. C31H37NO3Si requires C, 74.51;H, 7.46; N, 2.80%).

4.1.15. Methyl (2R,3S)-3-(tert-butyldimethylsilyl)oxy-5-hydroxy-2-[(9-phenyl-9-fluorenyl)-amino] pentanoate 19

To a solution of compound 18 (4.00 g, 8.00 mmol) in THF (41 mL) were added BH3(CH3)2S (12.00 mL, 24.00 mmol) at 0°C. After stirring of the mixture for 10 h at room temperature, the reaction mixture was quenched by sequential addition of water (2.5 mL), 3 M sodium hydroxide (3.15 mL), 30% hydrogen peroxide (5.35 mL). The mixture was extracted with EtOAc (40 mL×3). After evaporation of combined extracts, the residue was chromatographed on silica gel [hexane–EtOAc (4:1)] to give compound 19 (3.23 g, 78%) as a solid, mp 117–120°C; [α]D20=+381.0 (c 1.26, CHCl3); IR (KBr): 3490, 3030, 1720 cm?1; δH (500 MHz; CDCl3) ?0.25 (3H, s), 0.00 (3H, s), 0.91 (9H, s), 1.76 (1H, m), 2.24 (1H, m), 2.82 (1H, d, J=4.6 Hz), 3.44 (3H, s), 3.77 (2H, m), 3.90 (1H, m), 7.29–7.85 (13H, m, Pf); δC (125 MHz; CDCl3) ?5.3, ?5.2, 17.8, 25.7, 34.8, 51.3, 59.1, 59.8, 60.0, 73.0, 119.9, 120.1, 125.4, 126.1, 126.2, 127.3, 127.5, 128.0, 128.4, 128.6, 128.7, 140.4, 141.4, 144.0, 148.6, 149.1, 174.6 (Found: C, 71.88; H, 76.2; N, 2.73. C31H39NO4Si requires C, 71.92; H, 7.59; N, 2.71%).

4.1.16. cis-3-O-(tert-Butyldimethylsilyl)-1-(9-phenyl-9-fluorenyl)-d-proline methyl ester 20

To a solution of alcohol 19 (2.40 g, 4.63 mmol) in THF (23 mL) were added triethylamine (1.29 mL, 9.26 mmol) and MsCl (0.54 mL, 7.0 mmol). The reaction mixture was stirred for 3 h at 0°C, then was quenched with saturated aqueous NaHCO3 (30 mL). The organic phase was separated, and the aqueous phase was treated with EtOAc (40 mL×3). The extract was concentrated and the resulting residue was chromatographed on silica gel [hexane–EtOAc (15:1)] to give compound 20 (2.08 g, 90%) as a oil, [α]D20=?248.7 (c 1.73, CHCl3); IR (neat): 3020, 2910, 1730 cm?1; δH (500 MHz; CDCl3) 0.00 (3H, s), 0.04 (3H, s), 0.88 (9H, s), 1.91 (1H, m), 2.17 (1H, m), 2.84 (1H, m), 3.37 (2H, m), 3.51 (3H, s), 4.14 (1H, m), 7.20–7.81 (13H, m, Pf); δC (125 MHz; CDCl3) ?4.9, 17.9, 25.6, 33.1, 46.1, 50.9, 65.0, 73.6, 76.5, 119.8, 120.0, 126.3, 126.6, 127.3, 127.3, 127.5, 127.6, 128.3, 128.3, 128.4, 140.0, 141.2, 142.8, 146.8, 148.2, 173.7 (Found: C, 74.47; H, 7.49; N, 2.79. C31H37NO3Si requires C, 74.51; H, 7.46; N, 2.80%).

4.1.17. trans-3-Hydroxy-l-proline 1

The protected proline 12 (0.70 g, 1.40 mmol) and 10% Pd/C (0.07 g) were stirred in CH3OH (14 mL) under an atmosphere of hydrogen at 60°C for 3 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated. A solution of remaining residue and Dowex 50W-X8 (0.18 g) in THF–H2O (4:2 mL) was refluxed for overnight, cooled to room temperature. The mixture was filtered, and then the insoluble material was washed with CH3OH (50 mL). The remaining residue was eluted with 3N NH4OH. The ammoniacal solution was evaporated, then co-evaporation with toluene to give the compound 1 (0.14 g, 76%) as a solid, mp 231–234°C (decomp.); [α]D20=?23.3 (c 0.92, H2O); {lit., 9 [α]D20=?18.8 (c 0.14, H2O), mp 232°C}; IR (KBr): 3410, 2920 cm?1; δH (500 MHz; D2O) 2.04 (2H, m), 3.48 (1H, m), 3.58 (1H, m), 4.06 (1H, s), 4.67 (1H, m); δC (125 MHz; D2O) 30.1, 42.8, 67.6, 72.5, 170.2; MS: m/z 131 (M+); [found (HRMS): (M+), 131.0567. Calcd for C5H9NO3: 131.0582].

4.1.18. trans-3-Hydroxy-l-prolinol 2

The N-protected prolinol 13 (0.30 g, 0.84 mmol) and 10% Pd/C (0.03 g) were stirred in CH3OH (4 mL) under an atmosphere of hydrogen at 60°C for 3 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The remaining oil was subjected to ion-exchange chromatography (Dowex 50W-X8, eluting with 3N NH3 in water), and free base 2 was obtained as an oil in 93% yield, [α]D20=+45.8 (c 0.5, H2O); {lit., 18 [α]D20=+46.5 (c 1.0, H2O)}; IR (neat): 3450, 2895 cm?1; δH (500 MHz; D2O) 1.78 (1H, m), 2.02 (1H, m), 3.03 (3H, m), 3.55 (1H, m), 3.64 (1H, m), 4.14 (1H, m); δC (125 MHz; D2O) 34.0, 44.3, 62.2, 67.4, 73.6; MS: m/z 117 (M+); [Found (HRMS): (M+), 117.0792. Calcd for C5H11NO2: 117.0790].

4.1.19. cis-3-Hydroxy-d-proline 3

The protected proline 20 (0.70 g, 1.40 mmol) and 10% Pd/C (0.07 g) were in CH3OH (14 mL) under an atmosphere of hydrogen at 60°C 3 h. The reaction mixture was filtered through Celite, and the filtrate concentrated. A solution of remaining residue and Dowex 50W-X8 (0.17 g) in THF–H2O (4:2 mL) was refluxed for overnight, cooled to room temperature. The mixture was filtered, and then the insoluble material was washed with CH3OH (50 mL). The remaining residue was eluted with 3N NH4OH. The ammoniacal solution was evaporated, then co-evaporation with toluene to give the compound 3 (0.15 g, 84%) as a solid, mp 210–217°C (decomp.); [α]D20=+96.3 (c 0.92, H2O); {lit., 10 [α]D20=+89.0} (c 0.7, H2O), mp 225–235°C (decomp.)}; IR (KBr): 3400, 2910 cm?1; δH (500 MHz; D2O) 2.12 (1H, m), 2.21 (1H, m), 3.47 (1H, m), 3.57 (1H, m), 4.13 (1H, d, J=4.1 Hz), 4.72 (1H, m); δC (125 MHz; D2O) 32.3, 42.9, 66.7, 70.0, 169.7; MS: m/z 131 (M+); [Found (HRMS): (M+), 131.0580. Calcd for C5H9NO3: 131.0582].

4.1.20. cis-3-Hydroxy-d-prolinol 4

To an ice-cooled solution of LAH (0.08 g, 2.10 mmol) in THF (7 mL) was added a solution of proline 20 (0.70 g, 1.40 mmol) in THF (10 mL). The reaction mixture was warmed to room temperature, stirred for 7 h and then quenched by sequential addition of water (0.8 mL), 15% aqueous NaOH (0.8 mL), and water (2.4 mL). The mixture was filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel [hexane–EtOAc (2:1)] to give compound. The N-protected prolinol and 10% Pd/C (0.03 g) were stirred in CH3OH (4 mL) under an atmosphere of hydrogen at 60°C for 3 h. The mixture was filtered through Celite, and the filtrate was concentrated. The remaining oil was subjected to ion-exchange chromatography (Dowex 50W-X8, eluting with 3N NH3 in water), and free base 4 was obtained as an oil in 75% yield, [α]D20=?23.2 (c 0.76, H2O); IR (neat): 3310, 2890 cm?1; δH (500 MHz; D2O) 1.93 (1H, m), 2.14 (1H, m), 3.14 (1H, m), 3.30 (2H, m), 3.78 (1H, m), 3.38 (1H, dd, J=11.7, 5.5 Hz), 4.46 (1H, s); δC (125 MHz; D2O) 33.8, 43.5, 59.3, 64.8, 71.2; MS: m/z 117 (M+); [Found (HRMS): (M+), 117.0804. Calcd for C5H11NO2: 117.0790].