(2S)-2-amino-2-phenylethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Then (S)-2-amino-2-phenylethanol (0.494 g, 3.6 mmol) in dichloromethane/N,N-dimethylformamide (5:1, 40 mL) was added to the crude 4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonyl chloride. The mixture was stirred at room temperature for 3 days, then sodium carbonate (0.21 g, 2 mmol) and methanol (10 mL) were added. The mixture was stirred for an additional 30 minutes, then the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (m, 1H), 1.60-2.10 (m, 6H), 2.90-3.20 (m, 4H), 3.30-3.50 (m, 3H), 4.30 (m, 1H), 4.50 (m, 1H), 4.85 (m, 1H), 7.10 (m, 5H), 7.30 (m, 2H), 7.61 (m, 2H), 8.30 (br s, 1H); MS (ESI) m/z 430 (M+H)+. The mixture was stirred for an additional 30 minutes the reaction mixture was filtered the filtrate was concentrated The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrous dichloromethane (40 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (0.189 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 min at room temperature. Then sodium carbonate (0.48 g, 4.52 mmol) was added. The mixture was stirred at room temperature overnight. Then (S)-2-amino-2-phenylethanol (0.274 g, 2.0 mmol) in N,N-dimethylformamide (10 mL) was added. The mixture was stirred at room temperature for 4 days. Then methanol (5 mL) was added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (methanol/dichloromethane=1:12) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.30 (m, 1H), 1.60-2.10 (m, 6H), 2.80-3.10 (m, 4H), 3.40 (m, 3H), 4.25 (m, 1H), 4.40-4.60 (m, 1H), 4.82 (t, 1H, J=4 Hz), 7.10 (m, 5H), 7.44 (m, 2H), 7.60 (s, 1H), 7.65 (m, 1H), 8.30 (d, 1H, J=7 Hz); MS (ESI) m/z 430 (M+H)+. The mixture was stirred at room temperature for 4 days the mixture was stirred for 20 minutes filtered concentrated The residue was purified by chromatography on silica gel (methanol/dichloromethane=1:12)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-2-amino-2-phenylethanol (2.28 g, 16.6 mmol) and 4-cyclopropyl-4-oxobutanoic acid (1.97 g, 13.8 mmol) in toluene (35 mL) was heated at reflux for about 6 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed with aqueous HCl (1.0 N), saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on a Biotage silica gel column eluting with heptane/EtOAc (3:2) to afford (3S,7aS)-7a-cyclopropyl-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (2.54 g, 10.4 mmol) as a bright yellow needle-like solid. RP-HPLC (Table 1, Method a) Rt 1.77 min; m/z: (M+H)+ 244. was heated at reflux for about 6 h washed with aqueous HCl (1.0 N), saturated NaHCO3, brine dried over MgSO4 filtered concentrated in vacuo The residue was purified on a Biotage silica gel column eluting with heptane/EtOAc (3:2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Then (S)-2-amino-2-phenylethanol (0.494 g, 3.6 mmol) in dichloromethane/N,N-dimethylformamide (5:1, 40 mL) was added to the crude 4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl]benzenesulfonyl chloride. The mixture was stirred at room temperature for 3 days, then sodium carbonate (0.21 g, 2 mmol) and methanol (10 mL) were added. The mixture was stirred for an additional 30 minutes, then the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (m, 1H), 1.60-2.10 (m, 6H), 2.90-3.20 (m, 4H), 3.30-3.50 (m, 3H), 4.30 (m, 1H), 4.50 (m, 1H), 4.85 (m, 1H), 7.10 (m, 5H), 7.30 (m, 2H), 7.61 (m, 2H), 8.30 (br s, 1H); MS (EST) m/z 430 (M+H)+. The mixture was stirred for an additional 30 minutes the reaction mixture was filtered the filtrate was concentrated The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrous dichloromethane (40 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (0.189 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 min at room temperature. Then sodium carbonate (0.48 g, 4.52 mmol) was added. The mixture was stirred at room temperature overnight. Then (S)-2-amino-2-phenylethanol (0.274 g, 2.0 mmol) in N,N-dimethylformamide (10 mL) was added. The mixture was stirred at room temperature for 4 days. Then methanol (5 mL) was added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (methanol/dichloromethane=1:12) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.30 (m, 1H), 1.60-2.10 (m, 6H), 2.80-3.10 (m, 4H), 3.40 (m, 3H), 4.25 (m, 1H), 4.40-4.60 (m, 1H), 4.82 (t, 1H, J=4 Hz), 7.10 (m, 5H), 7.44 (m, 2H), 7.60 (s, 1H), 7.65 (m, 1H), 8.30 (d, 1H, J=7 Hz); MS (ESI) m/z 430 (M+H)+. The mixture was stirred at room temperature for 4 days the mixture was stirred for 20 minutes filtered concentrated The residue was purified by chromatography on silica gel (methanol/dichloromethane=1:12)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-(+)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone was synthesized in an analogous manner used for the production of(R)-(-)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (S)-(+)-Phenylglycinol was used to resolve the methyl (S)-(+)-2-(4-isobutylphenyl)propionate enantiomer, of which 1.2 g (5 mmol) was converted into 250 mg (19% yield) of (S)-(+)-3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a white crystalline material: mp 175-177° C. dec. (CHCl3 /hexanes); [α]25D +132° (c=1.55; MeOH) 1H NMR (acetone-d6) δ 7.44-7.14 (m, 4H), 2.48 (d, 2H, J=7.1 Hz), 1.87-1.82 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H, J=6.5 Hz). Anal Calcd for C15H18O4 : C, 68.68; H, 6.92. Found: C, 68.08; H, 6.90. (S)-(+)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone was synthesized in an analogous manner

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-(-)-5-[(1,1'-Biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone was prepared in an analogous manner as described for (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with 1.9 g (5.0 mmol) of the diastereomerically pure salt of (R)-(-)-2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionic acid and (S)-(+)-phenylglycinol to provide 280 mg (19% yield) of(R)-(-)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone as a white crystalline material: mp 197-199° C. dec. (CHCl3 /hexanes); [α]25D -182° (c=1.42; MeOH); 1H NMR (acetone-d6) δ 7.65-7.41 (m, 9H), 1.89 (s, 3H). Anal Calcd for C17H14O4 +0.25 H2O: C, 71.20; H, 5.10. Found: C, 71.19; H, 4.74.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (4.0 g; 9.22 mmol; see Example 4(a) above) and (S)-(+)-phenylglycinol (1.26 g; 9.22 mmol; 1 eq.) and CH2Cl2 (160 mL). The reaction mixture was stirred overnight and then washed with saturated aqueous KHSO4, saturated aqueous Na2CO3, brine, dried with Na2SO4, filtered and concentrated to dryness. The residue was triturated with ether to obtain 3.8 g of the sub-title compound as a white solid. Prepared washed with saturated aqueous KHSO4, saturated aqueous Na2CO3, brine dried with Na2SO4 filtered concentrated to dryness The residue was triturated with ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S)-1-Phenyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1-phenylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-3-isobutyl-1,3-thiazolidine HCl salt.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S)-1-Phenyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1-phenylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-3-isobutyl-1,3-thiazolidine HCl salt.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-chloro-6,7-dimethoxyquinazoline (225 mg, 1 mmol), (S)-2-phenylglycinol (137.2 mg, 1 mmol) and triethylamine (304 mg, 3 mmol) in isopropanol (7 ml) was heated to reflux for about 8 h. Then the mixture was evaporated under vacuum to dryness and the residue purified by gradient elution chromatography on silica gel using as eluant dichloromethane/ethanol 2-6%. Thus pure title compound was obtained in 70% yield (228 mg). to reflux for about 8 h Then the mixture was evaporated under vacuum to dryness the residue purified by gradient elution chromatography on silica gel using as eluant dichloromethane/ethanol 2-6%

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-Phenylglycinol (28.9 g) was added in two portions to a solution of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (40 g) and N,N-di-iso-propylethylamine (48.9 ml) in THF (500 ml) under nitrogen. After 4 h the resulting white precipitate was removed by filtration and the mother liquor concentrated in vacuo to give an orange oil. Acetonitrile (40 ml) was added and then removed in vacuo to give a light orange solid which was pulverised and triturated with cold acetonitrile (50 ml). The resulting solid was collected by filtration and washed with acetonitrile (2×30 ml) to give the title compound (38.5 g) as a white solid. After 4 h the resulting white precipitate was removed by filtration the mother liquor concentrated in vacuo to give an orange oil removed in vacuo to give a light orange solid which triturated with cold acetonitrile (50 ml) The resulting solid was collected by filtration washed with acetonitrile (2×30 ml)