(2R)-2-amino-2-phenylethanol

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

Procedure: This was prepared from R-(−)-2-phenylglycinol and cis-1,4-dichloro-2-butene in 58% yield according to the procedures similar to those described in Preparation 1. those described in Preparation 1

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

Procedure: A solution of (R)-(-)-phenylglycinol (2.20 g, 16.1 mmol) and (3R)-N-tert-butyloxycarbonyl-3-methylsulphonyloxymethylpyrrolidine (Intermediate 1 part b; 1.0 g, 3.58 mmol), in toluene (20 ml), was heated at 150° C. for 6 h in a sealed pressure tube (Aldrich). The solvent was then removed under vacuum and the residue taken up into ethyl acetate (200 ml) and washed with water (×4). The organic was dried (MgSO4) and evaporated and the crude product chromatographed on silica gel eluting with CH2Cl2 /MeOH (97:3) to give the title-α-(hydroxymethyl) benzylaminomethylpyrrolidine (1.0 g, 87%), δ (360 MHz,CDCl3) 1.45 (9H, s, OC(Me)3), 1.52-2.60 (5H, m, CH2 and CH), 2.90-3.76 (7H, m, 3 of CH2 and CH), 7.25-7.39 (5H, m, Ar--H). The solvent was then removed under vacuum washed with water (×4) The organic was dried (MgSO4) evaporated the crude product chromatographed on silica gel eluting with CH2Cl2 /MeOH (97:3)

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

Procedure: (R)-(-)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone was synthesized in an analogous manner used for the production of (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (R)-(-)-Phenylglycinol was used to resolve the methyl (R)-(-)-2-(4-isobutylphenyl)propionate enantiomer, of which 1.2 g, (5 mmol) was converted into 190 mg (15% yield) of (R)-(-)-3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a white crystalline material: mp 180-181° C. dec. (CHCl3 /hexanes); [α]25D -137° (c=1.27; 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, 68.52; H, 7.01. (R)-(-)-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: Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (5.0 g; 11.5 mmol; see Example 4(a) above), (R)-(-)-phenylglycinol (1.58 g; 11.5 mmol) and 160 mL of CH2Cl2, yielding 3.9 g of the sub-title compound as a white solid. Prepared

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

Procedure: A suspension mixture of (R)-(-)-2-phenylglycinol(686 mg, 5 mmol), 1,5-dibromopentane (0.82 ml, 6 mmol), and K2CO3 (1.38 g, 10 mmol) in ethanol (15 ml) was refluxed with stirring for 23 h. After cooling down to rt, the white solid was removed by filtration and the filtrate was concentrated to give white solid oil mixture. This was suspended in CH2Cl2 (30 ml), washed with water and saturated NaHCO3 aqueous solution, dried (Na2SO4), and concentrated to give 1.42 g of clear yellow oil. This was purified by column chromatography (silica gel: 50 g, CH2Cl1 /MeOH:30/1 to 20/1) to afford 955 mg (93%) of desired compound as clear light yellow oil. was refluxed the white solid was removed by filtration the filtrate was concentrated to give white solid oil mixture washed with water and saturated NaHCO3 aqueous solution dried (Na2SO4) concentrated

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

Procedure: Compound 70 was prepared according to the procedure described for the synthesis of compound 37 by replacing tert-leucine methylamide with (R)-2-amino-2-phenylethanol. LCMS (+ESI) m/z=431.2 [M+H]+.

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

Procedure: Compound 70 was prepared according to the procedure described for the synthesis of compound 37 by replacing tert-leucine methylamide with (R)-2-amino-2-phenylethanol. LCMS (+ESI) m/z=431.2 [M+H]+.

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

Procedure: To a solution of monomethyl fumarate (3.0 g, 23 mmol) in ethyl acetate (40 mL) was added 1-hydroxybenzotriazole hydrate (3.0 g, 22 mmol), followed by N,N'-dicyclohexylcarbodiimide (4.5 g, 22 mmol) and the reaction stirred at ambient temperature for 1 hour. The solid was filtered off and discarded. To the filtrate was added (R)-α-phenylglycinol (3.0 g, 22 mmol ) and stirring continued for 20 minutes. The volatiles were removed in vacuo (40° C.) and the residue purified by flash chromatography on normal phase silica gel using hexane: ethyl acetate (1:1) as eluant. Recovered 2.5 g (46%) of (18) as a white solid, m.p. 75°-77° C.; IR (neat) 3250 (OH), 1729 (C=O ester), 1666 (C=O amide), 1640 (C=C)cm-1 ;NMR (CDCl3) δ 7.3-7.4 (5H, m, Ph), 7.0 (1H, d, J 15 Hz, trans alkene), 6.8 (1H, d, J 15 Hz, trans alkene), 6.6 (1H, br d, NH), 5.2 (1H, m, CH), 3.9 (2H, t, J 3 Hz, CH2), 3.8 (3H, s, CH3), 2.3 (1H, t, J 5 Hz, OH); [α]D -53° (CHCl3, 24° C., c=1); anal C13H15NO4 ; requires C 62.64% H 6.07% N 5.62%; found C 62.72% H 5.92% N 5.48%. The solid was filtered off stirring continued for 20 minutes The volatiles were removed in vacuo (40° C.) the residue purified by flash chromatography on normal phase silica gel Recovered 2.5 g (46%) of (18) as a white solid, m.p. 75°-77° C. [α]D -53° (CHCl3, 24° C., c=1)

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

Procedure: To a solution of (R)-2-amino-2-phenyl-ethanol (0.5 g, 3.64 mmol) in 2-propanol (40 mL) were added sodium carbonate (1 g, 9.48 mmol), 1,4-dibromobutane (0.57 mL, 4.74 mmol) and potassium iodide (catalytic) in succession, and the mixture was refluxed overnight. After filtration, the solvent was removed under reduced pressure and the crude was used without further purification (0.53 g, 76%). LCMS method: 2, RT: 2.27 min; MI: 191-193 [M+1]. the mixture was refluxed overnight After filtration the solvent was removed under reduced pressure the crude was used without further purification (0.53 g, 76%)

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

Procedure: (R)-(−)-2-Phenylglycinol (5.043 g, 36.8 mmol) was placed in a 250-mL RBF and placed under a nitrogen atmosphere. DMF (100 mL) was added and the reaction was stirred until a clear, colourless solution resulted. NaH (2.206 g, 55.1 mmol) was then added, followed by DMF (10 mL) as a wash, producing a vigorous reaction (gas evolution). The reaction was stirred at room temperature until the gas evolution had subsided, leaving a reddish heterogeneous mixture. 5-Fluoro-2-nitroaniline (6.89 g, 44.1 mmol) was then added, followed by DMF (10 mL), which immediately produced a bright red colour. The reaction was left stirring at room temperature and monitored by LC-MS. The reaction was quenched by its addition to an Erlenmeyer flask containing ethyl acetate (200 mL) and dilute aqueous NaHCO3 (250 mL). The phases were separated in a separatory funnel, and the organic layer was washed with water (150 mL), then brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The reaction was then purified by silica gel column (5-75% EtOAc in n-heptane), yielding two fractions of high purity 5-[(2R)-2-amino-2-phenylethoxy]-2-nitroaniline, both contaminated with residual DMF, as a yellow-orange oil. LRMS (ESI) calc'd for (C14H16N3O3) [M+H]+, 274.1; found 274.1. resulted producing a vigorous reaction (gas evolution) The reaction was stirred at room temperature until the gas evolution leaving a reddish heterogeneous mixture immediately produced a bright red colour The reaction was left stirring at room temperature The reaction was quenched by its addition to an Erlenmeyer flask containing ethyl acetate (200 mL) and dilute aqueous NaHCO3 (250 mL) The phases were separated in a separatory funnel the organic layer was washed with water (150 mL) brine (100 mL), dried over anhydrous Na2SO4 concentrated in vacuo The reaction was then purified by silica gel column (5-75% EtOAc in n-heptane)

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

Procedure: (R)-(−)-2-Phenylglycinol (5.043 g, 36.8 mmol) was placed in a 250-mL RBF and placed under a nitrogen atmosphere. DMF (100 mL) was added and the reaction was stirred until a clear, colourless solution resulted. NaH (2.206 g, 55.1 mmol) was then added, followed by DMF (10 mL) as a wash, producing a vigorous reaction (gas evolution). The reaction was stirred at room temperature until the gas evolution had subsided, leaving a reddish heterogeneous mixture. 5-Fluoro-2-nitroaniline (6.89 g, 44.1 mmol) was then added, followed by DMF (10 mL), which immediately produced a bright red colour. The reaction was left stirring at room temperature and monitored by LC-MS. The reaction was quenched by its addition to an Erlenmeyer flask containing ethyl acetate (200 mL) and dilute aqueous NaHCO3 (250 mL). The phases were separated in a separatory funnel, and the organic layer was washed with water (150 mL), then brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The reaction was then purified by silica gel column (5-75% EtOAc in n-heptane), yielding two fractions of high purity 5-[(2R)-2-amino-2-phenylethoxy]-2-nitroaniline, both contaminated with residual DMF, as a yellow-orange oil. LRMS (ESI) calc'd for (C14H16N3O3) [M+H]+, 274.1; found 274.1. resulted producing a vigorous reaction (gas evolution) The reaction was stirred at room temperature until the gas evolution leaving a reddish heterogeneous mixture immediately produced a bright red colour The reaction was left stirring at room temperature The reaction was quenched by its addition to an Erlenmeyer flask containing ethyl acetate (200 mL) and dilute aqueous NaHCO3 (250 mL) The phases were separated in a separatory funnel the organic layer was washed with water (150 mL) brine (100 mL), dried over anhydrous Na2SO4 concentrated in vacuo The reaction was then purified by silica gel column (5-75% EtOAc in n-heptane)

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

Procedure: 7.54 g (55 mmol) of (2R)-(-)-2-amino-2-phenylethanol are dissolved in 8 ml (61 mmol) of diethyl carbonate, 770 mg (5.5 mmol) of K2CO3 are added, and ethanol is removed by distillation via a column. The crude product is recrystallized from ether/petroleum ether. ethanol is removed by distillation via a column The crude product is recrystallized from ether/petroleum ether