(1R)-1-phenylpropan-1-ol

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.7 g) was dissolved in 10 mL dry THF and 1320 mg triphenylphosphine and 691 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 minutes, then 992 μL DIAD was added dropwise. The reaction was stirred at room temperature for 3 hours and was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc). The resulting residue was dissolved in 20 mL dry DMF, then 526 μL mercaptoacetic acid and 2.5 mL DBU were added at room temperature. The reaction was stirred for 30 minutes and was partitioned between saturated aqueous NaHCO3 and diethyl ether. The aqueous layer was washed again with diethyl ether and the organic layers were combined. The organic layer was washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc (first column)) and (hexanes to 1:1 DCM-hexanes to DCM to 9:1 DCM-EtOAc (second column)) to give 1.05 g of the product after drying. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.45 (d, 1H), 7.35 (m, 2H), 7.27-7.19 (m, 4H), 7.12 (m, 2H), 6.98 (m, 2H), 6.83 (d, 1H), 6.66 (d, 1H), 6.58 (m, 1H), 5.12-5.08 (m, 3H), 4.30 (m, 1H), 4.00 (m, 1H), 3.66 (s, 3H), 3.42 (m, 1H), 3.23 (m, 1H), 2.77 (m, 2H), 1.7-1.5 (m, 2H), 0.78 (t, 3H). LCMS: m/z 607. The reaction was stirred at room temperature for 3 hours was evaporated The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc) The resulting residue was dissolved in 20 mL dry DMF 526 μL mercaptoacetic acid and 2.5 mL DBU were added at room temperature The reaction was stirred for 30 minutes was partitioned between saturated aqueous NaHCO3 and diethyl ether The aqueous layer was washed again with diethyl ether The organic layer was washed with aqueous NaHCO3 dried over Na2SO4 evaporated The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc (first column)) and (hexanes to 1:1 DCM-hexanes to DCM to 9:1 DCM-EtOAc (second column))

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (0.37 g) was dissolved in 2 mL dry THF and triphenylphosphine (0.29 g) and (R)-(+)-1-phenyl-1-propanol (0.15 g) were added. The mixture was stirred at 0° C. for 10 min, then DIAD 933 μL (0.22 g, 1.1 mmol) was added over 2 minutes. The reaction stirred at room temperature for 5 hours, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give (S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-[(4-nitro-benzenesulfonyl)-((S)-1-phenyl-propyl)-amino]-propionic acid methyl ester (0.42 g). This material was dissolved in DMF (0.7 mL), and then mercapto acetic acid (0.15 g) and DBU (0.48 g) were added and stirred at room temperature for 2 hours. The reaction was quenched by addition of NaHCO3 solution (4 mL) and product was extracted with ether. The ether layer was washed with water and brine, and then dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column (5% EtOAc in hexanes to 15% EtOAc in hexanes) to get pure (S)-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (0.2 g). LCMS (m/z): 607. The reaction stirred at room temperature for 5 hours was evaporated The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-[(S)-2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (230 mg) was dissolved in 4 mL dry THF and 262 mg triphenylphosphine and 136 mg (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 min, then 200 μL DIAD was added over 2 min. The reaction stirred at rt for 5 h, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 270 mg desired product LCMS (m/z): 676. The reaction stirred at rt for 5 h was evaporated The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.6 g) was dissolved in 4 mL dry THF and 1247 mg triphenylphosphine and 650 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 min, then 933 μL DIAD was added over 2 min. The reaction stirred at rt for 5 h, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 1.8 g desired product after drying. 1H NMR (400 MHz, acetone-d6): 8.35 (m, 2H), 7.96 (m, 2H), 7.72 (d, 1H), 7.62 (d, 1H), 7.51-7.42 (m, 3H), 7.29 (m, 5H), 7.10 (m, 2H), 6.88-6.80 (m, 3H), 5.21 (s, 2H), 5.11 (m, 1H), 4.82 (m, 1H), 4.45 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.49 (m, 1H), 3.35 (s, 3H), 3.04 (m, 1H), 2.31 (m, 1H), 1.81 (m, 1H), 0.77 (t, 3H). The reaction stirred at rt for 5 h was evaporated The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc)

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

Procedure: Reaction of benzaldehyde with diethylzinc in the presence of (R)-3,3'-bis(2",5"-dihexyloxyphenyl)-1,1'-bi-2-naphthol to give (R)-1-phenyl-1-propanol. (R)-3,3'-bis(2",5"-dihexyloxyphenyl)-1,1'-bi-2-naphthol (42 mg, 0.05 mmol) and diethylzinc (0.21 mL, 2 mmol) were added to a Schlenk flask containing toluene (10 mL, dried with Na and degassed with N2) , under nitrogen and at room temperature, to form the organozinc species. The resulting mixture was stirred at r.t. for ca. 15 min. The flask was cooled to 0° C. and benzaldehyde (0.1 mL, 1 mmol) was then added dropwise. The yellow color of the mixture faded in 4 hours, which indicated the completion of the reaction. 1N HCl was added to quench the reaction at 0° C. and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine until pH=7 and then dried over anhydrous Na2SO4. The purification by column chromatography on silica gel with EtOAc/hexanes (1:5) gave (R)-1-phenylpropanol as a colorless liquid (129 mg, 95%). HPLC analysis on a Chiracel-OD column (eluent: isopropanol/hexane=1/9; 1 mL/min) indicated an ee of 99.3%. The retention time of the (R)-isomer is 7.45 min and (S)-isomer is 8.8 min. 1H NMR (270 MHz, CDCl3): 0.90 (t, J=7.5, 3H), 1.74 (m, 2H), 2.73 (s, 1H), 4.52 (t, J=6.5, 1H), 7.23-7.38 (m, 5H).

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

Procedure: Reaction of benzaldehyde with diethylzinc in the presence of the polymer of Example 6 to give (R)-1-phenyl-1-propanol. The polymer of Example 6 (Mw=24,300 and Mn=9900, PDI=2.45) was used to catalyze the addition reaction of diethylzinc to an aldehyde according to the procedure of Example 4. For benzaldehyde, the yield was 90% with ee of 92.7% ((R) product). For p-chloro-benzaldehyde, the yield was 95% with ee of 93.8% ((R) product).

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

Procedure: Reaction of benzaldehyde with diethylzinc in the presence of the polymer of Example 2 to give (R)-1-phenyl-1-propanol. The polymer of Example 2 (28.6 mg, 0.1 mmol based on the 2,2'-substituted biphenyl subunit) and diethylzinc (0.42 mL, 4 mmol) were added to a Schlenk flask containing degassed dry dichloromethane (10 mL), to form an organozinc species. The resulting mixture was stirred at r.t. for 2.5 h. Benzaldehyde (0.2 mL, 2 mmol) was then added and the reaction mixture was stirred at r.t. for 112 h. Water (5 mL) and 1N HCl (5 mL) were added to quench the reaction. The polymer catalyst was filtered off and recovered. The organic layer in the filtrate was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. 1H NMR spectroscopic analysis of this crude product indicated a complete conversion and the ratio of 1-phenyl-1-propanol to benzyl alcohol (a side product) was 53:47. Column chromatography on silica gel (eluent: EtOAc/hexanes=1/4) gave 1-phenyl-1-propanol as a colorless liquid (117 mg, 43%). GC analysis on a chiral column (β-Dex capillary column, Supelco Company) showed an ee of 13%.

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

Procedure: Reaction of benzaldehyde with diethylzinc in the presence of the polymer of Example 1 to give (R)-1-phenyl-1-propanol. The polymer of Example 1 (28 mg, 0.05 mmol based on the 2,2'-substituted biphenyl subunit) and diethylzinc (0.14 mL, 1.3 mmol) were added to a Schlenk flask containing toluene (10 mL) (dried with Na and degassed with N2), under N2 and at room temperature, to form an organozinc species. After ca. 15 min, the flask was cooled to 0° C. and benzaldehyde (0.1 mL, 1 mmol) was added in a dropwise manner. Stirring was continued at this temperature for 10 h. The 1H NMR spectrum of the crude mixture showed 100% conversion with no side product. The reaction was then quenched at 0° C. with the addition of 1N HCl and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with brine until pH 7 and then dried over anhydrous Na2SO4. Concentration in vacuum gave a pale yellow oil, which upon treatment with MeOH (20 mL) precipitated the polymer. The filtrate was concentrated and purified by column chromatography on silica gel (eluent: EtOAc/hexanes 1/4) to afford (R)-1-phenyl-1-propanol as a colorless liquid (122 mg, 89%). 1H NMR (270 MHz, CDCl3) δ 0.91 (t, J=7.4, 3H), 1.78 (dq, J=7.3, 6.4, 2H), 1.89 (br, 1H), 4.58 (t, J=6.5, 1H), 7.25-7.37 (m, 5H) . [α]D =42.91 (c=2.44, CHCl3). The ee value was determined to be 92.2% on GC with a chiral column (β-Dex capillary column, Supelco Company). The recycled catalyst showed the similar reactivity and the same ee for the product.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.7 g) was dissolved in 10 mL dry THF and 1320 mg triphenylphosphine and 691 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 minutes, then 992 μL DIAD was added dropwise. The reaction was stirred at room temperature for 3 hours and was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc). The resulting residue was dissolved in 20 mL dry DMF, then 526 μL mercaptoacetic acid and 2.5 mL DBU were added at room temperature. The reaction was stirred for 30 minutes and was partitioned between saturated aqueous NaHCO3 and diethyl ether. The aqueous layer was washed again with diethyl ether and the organic layers were combined. The organic layer was washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc (first column)) and (hexanes to 1:1 DCM-hexanes to DCM to 9:1 DCM-EtOAc (second column)) to give 1.05 g of the product after drying. The reaction was stirred at room temperature for 3 hours was evaporated The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc) The resulting residue was dissolved in 20 mL dry DMF 526 μL mercaptoacetic acid and 2.5 mL DBU were added at room temperature The reaction was stirred for 30 minutes was partitioned between saturated aqueous NaHCO3 and diethyl ether The aqueous layer was washed again with diethyl ether The organic layer was washed with aqueous NaHCO3 dried over Na2SO4 evaporated The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc (first column)) and (hexanes to 1:1 DCM-hexanes to DCM to 9:1 DCM-EtOAc (second column))

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (0.37 g) was dissolved in 2 mL dry THF and triphenylphosphine (0.29 g) and (R)-(+)-1-phenyl-1-propanol (0.15 g) were added. The mixture was stirred at 0° C. for 10 min, then DIAD 933 μL (0.22 g, 1.1 mmol) was added over 2 minutes. The reaction stirred at room temperature for 5 hours, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give (S)-3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-[(4-nitro-benzenesulfonyl)-((S)-1-phenyl-propyl)-amino]-propionic acid methyl ester (0.42 g). This material was dissolved in DMF (0.7 mL), and then mercapto acetic acid (0.15 g) and DBU (0.48 g) were added and stirred at room temperature for 2 hours. The reaction was quenched by addition of NaHCO3 solution (4 mL) and product was extracted with ether. The ether layer was washed with water and brine, and then dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column (5% EtOAc in hexanes to 15% EtOAc in hexanes) to get pure (S)-3-{(S)-2-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (0.2 g). LCMS (m/z): 607. The reaction stirred at room temperature for 5 hours was evaporated The residue was purified by silica gel flash chromatography (9:1 to 7:3 hexanes/EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-[(S)-2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (230 mg) was dissolved in 4 mL dry THF and 262 mg triphenylphosphine and 136 mg (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 min, then 200 μL DIAD was added over 2 min. The reaction stirred at rt for 5 h, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 270 mg desired product LCMS (m/z): 676. The reaction stirred at rt for 5 h was evaporated The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.6 g) was dissolved in 4 mL dry THF and 1247 mg triphenylphosphine and 650 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 min, then 933 μL DIAD was added over 2 min. The reaction stirred at rt for 5 h, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 1.8 g desired product after drying. 1H NMR (400 MHz, acetone-d6): 8.35(m, 2H), 7.96 (m, 2H), 7.72 (d, 1H), 7.62 (d, 1H), 7.51-7.42 (m, 3H), 7.29 (m, 5H), 7.10 (m, 2H), 6.88-6.80 (m, 3H), 5.21 (s, 2H), 5.11 (m, 1H), 4.82 (m, 1H), 4.45 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.49 (m, 1H), 3.35 (s, 3H), 3.04 (m, 1H), 2.31 (m, 1H), 1.81 (m, 1H), 0.77 (t, 3H). The reaction stirred at rt for 5 h was evaporated The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc)