ethyl 2-ethyl-4-hydroxycyclopentane-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A mixture of copper (I) chloride (0.136 g, 1.37 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.854 g, 1.37 mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was stirred at ambient temperature for about 15 min then cooled to about 5° C. and polymethylhydrosiloxane (12 mL, 55 mmol) was added. The reaction mixture was stirred for about 40 min at about 5° C. then cooled to about −12° C. A solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g, 27.4 mmol) and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added in one portion and the reaction mixture was stirred for about 16 h at about −12° C. The reaction mixture was quenched by the addition of MeOH (50 mL). The solvents were removed under reduced pressure. The residue was dissolved in MeOH (35 mL) and filtered through a pad of Celite®. The filtrate was concd under reduced pressure and the residue was triturated with EtOAc (100 mL) and filtered. The filtrate was concd under reduced pressure and the residue was purified using silica gel chromatography eluting with a gradient of 0-10% EtOAc in heptane to give a scalemic mixture enriched with (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%): 1H NMR (CDCl3) δ 4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td, J=2.1, 7.1 Hz, 1H), 2.40 (dt, J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m, 3H), 1.52-1.31 (m, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H). then cooled to about 5° C. The reaction mixture was stirred for about 40 min at about 5° C. then cooled to about −12° C the reaction mixture was stirred for about 16 h at about −12° C The reaction mixture was quenched by the addition of MeOH (50 mL) The solvents were removed under reduced pressure The residue was dissolved in MeOH (35 mL) filtered through a pad of Celite® the residue was triturated with EtOAc (100 mL) filtered the residue was purified eluting with a gradient of 0-10% EtOAc in heptane to give a scalemic mixture

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

Procedure: A 2 L flask was charged with freshly ground sodium hydroxide (9.55 g, 239 mmol). Ethanol (500 mL) was added and the mixture was stirred until all solid went into solution. A solution of a scalemic mixture enriched in (1R,3S,4R)-3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate (16.02 g, 47.8 mmol) in ethanol (120 mL) was added through an additional funnel. The reaction mixture was stirred at ambient temperature overnight. The solid was filtered off while washing with DCM (100 mL). Saturated aqueous NaHCO3 (800 mL) was added to the filtrate and mixture was stirred for about 30 min. The solid formed was filtered off while washing with DCM (500 mL). The filtrate was washed with saturated aqueous NaHCO3 (2×200 mL) and brine (300 mL). The organic layer was dried over anhydrous MgSO4, filtered and concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 0-60% EtOAc in DCM to give a scalemic mixture enriched in (1S,2R,4R)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (5.49 g, 62%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.53 (m, 1H), 4.11 (m, 2H), 3.09 (m 1H), 2.40 (m, 1H), 2.28 (m, 1H), 1.80 (m, 1H), 1.68 (m, 1H), 1.44 (m, 2H), 1.26 (t, 3H), 1.18 (m, 1H), 0.92 (t, 3H). was added through an additional funnel The reaction mixture was stirred at ambient temperature overnight The solid was filtered off while washing with DCM (100 mL) Saturated aqueous NaHCO3 (800 mL) was added to the filtrate and mixture was stirred for about 30 min The solid formed was filtered off while washing with DCM (500 mL) The filtrate was washed with saturated aqueous NaHCO3 (2×200 mL) and brine (300 mL) The organic layer was dried over anhydrous MgSO4 filtered The residue was purified eluting with 0-60% EtOAc in DCM to give a scalemic mixture

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

Procedure: A mixture of copper (I) chloride (0.136 g, 1.37 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.854 g, 1.37 mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was stirred at ambient temperature for about 15 min then cooled to about 5° C. and polymethylhydrosiloxane (12 mL, 55 mmol) was added. The reaction mixture was stirred for about 40 min at about 5° C. then cooled to about −12° C. A solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g, 27.4 mmol) and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added in one portion and the reaction mixture was stirred for about 16 h at about −12° C. The reaction mixture was quenched by the addition of MeOH (50 mL). The solvents were removed under reduced pressure. The residue was dissolved in MeOH (35 mL) and filtered through a pad of Celite®. The filtrate was concd under reduced pressure and the residue was triturated with EtOAc (100 mL) and filtered. The filtrate was concd under reduced pressure and the residue was purified using silica gel chromatography (280 g) eluting with a gradient of 0-10% EtOAc in heptane to give a scalemic mixture enriched with (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%): 1H NMR (CDCl3) δ 4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td, J=2.1, 7.1 Hz, 1H), 2.40 (dt, J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m, 3H), 1.52-1.31 (m, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H). then cooled to about 5° C. The reaction mixture was stirred for about 40 min at about 5° C. then cooled to about −12° C the reaction mixture was stirred for about 16 h at about −12° C The reaction mixture was quenched by the addition of MeOH (50 mL) The solvents were removed under reduced pressure The residue was dissolved in MeOH (35 mL) filtered through a pad of Celite® the residue was triturated with EtOAc (100 mL) filtered the residue was purified eluting with a gradient of 0-10% EtOAc in heptane to give a scalemic mixture

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

Procedure: To a solution of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (10.0 g, 53.7 mmol) in DMF (18 mL) was added TBDMS-Cl (9.72 g, 64.5 mmol) and imidazole (9.15 g, 134 mmol). The reaction mixture was stirred at ambient temperature for about 3 h. Heptane (50 mL) was added to the reaction and the layers were separated. The bottom layer was extracted with heptane (2×30 mL). The combined organic extracts were washed with water (2×30 mL), brine (30 mL), dried over anhydrous MgSO4, filtered and concd to give ethyl 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (15.87 g, 52.8 mmol, 98%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.13 (m, 3H), 2.79 (m, 1H), 2.09 (m, 1H), 1.99 (m, 3H), 1.50-1.24 (m, 6H), 0.89 (m, 12H), 0.05 (s, 6H). the layers were separated The bottom layer was extracted with heptane (2×30 mL) The combined organic extracts were washed with water (2×30 mL), brine (30 mL) dried over anhydrous MgSO4 filtered

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

Procedure: To a solution of ethyl 2-ethyl-4-oxocyclopentanecarboxylate (12.82 g, 69.6 mmol, 86% ee, predominantly 1S,2R) in MeOH (183 mL) was added sodium borohydride (3.29 g, 87 mmol) portion-wise. The suspension was stirred at ambient temperature for about 16 h. Saturated aqueous NH4Cl (200 mL) was added and the reaction was stirred for about 3 h. The white precipitate that formed was filtered and washed with Et2O (100 mL). The filtrate was poured into Et2O (300 mL). The solid was filtered and washed with Et2O (50 mL). The layers were separated and the aqueous layer was extracted with Et2O (2×150 mL). The combined organic layers were washed with brine (2×150 mL), dried over anhydrous MgSO4, filtered and concd under reduce pressure (keeping bath temperature about 25° C. and vacuum >50 psi) to give a crude product as a thick light yellow oil. The oil was washed with pentane (5×80 mL). The combined pentane layers were dried over anhydrous MgSO4, filtered and concd to give an oil which was purified by silica gel chromatography using 1:1 EtOAc:pentane to give ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate as a scalemic mixture of diastereomers predominantly (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (12.38 g, 96%) as a clear oil; 1H NMR (400 MHz, CDCl3) δ 4.34-4.25 (m, 1H), 4.23-4.09 (m, 2H), 3.43-3.17 (m, 1H), 2.88 (td, J=7.1, 2.2, 1H), 2.40 (dt, J=14.0, 7.8, 1H), 2.09-1.91 (m, 3H), 1.33-1.24 (m, 4H), 0.95 (t, J=7.4, 3H). the reaction was stirred for about 3 h The white precipitate that formed was filtered washed with Et2O (100 mL) The filtrate was poured into Et2O (300 mL) The solid was filtered washed with Et2O (50 mL) The layers were separated the aqueous layer was extracted with Et2O (2×150 mL) The combined organic layers were washed with brine (2×150 mL) dried over anhydrous MgSO4 filtered pressure (keeping bath temperature about 25° C. and vacuum >50 psi) to give a crude product as a thick light yellow oil The oil was washed with pentane (5×80 mL) The combined pentane layers were dried over anhydrous MgSO4 filtered to give an oil which was purified by silica gel chromatography

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

Procedure: To ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (3.52 g, 18.9 mmol, Preparation #P.1) in DCM (21 mL) at about 0° C. was added aqueous potassium hydroxide (50%, 21 mL, 189 mmol), tetrabutylammonium hydrogen sulfate (0.64 g, 1.891 mmol) and 2,2,2-trichloroacetonitrile (9.5 mL, 95 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for about 14 h. The layers were separated and the aqueous layer was extracted with DCM (4×60 mL). The combined organic layers were washed with water (2×50 mL), brine (60 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 15-50% EtOAc in heptane to afford ethyl 2-ethyl-4-(2,2,2-trichloro-1-iminoethoxy)cyclopentanecarboxylate (2.80 g, 45%) as a colorless oil: LC/MS (Table 1, Method b) Rt=2.91 min; MS m/z: 330 (M+H)+. The layers were separated the aqueous layer was extracted with DCM (4×60 mL) The combined organic layers were washed with water (2×50 mL), brine (60 mL) dried over anhydrous MgSO4 filtered The material was purified by silica gel chromatography eluting with a gradient of 15-50% EtOAc in heptane