methyl 3-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:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methanesulfonyl chloride (4.7 ml, 60 mmol) in 25 ml of CH2Cl2 was added dropwise with stirring to a solution of methyl 3-hydroxycyclopentanecarboxylate (6.5 g, 45 mmol) and triethylamine (9.0 ml, 65 mmol) in CH2Cl2 (65 ml) at 0° C. The solution was stirred at 23° C. for 24 h and then washed with water (3×50 ml). The washes were extracted with CH2Cl2 and the combined organic extracts were dried, treated with charcoal and filtered. The solvent was evaporated in vacuo to give the title compound as a yellow liquid, 9.1 g (91% yield), and as a mixture of isomers: ir (liq.) νmax : 1730 cm-1 : 1Hmr (CDCl3) δ: 5.13 (m, 1H, H-3), 3.68 (2×s, 3H, CO2Me), 3.00 (s, 3H, SO3Me), 2.8 (m, 1H, H-1) and 2.4-1.7 ppm (m, 6H, CH2). washed with water (3×50 ml) The washes were extracted with CH2Cl2 the combined organic extracts were dried treated with charcoal filtered The solvent was evaporated in vacuo

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 3-oxocyclopentanecarboxylate (9.58 g, 67.5 mmol) in THF (100 ml) was added to a slurry of sodium borohydride (3.8 g, 100 mmol) in THF (100 ml). The mixture was stirred at 23° C. for 2 h, cooled to 0° C. and acidified to pH 6 with 1M hydrochloric acid. The mixture was extracted with EtOAc (2×100 ml) and the organic extracts were washed with water and saturated sodium chloride (100 ml each). The extracts were dried and the solvent was evaporated in vacuo to give the title compound as a colorless liquid, 6.66 g (68% yield), (a mixture of two isomers); ir (liq.) νmax : 3450, 1725 cm-1 : 1Hmr (CDCl3) δ: 4.30 (m, 1H, H-3), 3.70-3.67 (2×s, 3H, OMe), 2.9 (m, 1H, H-1), 2.8 (s, 1 H, OH) and 2.3-1.6 ppm (m, 6H, CH2). cooled to 0° C. The mixture was extracted with EtOAc (2×100 ml) the organic extracts were washed with water and saturated sodium chloride (100 ml each) The extracts were dried the solvent was evaporated in vacuo

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

Procedure: A solution of methyl 3-hydroxycyclopentanecarboxylate A-11 (500.0 mg, 3.00 mmol) in anhydrous toluene (10.0 mL) was added to a solution of 5-bromopyridin-2-ol (522.0 mg, 3.00 mmol) in anhydrous toluene (10.0 mL) at room temperature. Diisopropyl azodicarboxylate (1.57 g, 6.00 mmol) was then added dropwise, and the yellow-orange solution was stirred at room temperature for 12 h. The reaction mixture was then quenched with methanol (1.0 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give methyl 3-(5-bromopyridin-2-yloxy)cyclopentane carboxylate A-12 (462.0 mg, Yield=51%). MS (ESI), [M+Na]+ 321, 323. The reaction mixture was then quenched with methanol (1.0 mL) concentrated to dryness under reduced pressure The residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient)

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

Procedure: A solution of methyl 3-hydroxycyclopentanecarboxylate A-11 (500.0 mg, 3.00 mmol) in anhydrous toluene (10.0 mL) was added to a solution of 5-bromopyridin-2-ol (522.0 mg, 3.00 mmol) in anhydrous toluene (10.0 mL) at room temperature. Diisopropyl azodicarboxylate (1.57 g, 6.00 mmol) was then added dropwise, and the yellow-orange solution was stirred at room temperature for 12 h. The reaction mixture was then quenched with methanol (1.0 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give methyl 3-(5-bromopyridin-2-yloxy)cyclopentane carboxylate A-12 (462.0 mg, Yield=51%). MS (ESI), [M+Na]+ 321, 323. The reaction mixture was then quenched with methanol (1.0 mL) concentrated to dryness under reduced pressure The residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient)

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

Procedure: Sodium borohydride (442.6 mg, 11.70 mmol) was added portionwise to a solution of methyl 3-oxocyclopentane-carboxylate A-10 (1.66 g, 11.70 mmol) in absolute ethanol (42.0 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 90 mins, then quenched slowly with a 1 N aqueous solution of hydrogen chloride (10 mL), and concentrated to ca. 15 mL under reduced pressure. The aqueous layer was extracted with methylene chloride (3×50 mL); the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give crude methyl 3-hydroxycyclopentanecarboxylate A-11 as a yellow oil (1.33 g, Yield=79%). This material was used for next step without purification. MS (ESI), [M+1]+ 145. at 0° C quenched slowly with a 1 N aqueous solution of hydrogen chloride (10 mL) concentrated to ca. 15 mL under reduced pressure The aqueous layer was extracted with methylene chloride (3×50 mL) the combined extracts were dried over anhydrous magnesium sulfate filtered concentrated to dryness under reduced pressure

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methanesulfonyl chloride (4.7 ml, 60 mmol) in 25 ml of CH2Cl2 was added dropwise with stirring to a solution of methyl 3-hydroxycyclopentanecarboxylate (6.5 g, 45 mmol) and triethylamine (9.0 ml, 65 mmol) in CH2Cl2 (65 ml) at 0° C. The solution was stirred at 23° C. for 24 h and then washed with water (3×50 ml). The washes were extracted with CH2Cl2 and the combined organic extracts were dried, treated with charcoal and filtered. The solvent was evaporated in vacuo to give the title compound as a yellow liquid, 9.1 g (91% yield), and as a mixture of isomers: ir (liq.) νmax : 1730 cm-1 : 1Hmr (CDCl3) δ: 5.13 (m, 1H, H-3), 3.68 (2×s, 3H, CO2Me), 3.00 (s, 3H, SO3Me), 2.8 (m, 1H, H-1) and 2.4-1.7 ppm (m, 6H, CH2). washed with water (3×50 ml) The washes were extracted with CH2Cl2 the combined organic extracts were dried treated with charcoal filtered The solvent was evaporated in vacuo

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 3-oxocyclopentanecarboxylate (9.58 g, 67.5 mmol) in THF (100 ml) was added to a slurry of sodium borohydride (3.8 g, 100 mmol) in THF (100 ml). The mixture was stirred at 23° C. for 2 h, cooled to 0° C. and acidified to pH 6 with 1M hydrochloric acid. The mixture was extracted with EtOAc (2×100 ml) and the organic extracts were washed with water and saturated sodium chloride (100 ml each). The extracts were dried and the solvent was evaporated in vacuo to give the title compound as a colorless liquid, 6.66 g (68% yield), (a mixture of two isomers); ir (liq.) νmax : 3450, 1725 cm-1 : 1Hmr (CDCl3) δ: 4.30 (m, 1H, H-3), 3.70-3.67 (2×s, 3H, OMe), 2.9 (m, 1H, H-1), 2.8 (s, 1 H, OH) and 2.3-1.6 ppm (m, 6H, CH2). cooled to 0° C. The mixture was extracted with EtOAc (2×100 ml) the organic extracts were washed with water and saturated sodium chloride (100 ml each) The extracts were dried the solvent was evaporated in vacuo

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 3-oxocyclopentanecarboxylate (9.58 g, 67.5 mmol) in THF (100 ml) was added to a slurry of sodium borohydride (3.8 g, 100 mmol) in THF (100 ml). The mixture was stirred at 23° C. for 2 h, cooled to 0° C. and acidified to pH 6 with 1M hydrochloric acid. The mixture was extracted with EtOAc (2×100 ml) and the organic extracts were washed with water and saturated sodium chloride (100 ml each). The extracts were dried and the solvent was evaporated in vacuo to give the title compound as a colorless liquid, 6.66 g (68% yield), (a mixture of two isomers); ir (liq.) νmax : 3450, 1725 cm-1 : 1Hmr (CDCl3) δ: 4.30 (m, 1H, H-3), 3.70-3.67 (2×s, 3H, OMe), 2.9 (m, 1H, H-1), 2.8 (s, 1 H, OH) and 2.3-1.6 ppm (m, 6H, CH2). cooled to 0° C. The mixture was extracted with EtOAc (2×100 ml) the organic extracts were washed with water and saturated sodium chloride (100 ml each) The extracts were dried the solvent was evaporated in vacuo