9-methoxy-9-oxononanoic acid

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 benzoin (6.00 g, 28 mmol), azelaic acid monomethyl ester (7.17 g of 92% pure material, 32 mmol), 1,3-dicyclohexylcarbodiimide (7.00 g, 34 mmol), 4-dimethylaminopyridine (catalytic amount) and dichloromethane (120 mL) was stirred at room temperature. After 16 hours, the mixture was filtered and the solvent evaporated. Ammonium acetate (10.90 g, 141 mmol) and acetic acid (150 mL) were added to the residue and the mixture heated at reflux for 65 minutes before being cooled and diluted with water. The mixture was extracted with diethyl ether, the combined extracts dried over sodium sulfate and concentrated in vacuo. The residual oil was chromatographed on a column of silica gel using a mixture of hexanes and diethyl ether (7:3) as eluent to give methyl 4,5-diphenyl-2-oxazoleoctanoate (8.24 g, 77%) as an oil. the mixture was filtered the solvent evaporated the mixture heated at reflux for 65 minutes before being cooled The mixture was extracted with diethyl ether the combined extracts dried over sodium sulfate concentrated in vacuo The residual oil was chromatographed on a column of silica gel using a mixture of hexanes and diethyl ether (7:3) as eluent

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

Procedure: A mixture of benzoin (6.00 g, 28 mmol), azelaic acid monomethyl ester (7.17 g of 92% pure material, 32 mmol), 1,3-dicyclohexylcarbodiimide (7.00 g, 34 mmol), 4-dimethylaminopyridine (catalytic amount) and dichloromethane (120 mL) was stirred at room temperature. After 16 hours, the mixture was filtered and the solvent evaporated. Ammonium acetate (10.90 g, 141 mmol) and acetic acid (150 mL) were added to the residue and the mixture heated at reflux for 65 minutes before being cooled and diluted with water. The mixture was extracted with diethyl ether, the combined extracts dried over sodium sulfate and concentrated in vacuo. The residual oil was chromatographed on a column of silica gel using a mixture of hexanes and diethyl ether (7:3) as eluent to give methyl 4,5-diphenyl-2-oxazoleoctanoate (8.24 g, 77%) as an oil. the mixture was filtered the solvent evaporated the mixture heated at reflux for 65 minutes before being cooled The mixture was extracted with diethyl ether the combined extracts dried over sodium sulfate concentrated in vacuo The residual oil was chromatographed on a column of silica gel using a mixture of hexanes and diethyl ether (7:3) as eluent

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

Procedure: To a solution of nonanedioic acid monomethyl ester (4.80 g, 20 mmol) in THF (20 mL) at −20° C. was added a solution of borane-dimethylsulfide in THF (2.0 M, 10 mL) over 10 min. The resulting mixture was stirred for an additional 10 min, and then allowed to stir at room temperature overnight. Aqueous K2CO3 solution was added, and the product was extracted with ethyl ether (3×). The crude product was purified by flash column chromatography (hexane/EtOAc:2/1) to yield 9-hydroxy-nonanoic acid methyl ester 4-B (2.0 g, 55%). to stir at room temperature overnight the product was extracted with ethyl ether (3×) The crude product was purified by flash column chromatography (hexane/EtOAc:2/1)

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

Procedure: To a solution of nonanedioic acid monomethyl ester (4.80 g, 20 mmol) in THF (20 mL) at −20° C. was added a solution of borane-dimethylsulfide in THF (2.0 M, 10 mL) over 10 min. The resulting mixture was stirred for an additional 10 min, and then allowed to stir at room temperature overnight. Aqueous K2CO3 solution was added, and the product was extracted with ethyl ether (3×). The crude product was purified by flash column chromatography (hexane/EtOAc:2/1) to yield 9-hydroxy-nonanoic acid methyl ester 4-B (2.0 g, 55%). to stir at room temperature overnight the product was extracted with ethyl ether (3×) The crude product was purified by flash column chromatography (hexane/EtOAc:2/1)

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

Procedure: To a solution of nonanedioic acid monomethyl ester (4.80 g, 20 mmol) in THF (20 mL) at −20° C. was added a solution of borane-dimethylsulfide in THF (2.0 M, 10 mL) over 10 min. The resulting mixture was stirred for an additional 10 min, and then allowed to stir at room temperature overnight. Aqueous K2CO3 solution was added, and the product was extracted with ethyl ether (3×). The crude product was purified by flash column chromatography (hexane/EtOAc:2/1) to yield 9-hydroxy-nonanoic acid methyl ester 4-B (2.0 g, 55%). to stir at room temperature overnight the product was extracted with ethyl ether (3×) The crude product was purified by flash column chromatography (hexane/EtOAc:2/1)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a separate process, 23.9 g of azelaic monomethylester was dissolved in 30 ml chloroform. Oxalylchloride (15 ml) was added, all at once, and the mixture refluxed 2 hours at 50° C. The mixture was cooled; excess solvent and oxalylchloride were evaporated. After distillation, 25.8 g of CH3OCO(CH2)7COCl was obtained. The mixture was cooled excess solvent and oxalylchloride were evaporated After distillation

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a separate process, 23.9 g of azelaic monomethylester was dissolved in 30 ml chloroform. Oxalylchloride (15 ml) was added, all at once, and the mixture refluxed 2 hours at 50° C. The mixture was cooled; excess solvent and oxalylchloride were evaporated. After distillation, 25.8 g of CH3OCO(CH2)7COCl was obtained. The mixture was cooled excess solvent and oxalylchloride were evaporated After distillation

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

Procedure: A mixture of benzoin (6.00 g, 28 mmol), azelaic acid monomethyl ester (7.17 g of 92% pure material, 32 mmol), 1,3-dicyclohexylcarbodiimide (7.00 g, 34 mmol), 4-dimethylaminopyridine (catalytic amount) and dichloromethane (120 mL) was stirred at room temperature. After 16 hours, the mixture was filtered and the solvent evaporated. Ammonium acetate (10.90 g, 141 mmol) and acetic acid (150 mL) were added to the residue and the mixture heated at reflux for 65 minutes before being cooled and diluted with water. The mixture was extracted with diethyl ether, the combined extracts dried over sodium sulfate and concentrated in vacuo. The residual oil was chromatographed on a column of silica gel using a mixture of hexanes and diethyl ether (7:3) as eluent to give methyl 4,5-diphenyl-2-oxazoleoctanoate (8.24 g, 77%) as an oil. the mixture was filtered the solvent evaporated the mixture heated at reflux for 65 minutes before being cooled The mixture was extracted with diethyl ether the combined extracts dried over sodium sulfate concentrated in vacuo The residual oil was chromatographed on a column of silica gel using a mixture of hexanes and diethyl ether (7:3) as eluent

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

Procedure: To prepare 4, a solution of nonanedioic acid monomethyl ester (3) (923 mg, 4.6 mmol) in dry THF (3 ml) at −20° C. was treated with 1 M BH3 in THF (4.6 ml, 4.6 mmol) over 10 minutes. After stirring at room temperature for 4 hours, the reaction was quenched with 0.77 M aqueous K2CO3 solution (10 ml) at 0° C. The product was extracted with diethyl ether (3×20 ml), washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated in vacuum to afford methyl 9-hydroxynonanoate (4) (Kai K. et al., Tetrahedron 64:6760-69 (2008), which is hereby incorporated by reference in its entirety) (850 mg, 99% yield) as a colorless oil, which was used directly without any further purification. 1H NMR (400 MHz, chloroform-d1): δ 1.27-1.37 (8H, m), 1.50-1.66 (4H, m), 2.29 (2H, t, J=7.5 Hz), 3.62 (2H, t, J=6.5 Hz), 3.66 (3H, s). See FIG. 75C. To prepare 4 the reaction was quenched with 0.77 M aqueous K2CO3 solution (10 ml) at 0° C The product was extracted with diethyl ether (3×20 ml) washed with saturated aqueous NaCl solution dried over Na2SO4 concentrated in vacuum

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

Procedure: To a solution of 165 mL (165 mmol) of a 1.0M solution of boranetetrahydrofuran complex in tetrahydrofuran in 200 mL of dry diethyl ether at 0° C. is added dropwise 25.0 g (123 mmol) of azelaic acid monomethyl ester, added at such a rate as to prevent excessive release of gas and exothermicity. The solution is allowed to warm to room temperature overnight and is worked up by slowly adding water until gas evolution ceases. Then solid potassium carbonate is added and the organic layer is separated. The aqueous layer is extracted three times with diethyl ether. The combined extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 8-carbomethoxyoctan-1-ol as a colorless oil. added at such a rate as the organic layer is separated The aqueous layer is extracted three times with diethyl ether The combined extracts are washed with brine dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: To prepare 4, a solution of nonanedioic acid monomethyl ester (3) (923 mg, 4.6 mmol) in dry THF (3 ml) at −20° C. was treated with 1 M BH3 in THF (4.6 ml, 4.6 mmol) over 10 minutes. After stirring at room temperature for 4 hours, the reaction was quenched with 0.77 M aqueous K2CO3 solution (10 ml) at 0° C. The product was extracted with diethyl ether (3×20 ml), washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated in vacuum to afford methyl 9-hydroxynonanoate (4) (Kai K. et al., Tetrahedron 64:6760-69 (2008), which is hereby incorporated by reference in its entirety) (850 mg, 99% yield) as a colorless oil, which was used directly without any further purification. 1H NMR (400 MHz, chloroform-d1): δ 1.27-1.37 (8H, m), 1.50-1.66 (4H, m), 2.29 (2H, t, J=7.5 Hz), 3.62 (2H, t, J=6.5 Hz), 3.66 (3H, s). See FIG. 75C. To prepare 4 the reaction was quenched with 0.77 M aqueous K2CO3 solution (10 ml) at 0° C The product was extracted with diethyl ether (3×20 ml) washed with saturated aqueous NaCl solution dried over Na2SO4 concentrated in vacuum