methyl (3R)-3-hydroxytetradecanoate

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

Procedure: A 500 ml autoclave was charged in a glove box (O2 content <1 ppm) with 46.2 g (180 mmol) of methyl 3-oxotetradecanoate, 131 ml of methanol and a solution of 2.1 mg (0.0036 mmol) of (R)-MeOBIPHEP and 1.08 mg (0.0018 mmol) of Ru2Cl4 (COD)2 (CH3CN) [Lit.: E. Singleton et al., S. Afr. Tydskr. Chem. 40, 183 (1987)] in 5 ml of dichloromethane. The hydrogenation was effected at 80° C. and 35 bar. The conversion amounted to >99% after 19 hours. The hydrogenation solution was concentrated at 50° C./17 mbar and the crystalline residue was taken up in 500 ml of diethyl ether. In order to separate the catalyst, the ethereal solution was filtered over 100 g of silica gel; e.e.=97.1%. After concentrating and drying the filtered ethereal phase there were obtained 45.8 g of methyl (R)-3-hydroxytetradecanoate as white crystals; e.e.=97.1%. After recrystallization from n-hexane there were obtained 41.9 g of pure methyl (R)-3-hydroxytetradecanoate; m.p. 42°-43° C.; e.e. 99.8%; [α]D20 : -16.4° (c=3.8, CCl4). was effected at 80° C. The hydrogenation solution was concentrated at 50° C./17 mbar In order to separate the catalyst the ethereal solution was filtered over 100 g of silica gel After concentrating drying the filtered ethereal phase there

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

Procedure: To a rapidly-stirred slurry of 1.29 g (4.99 mmol) methyl (R)-3-hydroxytetradecanoate and 0.45 mL (5.2 mmol) bromoacetyl bromide in 25 mL hexanes at 0° C. in a flame-dried flask under N2 was added 0.42 mL (5.2 mmol)pyridine all at once. The mixture was removed from the cold bath for 30 min. The mixture was suction filtered through celite, washing with 75 mL ether. The filtrate was washed with 2×100 mL H2O and with 50 mL 10% NaHCO3. The ether was dried over MgSO4 and removed by rotary evaporation, giving 1.70 g (90%) crude (R)-3-[(bromoacetyl)oxy]tetradecanoic acid methyl ester as a yellow oil. Analytically pure samples could be prepared by subjecting the oil to radial chromatography, eluting with CH2Cl2. The mixture was removed from the cold bath for 30 min filtered through celite washing with 75 mL ether The filtrate was washed with 2×100 mL H2O and with 50 mL 10% NaHCO3 The ether was dried over MgSO4 removed by rotary evaporation

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

Procedure: 98 mg(3.3 mmol)Sodium hydride(80% in mineral oil)was added to a solution of 764 mg (2.96 mmol) methyl(R)-3-hydroxytetradecanoate in 20.0 mL tetrahydrofuran. After 25 minutes, a solution of 732 mg (3.03 mmol) 2-bromooctanoyl chloride in 10.0 mL tetrahydrofuran was added dropwise via syringe to the cloudy offwhite mixture. After 10 minutes at 0° C., the reaction flask was removed from the cold bath for 24 hours. The mixture was poured into 100 mL 10% NaHCO3 and extraction with ether (3×50 mL) was performed. Drying over MgSO4 and removal of the solvent by rotary evaporation gave yellow oil. Purification by flash chromatography (3×24 cm column, 50% CH2Cl2 /hexane) gave 407 mg (30% yield based on methyl (R)-3-hydroxytetradecanoate)(R)-3-[2-bromo-1-oxooctyl)oxy]tetradecanoic acid methyl ester. After 10 minutes at 0° C. the reaction flask was removed from the cold bath for 24 hours The mixture was poured into 100 mL 10% NaHCO3 and extraction with ether (3×50 mL) Drying over MgSO4 and removal of the solvent by rotary evaporation gave yellow oil Purification by flash chromatography (3×24 cm column, 50% CH2Cl2 /hexane)

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

Procedure: To a rapidly-stirred slurry of 5.18 g (20.0 mmol) methyl (R)-3-hydroxytetradecanoate and 5.03 g (20.8 mmol) 2-bromooctanoyl chloride in 100 mL hexanes at 0° C. in a flame-dried flask under N2 was added 1.67 mL (20.6 mmol) pyridine all at once. After stirring for 10 minutes the cloudy white mixture was poured into a separatory funnel containing a mixture of 200 mL tap H2O/100 mL ether. This mixture was shaken and the layers separated. The aqueous layer was extracted with 2×100 mL ethr. The combined ether layers were washed with 200 mL brine, and 3×200 mL H2O. The ether was dried over MgSO4 and removed by rotary evaporation, giving 8.95 g crude product. This yellow oil was dissolved in 30 mL CH2Cl2 and suction filtered through a 1" pad of silica gel 60 in a 60 mL coarse sintered glass funnel, washing with 150 mL CH2Cl2. Rotary evaporation gave 8.10 g (87%) (R)-3-[(2-bromo-1-oxooctyl)oxy]tetradecanoic acid methyl ester as a yellow oil. The oil was found to be suitable for use in the cyclization reaction producing the lactone of Example 5. Analytically pure samples could be prepared by subjecting the oil to radial chromatography, eluting with CH2Cl2. was poured into a separatory funnel containing a mixture of 200 mL This mixture was shaken the layers separated The aqueous layer was extracted with 2×100 mL ethr The combined ether layers were washed with 200 mL brine, and 3×200 mL H2O The ether was dried over MgSO4 removed by rotary evaporation giving 8.95 g crude product suction filtered through a 1" pad of silica gel 60 in a 60 mL coarse sintered glass funnel washing with 150 mL CH2Cl2 Rotary evaporation

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

Procedure: 50 g of methyl (R)-3-hydroxytetradecanoate, 35 g of t-butyldimethylchlorosilane, 6.1 g of 4-dimethylaminopyridine and 29.4 g of triethylamine were dissolved in 200 ml of methylene chloride and stirred at room temperature for 30 hours as well as under reflux for 16 hours. Thereupon, a further 2 g of t-butyldimethylchlorosilane were added. After a further 24 hours under reflux the precipitated triethylamine hydrochloride salt was filtered off, washed with ether and the filtrate was concentrated. The residue was dissolved in ether and washed in sequence with water, 0.5M citric acid, again with water and saturated sodium chloride solution, dried, concentrated and subsequently freed from volatile material at 5° C. in a high vacuum for 5 hours. There were obtained 71.8 g of (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanoic acid, IR (cm-1): 1745, 1254, 895, 776. under reflux for 16 hours was filtered off washed with ether the filtrate was concentrated The residue was dissolved in ether washed in sequence with water, 0.5M citric acid, again with water and saturated sodium chloride solution dried concentrated subsequently freed from volatile material at 5° C. in a high vacuum for 5 hours

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

Procedure: 50 g of methyl (R)-3-hydroxytetradecanoate, 35 g of t-butyldimethylchlorosilane, 6.1 g of 4-dimethylaminopyridine and 29.4 g of triethylamine were dissolved in 200 ml of methylene chloride and stirred at room temperature for 30 hours as well as under reflux for 16 hours. Thereupon, a further 2 g of t-butyldimethylchlorosilane were added. After a further 24 hours under reflux the precipitated triethylamine hydrochloride salt was filtered off, washed with ether and the filtrate was concentrated. The residue was dissolved in ether and washed in sequence with water, 0.5M citric acid, again with water and saturated sodium chloride solution, dried, concentrated and subsequently freed from volatile material at 5° C. in a high vacuum for 5 hours. There were obtained 71.8 g of (R)-3-[(1,1-dimethylethyl)dimethylsilyloxy]tetradecanoic acid, IR (cm-1): 1745, 1254, 895, 776. under reflux for 16 hours was filtered off washed with ether the filtrate was concentrated The residue was dissolved in ether washed in sequence with water, 0.5M citric acid, again with water and saturated sodium chloride solution dried concentrated subsequently freed from volatile material at 5° C. in a high vacuum for 5 hours

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

Procedure: Lithium hydroxide monohydrate (1.98 g, 47.2 mmol) was added to a solution of (R)-methyl 3-hydroxytetradecanoate (42, 8.17 g, 31.5 mmol) in THF (66 mL) and water (66 mL) and stirred at room temperature for 2 h. The mixture was then diluted with diethyl ether (1 L) and the pH adjusted to ˜3 with a solution of hydrochloric acid (1 N). The solution was then extracted with diethyl ether (200 mL), and the organic fractions were combined and dried over Na2SO4. Na2SO4 was removed by filtration and the filtrate was concentrated in vacuo to provide (R)-3-hydroxytetradecanoic acid (36, 7.59 g, 98%) as an off-white solid. 1H NMR (CDCl3) δ 3.99-3.94 (m, 1H), 2.45-2.39 (m, 2H), 1.47 (br s, 3H), 1.29 (br s, 17H), 0.89 (t, J=7.0 Hz, 3H). The solution was then extracted with diethyl ether (200 mL) dried over Na2SO4 Na2SO4 was removed by filtration the filtrate was concentrated in vacuo

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

Procedure: To a solution of compound 30 (3.50 g, 12.9 mmol) and 4-methoxybenzyl trichloroacetimidate (4.65 g, 17.3 mmol) in DCM (100 mL) was added camphorsulfonic acid (450 mg, 1.92 mmol). The mixture was stirred overnight at room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and dried over Na2SO4. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 70 min, 85 mL/min) to give the product 32 (4.01 g, 81%) as a colorless liquid. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) dried over Na2SO4 The drying agent was removed by filtration the solvents removed a rotary evaporator The residue was purified by chromatography on silica gel (120 g RediSep column eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 70 min

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

Procedure: To a solution of compound 30 (3.50 g, 12.9 mmol) and 4-methoxybenzyl trichloroacetimidate (4.65 g, 17.3 mmol) in DCM (100 mL) was added camphorsulfonic acid (450 mg, 1.92 mmol). The mixture was stirred overnight at room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and dried over Na2SO4. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 70 min, 85 mL/min) to give the product 32 (4.01 g, 81%) as a colorless liquid. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) dried over Na2SO4 The drying agent was removed by filtration the solvents removed a rotary evaporator The residue was purified by chromatography on silica gel (120 g RediSep column eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 70 min

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

Procedure: To a solution of compound 30 (2.8 g, 10.83 mmol) and benzyl trichloroacetimidate (3.4 g, 14 mmol) in DCM (100 mL) was added trifluoromethanesulfonic acid (0.24 mL, 2.7 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 6 h and warmed to room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and the organic layer dried over Na2SO4. The drying agent was removed by filtration, and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (80 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 60 min, 60 mL/min) to give the product 31 (1.2 g, 32%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 4.51 (s, 2H), 3.90-3.80 (m, 1H), 3.70 (s, 3H), 2.58-2.45 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.20 (m, 18H), 0.85 (t, J=5.8 Hz, 3H). warmed to room temperature The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) the organic layer dried over Na2SO4 The drying agent was removed by filtration the solvents removed a rotary evaporator The residue was purified by chromatography on silica gel (80 g RediSep column eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 60 min

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

Procedure: A slurry of methyl 3-oxotetradecanoate (29, 29.0 g, 113 mmol) in methanol (120 mL) was purged in a 300 mL high pressure reactor glass sleeve with N2 for 10 minutes. Dichloro-R-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl ruthenium (897 mg, 1.10 mmol) was added. The mixture was placed in a Parr 5500 series compact reactor. The reactor was charged with H2 (60 psi) and vented 3 times. The reactor was charged with H2 (60 psi) and stirred (1200 rpm) and heated to 50° C. for 20 h. The reactor was cooled to room temperature, and the resulting orange solution was concentrated in vacuo. The residue was purified by silica gel chromatography (120 g RediSep column, eluting with a gradient of 0% through 40% ethyl acetate/hexanes over 60 min, 85 mL/min) to provide product 30 (28.5 g, 97% yield) as a white solid. The reactor was charged with H2 (60 psi) The reactor was charged with H2 (60 psi) The reactor was cooled to room temperature the resulting orange solution was concentrated in vacuo The residue was purified by silica gel chromatography (120 g RediSep column eluting with a gradient of 0% through 40% ethyl acetate/hexanes over 60 min

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

Procedure: A 500 ml autoclave was charged in a glove box (O2 content <1 ppm) with 46.2 g (180 mmol) of methyl 3-oxotetradecanoate, 131 ml of methanol and a solution of 2.1 mg (0.0036 mmol) of (R)-MeOBIPHEP and 1.08 mg (0.0018 mmol) of Ru2Cl4 (COD)2 (CH3CN) [Lit.: E. Singleton et al., S. Afr. Tydskr. Chem. 40, 183 (1987)] in 5 ml of dichloromethane. The hydrogenation was effected at 80° C. and 35 bar. The conversion amounted to >99% after 19 hours. The hydrogenation solution was concentrated at 50° C./17 mbar and the crystalline residue was taken up in 500 ml of diethyl ether. In order to separate the catalyst, the ethereal solution was filtered over 100 g of silica gel; e.e.=97.1%. After concentrating and drying the filtered ethereal phase there were obtained 45.8 g of methyl (R)-3-hydroxytetradecanoate as white crystals; e.e.=97.1%. After recrystallization from n-hexane there were obtained 41.9 g of pure methyl (R)-3-hydroxytetradecanoate; m.p. 42°-43° C.; e.e. 99.8%; [α]D20 : -16.4° (c=3.8, CCl4). was effected at 80° C. The hydrogenation solution was concentrated at 50° C./17 mbar In order to separate the catalyst the ethereal solution was filtered over 100 g of silica gel After concentrating drying the filtered ethereal phase there