(3S,4S)-3-Hexyl-4-((R)-2-hydroxytridecyl)-2-oxetanone

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

Procedure: 1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4 Å) were treated with 20 ml of THF and cooled to 0° C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate were added. After warming to room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1). There were obtained 0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-benzamide, MS: 474 (M+H)+. After warming to room temperature was concentrated the residue was partitioned between methanol/water (70:30) and hexane extracted with hexane The hexane phase was dried concentrated the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1)

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

Procedure: 1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4 Å) were treated with 20 ml of THF and cooled to 0° C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate were added. After warming to room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1). There were obtained 0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-benzamide, MS: 474 (M+H)+. After warming to room temperature was concentrated the residue was partitioned between methanol/water (70:30) and hexane extracted with hexane The hexane phase was dried concentrated the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1)

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

Procedure: To a solution of 100 mg of rac-3-hexyl -4-(2-hydroxy-tridecyl)-2-oxetanone(2R,3S,4S:2S,3R,4R) or of 100 mg of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 74 mg of triphenylphosphine and 45 mg of N-formyl-L-leucine in 2 ml of THF are added dropwise while stirring 44.3 μl of diethyl azodicarboxylate. After stirring overnight the organic phase is evaporated in vacuo and the residue is purified by chromatography on silica gel with toluene-ethyl acetate (9:1). There are obtained 20 or 37 mg of N-formyl-L-leucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, [α]D20 =-33° C. (c=0.36, CHCL3). is evaporated in vacuo the residue is purified by chromatography on silica gel with toluene-ethyl acetate (9:1)

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

Procedure: 166 g of (3S,4S)-3-hexyl-4-((R)-2-hydroxy tridecyl)-2-oxetanone obtained from Reference Example 1 was dissolved in 830 mL of tetrahydrofuran. After the addition of 160 g of triphenylphosphine (PPh3) and 86 g of N-formyl-L-leucine, the reaction mixture was cooled to 0° C. A mixed solution where 120 mL of diisopropylazodicarboxylate (DIAD) was diluted in 332 mL of tetrahydrofuran, was continuously added thereto over 1.5 hours. After stirring for further 30 minutes, the reaction mixture was stirred for 4 hours while slowly raising its temperature. After removing the solvent, 832 mL of hexane was added thereto, and the reaction mixture was stirred for 5 hours. The formed solid was removed therefrom by filtration, and the hexane layer thereof was washed with 499 mL of 55% methanol/distilled water three times. The remaining organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was removed under a reduced pressure. Then, 2.5 L of hexane was added thereto, and the reaction mixture was cooled to 10° C. and stirred for 1 hour, followed by addition of a seed of orlistat solid. The reaction mixture was slowly cooled to 0° C. again, and stirred overnight. The obtained solid was filtered, washed with 500 mL of cold hexane, and dried, to obtain 192.5 g of the title compound (yield: 83%) as a white solid. was continuously added the reaction mixture was stirred for 4 hours while slowly raising its temperature After removing the solvent, 832 mL of hexane was added the reaction mixture was stirred for 5 hours The formed solid was removed by filtration the hexane layer thereof was washed with 499 mL of 55% methanol/ distilled water three times The remaining organic layer was dried over anhydrous magnesium sulfate filtered the solvent was removed under a reduced pressure Then, 2.5 L of hexane was added the reaction mixture was cooled to 10° C. stirred for 1 hour followed by addition of a seed of orlistat solid The reaction mixture was slowly cooled to 0° C. again stirred overnight The obtained solid was filtered washed with 500 mL of cold hexane dried

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

Procedure: 1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4 Å) were treated with 20 ml of THF and cooled to 0° C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate were added. After warming to room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1). There were obtained 0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-benzamide, MS: 474 (M+H)+. After warming to room temperature was concentrated the residue was partitioned between methanol/water (70:30) and hexane extracted with hexane The hexane phase was dried concentrated the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1)

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

Procedure: 1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4 Å) were treated with 20 ml of THF and cooled to 0° C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate were added. After warming to room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1). There were obtained 0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-benzamide, MS: 474 (M+H)+. After warming to room temperature was concentrated the residue was partitioned between methanol/water (70:30) and hexane extracted with hexane The hexane phase was dried concentrated the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1)

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

Procedure: 1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4 Å) were treated with 20 ml of THF and cooled to 0° C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate were added. After warming to room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1). There were obtained 0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-benzamide, MS: 474 (M+H)+. After warming to room temperature was concentrated the residue was partitioned between methanol/water (70:30) and hexane extracted with hexane The hexane phase was dried concentrated the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1)

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

Procedure: Prepared according to representative procedure described in Example 63, above. E/Z-mixture of β-lactone 20a (5.8 mg, 0.016 mmol) and 5 wt % palladium on carbon (5 mg) in 2 mL of THF was stirred at ambient temperature for 12 h under H2 atmosphere. Filtration gave the desired β-lactone 13d (5.9 mg, 99%) as a white solid. Prepared Filtration

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

Procedure: Prepared according to representative procedure described in Example 63, above. E/Z-mixture of β-lactone 20a (5.8 mg, 0.016 mmol) and 5 wt % palladium on carbon (5 mg) in 2 mL of THF was stirred at ambient temperature for 12 h under H2 atmosphere. Filtration gave the desired β-lactone 13d (5.9 mg, 99%) as a white solid. Prepared Filtration

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

Procedure: 1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4Å) were treated with 20 ml of THF and cooled to 0° C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate were added. After warming to room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1). There were obtained 0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-benzamide, MS: 474 (M+H)+. After warming to room temperature was concentrated the residue was partitioned between methanol/water (70:30) and hexane extracted with hexane The hexane phase was dried concentrated the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1)

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

Procedure: To a solution of 100 mg of rac-3-hexyl -4-(2-hydroxy-tridecyl)-2-oxetanone(2R,3S,4S:2S,3R,4R) or of 100 mg of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 74 mg of triphenylphosphine and 45 mg of N-formyl-L-leucine in 2 ml of THF are added dropwise while stirring 44.3 μl of diethyl azodicarboxylate. After stirring overnight the organic phase is evaporated in vacuo and the residue is purified by chromatography on silica gel with toluene-ethyl acetate (9:1). There are obtained 20 or 37 mg of N-formyl-L-leucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, [α]D20 =-33° C. (c=0.36, CHCL3). is evaporated in vacuo the residue is purified by chromatography on silica gel with toluene-ethyl acetate (9:1)

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

Procedure: 166 g of (3S,4S)-3-hexyl-4-((R)-2-hydroxy tridecyl)-2-oxetanone obtained from Reference Example 1 was dissolved in 830 mL of tetrahydrofuran. After the addition of 160 g of triphenylphosphine (PPh3) and 86 g of N-formyl-L-leucine, the reaction mixture was cooled to 0° C. A mixed solution where 120 mL of diisopropylazodicarboxylate (DIAD) was diluted in 332 mL of tetrahydrofuran, was continuously added thereto over 1.5 hours. After stirring for further 30 minutes, the reaction mixture was stirred for 4 hours while slowly raising its temperature. After removing the solvent, 832 mL of hexane was added thereto, and the reaction mixture was stirred for 5 hours. The formed solid was removed therefrom by filtration, and the hexane layer thereof was washed with 499 mL of 55% methanol/distilled water three times. The remaining organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was removed under a reduced pressure. Then, 2.5 L of hexane was added thereto, and the reaction mixture was cooled to 10° C. and stirred for 1 hour, followed by addition of a seed of orlistat solid. The reaction mixture was slowly cooled to 0° C. again, and stirred overnight. The obtained solid was filtered, washed with 500 mL of cold hexane, and dried, to obtain 192.5 g of the title compound (yield: 83%) as a white solid. was continuously added the reaction mixture was stirred for 4 hours while slowly raising its temperature After removing the solvent, 832 mL of hexane was added the reaction mixture was stirred for 5 hours The formed solid was removed by filtration the hexane layer thereof was washed with 499 mL of 55% methanol/ distilled water three times The remaining organic layer was dried over anhydrous magnesium sulfate filtered the solvent was removed under a reduced pressure Then, 2.5 L of hexane was added the reaction mixture was cooled to 10° C. stirred for 1 hour followed by addition of a seed of orlistat solid The reaction mixture was slowly cooled to 0° C. again stirred overnight The obtained solid was filtered washed with 500 mL of cold hexane dried