H-ASP(OBZL)-OBZLHCL

A) (S)-Dibenzyl 2-((2-(benzyloxy)-2-oxoethyl)amino)succinate Benzyl 2-bromoacetate (0.377 mL) was added to a mixture of C) (S)-Dibenzyl 2-((S)-1-(10-amino-13-oxo-6, 7, 8, 13-tetrahydrodibenzo[b, f][1, 4]dioxecine-4-carbonyl)pyrrolidine-2-carboxamide)succinate A mixture of (S)-1-(10-amino-13-oxo-6, 7, 8, 13-tetrahydrodibenzo[b, f][1, 4]dioxecine-4-carbonyl)pyrrolidine-2-carboxylic acid hydrochloride (263 mg), G) (S)-Dibenzyl 2-(3-amino-16-oxo-6, 7, 8, 9, 10, 16-hexahydro-5H-dibenzo[b, j][1]oxacyclododecine-11-carboxamide)succinate A mixture of 3-amino-16-oxo-6, 7, 8, 9, 10, 16-hexahydro-5H-dibenzo[b, j][1]oxacyclododecine-11-carboxylic acid hydrobromate (53.0 mg), I) (S)-Dibenzyl 2-(3-amino-15-oxo-5, 6, 7, 8, 9, 15-hexahydrodibenzo[b, i][1]oxacycloundecine-10-carboxamide)succinate A mixture of 3-amino-15-oxo-5, 6, 7, 8, 9, 15-hexahydrodibenzo[b, i][1]oxacycloundecine-10-carboxylic acid hydrobromate (216 mg), D) (S, E)-Dibenzyl 2-(3-(2-hydroxy-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)acrylamide)succinate (S)-Dibenzyl 2-aminosuccinate hydrochloride (932 mg), N, N-diisopropylethylamine (1.0 mL), WSC hydrochloride (511 mg), and HOBt.H2O (408 mg) were added to a mixture of (E)-3-(2-hydroxy-3-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)acrylic acid (689.1 mg) and DMF (10 mL) at 0 C., followed by stirring at room temperature overnight. Water was added to the reaction mixture at 0 C., followed by extraction with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, water, a saturated sodium hydrogen carbonate aqueous solution, and a saturated saline solution and was then dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.311 g). MS: [M+H]+ 606.3.C) (S)-Dibenzyl 2-(2-allyl-3-hydroxy-5-methoxybenzamide)succinate (0974) A mixture of 646 ethyl 2-allyl-3-hydroxy-5-methoxybenzoate (1 g), 2 N 30 sodium hydroxide aqueous solution (7 mL), and 24 methanol (7 mL) was stirred at room temperature overnight and was then stirred at 50 C. for 5 hours. A 2 N sodium hydroxide aqueous solution (4 mL) was added to the reaction mixture at room temperature, followed by stirring 50 C. overnight. One normal 33 hydrochloric acid (22 mL) was added to the reaction mixture at 0 C. to make the mixture acidic, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated saline solution and was then dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. A mixture of the residue, 93 General procedure: To a stirring solution of compound 5 (514 mg, 1.0 mmol) inanhydrous THF at 0 C was added 1.2 mmol of N-Hydroxybenzotriazole(HOBT) and 1.2 mmol of N, N0-dicyclo-hexylcarbodiimide(DCC). After stirring for 10 min, a suspension of 1.2 mmol of aminoacid benzylester hydrochloride in 5 mL of anhydrous THF wasadded. The reaction mixture was adjusted with N-methyl morpholineto pH 8-9 and then stirred at room temperature overnightuntil TLC indicated that the starting material had been completelyconsumed. After evaporation, the residue was dissolved in 40 mL ofethyl acetate. The solution was washed extensively with 5%sodium bicarbonate, 5% KHSO4, and saturated sodium chloride.The organic layers were separated and dried over anhydrous Na2-SO4. Following filtration and evaporation under reduced pressure, the crude residue was purified by flash column chromatographyon silica gel to yield compounds 6a-s.