methyl (2R)-2-amino-3-phenylpropanoate;hydrochloride → Methyl 3-cyclohexyl-D-alaninate--hydrogen chloride (1/1)

Participants

Reaction Steps

Commercially available D-phenylalanine methyl ester hydrochloride (12 g) was hydrogenated with 5% rhodium on carbon (1.2 g) in 250 mL of methyl alcohol to yield (2R)-2-amino-3-cyclohexyl propanoic acid methyl ester hydrochloride in 97% yield. This (5.0 g, 18.4 mmol) was coupled with Boc-L-proline (3.97 g, 18.4 mmole)by standard methods [(1-hydroxybenzotriazole monohydride (HOBt) (2.74 g, 20 mmol), N-methylmorpholine (NMM) (2.23 mL, 20 mmol) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC) (3.89 g, 20 mmol) as exemplified by the methods described in "Peptide Synthesis" Second Edition, Bodanszky, M; Klausner, Y. S. and Ondetti, M. A., (1976) in 71% yield. The Boc-group was cleaved with 4 N hydrochloric acid in dioxane, and the obtained prolyl-(2R) -2-amino-3-cyclohexylpropanoic acid methyl ester hydrochloride was reacted with N-alpha-Cbz-N-epsilon-Boc-lysine (quantitative yield) according to the method mentioned above. The N-alpha-Cbz group was removed by hydrogenolysis (20%-palladium on charcoal 10% w/w) in acetic acid-isopropanol, and the obtained product was coupled with Boc-(N-methyl)phenylalanine by the above method to obtain N-Boc-(N-methyl) phenylalanyl-lysyl(N-epsilon-Boc)-prolyl-{(2R)-2-amino-3-cyclohexylpropanoic acid methyl ester} in quantitative yield. Finally, the methyl ester (7.33 g, 9.5 mmole) was cleaved by treatment with 1.5 molar equivalents of lithium hydroxide (598 mg, 14.25 mmol) in 115 mL of methanolwater (2:1) mixture to obtain N-Boc-(N-methyl)phenylalanyllysyl (N-epsilon-Boc)-prolyl-{(2R)-2-amino-3-cyclohexylpropanoic acid} in 83% yield.

Provenance & Evidence