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

HRID 273877Notes

Reaction equation

HRID 273877 reaction equation
[ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6]>CO.[Rh]>[ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@H:5]([NH2:6])[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1

Participants

4

Reactant 1

HCID 11481330methyl (2R)-2-amino-3-phenylpropanoate;hydrochloride

Product 1

HCID 56777179Methyl 3-cyclohexyl-D-alaninate--hydrogen chloride (1/1)Yield 97%

Reagents, catalysts & solvents 2

HCID 23948RhodiumCatalystHCID 887MethanolSolvent

Procedure

Commercially available D-Phenylalanine methyl ester hydrochloride (12 g) was hydrogenated using 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 mmole) was coupled with Boc-L-Proline (3.97 g, 18.4 mmole) by using standard methods [(1-hydroxybenzotriazole monohydrate (HOBt) (2.74 g, 20 mmole), N-Methylmorpholine (NMM) (2.23 mL, 20 mmole) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC) (3.89 g, 20 mmole) 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, and the obtained prolyl-(2R)-2-amino-3-cyclohexylpropanoic acid methyl ester hydrochloride was reacted with N-alpha-Cbz-N-epsilon-Boc-Lysine in 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 method described above 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 saponified by treatment with 1.5 equivalent molar of lithium hydroxide (598 mg, 14.25 mmole) in 115 mL of methanol-water (2:1) mixture to obtain the title compound in 83% yield.

Sources & evidence

ORD record
ord-cf0e2fc0cf174805a76ea1ca3cc31ab6
Source dataset
uspto-grants-1995_02
Patent number
US05387671

Reaction notes

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