Diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres

The diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres in protected form was achieved by starting from optically active 1,1-diethoxyethyl(aminomethyl)phosphinate. Our methodology involves diastereoselective α-alkylation and β′-alkylation of phosphinate derivatives with an asymmetric center at the phosphorus atom.

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(RP)-Ethyl 1,1-diethoxyethyl{[(diphenylmethylene)amino]methyl}phosphinateC22H30NO4P[α]D20=-17.2 (c 0.8, CHCl3)Source of chirality: lipase AKAbsolute configuration: (RP)

(1R,RP)-Ethyl 1,1-diethoxyethyl{1-[(diphenylmethylene)amino]-4-hydroxybutyl}phosphinateC25H36NO5P[α]D27=+29.25 (c 0.18, CHCl3)Source of chirality: lipase AKAbsolute configuration: (1R,RP)

(1R,RP)-Ethyl 1,1-diethoxyethyl{[1-(4-methylphenyl)sulfonyl]-2-pyrrolidinyl}phosphinateC19H32NO6PS[α]D27=-82.5 (c 0.05, CHCl3)Source of chirality: lipase AKAbsolute configuration: (1R,RP)

(1R,SP)-Ethyl{[1-(4-methylphenyl)sulfonyl]-2-pyrrolidinyl}phosphinateC13H20NO4PS[α]D27=-109.0 (c 0.19, CHCl3)Source of chirality: lipase AKAbsolute configuration: (1R,SP)

(1R,SP)-tert-Butyl 3-[ethoxy(1-{[(4-methylphenyl)sulfonyl]-2-pyrrolidinyl})phosphoryl]propanoateC20H32NO6PS[α]D29=-68.3 (c 0.27, CHCl3)Source of chirality: lipase AKAbsolute configuration: (1R,SP)

(1R,SP,2R)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methylphenyl)sulfonyl]-2-pyrrolidinyl})phosphoryl]propanoateC27H38NO6PS[α]D29=-72.8 (c 0.24, CHCl3)Source of chirality: lipase AKAbsolute configuration: (1R,SP,2R)