Synthesis of the four stereoisomers of cyclobutane analogues of phenylalanine in enantiomerically pure form

All stereoisomers of 1-amino-2-phenylcyclobutanecarboxylic acid—c4Phe—have been synthesized and the series cnPhe has thus been completed. The use of two different strategies based on a cyclization reaction, starting from ethyl isocyanoacetate and dialkyl malonate, respectively, gave both cis-c4Phe and trans-c4Phe in racemic form. HPLC resolution of one of the intermediates using a cellulose-derived chiral stationary phase allowed the isolation of the corresponding enantiomerically pure N-protected amino acids, prepared for incorporation into peptides. The relative stereochemistry of enantiopure compounds has been unambiguously assigned.

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Ethyl (1S,2R)-N-tert-butoxycarbonyl-1-amino-2-phenylcyclobutane-1-carboxylateC18H25NO4Ee = >98%[α]D25=+80.9 (c 0.75, CHCl3)Source of chirality: resolution by chiral HPLCAbsolute configuration: (1S,2R)

Ethyl (1R,2S)-N-tert-butoxycarbonyl-1-amino-2-phenylcyclobutane-1-carboxylateC18H25NO4Ee = >98%[α]D25=-79.6 (c 0.79, CHCl3)Source of chirality: resolution by chiral HPLCAbsolute configuration: (1R,2S)

(1S,2R)-N-tert-Butoxycarbonyl-1-amino-2-phenylcyclobutane-1-carboxylic acidC16H21NO4Ee = >98%[α]D25=+80.5 (c 0.59, CHCl3)Source of chirality: resolution by chiral HPLCAbsolute configuration: (1S,2R)

(1R,2S)-N-tert-Butoxycarbonyl-1-amino-2-phenylcyclobutane-1-carboxylic acidC16H21NO4Ee = >98%[α]D25=-77.7 (c 0.66, CHCl3)Source of chirality: resolution by chiral HPLCAbsolute configuration: (1R,2S)

Ethyl (1R,2R)-N-benzyloxycarbonyl-1-amino-2-phenylcyclobutane-1-carboxylateC21H23NO4Ee = >98%[α]D25=-20.9 (c 0.97, CHCl3)Source of chirality: resolution by chiral HPLCAbsolute configuration: (1R,2R)

Ethyl (1S,2S)-N-benzyloxycarbonyl-1-amino-2-phenylcyclobutane-1-carboxylateC21H23NO4Ee = >98%[α]D25=+20.1(c 1.00, CHCl3)Source of chirality: resolution by chiral HPLCAbsolute configuration: (1S,2S)

(1R,2R)-N-Benzyloxycarbonyl-1-amino-2-phenylcyclobutane-1-carboxylic acidC19H19O4Ee = >98%[α]D25=-39.8 (c 0.73, CHCl3)Source of chirality: resolution by chiral HPLCAbsolute configuration: (1R,2R)

(1S,2S)-N-Benzyloxycarbonyl-1-amino-2-phenylcyclobutane-1-carboxylic acidC19H19O4Ee = >98%[α]D25=+40.1 (c 0.86, CHCl3)Source of chirality: resolution by chiral HPLCAbsolute configuration: (1S,2S)