Synthesis, separation, and resolution of cis - and trans -3-ethylproline

Abstract

The synthesis, separation, and optical resolution of cis - and trans -3-ethylproline are described. Two different approaches were employed: (1) The Michael addition reaction of 2-pentenal with diethyl-N-carbobenzyloxyaminomalonate gave the intermediate 3-ethyl-5-hydroxy-N-benzyloxypyrrolidine. Hydrogenolysis of this intermediate followed by acid hydrolysis gave a mixture of cis - and trans -3-ethylproline. Separation of the isomers was accomplished by selective saponification of N-( p -toluenesulfonyl)- cis - and trans -3-ethylproline methyl esters using 0.25 N methanolic sodium hydroxide. (2) The Michael condensation of diethyl acetamidomalonate with 2-pentenoic acid ethyl ether produced the intermediate 5,5-bis(ethoxycarbonyl)-4-ethylpyrrolidine. Partial saponification followed by decarboxylation afforded a mixture of cis - and trans -isomers of ethyl-3-ethylpyroglutamate. The diastereoisomers were separated using low temperature fractional crystallization. Reduction of these isomers and tosylation in situ afforded the corresponding N-( p -toluenesulfonyl)- cis - and trans -3-ethylprolinols. Chromic acid oxidation gave N-( p -toluenesulfonyl)- cis - and trans -3-ethylproline. Reaction of these tosylates with 30% hydrogen bromide in acetic acid gave cis - and trans -3-ethylproline. Both optically active isomers of D(+)-and L(-)- trans -3-ethylproline were successfully resolved using (+)-dibenzoyl- D -tartaric acid and (-)-dibenzoyl- L -tartaric acid as resolving agents. The absolute configurations of the optically active isomers were determined by circular dichroism spectroscopy.