CHEMOTHERAPY OF CANCER,IV.SYNTHESIS OF β-(5-SUBSTITUTED-2-THIENYL)-ALANINE AND SOME OF ITS DERIVATIVES

Sulfur-containing amino acids were prepared and tested by various authors as possible antimetabolites for carcinostatic action.Thus β-alkylmercapto-α-aminopropionic acid,γ- ethylmercapto-α-aminobutyric acid and γ-(N-substituted-sulfamido)-α-aminobutyric acid have been synthesized.One of us (Yuen) has reported the inhibiting action of δ-mercapto- α-aminovaleric acid and ε-amino-α-mercaptocaproic acid on the growth of rat tumor. β-2-Thienyl alanine,being an isostere of phenyl alanine,is known as the antimetabo- lite of the latter.It is capable to produce some inhibition of the growth of the rat tumor. The present paper is concerned with the synthesis of various derivatives of β-(5-substituted- 2-thienyl)-alanine with the general formula X=H,NO₂,NHCOCH₃ R=H,OH,SR Described are the synthesis of β-(5-substituted-2-thienyl) alanine,-serine and -cystein by the sequence of reactions as shown by the scheme in the Chinese text. β-2-Thienyl serine (Ⅱa) as well as β-(5-acetamido-2-thienyl) serine (Ⅱc) were prepared by the condensation of the corresponding thiophene aldehyde (Ⅰ) with glycine in the presence of alkali and followed by acid cleavage of the resulting addition products.It was shown that 5-nitro-2-thiophene aldehyde was resistant to this reaction owing to the extreme unstabi- lity of the aldehyde toward alkali.As shown by paper chromatography,this aldehyde was decomposed completely before condensation.Consequently,β-(5-nitro-2-thienyl)-serine (Ⅱb) was prepared by condensation of 5-nitro-2-thiophene aldehyde with glycine ethyl ester in neutral medium. By the Erlenmeyer reaction,5-substituted-2-thiophene aldehyde was easily converted to 2-phenyl-4-(5′-substituted-2′-thenylidene)-5-azlactone (Ⅲ),the key intermediate in our synthesis.However,the conversion of the azlactone to corresponding amino acid by reductive hydrolysis,as previously reported for the synthesis of phenyl alanine,could not be applied to the compounds containing nitroacetamido-,thiophene and ester group. Catalytical reduction or by treatment with LiAlH₄ was also unsuccessful. Alcoholysis of the azlactone afforded the ethyl-(5-substituted-2-thienyl)-α-benzoyl amido- acrylate (Ⅴ) from which β-(5-substituted-2-thienyl)-S-alkylated cystein ethyl ester (Ⅳ) were synthesized by the addition of corresponding mercaptans.Unsuccessful attempts were made to hydrolyze the benzoyl and ester groups in the acid medium. The R_f of the mentioned racemic amino acids in various solvent systems were deter- mined.The anticancer activity of these compounds will be published elsewhere.