Cyclic GABA-GABOB analogues. II - Synthesis of new 2-oxo and 2,5-dioxo-delta3-pyrroline derivatives.

Within the framework of a research program on new compounds potentially active on learning and memory processes, some esters and amides of 2-oxo- and 2,5-dioxo-delta3-pyrroline-1-acetic acids were synthesized. Such compounds can be regarded either as dehydration products of the corresponding 4-hydroxy-2-pyrrolidinones or as cyclic derivatives of 4-aminoisocrotonic acid. Two approaches were used in an attempt to synthesize pyrrolinone derivatives. One method involved the direct alkylation with ethyl bromoacetate of 1,5-dihydro-2H-pyrrol-2-one (III b), obtained for the first time in pure form by cyclization of 4-amino-3-hydroxybutyric acid (GABOB). Another approach involved the preparation of the ethyl 3-bromo-2-oxo-1-pyrrolidineacetate (VI), by cyclization of N-(2,4-dibromobutyryl)glycine ethyl ester (V), and its 4-bromo isomer (X b) by bromination of ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate (X a). While the dehydrobromination of (VI) was unsuccessful, heating of (X b) with TEA afforded ethyl 2,5-dihydro-2-oxo-1H-pyrrole-1-acetate (IV a). Alternatively, (X a) was treated with methanesulfonyl chloride, then with TEA to give (IV a). Final ammonolysis of (IV a) provided the corresponding amide (IV b). For the synthesis of the maleimide analogue (XIII b), the N-(carboxymethyl)maleamic acid (XII a) was treated with PCl5 and then with anhydrous ammonia.