Cyclic Gaba-Gabob analogues I - Synthesis of new 4-hydroxy-2-pyrrolidinone derivatives

In the event that the GABA-GABOB system is involved in the initial phases of the learning and memory process, some new derivatives of 4-hydroxy-2-pyrrolidinone (I a) have been synthesized. The cyclic compounds of general formula (A) are more lipophilic than GABOB and should better enter brain fluids. The N-hydroxymethyl derivatives (II a...c) were prepared by addition of the suitable aldehydes to 4-acetoxy-2-pyrrolidinone (I b). In order to obtain the ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate (IV a) some synthetic routes starting from (I b), (III b) and from the 3-diazotetramic acid (V) were explored. However, the N-ethoxycarbonylmethyltetramic acid (X), obtained by Dieckmann cyclization of triester (VIII) and subsequent de-etho-xycarbonylation was reduced to (IV a). Ammonolysis of (IV a) afforded the acetamide (XI a). The O-acetyl derivatives (IV b) and (XI b) were also prepared.