合成路线1

A new synthesis for (-)-(R)-rolipram has been described: The cyclization of (S)-2-hydroxy-1-phenylethylamine (I) with 3-formylpropionic acid (II), or the reductocyclization of N-[2-hydroxy-1(S)-phenylethyl]succinimide (III) with NaBH4, yields the bicyclic amine (IV), which is treated with benzyl chloroformate and phenylselenyl bromide to afford the bicyclic ketoester (V). The stereocontrolled arylation of (V) with 4-bromo-2-(cyclopentyloxy)anisole by means of tert-butyllithium in THF gives the arylated ketoester (VII), which is decarboxylated with ammonium formate and Pd/C in methanol to the bicyclic pyrrolidone (VIII). The ring cleavage of (VIII) with Ca metal in liquid ammonia affords the hydroxypyrrolidone (IX), which is finally reduced with sodium cyanoborohydride in THF-methanol.