The Synthesis of Aracemic 4-Substituted Pyrrolidinones and 3-Substituted Pyrrolidines. An Asymmetric Synthesis of (-)-Rolipram

Article abstract of DOI:10.1021/jo00053a012

Conjugate additions of RCuCNLi to the chiral α,β-unsaturated lactam 4 gives almost exclusive exo addition - a reversal in stereochemistry when cuprates were added to chiral lactam 1.The lactams 5 were transformed into 4-substituted pyrrolidinones 8 via a three-step sequence which involved decarbalkoxylation, silane reduction and metal-ammonia benzylamine cleavage.The chemical yields as well as the enantiomeric purity were very high for this process.As an example of the usefulness of this scheme, the antidepressant (-)-Rolipram was prepared in good overall yield.Furthermore, the bicyclic lactams 6 were readily transformed, using alane as the reducing agent, to 3-substituted pyrrolidines 11.Absolute configurations of 8 and 11 were confirmed by comparison with literature assignments which also gave strong support to the facial addition of the cuprates to 4.