Concise synthesis of spirocyclic, bridged gamma-butyrolactones via stereospecific, dyotropic rearrangements of beta-lactones involving 1,2-acyl and delta-lactone migrations.

Dyotropic processes involving unprecedented 1,2-acyl migrations provide access to novel spirocyclic, bridged keto-gamma-lactones from a series of fused, tricyclic-beta-lactones, available via biscyclization of ketoacids including a new asymmetric variant. In addition, a spirocyclic bis-gamma-lactone was generated via a dyotropic process involving a 1,2-beta-lactone/sigma-lactone interchange. Overall, this sequence provides a simple, two-step process for conversion of diketoacids to complex spiro[5.

Alkyl C-O ring cleavage of bicyclic beta-lactones with Normant reagents: synthesis of a Merck IND intermediate.

Highly diastereoselective Cu(I)-mediated, bicyclic beta-lactone ring cleavage reactions with either alkyl or aryl cuprates proceeded with inversion of stereochemistry to give optically active trans-substituted cyclopentanes and cyclohexanes. Optimization of typically problematic aryl cuprate additions was made possible by minimization of a competing bromide-induced ring cleavage process. The utility of this process was demonstrated by an efficient synthesis of a Merck investigational new drug (IND) intermediate for an anti-HIV CCR5 antagonist.