A stereo-controlled access to functionalized macrolactams via an aza-Claisen rearrangement

A novel and stereo-controlled method for the preparation of functionalized macrolactams was developed. The process involves stereoselective enol ether formation, followed by an azacyclic ring expansion via an aza-Claisen rearrangement. Herewith, we describe a systematic investigation of an aza-Claisen rearrangement-induced ring expansion of azacycles prepared by appending E/Z-enol ethers to the medium-sized lactams as well as the stereochemical outcome. In addition, the strategy was successfully applied to the total synthesis of fluvirucinine A₁ and 3-epi-fluvirucinine A₁. This method offers an attractive alternative to the intramolecular amide-aldol reaction for the elaboration of β-alkoxy- α-substituted motifs.