Grob-Type Fragmentation Releases Paracyclophane Ring Strain in a Late-Stage Precursor of Haouamine A.

A ketene [2 + 2]-addition, an intramolecular aldol reaction, a Suzuki-Miyaura coupling, and a chemoselective lactam reduction were used to prepare a late-stage precursor of haouamine A. Exposure to acid led to a Grob-type fragmentation of the strained 3-aza[7]paracyclophane ring, followed by a tandem Pictet-Spengler reaction of the intermediate iminium ion and conversion to a novel 1,4a-propanocyclopenta[ b]pyridine. This cascade reaction might also be relevant for the mechanism of action of the natural product.