Synthesis of benzo-fused 1-azabicyclo[m.n.0] alkanes via the Schmidt reaction: A formal synthesis of gephyrotoxin

The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzoc yclohexyl carbocations 7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement with loss of dinitrogen to produ ce benzo-fused iminium ions resulting from either aryl (9) or alkyl (10) mi gration to the electron-deficient nitrogen atom. Reduction of the iminium i ons affords regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., ben zopyrrolizidines, benzoindolizidines, benzoquinolizidines, or perhydrobenzo [f]pyrrolo[1,2-a]azepines in two regioisomeric versions, anilines (e.g., 11 -14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrat ions, respectively. Generally, aryl migration is preferred, despite modelin g that shows that the lowest energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperiplanar to the migrating alk yl group rather than the aryl group. The utility of this methodology was il lustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependenc e on the efficiency and regioselectivity of the Schmidt reaction upon subtl e changes in the structure of the cation precursor was observed, necessitat ing the exploration of a variety of substrate. Fortunately, these materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl s ide-chain was useful for the Schmidt reaction, producing the known benzo-fu sed indolizidine 49, which had been transformed by Ito et al. into gephyrot oxin 4. The synthesis of 49 required nine steps (five purifications) from c ommercially available bmethoxy-1-indanone 60 and proceeded in 22% overall y ield.