Jens Christoffers and colleagues at Carl von Ossietzky Universitat Oldenburg, Germany, have developed a method to prepare cyclopenta-, benzo-, and cyclohepta[b]-annulated azepane scaffolds from optically active cyclic α-allyl-β-oxoesters. This is achieved in just two steps, which makes the process efficient.
The first step involves using ruthenium-catalyzed olefin cross metathesis with acrylonitrile. In the second step, palladium-catalyzed dihydrogenation is used, which includes three consecutive processes. The C–C double and C–N triple bonds are hydrogenated, followed by the reductive amination via the iminium ion formed in situ from the primary amino function and the endocyclic carbonyl group. This step gives stereoselective annulated azepanes with relative trans-configuration.
The amino function and the ester group can be used as starting points for further diversification of the scaffolds. The team preaperd several derivatives. The enantiopurity of the products was determined to be 97–98 % ee by GLC on a chiral phase, using trifluoroacetyl derivatives. The relative trans-configurations and, in one case, the absolute (R,R)-configuration, were established by X-ray.
- Enantioselective Synthesis of [b]-Annulated Azepane Scaffolds,
Enno Aeissen, Aaron R. von Seggern, Marc Schmidtmann, Jens Christoffers,
Eur. J. Org. Chem. 2023.