Total Synthesis of (±)-Eucophylline. A Free-Radical Approach to the Synthesis of the Azabicyclo[3.3.1]nonane Skeleton

The first total synthesis of eucophylline was reported in 10 steps and 10% overall yield. The naphthyridine core of eucophylline was prepared through the coupling between a strained azabicyclo[3.3.1]nonan-2-one and a trisubstituted benzonitrile, followed by a cyclization of the corresponding amidine. This coupling reaction was shown to proceed through a stable bicyclic chloroenamine intermediate. The azabicyclo[3.3.1]nonan-2-one skeleton was in turn accessible through a straightforward sequence including a free-radical three-component olefin carbo-oximation as a key step.