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.

No abstract

The free-radical three-component carbocyanation of electron-rich olefins was investigated with p-tosyl cyanide as cyanide source. The scope and limitations of the process were established by varying the nature of the alkene and radical precursor. Carbocyanation of chiral allylsilanes was shown to occur with high diastereocontrol, leading to syn β-silyl nitriles. The origin of the stereocontrol was rationalized by a Felkin-Anh-type transition-state model. Finally, a tin-free carbocyanation process was also devised, based on the use of a new alkylsulfonyl cyanide incorporating both carbon fragments to be added across the olefinic π system.