Enantioselective Total Synthesis of (+)-Eucophylline

The total enantioselective synthesis of (+)-eucophylline 1 was achieved using as a key-structural motif a chiral piperidinone bearing the natural product all-carbon quaternary stereocenter. The elaboration of the latter is based on two strategies relying on the free-radical carbo-cyanation and sulfonyl-cyanation respectively of enantiopure substituted cyclopropenes and cyclobutenes. Co- or Ni-boride reduction of the nitrile functional group along with the cyclopropane and cyclobutane ring-opening then led to the formation of the chiral piperidinone ring. Further elaboration of the latter into the key 1-azabicyclo[3.3.1]nonane motif followed by its coupling with a 2-cyanoaniline allowed the formation of the tetrahydrobenzo[b][1,8]-naphthyridine skeleton of 1, which was finally accessible in 17 steps and 5.9 % overall yield from 1,1-dibromobutene.

Automated summary

The total enantioselective synthesis of (+)-eucophylline 1 was achieved using a chiral piperidinone as a key structural motif. The synthesis involved two strategies, carbo-cyanation and sulfonyl-cyanation, starting from enantiopure cyclopropenes and cyclobutenes. The final compound was obtained in 17 steps and with an overall yield of 5.9% from 1,1-dibromobutene.