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. Two strategies based respectively on the free‐radical carbo‐ and sulfonyl‐cyanation of cyclopropenes and cyclobutenes were developed to achieve the total enantioselective synthesis of (+)‐eucophylline, a monoterpene alkaloid isolated from Leuconotis eugenifolius.