Enantioselective Total Synthesis of (+)‐Eucophylline

Abstract

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.

Quinoline, Indole, and Isogranatanine Alkaloids from Malayan Leuconotis eugeniifolia

“…A literature search revealed a compound similar to 7 was synthesized as the key intermediate during the enantioselective total synthesis of (+)-eucophylline by Landais and co-workers. 40 Natural 7 has similar spectroscopic data, including the sign for the specific rotation data value, when compared to synthetic 7 (Tables S68 and S69, Supporting Information). Therefore, the absolute configuration at C-20 for natural 7 is deduced to be similar to that of synthetic 7 (20R).…”

“…The above data allow the construction of the 2D structure of 7 . A literature search revealed a compound similar to 7 was synthesized as the key intermediate during the enantioselective total synthesis of (+)-eucophylline by Landais and co-workers . Natural 7 has similar spectroscopic data, including the sign for the specific rotation data value, when compared to synthetic 7 (Tables S68 and S69, Supporting Information).…”

Stereoselective synthesis of highly substituted 1-isomorphans (1-azabicyclo[3.3.1]nonanes)

“…A second strategy took advantage of the fused aromatic rings of the product by planning the synthesis through consecutive S E Ar reactions 6 (Scheme 1b). A third approach began with a symmetric substrate to obtain a lactam, which after further transformations and a final nucleophilic substitution, afforded the product 7,8 (Scheme 1c). A general stereoselective approach was made by Drège and Joseph using an intramolecular Michael addition promoted by aminocatalysis 9 (Scheme 1d).…”