Codeine Analogues. Synthesis of Spiro and Octahydro-1H-benzofuroisoquinolines

Article abstract of DOI:10.1021/jo00338a003

A synthesis of highly functionalized spiro and octahydro-1H-benzofuro<3,2-e>isoquinolines, analogues of codeine containing the benzofuran/piperidine and benzofuran/decahydroisoquinoline ring fragments, has been developed.The process extends to the dimethoxyphenyl series earlier work in the synthesis of 4a-aryldecahydroisoquinolines involving the α-methylene lactam rearrangement and utilizes a novel α-chloro ortho ester Claisen rearrangement to establish the requisite functionality for oxide ring closure.Selective ether cleavage is achieved with methanesulfonic acid/methionine to afford a spiro, and base-promoted rearrangement then yields the desired spiro.The C-ring is closed by Michael addition of a β-keto ester to the α-methylene lactam moiety, subsequently affording a protected benzofuroisoquinolone.Finally, amide reduction followed by ketone deprotection gives the desired cis- and trans-benzofuroisoquinolines.The entire synthesis can be performed by starting from o-vanillin with six purifications in 10percent overall yield, and the various intermediates additionally provide entries into the synthesis of 4-arylpiperidines, benzomorphans, and 4a-aryldecahydroisoquinolines.Functionality is built in to allow preparation of typical morphine patterns.