title: Concise syntheses of (-)-galanthamine and (+/-)-codeine via intramolecular alkylation of a phenol derivative.
abstract: Suzuki coupling of 7 to 8 gave the biphenyl derivative 9. Reaction of 9 with ethyl vinyl ether/bromine/base gave 10, which on treatment with CsF/DMF at 130 degrees C resulted in the cross-conjugated 2,5-cyclohexadienone 6. Acid hydrolysis of 6 gave 11, which was reductively aminated to give (+/-)-narwedine 2. Since 2 has been converted into (-)-galanthamine 1 in two steps, this synthesis proceeds in eight steps with an overall yield of 63%. Also treatment of the cross-conjugated cyclohexadienone 6 with nitromethane/base gave 12, which was reduced to provide 13. Reduction of the nitro group in 13 to an amine, followed by reductive amination under acidic conditions, arrives at the codeine skeleton 15. Elaboration of 15 into (+/-)-codeine proceeds via the previously unknown alpha-epoxide derivative 18. This is the shortest synthesis of codeine (13 steps, 20% overall yield) and, for the first time, allows access to codeine without having to reduce codeinone.
authors.affiliation: Department of Chemistry and Biochemistry, University of Texas at Austin, 1 University Station A5300, Austin, Texas 78712-1167, USA. p.magnus@mail.utexas.edu
authors.forename: Philip
authors.initials: P
authors.lastname: Magnus
authors.forename: Neeraj
authors.initials: N
authors.lastname: Sane
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.forename: Vince
authors.initials: V
authors.lastname: Lynch
mesh_terms: D000478:Alkylation; D003061:Codeine / Q000138:chemical synthesis*; D005702:Galantamine / Q000138:chemical synthesis*; D010636:Phenols / Q000737:chemistry*
chemical_list: D010636:Phenols; D005702:Galantamine; D003061:Codeine