Chemoenzymatic Total Synthesis of Hydromorphone by an Oxidative Dearomatization/Intramolecular [4 + 2] Cycloaddition Sequence: A Second-Generation Approach.
A second-generation approach to the synthesis of hydromorphone by oxidative dearomatization/Diels-Alder cycloaddition was investigated. Detailed analysis of the stereochemical outcome of the [4 + 2] cycloaddition was performed first on a truncated model system as well as on the material leading to ent-hydromorphone. The stereochemical assignments were made by NMR and X-ray methods. The second-generation synthesis of hydromorphone was completed in both enantiomeric series. Improvements in the dearomatization conditions were attained using hypervalent iodine reagents instead of Pb(OAc)4. Electrochemical methods of oxidative dearomatization were also investigated. New conditions enabling the rearomatization of ring A from the methoxyketal were developed, and a formal synthesis of the natural enantiomer of hydromorphone was completed. Experimental and spectral data are provided for all new compounds.
Department of Chemistry and Centre for Biotechnology, Brock University , 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada.
Lukas
L
Rycek
Department of Chemistry and Centre for Biotechnology, Brock University , 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada.
John J
JJ
Hayward
Department of Chemistry, Virginia Tech , Blacksburg, Virginia 24061, United States.
Marwa Abdel
MA
Latif
Department of Chemistry, Virginia Tech , Blacksburg, Virginia 24061, United States.
James
J
Tanko
Department of Chemistry and Centre for Biotechnology, Brock University , 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada.
Razvan
R
Simionescu
Department of Chemistry and Centre for Biotechnology, Brock University , 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada.
Tomas
T
Hudlicky