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.