A Rapid Synthesis of Hydroxymethylacylfulvene (HMAF) Using the Allenic Pauson−Khand Reaction. A Synthetic Approach to Either Enantiomer of This Illudane Structure

An allenic Pauson−Khand reaction has been employed in the preparation of (±)-hydroxymethylacylfulvene (HMAF), an anticancer agent that is currently in Phase II clinical trials for a variety of solid tumor types. The synthesis is effected in 11 steps from commercially available starting materials. In addition, an asymmetric route to the title compound has been established by intersecting the racemic synthesis with an enantiomerically pure intermediate. The preparation of the enantiomerically pure intermediate involved the Sharpless asymmetric dihydroxylation (AD) of a trisubstituted olefin of an enyne system. This approach provides access to both enantiomers of HMAF simply by changing the ligands in the Sharpless AD reaction. Optimized conditions for the stereospecific synthesis of <i>E</i> or <i>Z</i> trisubstituted enynes from an aliphatic ketone using either Peterson olefination or Horner−Wadsworth−Emmons protocols are reported. Finally, a better understanding of the stereoelectronic requirements of the allenic P−K reaction is recognized.