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A Rapid Synthesis of Hydroxymethylacylfulvene (HMAF) Using the Allenic Pauson−Khand Reaction. A Synthetic Approach to Either Enantiomer of This Illudane Structure
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posted on 2000-05-04, 00:00 authored by Kay M. Brummond, Jianliang Lu, Jeffrey PetersenAn 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 E or Z 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.
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enyne systemPeterson olefinationallenicstereospecific synthesistrisubstituted olefintitle compoundPausonOptimized conditionsRapid SynthesisenantiomericallyIlludane StructurePhase IIZ trisubstituted enynesSharpless AD reactionSynthetic Approachtumor typesanticancer agentpreparationstereoelectronic requirementsracemic synthesis11 stepsaliphatic ketoneHMAF
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