4-Hydroxybicyclo[2.2.1]heptane-1-carboxylic acid and its O-protected derivatives (1 ) has been increasingly utilized in potential therapeutics.  However, there is limited information regarding practical syntheses of 1 , primarily due to the challenges of generating the O-substituted bridgehead on a highly constrained [2.2.1]bicyclic scaffold.  Starting from norbornene, we have significantly improved a reported 4-step synthesis of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (2 ).  Conversion of the carboxylic acid function in 2  to a ketone sets the stage for the key Baeyer-Villiger oxidation to install the bridgehead hydroxyl functionality.  Development of the highly regioselective Baeyer-Villiger oxidation will be presented.  The final saponification of the methyl ester provided the target molecule 1  with an overall 25% yield in 8 steps.  We will also present details of process development work to enable this synthesis on kg-scale.

Novel synthesis of <i>O</i>-protected 4-hydroxybicyclo[2.2.1]heptane-1-carboxylic acid

243rd National Meeting (2012)

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Novel synthesis of O-protected 4-hydroxybicyclo[2.2.1]heptane-1-carboxylic acid