Enantiospecific Synthesis of Natural (−)-Cocaine and Unnatural (+)-Cocaine from d- and l-Glutamic Acid

Natural (−)-cocaine and unnatural (+)-cocaine have been synthesized enantiospecifically from d- and l-glutamic acid, respectively. The axial−equatorial substitutents were introduced by a stereo- and regiospecific dipolar cycloaddition to the corresponding (1R,5S)- and (1S,5R)-N-BOC-nortropenes with (ethoxycarbonyl)formonitrile N-oxide. A sequence of subsequent stereochemically controlled transformations converted the fused isoxazoline to the requisite β-hydroxy ester. Synthesis of the key intermediate N-BOC-nortropenes involved construction of the 8-azabicyclo[3.2.1]octane framework by Dieckmann condensation of cis-5-substituted d- and l-proline esters. For comparison, (1R,5S)-N-BOC-nortropene also was derived by degradation from natural cocaine. The cis-5-substituted d- and l-proline esters were obtained by sulfide contraction and subsequent catalytic hydrogenation to induce stereospecifically the C-5 stereochemistry from d- and l-thiopyroglutamate, which in turn were prepared from d- and l-glutamic acid...