ENANTIOSPECIFIC SYNTHESIS OF NATURAL (-)-COCAINE AND UNNATURAL (-COCAINE FROM D-GLUTAMIC AND L-GLUTAMIC ACID())

Natural (-)-cocaine and unnatural (+)-cocaine have been synthesized en antiospecifically from D- and L-glutamic acid, respectively. The axial -equatorial substitutents were introduced by a stereo- and regiospecif ic dipolar cycloaddition to the corresponding (LR,5S)- and (1S,5R)-N-B OC-nortropenes with (ethoxycarbonyl)formonitrile N-oxide. A sequence o f subsequent stereochemically controlled transformations converted the fused isoxazoline to the requisite P-hydroxy ester. Synthesis of the key intermediate N-BOC-nortropenes involved construction of the 8-azab icyclo[3.2.1]octane framework by Dieckmann condensation of cis-5-subst ituted D-and L-proline esters. For comparison, (1R,SS)-N-BOC-nortropen e also was derived by degradation from natural cocaine. The cis-5-subs tituted D-and L-proline esters were obtained by sulfide contraction an d 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 acids, respectively.