• Chemoenzymatic Total Synthesis of ent-Oxycodone

      Makarova, Mariia; Department of Chemistry
      This thesis describes the approach towards chemoenzymatic total synthesis of ent-dihydroisocodeine and chemoenzymatic total synthesis of ent-oxycodone as well as the development of a new method for the preparation of rearranged allylic isocyanates. The synthesis of ent-dihydroisocodeine started from phenethyl acetate and included a microbial oxidation of phenethyl acetate by E. coli JM109 (pDTG601A), a Mitsunobu reaction to the couple A- and C-rings, Heck cyclization to construct the E-ring and Henry reaction to introduce the nitrogen functionality as key steps. The construction of the B-ring proved to be challenging and neither radical cyclization nor attempts to perform photochemistry or nucleophilic opening of an epoxide gave any positive results. The chemoenzymatic total synthesis of ent-oxycodone was accomplished starting from phenethyl acetate in 23 steps. The tricyclic intermediate was furnished in the same manner as described above. The olefin to ketone conversion and a double Henry reaction allowed the construction of the B-ring. Unfortunately, it was established that the resulting hydroxyl group at C14 and amino group at C9 were of the undesired trans stereochemistry. To complete the morphine skeleton the transformation of the side chain at C13 to an N-methyl-p-toluenesufonamide via Mitsunobu reaction as well as the elimination of the amino group at C9 via formation of an N-oxide were performed. Subsequent radical cyclization of the side chain at the C9 position formed the last D-ring. The silyl ether deprotection followed by oxidation provided ent-oxycodone. The other approach to construct the D-ring was based on the formation of a lactone and the elimination of the amino group via an N-oxide. The nitrogen functionality was reinstalled using sodium azide and was accompanied by the introduction of the C10 hydroxyl group. Reduction of the azide and subsequent formation of the amide allowed access to the core skeleton of the target compound. The removal of the C10 hydroxyl group accomplished the synthesis. The last project involved the development of a new method for the preparation of rearranged allylic isocyanates from allylic alcohols using 1-cyano-4-dimethylaminopyridinium as the source of electrophilic cyanide. Experimental and spectral data are provided for all the compounds.