Synthesis Of The Anti-Influenza Neuramidase Inhibitor Tamiflu And Analog Of Tonghaosu

This dissertation includes two independent parts. The first part deals with development of new methodologies for the synthesis of epoxy functionality-containing spirocycles. The need for such methodologies stems from our earlier investigations on natural antifeedant Tonghaosu, where an expeditious access to the spirobicyclic framework based on rearrangement of 2,5-disubstituted furan was established but selective introduction of an epoxy group in the spirocycle repeatedly failed. In the present work efforts were made again in construction of an epoxy ring at the carbonsα,βto the spiroketal center. However, instead of direct modification of the spirobicyclic dienes as in the earlier endeavors, incorporation of the epoxy functionality now was attempted before the target framework took the final shape. A successful route was eventually established, consisting of m-CPBA mediated spiroketalization of the 2,5-disubstituted furan, a region- and stereo-selective Luche reduction of the intermediate enone, an epoxidation with m-CPBA, a CSA-mediated intramolecular ketal exchange reaction (which led to rearrangement of the initial spirocycle into the desired final framework), and a selenium mediated dehydration to introduce the exocyclic carbon-carbon double bond. Attempts in applying the newly established method in synthesis of (?)-AL-2, a natural product with a similar bicyclic spiro-structure, are also detailed.The second part of this thesis presents the studies on development of practical routes to the marketed anti-flu drug Tamiflu. Efforts along this line were first directed to the racemic product, which eventually led to a 12-step efficient route to Tamiflu with an overall yield of 12%. The cyclohexane framework was constructed using a Diels-Alder reaction between a protected pyrrole and a bromoacetylene, which allowed for introduction of one nitrogen atom with desired configuration from the inexpensive pyrrole after converting the initial bridged adduct into the cyclohexane by a base mediated elimination. Introduction of the second nitrogen atom of the target structure was achieved via a ring-opening substitution of a cyclic sulfate derived from the corresponding cis vicinal diol, with the relative configurations decided by the stereochemistry of the initial Diels-Alder adduct. Separation of the diastereomers of a key intermediate with the aid of an amino acid derived oxazolidinethione, the advanced intermediate was also obtained in enantiopure form, which allowed for synthesis of optically active Tamiflu.