Synthesis of gemcitabine and it's tetrafluorinated analogues

A novel synthesis of the 2-deoxy-2,2-difluorocytidine nucleoside analogue gemcitabine has been achieved. Starting from the known 3,5-O-dibenzoyl-2- deoxy-2,2-difluororibose, the nucleobase moiety is constructed in a linear fashion, using amino- or urea glycosylation methodology. This methodology has also been employed to synthesise nucleosides containing a tetrafluorinated ribose sugar and has been compared to conventional convergent nucleobase introduction methods. In this respect, a high-yielding Mitsunobu-based protocol has also been developed. Both purine and pyrimidine analogues have been synthesised. The aminoglycosylation methodology has been investigated with a range of amines. The methodology proves high-yielding for primary amines and lesshindered secondary amines. In contrast to expectations, their stability in acidic media was not very high. Anomerisation and ring isomerisation studies have been conducte