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ProTides comprise an important class of prodrugs currently marketed and developed as antiviral and anticancer therapies. The ProTide technology employs a phosphate masking groups capable of providing more favorable drug-like properties and an intracellular activation mechanism for enzyme-mediated release of a nucleoside monophosphate. Herein we describe the application of phosphoramidate chemistry to 1,3,4-O-acetylated N-acetylmannosamine (Ac3ManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG) caused by mutations in GNE that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac3ManNAc-6phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug 12b showed rapid activation in a carboxylesterase (CPY) enzymatic assay and favorable ADME properties, while also being more effective than ManNAc at increasing sialic acid levels in GNE-deficient cell lines than ManNAc. These 2 results provide a potential platform to address substrate deficiencies in GNE myopathy and other CDGs.

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This review summarizes recent contributions on the use of fluoride catalysts immobilized on polymer supports. Besides the commercially available Amberlyst fluoride, TBAF on silica gel, and TBAF on alumina, that have proved widely useful for several interesting and valuable synthetic C-N, CO , and CC bond transformations, novel catalysts based on the DABCO moiety have allowed access to very useful, new transformations. 1 Introduction 2 Polystyryl-DABCOF 2 3 Polystyryl-DABCOF 4 Amberlyst Fluoride (Amb-F) 5