Scalable syntheses of traceable ribosylated NAD⁺ precursors

Nicotinamide adenine dinucleotide, NAD⁺, is an essential cofactor and substrate for many cellular enzymes. Its sustained intracellular levels have been linked to improved physiological end points in a range of metabolic diseases. Biosynthetic precursors to NAD⁺ include nicotinic acid, nicotinamide, the ribosylated parents and the phosphorylated form of the ribosylated parents. By combining solvent-assisted mechanochemistry and sealed reaction conditions, access to the ribosylated NAD⁺ precursors and to the isotopologues of NAD⁺ precursors was achieved in high yields and levels of purity. The latter is critical as it offers means to better trace biosynthetic pathways to NAD⁺, investigate the multifaceted roles of the intracellular NAD⁺ pools, and better exploit NAD⁺ biology.