Nucleoside analogues are ubiquitous in nature and are critical component of life-saving therapies used in the treatment of viral disease and cancer. Despite their widespread use and commercial value, the state-of-the-art methods for their preparation in drug discovery, drug development and eventual commercialization are lacking and remain a poorly solved problem in organic synthesis. In addition to posing synthetic challenges, custom nucleoside total synthesis presents several challenges with respect to green and sustainable chemistry, where current methods largely rely on chiral pool feedstocks and protecting group chemistry. We have developed a suite of novel methods for the synthesis and scale-up of nucleosides, as exemplified by the synthesis of MK-8591 for the treatment of HIV infection. These efforts have culminated in an aspirational synthesis from commodity chemicals using a biocatalytic in-vitro cascade for construction of the nucleoside.