Synthesis of Isotopically Labeled Anti-HIV Nucleoside Islatravir through a One-Pot Biocatalytic Cascade Reaction

Abstract

We report the synthesis of the carbon-14-labeled unnatural nucleoside islatravir, an investigational HIV drug, through a one-pot biocatalytic cascade starting from acetaldehyde-2-14 C. Combining enzymatic reactions into multistep biocatalytic cascades accelerates delivery and increases the yield, and in this synthesis it has the added benefits of eliminating handling of radioactive intermediates and minimizing radioactive waste.

Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges

“…This labeled adenosine-based nucleoside reverse transcriptase translocation inhibitor, under investigation for the treatment of HIV infection, was required to support drug metabolism and pharmacokinetics studies. 99 …”

“…In 2021, Ren and co-workers from Merck published a biocatalytic synthesis of [ 14 C]­islatravir 46 (Scheme , top). This labeled adenosine-based nucleoside reverse transcriptase translocation inhibitor, under investigation for the treatment of HIV infection, was required to support drug metabolism and pharmacokinetics studies …”

“…98 In 2021, Ren and co-workers from Merck published a biocatalytic synthesis of [ 14 translocation inhibitor, under investigation for the treatment of HIV infection, was required to support drug metabolism and pharmacokinetics studies. 99 Their chemical radiosynthesis started from [ 14 C]t-butyl acetate 45, providing 46 in an overall 6% RCY, in 9 linear steps. The low yield and the high cost, time, and waste generated by this approach necessitated the development of a "greener" alternative.…”

The Catalysis Laboratory at Merck: 20 Years of Catalyzing Innovation

“…Capitalizing on the recent biocatalytic cascade synthesis of islatravir, 115 our team was able to substitute 2-14 C-acetadehyde (93) into the unlabeled synthetic scheme to prepare [ 14 C]islatravir (94) in an efficient, inexpensive, and safe fashion (Scheme 30). 116 Compared to the previous radiolabeled synthesis, this new process resulted in a 5-fold improvement in radiochemical yield and a 6-fold reduction in manufacturing time, showing the value of biocatalytic transformations in the synthesis of complex radiolabeled pharmaceutical molecules.…”

Chemical and chemoenzymatic stereoselective synthesis of β-nucleosides and their analogues

“…This groundbreaking biocatalytic total synthesis of islatravir, involving a one-pot biocatalytic cascade of highly diastereoselective aldol-glycosylation, phosphorylation, and transglycosylation, was able to compete with the chemoenzymatic synthesis of islatravir. 68…”