34S: A new opportunity for the efficient synthesis of stable isotope labeled compounds

The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on 2H, 13C, and 15N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of 34S. The synthetic utility of 34S was demonstrated with the efficient synthesis of [34S]phosphorothioates [34S2]‐PS‐ODNs‐TTT and [13C, 15N, 34S]‐ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [34S]phosphorothioates using elemental 34S without isotope dilution was developed.