The synthesis of stable isotope labeled (SIL) complex drug molecules with >= 3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on H-2, C-13, and N-15 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 S-34. The synthetic utility of S-34 was demonstrated with the efficient synthesis of [S-34]phosphorothioates [S-34(2)]-PS-ODNs-TTT and [C-13, N-15, S-34]-ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [S-34]phosphorothioates using elemental S-34 without isotope dilution was developed.
