S: 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 H, C, and N 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. The synthetic utility of S was demonstrated with the efficient synthesis of [ S]phosphorothioates [ S ]-PS-ODNs-TTT and [ C, N, S]-ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [ S]phosphorothioates using elemental S without isotope dilution was developed.