Ir-Catalyzed Borylation as an Efficient Route to a Nicotine Hapten

The process development of a nicotine analog or hapten (<b>1</b>) for conjugation to a protein as an antigen is described. The original process in early development used an Ir-catalyzed borylation reaction to enable rapid derivatization of nicotine with the desired regiocontrol. While the process was very efficient, it required chromatography to meet purity targets. A related process was later developed that possessed crystalline intermediates to better control levels of process-related impurities and heavy metals in <b>1</b>. This control strategy for <b>1</b> was essential due to the strict purity requirements for conjugation of <b>1</b> when forming an antigen. In addition, the Ir-catalyzed borylation was studied to enable robust manufacture via this methodology which led to an efficient process for the preparation of <b>1</b>

Synthesis of Filibuvir. Part II. Second-Generation Synthesis of a 6,6-Disubstituted 2<i>H</i>‑Pyranone via Dieckmann Cyclization of a β‑Acetoxy Ester

This paper describes an improved sequence for the conversion of an oxazolidinone (<b>3</b>) to a β-keto lactone (<b>5</b>). The primary drivers behind this change were the modest and variable yields observed in the intramolecular cyclization to generate the β-keto lactone. Changing the cyclization substrate from oxazolidinone to alkyl ester offered a significantly improved cyclization, as well as improvements in the alkyne hydrogenation. Selection of the optimal substrates for methanolysis and intermediate salt formation are also described