Inhibition of Kornblum Reaction with Lithium Salts in SN2 Reactions of Sulfonates and a Nucleophile Containing a Pyridine N-Oxide Moiety: Convergent and Selective Synthesis of an MRGPRX2 Antagonist

A critical step in the development of a convergent synthesis of an MRGPRX2 antagonist (1) was the S_N2 reaction with a highly functionalized lactamide electrophile and a unique difluoropiperidine nucleophile containing a pyridine N-oxide moiety. Initial reactions with sulfonate leaving groups exhibited superb stereoselectivity, but yields were very low due to side reactions originated from competitive Kornblum reactions of the pyridine N-oxide and the sulfonates. Markedly improved reaction profiles were achieved by including stoichiometric lithium triflate. NMR data provided insights into how the lithium cation impacted the pyridine N-oxide through coordination and attenuating its nucleophilicity, leading to the inhibition of the undesired Kornblum reactions. Our approach is highly relevant to preservation of the N-oxide, a structural motif known to several marketed products and emerging as an important class in drug discovery in nucleophilic substitutions. Application of this method enabled the production of the target (1 and its HCl salt 1a) up to multikilogram scale with high selectivity and in much improved yield.