| Autor: |
Chen, Heng, Gurung, Sing R., Nieves-Quinones, Yexenia, Hruszkewycz, Damian P., Nilson, Mark G., Jakka, Kavitha, Yin, Kehua, Hawkins, Benjamin R., Splaine, Kevin J., Slepian, Holly A., Xie, Shiping |
| Zdroj: |
The Journal of Organic Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
A critical step in the development of a convergent synthesis of an MRGPRX2 antagonist (1) was the SN2 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 (1and its HCl salt 1a) up to multikilogram scale with high selectivity and in much improved yield. |
| Databáze: |
Supplemental Index |
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