Enantioselective Synthesis of Chiral α‑Azido and α‑Aryloxy Quaternary Stereogenic Centers via the Phase-Transfer-Catalyzed α‑Alkylation of α-Bromomalonates, Followed by S_N2 Substitution

A new efficient synthetic method for chiral α-azido-α-alkylmalonates and α-aryloxy-α-alkylmalonates was developed. The enantioselective α-alkylation of diphenylmethyl <i>tert</i>-butyl α-bromomalonate under phase-transfer catalytic conditions [(<i>S</i>,<i>S</i>)-3,4,5-trifluorophenyl-NAS bromide, 50% KOH, toluene, and −40 °C) provided the corresponding α-bromo-α-alkylmalonates in high chemical yields (≤98%) and high optical yields (≤99% ee). The resulting α-alkylated products were converted to α-azido-α-alkylmalonates (≤96%, ≤97% ee) and α-aryloxy-α-alkylmalonates (≤79%, ≤93% ee) by S_N2 substitution with sodium azide and aryloxides, respectively

Discovery of 2‑((<i>R</i>)‑4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)‑<i>N</i>‑((1<i>R</i>,2<i>s</i>,3<i>S</i>,5<i>S</i>,7<i>S</i>)‑5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide (SKI2852): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11β-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound <b>9</b>. The combination of the replacement of a pyridine ring of <b>9</b> with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, <b>18a</b> (SKI2852), which demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity. Repeated oral administration of <b>18a</b> significantly reduced blood glucose and HbA1c levels and improved the lipid profiles in <i>ob</i>/<i>ob</i> mice. Moreover, the HbA1c-lowering effect of metformin was synergistically enhanced in combination with <b>18a</b>