Silapropofol: Carbon–Silicon Isosterism in a Key Anesthetic Scaffold

Propofol (2,6-di-<i>iso</i>-propylphenol) (<b>1</b>) is one of the most widely used intravenous anesthetics, yet its high lipophilicity, formulation challenges, and incompletely understood binding mode motivate the exploration of structural analogues. Here, we report the synthesis and comprehensive characterization of the first silicon analogues of propofol, monosilapropofol (<b>2</b>) and disilapropofol (<b>3</b>), in which one or both <i>iso</i>-propyl groups are replaced by dimethylsilyl substituents. Key steps involve optimized [1,3]-retro-Brook rearrangements, with <i>tert</i>-butyllithium-mediated Li/Br exchange enabling efficient access to both targets. Crystalline potassium phenolate <b>2-K</b> provided the first X-ray diffraction analysis of a silapropofol derivative, and complementary quantum chemical analysis based on orbital, topological, and localizability descriptors revealed pronounced polarization effects and bond umpolung in this pharmacologically relevant scaffold arising from carbon-silicon isosterism. Stability studies under physiological conditions uncovered a strong divergence between the two analogues: while <b>2</b> undergoes gradual hydrolysis to 2-<i>iso</i>-propylphenol and dimethylsilanol, <b>3</b> proved remarkably robust in neutral saline solution. These findings demonstrate that silicon substitution offers a powerful strategy to modulate both electronic properties and aqueous stability in propofol derivatives, highlighting carbon-silicon isosterism as a valuable concept for anesthetic drug design.