# Silapropofol: Carbon–Silicon Isosterism in a Key Anesthetic Scaffold

## TL;DR

Scientists created silicon-based versions of the anesthetic propofol and found that these analogs have different stability and electronic properties.

## Contribution

The first synthesis and characterization of silicon analogs of propofol, revealing new insights into carbon–silicon isosterism in drug design.

## Key findings

- Monosilapropofol (2) undergoes gradual hydrolysis under physiological conditions.
- Disilapropofol (3) is remarkably stable in neutral saline solution.
- Silicon substitution alters electronic properties and stability in propofol derivatives.

## Abstract

Propofol (2,6-di-iso-propylphenol) (1) 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 (2) and disilapropofol (3), in which one or both iso-propyl groups are replaced by dimethylsilyl substituents.
Key steps involve optimized [1,3]-retro-Brook rearrangements, with tert-butyllithium-mediated Li/Br exchange enabling efficient
access to both targets. Crystalline potassium phenolate 2-K 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 2 undergoes gradual hydrolysis to
2-iso-propylphenol and dimethylsilanol, 3 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.