The incorporation of silicon and synthesis of organosilicon small molecules provide unique opportunities for medicinal applications. The biological investigation of organosilicon small molecules is particularly interesting because of differences in their chemical properties that can contribute to enhanced potency and improved pharmacological attributes. Applications such as inhibitor design, imaging, drug release technology, and mapping inhibitor binding are discussed.

The importance of cooperative hydrogen-bonding effects and SiOH-acidification is described for silanediol catalysis. NMR binding, X-ray, and computational studies provide support for a unique dimer resulting from silanediol self-recognition. The significance of this cooperative hydrogen-bonding is demonstrated using novel fluorinated silanediol catalysts for the addition of indoles and N,N-dimethyl-m-anisidine to trans-β-nitrostyrene.

A series of new 1,3-disiloxanediols has been synthesized, including naphthyl-substituted and unsymmetrical siloxanes, and demonstrated as a new class of anion-binding catalysts. In the absence of anions, diffusion-ordered spectroscopy (DOSY) displays self-association of 1,3-disiloxanediols through hydrogen-bonding interactions. Binding constants determined for 1,3-disiloxanediol catalysts indicate strong hydrogen-bonding and anion-binding abilities with unsymmetrical siloxanes displaying different hydrogen-bonding abilities for each silanol group.

1,3-Disiloxanediols are effective hydrogen-bonding catalysts that exhibit enhanced activity relative to silanediols and triarylsilanols. The catalytic activity for a series of 1,3-disiloxanediols, including naphthyl-substituted and unsymmetrical siloxanes, has been quantified and compared relative to other silanol and thiourea catalysts using the Friedel Crafts addition of indole to trans-β-nitrostyrene. An in-depth kinetic study using reaction progress kinetic analysis (RPKA) has been performed to probe the catalyst behavior of 1,3-disiloxanediols. The data confirm that the disiloxanediol-catalyzed addition reaction is first order in catalyst over all concentrations studied with no evidence of catalyst self-association. 1,3-Disiloxanediols proved to be robust and recoverable catalysts with no deactivation under reaction conditions. No product inhibition is observed, and competitive binding studies with nitro-containing additives suggest that 1,3-disiloxanediols bind weakly to nitro groups but are strongly activating for catalysis.

We report the Lewis acid catalyzed additions of allylsilanes to N-Boc-iminooxindoles and the formation of novel silicon-containing spirocarbamates via intramolecular trapping of a β-silyl carbocation by an N-Boc group. Several transformations display the synthetic utility of these spirocarbamate oxindoles, including a reductive cyclization to access new silylated furoindoline derivatives.

The synthesis, isolation, and hydrogen-bonding properties of a series of amide-containing silanediols are described, including an enantioenriched silanediol. By incorporation of a 2,4,6-trimethylphenyl (mesityl) group, these functionalized silanediols are isolable by column chromatography and stable in the presence of standard acids (e.g., AcOH) and bases (e.g., NH 4 OH). NMR spectroscopy and X-ray crystallography provide evidence for the conformational rigidity and binding properties of amido-silanediols based on the parameters (e.g., sterics, hybridization, and ring size of hydrogen bonding) that affect intra-and intermolecular hydrogen bonding. Pyridine binding studies demonstrate that these conformational effects have implications for the existence of single versus multiple modes of hydrogen bonding.

X-ray crystallography showcases the distinct self-association and hydrogen-bonding patterns of organic silanediols, R2Si(OH)2, with bifunctional heterocycles for supramolecular assembly. Diffusion-ordered spectroscopy (DOSY) studies identify the dominant hydrogen-bonding patterns and structures in solution, which correlate with solid-state patterns at high concentrations.

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