General Last-Step Labeling of Biomolecule-Based Substrates by [¹²C], [¹³C], and [¹¹C] Carbon Monoxide

Alkaloid-, steroid-, biotin-, carbohydrate-, nucleoside-, and peptide-based bioconjugates are easily labeled with CO by a last-step palladium-catalyzed carbonylation. The choice of the [¹²C], [¹³C], or [¹¹C] isotope opens the way to a new class of potential tracers or ligands easily available for various applications

Diastereoselective Three-Component Vinylogous Mannich Reaction of Nitrogen Heterocycles, Acyl/Sulfonyl Chlorides, and Silyloxyfurans/pyrroles

A one-step, 3-component vinylogous Mannich reaction of trimethylsilyloxyfuran or <i>N</i>-protected <i>tert</i>-butyldimethylsilyloxypyrrole with a variety of nitrogen-containing heterocycles in the presence of diverse electrophiles is described. The reaction products were generally obtained in high yields and as a single diastereoisomer having the (<i>R</i>*,<i>R</i>*) relative configuration based on crystallographic studies of several derivatives. Several azaheterocycles were successfully used for this reaction, such as isoquinolines, quinoline, phenanthridine, quinazoline, phthalazine, and β-carboline, and electrophiles included acetyl chloride, methyl chloroformate, methyl chloromalonate, 2-bromobutanoyl chloride, and arylsulfonyl chlorides. The products of the vinylogous Mannich reactions were subjected to further transformations, leading to highly functionalized and stereochemically defined tetracyclic derivatives that are valuable building blocks for the preparation of natural products or medicinal agents

Diastereoselective Three-Component Vinylogous Mannich Reaction of Nitrogen Heterocycles, Acyl/Sulfonyl Chlorides, and Silyloxyfurans/pyrroles

A one-step, 3-component vinylogous Mannich reaction of trimethylsilyloxyfuran or <i>N</i>-protected <i>tert</i>-butyldimethylsilyloxypyrrole with a variety of nitrogen-containing heterocycles in the presence of diverse electrophiles is described. The reaction products were generally obtained in high yields and as a single diastereoisomer having the (<i>R</i>*,<i>R</i>*) relative configuration based on crystallographic studies of several derivatives. Several azaheterocycles were successfully used for this reaction, such as isoquinolines, quinoline, phenanthridine, quinazoline, phthalazine, and β-carboline, and electrophiles included acetyl chloride, methyl chloroformate, methyl chloromalonate, 2-bromobutanoyl chloride, and arylsulfonyl chlorides. The products of the vinylogous Mannich reactions were subjected to further transformations, leading to highly functionalized and stereochemically defined tetracyclic derivatives that are valuable building blocks for the preparation of natural products or medicinal agents

Last-Step Pd-Mediated [¹¹C]CO Labeling of a Moxestrol-Conjugated <i>o</i>‑Iodobenzyl Alcohol: From Model Experiments to in Vivo Positron Emission Tomography Studies

The fast, efficient, and functional group tolerant last-step radiolabeling of bioconjugates is crucial for positron emission tomography (PET) applications. In this context, <i>o</i>-iodobenzyl alcohol based structures were identified as ideal tags for an easy Pd-catalyzed carbonylation after bioconjugation, and a moxestrol-conjugated precursor was chosen as the model compound for the further studies. Despite scale and time constraints, conditions developed with [¹²C]­CO and [¹³C]­CO were easily transferred to the ¹¹C isotope, and the desired radioactive product was obtained in amounts up to 740 MBq with radiochemical purities higher than 99%. Radio-high-performance liquid chromatography analyses of rat blood samples demonstrated excellent in vivo stability within the time of the acquisition. MicroPET–magnetic resonance imaging showed excretion pathways similar to moxestrol, and molecular modeling was also performed to evaluate the potential ability of this conjugate to bind estrogen receptors α. Thus, being both synthetically and biologically suitable, this strategy clears the path to potential novel biotracers for preclinical PET imaging