Aurélien de la Torre

Chemo- and Stereoselective Transition-Metal-Free Amination of Amides with Azides.

The synthesis of α-amino carbonyl/carboxyl compounds is a contemporary challenge in organic synthesis. Herein, we present a stereoselective α-amination of amides employing simple azides that proceeds under mild conditions with release of nitrogen gas. The amide is used as the limiting reagent, and through simple variation of the azide pattern, various differently substituted aminated products can be obtained. The reaction is fully chemoselective for amides even in the presence of esters or ketones and lends itself to preparation of optically enriched products.

Flexible and Chemoselective Oxidation of Amides to α-Keto Amides and α-Hydroxy Amides

A suite of flexible and chemoselective methods for the transition-metal-free oxidation of amides to α-keto amides and α-hydroxy amides is presented. These highly valuable motifs are accessed in good to excellent yields and stereoselectivities with high functional group tolerance. The utility of the method is showcased by the formal synthesis of a potent histone deacetylase inhibitor.

Synthesis, Discovery, and Quantitation of Dihomo‐Isofurans: Biomarkers for In Vivo Adrenic Acid Peroxidation

The growing importance of lipidomics, and the interest of non-enzymatic metabolites of polyunsaturated fatty acids (PUFAs) prompted us to initiate the synthesis of novel dihomo-IsoF compounds. Such metabolites of adrenic acid, the main PUFA in white matter, were synthesized using a divergent approach based on an orthoester cyclization. LC-MS/MS investigation on pig brains showed the potential of this novel biomarker for the first time, as a powerful new tool for brain lipid peroxidation assessment.

Total Syntheses and In Vivo Quantitation of Novel Neurofuran and Dihomo‐isofuran Derived from Docosahexaenoic Acid and Adrenic Acid

Neurofurans (NeuroFs) and dihomo-isofurans (dihomo-IsoFs) are produced in vivo by non-enzymatic free-radical pathways from docosahexaenoic and adrenic acids, respectively. As these metabolites are produced in minute amounts, their analyses in biological samples remain challenging. Syntheses of neurofuran and dihomo-isofurans described are based on a pivotal strategy, thanks to an enantiomerically enriched intermediate, which allowed, for the first time, access to both families: the alkenyl and enediol. Owing to this formation, quantitation of specific NeuroF and dihomo-IsoFs in biological samples was attainable.

Direct Regioselective Synthesis of Tetrazolium Salts by Activation of Secondary Amides under Mild Conditions

Tetrazolium salts are biologically active molecules that have found broad applications in biochemical assays. A regioselective synthesis of tetrazolium salts is described through a formal (3 + 2) cycloaddition. The possibility of employing simple amides and azides as starting material and the mild conditions allow a broad functional group tolerance.

Ynamide Preactivation Allows a Regio- and Stereoselective Synthesis of α,β-Disubstituted Enamides

A novel ynamide preactivation strategy enables the use of otherwise incompatible reagents and allows preparation of α,β-disubstituted enamides with high regio- and stereoselectivity. Mechanistic analysis reveals the intermediacy of a triflate-bound intermediate as a solution-stable, effective keteniminium reservoir, whilst still allowing subsequent addition of organometallic reagents.

Reversing polarity: Carbonyl α-aminations with nitrogen nucleophiles

The synthesis of α-amino carbonyl compounds is an important challenge in synthesis en route to biologically essential structures. While classical approaches involve the use of enol or enolate chemistries in combination with an electrophilic source of nitrogen, those strategies usually necessitate further transformations to reach the desired targets. In recent years, a new approach arose involving the direct use of nucleophilic sources of nitrogen along with an oxidant. This approach advantageously leads, in one-pot, to the biologically relevant α-amino compound without requiring further transformation. This review highlights the recent advances in the emerging field of oxidative α-amination reactions using nucleophilic sources of nitrogen.

C−H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity

Abstract We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C−H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (−)‐quinine, the first synthesis of unnatural (+)‐quinine, and also provides access to unprecedented C3‐aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (−)‐quinine both in vitro and in mice infected with Plasmodium berghei.