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International audience; Bioorthogonal click and release reactions are powerful tools for chemical biology allowing, for example, the selective release of drugs in biological media, including inside animals. Here we developed two new families of iminosydnone mesoionic reactants that allow a bioorthogonal release of electrophilic species under physiological conditions. Their synthesis and reactivities as dipoles in cycloaddition reactions with strained alkynes have been studied in detail. Whereas the impact of the pH on the reaction kinetics was demonstrated experimentally, theoretical calculations suggest that the newly designed dipoles display reduced resonance stabilization energies compared to previously described iminosydnones explaining their higher reactivity. These mesoionic compounds react smoothly with cycloalkynes under physiological, copper-free reaction conditions to form a click pyrazole product together with a released alkyl-or aryl-isocyanate. With kinetic constants up to 1000 M-1 s-1 , this click and release reaction is among the fastest described to date, and represents the first bioorthogonal process allowing the release of isocyanate electrophiles inside living cells offering interesting perspectives in chemical biology.

Herein, we describe a methodology for iminosydnone chlorination and we demonstrate the high beneficial effect of this modification on the reactivity of these mesoionic dipoles in strain-promoted cycloaddition reactions. Exploiting their reaction with cyclooctynes, we used these new iminosydnones for bioorthogonal release of amide, urea and sulfonamide containing drugs. Notably, drugs containing a terminal amide function were released for the first time with good kinetic constants.

Two similar tridentate directing groups derived from glycine and 8-aminoquinoline were shown to enable the palladium-catalyzed anti-Markovnikov hydrofunctionalization of 4-pentenylamine with drastically different efficiencies. A computational investigation into the origin of the reactivity difference between these isomeric, carbonyl-transposed auxiliaries suggests that protonation state, thus charge of the substrate-metal complex prior to nucleopalladation is key. These investigations have culminated in a directing group design that can undergo Pd-catalyzed hydrofunctionalization under relatively mild conditions, as low as room temperature.

We describe the first thiourea-catalyzed C-F bond activation. The use of a thiourea catalyst and Ti(OiPr)4 as a fluoride scavenger allows the amination of benzylic fluorides to proceed in moderate to excellent yields. Preliminary results with S- and O-based nucleophiles are also presented. DFT calculations reveal the importance of hydrogen bonds between the catalyst and the fluorine atom of the substrate to lower the activation energy during the transition state.

A photoinitiated anti -hydropentafluorosulfanylation of terminal alkynes using SF 5 Cl and (TMS) 3 SiH as the hydrogen atom donor is reported. This transformation generates selectively ( Z ) - (1-alken-1-yl)pentafluoro-λ 6 -sulfanes ( Z:E : >85:15), thus allowing the preparation of this previously unknown geometrical isomer. DFT calculations highlight that the selectivity is due to the intrinsic preference of SF 5 -substituted vinylic radicals to adopt a cis geometry, and to increased steric contacts during the transition structures leading to the minor ( E )-products.

The first catalytic intermolecular desymmetrization of azetidines was reported by Sun and coworkers in 2015 using a BINOL-derived phosphoric acid catalyst (J. Am. Chem. Soc. 2015, 137, 5895–5898). To uncover the mechanism of the reaction and the origins of the high enantioselectivity, Density Functional Theory (DFT) calculations were performed at the B97D3/6-311+G(2d,2p)/SMD(toluene)//B97D3/6-31G(d,p)/CPCM(toluene) level of theory. Comparison of four possible activation modes confirms that this reaction proceeds through the bifunctional activation of the azetidine nitrogen and the thione tautomer of the 2-mercaptobenzothiazole nucleophile. Upon thorough conformational sampling of the enantiodetermining transition structures (TSs), a free energy difference of 2.0 kcal mol−1 is obtained, accurately reproducing the experimentally measured 88% e.e. at 80 °C. This energy difference is due to both decreased distortion and increased non-covalent interactions in the pro-(S) TS. To uncover the true origins of selectivity, the TSs optimized with the full catalyst were compared to those optimized with a model catalyst through steric maps. It is found that the arrangements displayed by the substrates are controlled by strict primary orbital interaction requirements at the transition complex, and their ability to fit into the catalyst pocket drives the selectivity. A general model of selectivity for phosphoric acid-catalyzed azetidine desymmetrizations is proposed, which is based on the preference of the nucleophile and benzoyl group to occupy empty quadrants of the chiral catalyst pocket., The origins of selectivity in azetidine desymmetrizations have been determined computationally. Comparison of structures with model and full catalysts provided key details missed by typical analyses of the stereodetermining transition structures.

The relative rates of arylation of primary alkylamines with different Pd-NHC catalysts have been measured, as have the relative rates of arylation of the secondary aniline product in an attempt to understand the key ligand design features necessary to have high selectivity for the monoarylated amine product. As the substituents on the N-aryl ring of the NHC increase in size, selectivity for monoarylation increases and this is further enhanced by chlorinating the back of the NHC ring. Computations have been performed on the catalytic cycle of this transformation in order to understand the selectivity obtained with the different catalysts.

We report a general and rapid chemoselective Kumada-Tamao-Corriu (KTC) cross-coupling of aryl bromides in the presence of chlorides or triflates with functionalized Grignard reagents at 0 °C in 15 min by using Pd-PEPPSI-IPentCl (C4). Nucleophiles and electrophiles (or both) can contain Grignard-sensitive functional groups (-CN, -COOR, etc.). Control experiments together with DFT calculations suggest that transmetallation is rate limiting for the selective cross-coupling of Br in the presence of Cl/OTf with functionalized Grignard reagents. One-pot sequential KTC/KTC cross-couplings with bromo-chloro arenes have been demonstrated for the first time. We also report the one-pot sequential KTC/Negishi cross-couplings using C4 showcasing the versatility of this methodology.

Alkenes bearing four carbon-based groups are ubiquitous motifs in chemical sciences due to their various applications from medicinal to materials chemistry, and as chemical platforms for the synthesis of complex, chiral molecules. As such, tremendous research efforts are currently ongoing in order to develop general procedures for the challenging stereoselective synthesis of all-carbon tetrasubstituted alkenes, especially for acyclic structures. Since classical approaches to carbon–carbon double bonds are not suitable for the high steric demand around tetrasubstituted alkenes, a variety of unique approaches to access these privileged functional groups have been developed in recent years. This review article highlights the most significant developments in the field from 2007 to 2020, with an emphasis on the mechanisms and remaining limitations of these contemporary methods. Specifically, recent advances in internal alkyne carbofunctionalizations, in multicomponent couplings or other cross-couplings from nucleophilic or electrophilic alkenyl partners, and in the development of miscellaneous methods, are discussed.

The first approach to pyrazole-containing helicenes via sydnone-aryne [3 + 2]-cycloaddition is described. An unprecedented regioselectivity in the cycloaddition step toward the more sterically constrained product was observed in the presence of extended aromatic scaffolds. DFT calculations enabled understanding the origin of this unexpected selectivity.

Density functional theory methods were used to elucidate the activation mode and origin of stereoselectivity in chiral phosphoric acid-catalyzed intramolecular oxetane desymmetrizations. Computed enantioselectivities are in excellent agreement with experiment. An unexpected, distortion-driven activation mode was observed, instead of the usual “bifunctional activation”. This mode is favored for only some intramolecular oxetane openings, highlighting an exception to known models. Stereoselectivity in these reactions can be explained by the balance of favorable noncovalent interactions of the substrates with both the aryl substituents and phosphoric acid functionality of the catalysts.

A practical method for radiofluorination of anilines with [18F]fluoride via N-arylsydnone intermediates is described. These precursors are stable, easy to handle and facilitate direct and regioselective 18F-labeling to prepare [18F]fluoroarenes. The value of this methodology is further highlighted by successful application to prepare an 18F-labeled neuropeptide.

Sulfonamide derivatives have been used in pharmaceutics for decades. Here we report a new approach to release sulfonamides efficiently using a bioorthogonal reaction of sulfonyl sydnonimines and dibenzoazacyclooctyne (DIBAC). The second-order rate constant of the cycloaddition reaction can be up to 0.62 M−1 s−1, and the reactants are highly stable under physiological conditions. Most significantly, we also discovered the mutual orthogonality between the sydnonimine–DIBAC and benzonorbornadiene–tetrazine cycloaddition pairs, which can be used for selective and simultaneous liberation of sulfonamide and primary amine drugs.

The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we report in vitro and computational analyses leading to the discovery of a hemocyanin-like protein AsqI from the Aspergillus nidulans aspoquinolone biosynthetic pathway that forms viridicatins via a conversion of the cyclopenin-type 6,7-bicyclic system into the viridicatin-type 6,6-bicyclic core through elimination of carbon dioxide and methylamine through methyl isocyanate., Viridicatin is a fungal alkaloid. Here, the authors identify and characterize the cyclopenase that catalyzes the last step of its biosynthesis in Aspergillus nidulans, the conversion of cyclopenin to viridicatin, and find that the reaction proceeds via an unusual elimination mechanism.

Experimental and theoretical evidence is reported for a rare type I dyotropic rearrangement involving a [1,2]-alkene shift, leading to the regio- and stereospecific ring contraction of bromocycloheptenes. This reaction occurs under mild conditions, with or without a Lewis acid catalyst. DFT calculations show that the reaction proceeds through a nonclassical carbocation-anion pair, which is crucial for the low activation barrier and enantiospecificity. The chiral cyclopropylcarbinyl cation may be a transition state or an intermediate, depending on the reaction conditions.

Experimental and computational studies pertaining to the Fischer azaindolization reaction are reported. These studies explain why pyridylhydrazines are poorly reactive in Fischer indolization reactions, in addition to the origin of hydrazine substituent effects. Additionally, an interrupted variant of Fischer azaindolization methodology is disclosed, which provides a synthetic entryway into fused azaindoline scaffolds.

The origins of the high enantioselectivity of chiral phosphoric acid-catalyzed oxetane desymmetrizations were investigated by density functional theory (DFT) calculations. Distortion of the catalyst structure, caused by steric crowding in the catalyst pocket of one enantiomeric transition state, is the main cause for stereochemical preference. A general model was developed to assist in the rational design of new catalysts for related transformations.

A Friedel-Crafts benzylation of arenes with benzyl fluorides has been developed. The reaction produces 1,1-diaryl alkanes in good yield under mild conditions without the need for a transition metal or a strong Lewis acid. A mechanism involving activation of the C-F bond through hydrogen bonding is proposed. This mode of activation enables the selective reaction of benzylic C-F bonds in the presence of other benzylic leaving groups.