Organolithium-mediated chemoselectivity in deep eutectic solvents: basicity vs. nucleophilicity.

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over‐addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale‐up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre‐activated amides, as recommended.

Ultrafast heteroatom-directed lateral lithiation of substituted toluene derivatives using choline chloride-based eutectic mixtures as bio-inspired sustainable reaction media.

A straightforward and efficient protocol to promote the metalation/anionic Fries rearrangements of O‐aryl carbamates, using for the first time a lithium amide as metalating agent under aerobic/ambient‐friendly reaction conditions, is reported. This approach enables the sustainable preparation of salicylamide derivatives with high levels of chemoselectivity within ultrafast reaction times, working at room temperature in the presence of air/moisture, and using environmentally responsible cyclopentyl methyl ether as a solvent. Furthermore, the regioselective manipulation of O‐2‐tolyl carbamates has been accomplished using interchangeably alkyllithiums or lithium amides, with an unexpected beneficial contribution from the employment of biorenewable protic eutectic mixtures as non‐innocent reaction media.

A straightforward protocol to promote the tetrahydropyranylation of alcohols, using for the first time bioinspired acidic natural deep eutectic solvents (NADESs) as non‐innocent reaction media under mild reaction conditions, was reported. This approach enables the preparation of several tetrahydropyranyl (THP) ethers starting from primary, secondary and tertiary alcohols in short reaction times and with high levels of chemoselectivity, working under air and without the need of additional catalyst. The sustainability of the methodology was further highlighted by its scalability and the easy recyclability of the NADES, allowing multigram preparations of THP ethers without any loss of the catalytic activity of the reaction media up to ten recycling steps. Telescoped, one‐pot tetrahydropyranylation/nucleophilic acyl substitution transformations using the same eutectic mixture were also demonstrated.

The gold(I)‐catalysed cyclization of N‐tosyl‐protected 5‐benzyl‐6‐((trimethylsilyl)ethynyl)‐1,2,3,4‐tetrahydropyridines, prepared by the Sonogashira coupling of lactam‐derived enol triflates, provides tetrahydrobenzo[g]quinolines whose skeleton represents a recurrent motif in natural compounds. The Au(I)‐catalysed reaction is carried out with (C6F5)3PAuCl/AgNTf2 as the catalyst system and proceeds via a 6‐exo‐dig cyclization to form an exocyclic double bond, which eventually isomerises to the aromatic tetrahydrobenzo[g]quinoline. The mode of cyclization is discussed and supported by DFT calculations.

A mild and efficient telescoped procedure for the stereoselective alkenylation of simple, non-activated amides using LiCH2SiMe3 and carbonyl compounds as surrogates of alkenyllithium reagents is reported. Our methodology relies on the formation of stable tetrahedral intermediates, which, upon collapse into highly reactive lithium enolates in a solvent-dependent fashion, allows for the assembly of α,β-unsaturated ketones in a single synthetic operation with high stereoselectivity.

The current SARS-CoV-2 pandemic and the likelihood that new coronavirus strains will emerge in the immediate future point out the urgent need to identify new pancoronavirus inhibitors. Strigolactones (SLs) are a class of plant hormones with multifaceted activities whose roles in plant-related fields have been extensively explored. Recently, we proved that SLs also exert antiviral activity toward herpesviruses, such as human cytomegalovirus (HCMV). Here we show that the synthetic SLs TH-EGO and EDOT-EGO impair β-coronavirus replication including SARS-CoV-2 and the common cold human coronavirus HCoV-OC43. Interestingly, in silico simulations suggest the binding of SLs in the SARS-CoV-2 main protease (M pro ) active site, and this was further confirmed by an in vitro activity assay. Overall, our results highlight the potential efficacy of SLs as broad-spectrum antivirals against β-coronaviruses, which may provide the rationale for repurposing this class of hormones for the treatment of COVID-19 patients.