A valuable and direct method to access 2-substituted-2-phenyloxetanes by electrophilic quenching of the corresponding 2-lithiated derivative has, for the first time, been described. 2-Lithiated-2-phenyloxetane was found to be configurationally unstable. Evidence is presented to show that electron-transfer processes are also operative in the coupling reactions with electrophiles.

Functionalized oxetanes are useful building blocks in the preparative chemistry as well as in synthesis of drugs, materials, agrochemicals [1]. In this communication we report the preliminary results of the first chemo-enzymatic synthesis of optically active 2,4-disubstituted oxetanes, prepared by cyclization of optically active 1,3-diols [2], in turn obtained by steroselective reduction of the corresponding 1,3-diketones with yeasts. The stereoselective reduction of symmetrical and nonsymmetrical substituted 1,3-diketones was investigated in the presence of some conventional and non-conventional yeast strains (Saccharomyces cerevisiae, Kluyveromyces marxianus, Baker’s yeast, etc.). Optically active aldols were obtained with high stereopreference by baker’s yeast, and then diastereoselectively converted in the corresponding diols (dr> 95%) which were then cyclized into the corresponding 2,4-disubstituted oxetanes in good yields, with high diastereoisomeric ratio (dr) and enantiomeri excess up to 80 %.

The reaction of ortho-lithiated aryloxiranes with various enaminones affords straightforwardly new functionalized isochromanes, as a mixture of two epimeric stereoisomers, in reasonable to very good yields (50-90%). The two diastereomers, which show a high structural variability, could be easily separated by column chromatography.

After a long adolescence, the chemistry of lithium carbenoids has currently been entering its maturity bringing a dowry of a more in-depth and less empirical knowledge of the structure and configurational stability of such double-faced intermediates; this, thanks in particular to the synergistic and harmonic cooperation between calculations and the most modern NMR techniques now at our disposal. Such a knowledge has stimulated the development of fruitful stereoselective applications in the field of organic synthesis providing as well a rationale to observed selectivities. Such aspects together with the role played by aggregation and solvation on the structure-reactivity relationship have been highlighted throughout this Minireview with selected examples extracted from recent literature.

In this communication we report the solution and the solid structure of -lithiated orthotrifluoromethyl styrene oxide 1-Li. Single crystal X-ray diffraction analysis of 1-Li reveals a self-assembled heterochiral dimeric structure with a rare central six-membered (O-Li-C)2 planar core, which is unprecedented in Li/oxygen carbenoids. Multinuclear magnetic resonance (1H, 13C, 19F, 7Li) studies suggest 1-Li exists in THF solution as a mixture of two interconverting diastereomeric dimeric aggregates, each one featuring a single -contact between lithium and a carbon atom.

A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer's disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC50=4.0-30.0 μΜ) and moderate ability for inhibition of Aβ1-42 self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ42 aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ1-42 induced toxicity. Structure-activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.

The presence of an electron-donating methoxy group at the 4-position of 4-phenyl-3,5-dimethyl-1,2,4-triazole is beneficial to lateral metalation/functionalization of this ring system once sBuLi is employed as the base and THF is used as the solvent at –78 °C; this opens up an alternative approach towards the synthesis of several 1,2,4-triazole derivatives. Both carbon- and heteroatom-based halides are competent electrophiles for this transformation, as are aliphatic and aromatic aldehydes and ketones, isocyanates, carboxylic acid derivatives, and alpha,beta-unsaturated carbonyl compounds. The easy elaboration of such a group to phenol derivatives also provides greater flexibility in synthetic design.

Oxetane nudges in the DoM direction! Regioselective ortho-lithiation induced by an oxetane ring has been achieved. The reaction provides easy access to ortho-functionalized 2-aryloxetanes also through a lithiation/borylation Suzuki–Miyaura cross-coupling. The lithiation-directing ability of oxetane and the proton transfer mechanism have been investigated by competitive metalation and kinetic isotope effect studies.

Reverse [3+2] cycloaddition of α-lithiated phenyltetrahydrofuran was successfully tamed at −78 °C in toluene in the presence of TMEDA, thereby providing easy access to diverse tetrahydrofuranyl-containing functional frameworks.

The National Interuniversities Consortium for Innovative Synthetic Methodologies and Processes (CINMPIS) currently includes 14 Italian universities and operates as an effective thematic network to promote technological innovation and scientific research jointly with institutions and corporates in multidisciplinary strategic sectors, spanning from agriculture, to sustainable chemistry, materials science, medicine and biotechnology.

The configurational stability of some lithiated fluorinated styrene oxides has been investigated. Chemical studies have shown that in ethereal solvents α-lithiated ortho-, meta-, and para-fluorostyrene oxides (2-Li, α-5-Li, and α-6-Li) are all configurationally stable in the reaction time scale, whereas a-lithiated ortho-, meta-, and paratrifluoromethylstyrene oxides (9-Li, 13-Li, and 14-Li) are configurationally unstable. Optically active oxiranyllithiums 2-Li and 9-Li, could be stereospecifically generated and quenched with electrophiles. The corresponding derivatives were then successfully subjected to regiospecific ring-opening reactions with amines to give fluorinated ßamino alcohols with a stereodefined quaternary carbinol center, which are useful synthons in medicinal chemistry. The barriers of inversion have been calculated (Eyring equation) for oxiranyllithiums 9-Li, 13-Li, and 14-Li by determining the enantiomeric ratios after electrophilic quenching on aging the enantioenriched organolithium for different times in THF; in the case of 9-Li, activation parameters have also been determined. Mechanisms that may be responsible of the racemization oxiranyllithiums 9-Li, 13-Li, and 14-Li undergo once generated are also discussed.

The configurational stability of some sulfurated styrene oxides has been investigated. Chemical studies have shown that in THF at 157 K α-lithiated ortho- and paraphenylthiostyrene oxides are configurationally unstable and undergo a fast racemization on the time scale of the reaction, whereas α-lithiated meta-phenylthiostyrene oxide retains its stereochemical integrity for at least 60 min. The deprotonation-trapping methodology has also been employed for the preparation of a sulfurated β-aminoalcohol effective for the fight against phytopathogenic fungi.

The conjugate addition of organometallics to nitroalkenes provides a useful method for nitro-alkylation. This type of addition is much pursued in organic synthesis as the nitro group can be easily transformed into various functional groups including carbonyl derivatives by the Nef reaction, amines by reduction, nitriles, imines by other transformations1. While 1,4-conjugated additions of organozinc reagents (R2Zn and RZnX) have been extensively studied2, applications of alkali-metal zincates in fundamental organic transformations are still in their infancy3. This type of reagents show unique, synergistic chemical characteristics which cannot be replicated by their monometallic (organolithium/organozinc) counterparts. In this Communication, we compare the kinetic reactivity of two different alkali-metal zincates (namely triorgano- and tetraorganozincates) in Deep Eutectic Solvents and under neat conditions towards variously substituted nitroalkenes. It will be shown that, under optimized reaction conditions (0 °C and with no added solvents) Michael additions promoted by aliphatic and aromatic organozincates take place with high regio- and chemoselectivity providing the expected nitroalkanes in yields to up to >98%, and with no replacement of the vinylic nitro group by the alkyl group, which often remains a complication. Isolation of key intermediates, and stereochemical aspects will be discussed as well.

The employment of hexane/TMEDA dramatically hampers racemization of those lithiated styrene oxides (trifluoromethyl-, chloro-, and thiophenyl-substituted) which have been proven to be configurationally unstable in THF on the time scale of their reactions. The barriers to inversion and the activation parameters calculated (Eyring equation) for reactions run in THF, THF/TMEDA, and hexane/TMEDA suggest the intervention of peculiar eantiomerization mechanisms for each case. The role of TMEDA in both coordinating and non-coordinating solvents has also been questioned and discussed in light of the kinetic data gathered, and a model of deprotonation in hexane/TMEDA has also been proposed. The synthetic benefits of our results became apparent by setting up an asymmetric synthesis of an industrially relevant antifungal agent.

The influence of the sulfinyl group as a chiral auxiliary in the stereoselective addition of oxiranyllithiums to (S)-2-p-tolylsulfinylbenzaldehyde has been studied. All reactions evolve with retention of configuration at the starting lithiated carbon. Completely stereoselective additions have been observed when configurations at sulfur and the lithiated carbon are different (matched pair), whereas variable dr’s values (ranging between 52:48 and >99:<1%) when they are identical (mismatched pair).

Three distinct stereoselective reactions, catalysed by using a chiral primary amine through different activation methods, have been successfully carried out for the first time in bio-based eutectic mixtures, thereby affording functionalised molecules in very high enantioselectivity. The use of these unconventional and biorenewable reaction media also provides opportunities for facilitating the recovery and the recycling of the chiral catalyst.

An efficient one-pot double Suzuki-Miyaura cross--coupling reaction between bifunctional phenylene-1,4-bis(potassium trifluoroborate) and aryl and heteroaryl bromides is described. The scope and limitations of this methodology that enables the synthesis of tri(hetero)aryl derivatives, potentially useful as drugs and in the field of materials science, have also been probed.

It has always been a firm conviction of the scientific community that the employment of both anhydrous conditions and water-free reaction media is required for the successful handling of organometallic compounds with highly polarised metal–carbon bonds. Herein, we describe how, under heterogeneous conditions, Grignard and organolithium reagents can smoothly undergo nucleophilic additions to gchloroketones, on the way to 2,2-disubstituted tetrahydrofurans, “on water”, competitively with protonolysis, under batch conditions, at room temperature and under air. The reactivity of the above organometallic reagents has also been investigated in conventional anhydrous organic solvents and in bio-based eutectic and low melting mixtures for comparison. The scope and limitations of this kind of reaction are discussed.