A new N-heterocyclic carbene (NHC)-catalyzed strategy for the regioselective monoesterification of isosorbide (IS) at either the endo (5-OH) or exo (2-OH) position is described. Site-selective acylation proceeds under oxidative conditions in the presence of a quinone oxidant using aldehydes as mild acylating agents. Experimental evidences suggest a role of the stereoelectronic features of the acyl azolium salt intermediate in determining the selectivity of the acylation process. The solvent effect was also investigated, considering conventional and sustainable solvents. Aromatic aldehydes, including bio-based furfural and 5-hydroxymethyl furfural, together with α,β-unsaturated aldehydes proved to be effective reaction partners affording monoacyl-isosorbides with satisfactory levels of regioselectivity (exo/endo: 5.3−3.5; endo/exo: 5.3−3.3). Additionally, the exo-selective triazolium salt promoter was successfully transferred into the heterogeneous phase and applied to continuous-flow catalysis. In particular, the polystyrenesupported version of the selected NHC showed a catalytic activity comparable to that of the homogeneous counterpart in terms of both conversion efficiency (turnover number = 108) and regioselectivity (exo/endo up to 5.3). Also, the corresponding packed-bed mesoreactor was operated with long-term stability (ca. 110 h on stream) to produce 2-benzoyl-IS (1.32 mmol h −1 mmol cat −1 ), which is the key intermediate in the synthesis of a commercial active pharmaceutical ingredient, namely, the vasodilator isosorbide-5mononitrate.

The polycondensation of diamines and dialdehydes promoted by an N‐heterocyclic carbene (NHC) catalyst in the presence of a quinone oxidant and hexafluoro‐2‐propanol (HFIP) is herein presented for the synthesis of oligomeric polyamides (PAs), which are obtained with a number‐average molecular weight (Mn) in the range of 1.7–3.6 kg mol−1 as determined by NMR analysis. In particular, the utilization of furanic dialdehyde monomers (2,5‐diformylfuran, DFF; 5,5’‐[oxybis(methylene)]bis[2‐furaldehyde], OBFA) to access known and previously unreported biobased PAs is illustrated. The synthesis of higher molecular weight PAs (poly(decamethylene terephthalamide, PA10T, Mn = 62.8 kg mol−1; poly(decamethylene 2,5‐furandicarboxylamide, PA10F, Mn = 6.5 kg mol−1) by a two‐step polycondensation approach is also described. The thermal properties (TGA and DSC analyses) of the synthesized PAs are reported.

A novel N‐heterocyclic carbene (NHC)‐promoted regiodivergent protocol for exo (2‐OH) and endo (5‐OH) isosorbide (IS) imidates synthesis is described. The disclosed strategy allows the straightforward synthesis of monoimidate‐isosorbides (MIIs) endowed with the biologically relevant benzothiazole (BTA) moiety under mild oxidative conditions, starting from easy‐accessible aldimines. Process optimization encompassed the use of stoichiometric diquinone as well as atmospheric oxygen as oxidant species, focusing on reaction dichotomy between oxidative and oxygenative pathways. The reaction scope was investigated on a representative selection of BTA‐containing aldimines and further extended to congeners bearing different biologically pivotal N‐heterocyclic rings (benzoxazole, thiazole and isoxazole), observing good levels of yield (up to 87 %) and regioselectivity (exo/endo up to 10.0; endo/exo up to 7.0). Furthermore, the employment of an immobilized‐NHC under heterogeneous conditions was assessed, showing satisfactory selectivity towards exo‐MIIs (exo/endo=3.8). Overall, the methodology presented provided an unprecedented collection of high value‐added products with potential applications in different fields.

4-Fluoro-threonine, the only fluoro amino acid of natural origin discovered so far, is an interesting target for both synthetic and theoretical investigations. In this work, we lay the foundation for spectroscopic characterization of 4-fluoro-threonine. First, we report a diastereoselective synthetic route, which is suitable to produce synthetic material for experimental characterization. The addition of the commercially available ethyl isocyanoacetate to benzyloxyacetaldehyde led to the corresponding benzyloxy-oxazoline, which was hydrolyzed and transformed into ethyl (4S*,5S*)-5-hydroxymethyl-2-oxo-4-oxazolidinecarboxylate in a few steps. Fluorination with diethylamino sulfur trifluoride (DAST) afforded ethyl (4S*,5S*)-5-fluoromethyl-2-oxo-4-oxazolidinecarboxylate, which was deprotected to give the desired diastereomerically pure 4-fluoro-threonine, in 8–10% overall yield. With the synthetic material in our hands, acid–base titrations have been carried out to determine acid dissociation constants and the isoelectric point, which is the testing ground for the theoretical analysis. We have used machine learning coupled with quantum chemistry at the state-of-the-art to analyze the conformational space of 4-fluoro-threonine, with the aim of gaining insights from the comparison of computational and experimental results. Indeed, we have demonstrated that our approach, which couples a last-generation double-hybrid density functional including empirical dispersion contributions with a model combining explicit first-shell molecules and a polarizable continuum for describing solvent effects, provides results and trends in remarkable agreement with experiments. Finally, the conformational analysis applied to fluoro amino acids represents an interesting study for the effect of fluorine on the stability and population of conformers.

A strategy for the immobilization of chiral 2,3-bisaminocyclopropenium salt (pre-catalyst) onto polystyrene and silica supports is presented together with a suitable procedure for the conversion into the corresponding cyclopropenimine superbase catalysts. The activity and recyclability of polystyrene-and silicasupported cyclopropenimines were initially tested under batch conditions in a model Michael addition detecting comparable efficiencies but a superior stability of the latter heterogeneous catalyst (5 cycles, accumulated TON of 27.1). The preferred silica-supported cyclopropenimine behaved very similarly to the soluble counterpart in the reaction of glycine imine with different Michael acceptors (48-92% yield; 60-98% ee) and it could be utilized as packing material for the fabrication of fixed-bed mesoreactors (pressure-resistant stainless-steel columns). Continuous-flow experiments were performed with satisfactory long-term stability (24 h on stream) with unaltered conversion efficiency and enantioselectivity.