ABSTRACT Glycals are unsaturated sugar derivatives constituting a large family of polyhydroxylated synthons which are widely exploited as synthetic intermediates in the synthesis of natural products and as final molecules for biochemical applications. We report the first investigation in the understudied area of structure–reactivity relationship and quantitative mapping of reactivity in endo ‐ and exo ‐glycals compounds. For quantifying the nucleophilicity of the C═C double bond of a series of endo ‐ and exo ‐glycals, we performed kinetic investigations of their C─C bond formation with reference electrophiles of known electrophilicity parameters. Fast spectroscopic techniques experiments (stopped‐flow and laser‐flash photolysis) enabled us to determine the rate constant of hundreds of reactions, which allows the first comprehensive mapping and structure–reactivity analysis of the nucleophilic reactivity of this wide family of cyclic enol ethers. Quantum–chemical calculations corroborate with kinetic investigations and highlight the crucial role of ring strain variations to explain the relative nucleophilicity of endo ‐ and exo ‐glycals. We examined also the influence of substitution and showed that alkoxy substituents decrease nucleophilicity through inductive effects and hyperconjugation.

Saturated carbocycles are common motifs in natural products and pharmaceuticals, and so methods for their construction, particularly with high diastereo- and enantiocontrol, are of high importance. Lithiation-borylation has emerged as powerful methodology for the stereocontrolled construction of acyclic carbon chains but has not previously been used for the stereocontrolled synthesis of carbocycles. Herein, we report that benzylic diethylcarbamates with a tethered vicinal bis-boronic ester moiety can be deprotonated with lithium amide bases, resulting in cyclization and 1,2-metallate rearrangement to give carbocycles. This intramolecular lithiation-borylation reaction is completely regioselective and, rather than being stereospecific like the acyclic variants, it is diastereoconvergent. Stereochemistry of the boronic ester is retained but the benzylic stereocenter undergoes epimerization, furnishing carbocycles with high diastereo- and enantiocontrol from easily accessible precursors. Site-selective transformations of the bis-boronic ester products are also demonstrated.

We report our results on the development of the Peterson olefination using gem-borylsilylmethane derivatives to synthesize di- and tri-substituted vinyl boronates. We show that the electronic properties of the carbonyl partner have no effect on the Peterson/boron-Wittig chemoselectivity whereas the nature of the silane group plays an important role. A DFT study helps explain observed reactivity, chemoselectivity and stereoseletivity

The prevalence of glutathionylated (G-) precursors of polyfunctional thiols (PFTs) over their free forms has prompted investigating how to optimize the enzymatic breakdown of these precursors with yeast during lager, ale, and non-alcoholic/low-alcoholic beer (NABLAB) fermentation trials. Some Saccharomyces cerevisiae yeasts have been selected for their higher β-lyase activity on the cysteinylated (Cys-) conjugates (up to 0.54% for SafAleTM K-97), yet some S. pastorianus strains and one maltose-negative S. cerevisiae var. chevalieri yeast have proved to release PFTs more efficiently from G-precursors (up to 0.21% for BRAS-45 and 0.19% for SafBrewTM LA-01). The present study aimed to explore the possibility and extent of direct release in the beer of 3-sulfanylhexanol from its synthetic γ-glutamylcysteinylated (γ-GluCys-) precursor. Release efficiency was determined by GC-PFPD after the fermentation (7 days at 24 °C and 3 days at 4 °C) of a 15 °Plato (°P) wort enriched with 15 mg/L of synthesized γ-GluCys-3SHol. Up to a 0.28–0.35% release was measured with S. pastorianus strains BRAS-45 and SafLagerTM E-30, while much lower activities (≤0.16%) were observed with S. cerevisiae yeasts, including the maltose-negative chevalieri variety. This β-lyase activity on γ-GluCys-3SHol has never been described before. Under our experimental conditions, the efficiency of release from γ-GluCys-3SHol was drastically reduced in low-density worts. A strongly strain-dependent impact of temperature was also observed.

A series of small molecule Cu(II) complexes based on tridentate N3 ligands relevant to the histidine brace of the active site of lytic polysaccharide monooxygenase were synthesized and characterized by X-ray crystallography and spectroscopic studies. In order to better understand the role of different structural features and to help bridge the differences between previously reported models, the methylation patterns, imidazole connectivity, linker nature, and type of heterocycle were systematically varied across the series. These modifications lead to important differences in the electrochemical properties of the complexes and their reactivity towards the oxidation of a model substrate.

Fatty acid amide hydrolase (FAAH) inhibition holds therapeutic promise by enhancing endocannabinoid signaling. We previously identified β-lactam compounds as reversible and selective hFAAH inhibitors with nanomolar potency. Here, we describe the synthesis of new β-lactam derivatives to evaluate the effect of imide conformational constraints on activity and to eliminate potential metabolic soft spots. Bicyclic derivatives were designed to lock the imide in a syn configuration, but showed reduced potency compared with non-cyclic analogs. Docking studies revealed that this weaker inhibition arises from an altered binding mode within the FAAH active site. In parallel, removal of ester and allyl groups did not affect inhibitory potency. Importantly, the optimized inhibitor enhanced N-acylethanolamine levels in J774 cells, supporting target engagement and suggesting improved metabolic stability. These results provide insights into the mode of action of β-lactam FAAH inhibitors and guide the development of more potent, stable derivatives.

Dihydropyranones are key structural motifs in biologically active polyketides. We report a reproducible and scalable method for synthesizing 3‐methoxy‐4,5‐dihydropyran‐2‐ones (MeO‐DHP‐2‐ones) via base‐promoted cyclization of hydroxy alkynes. Mechanistic and computational studies revealed that water content and reaction time critically influence lactonization efficiency. Two optimized protocols – using potassium carbonate (K2CO3) or in situ generated sodium methoxide (MeONa) – enabled consistent yields across multiple substrates. Cyclization in deuterated methanol provided deuterium‐enriched DHP‐2‐one scaffolds with high isotopic incorporation, valuable for mechanistic and medicinal applications. The transformation of DHP‐2‐ones into 4,5‐dihydropyran‐4‐ones (DHP‐4‐ones) was achieved via organometallic addition followed by a tailored workup involving aqueous hydrochloric acid and boron trifluoride diethyl etherate (BF3·OEt2). This protocol proved robust and scalable, compatible with both organolithium and organomagnesium reagents, although the latter afforded lower yields. Mechanistic analysis highlighted key steps including hemiacetal formation, oxonium activation, and controlled hydrolysis. The methodology enables multigram‐scale preparation of both DHP‐2‐one and DHP‐4‐one scaffolds and provides a streamlined route toward spiroacetal precursors.

Sterically hindered pyridines embedded in a three-dimensional triptycene framework have been synthesized, and their resolution by chiral HPLC enabled access to unprecedented enantiopure pyridines exceeding the known steric limits. The design principles for new axially chiral pyridine derivatives are then described. To rationalize their associations with Lewis acids and transition metals, a comprehensive determination of the steric and electronic parameters for this new class of pyridines was performed. This led to the general parameterization of the steric parameters (percent buried volume %VBur, Tolman cone angle θ, and He8_steric descriptor) for a large set of two- and three-dimensional pyridine derivatives. These parameters are shown to describe quantitatively their interactions with carbon- and boron-centered Lewis acids and were used to predict the ΔG° of association with the prototypical B(C6F5)3 Lewis acid widely used in frustrated Lewis pair catalysis. This first parameterization of pyridine sterics is a fundamental basis for the future development of predictive reactivity models and for guiding new applications of bulky and chiral pyridines in organocatalysis, frustrated Lewis pairs, and transition-metal catalysis.

Structure-reactivity investigations and quantum-chemical parametrization of steric and electronic properties of geometrically constrained iminophosphoranes enabled the design of new frustrated Lewis pairs and revealed unusual properties at the phosphonium center embedded in the cage-shaped triptycene tricyclic scaffold.

A one-carbon homologation of Knoevenagel adducts enabling the insertion of a CHAr fragment is reported. The strategy involves a sulfur ylide mediated cyclopropanation followed by the rearrangement of cyclopropanes and enables the synthesis of a series of benzhydryl derivatives. Mechanistic studies reveal that the cyclopropane rearrangement involves a Lewis acid catalyzed ring-opening followed by the 1,2-migration of an aryl group. The possibility of controlling the absolute stereochemistry of the generated stereogenic allylic carbon center using a chiral sulfonium ylide is demonstrated.

Allenoates are versatile building blocks which are primarily activated and controlled using chiral tert. phosphine and tert. amine Lewis bases. We herein report the first example of allenoate activation by using chiral isochalcogenoureas (IChU) for formal (4+2) cycloaddition reactions. Compared to established phosphine and amine catalysis, the use of these easily available Lewis bases enables new stereoselective reaction pathways proceeding with high enantioselectivities, diastereoselectivities, and in good yields. In addition, the factors governing enantioselectivity and the origin of the observed differences compared to other commonly used Lewis bases are explained.

Cysteinylated and glutathionylated precursors of sulfanylalkyl alcohols have been extensively studied in hop and grape matrices, in contrast to those of sulfanylalkyl aldehydes and sulfanylalkyl acetates. Here, cysteinylated and glutathionylated adducts of 3-sulfanylpentanal (Cys-3SPal and G-3SPal), 3-sulfanylhexanal (Cys-3SHal and G-3SHal), 3-sulfanylpentyl acetate (only Cys-3SPA), and 3-sulfanylhexyl acetate (Cys-3SHA and G-3SHA) were first synthesized. Next, the occurrence of these compounds was studied by RP-HPLC-ESI(+)-MRM and apotryptophanase-GC-PFPD in a few dual hops and Belgian grape must samples. None of the Cys-adducts of 3-sulfanylalkyl aldehydes were detected in hop or grape extracts, while G-3SPal was identified for the first time in a natural matrix. Concentrations ranging from 3 to 15 mg/kg were found in several hop varieties, including Citra, Mandarina Bavaria, Mosaic, Nelson Sauvin, Polaris, and Saaz, whereas G-3SHal was detected (below the quantitation limit) only in the four latters. As for esters, Cys-3SPA was found in hop (4 mg/kg in Mosaic), while G-3SHA was detected only in grape extracts (Belgian Chardonnay and Johanniter). Besides the ubiquitous G-3SHol, G-3SPol was identified here for the first time in grape must (up to 7 mg/kg in Johanniter).

An efficient protocol for the synthesis of enolizable alpha-substituted beta,gamma-unsaturated aldehydes is reported. The developed strategy involves two steps, epoxidation and Meinwald rearrangement, to result in a one-carbon homologation of alpha,beta-unsaturated aldehydes enabling the insertion of a CHR unit.

While cysteinylated (Cys-) and glutathionylated (G-) precursors of 3-sulfanylhexanol (3SHol) and 3-sulfanylpentanol (3SPol) appear to be ubiquitous in hop varieties, no data are available on precursors of their seven-carbon analogue 3-sulfanylheptanol (3SHptol), although the free form has been found in both hops and beer. Chemical synthesis of Cys- and G-3SHptol enabled determination of their chromatographic elution times (14.3-14.8 and 16.2-17.1 min, respectively) and ESI(+) mass spectra (main m/z fragments: 219 and 293, for Cys- and G- 3SHptol, respectively). Here, for the first time, we report the occurrence of G-3SHptol in a natural matrix. RP-HPLC-ESI(+) MRM analysis of selective extracts eluted from a cation exchange resin quantified G-3SHptol in green malt (0.10 mg/kg), while no trace was found after kilning. Neither the cysteinylated nor the glutathionylated conjugate was found in hop or grape extracts. G-3SHptol is formed in-situ from trans-2-heptenal and free glutathione, and its synthesis most likely involves aldol condensation between acetaldehyde and pentanal instead of lipid oxidation. © 2022 The Institute of Brewing & Distilling.

Vinylcyclopropanes are versatile intermediates in organic synthesis which undergo various rearrangements. We report a new rearrangement of vinylcyclopropane into skipped diene. A detailed mechanistic study revealed that this transformation involves regioselective ring-opening of the cyclopropane ring followed by 1,2-migration of one of the cyclopropane substituents. Interestingly, our investigations showed that skipped diene is the kinetic product of the process but formation of a more stable cyclopentene is also accessible. The fundamental understanding of the processes involved enabled the development of divergent methodologies allowing to obtain cyclopentene or skipped diene from vinylcyclopropane in a selective and controlled manner.

The stereocontrolled formation of medium-sized carbocycles is a major goal in modern organic chemistry due to their widespread occurrence in natural products and pharmaceutically active ingredients. One approach consists in the use of cycloaddition reactions which notably results in high selectivities and atom-economy. To this end, cyclopropanes are ideal substrates since they can provide readily functionalized three- or five-carbon synthons. Herein we report advances made in cycloaddition reactions of cyclopropanes towards the synthesis of medium-sized carbocycles via transition metal catalysis or Lewis acid catalysis.

ortho-Substituted and unsymmetrical 9-phospha-triptycenes were synthesized via two synthetic approaches involving densely functionalized ortho-halogenated triarylmethane or phosphine precursors. ortho-Substituents imposed a considerable steric shielding due to the tricyclic cage-shaped structure with the aryl rings p-systems orthogonal to the phosphorus electron pair. A series of Au(I) and Rh(I) complexes were analysed in the solid state to determine Tolman electronic parameters, cone angles and buried volumes of these unprecedented functionalized phosphines. Quantum chemical calculations of electronic and steric descriptors revealed that these cage-shaped phosphines are electron-poor and that single methyl substituent is enough to provide the largest effect on steric shielding reported so far in triarylphosphines. An unsymmetrically substituted 9-phosphatriptycene was resolved by chiral HPLC, opening the avenue towards stable P-chirogenic triarylphosphines with unlimited configurational stability for new catalyst development in asymmetric transition-metal catalysis.