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Cycloadditions of nitrones with alkynes usually occur best under heat activation. Due to the instability of the formed isoxazolines, alternative activation methods must be found. Here, hyperbaric conditions are used to transform nitrones generated from unprotected carbohydrates into the corresponding polyhydroxy-isoxazolines at room temperature. The reaction proved completely regioselective in favor of the 5-substituted 4-isoxazolines, and the products are obtained in good yields as mixtures of the two possible diastereoisomers. Further transformations into biologically valuable targets are described. The whole synthesis constitutes a very straightforward procedure for the transformation of aldoses, and is highly compatible with the principles of green chemistry. [ABSTRACT FROM AUTHOR]

IspG (also called GcpE) is an oxygen‐sensitive [4Fe‐4S] enzyme catalyzing the penultimate step of the methylerythritol phosphate (MEP) pathway, a validated target for drug development. It converts 2‐C‐methyl‐d‐erythritol‐2,4‐cyclo‐diphosphate (MEcPP) into (E)‐4‐hydroxy‐3‐methyl‐but‐2‐enyl‐1‐diphosphate (HMBPP). The reaction, assimilated to a reductive dehydration, involves redox partners responsible for the formal transfer of two electrons to substrate MEcPP. The 2‐vinyl analogue of MEcPP was designed to generate conjugated species during enzyme catalysis, with the aim of providing new reactive centers to be covalently trapped by neighboring amino acid residues. The synthesized substrate analogue displayed irreversible inhibition towards IspG. Furthermore, we have shown that electron transfer occurs prior to inhibition; this might designate conjugated intermediates as probable affinity tags through covalent interaction at the catalytic site. This is the first report of an irreversible inhibitor of the IspG metalloenzyme. [ABSTRACT FROM AUTHOR]

The diastereoselective access to cyclopentanols and N,O‐dimethylcyclopentylhydroxylamines from 4‐pentenoic acid‐derived Weinreb amides is described. Based on the concomitant generation of both the nucleophilic and the electrophilic poles by hydrozirconation of the amide and the C=C double bond, the cyclisation may be tuned towards cyclopentanols or N,O‐dimethylcyclopentylhydroxylamines depending on the ring‐closure promotor. An extension to cis 3‐substituted N,O‐dimethylcyclohexylhydroxylamines is also presented. [ABSTRACT FROM AUTHOR]

The development of new fluorine‐containing building blocks and their efficient synthetic access is currently a challenging research field. Herein, the highly regio‐ and stereoselective addition of a large range of aldehydes onto trifluoromethylated benzofulvenes was achieved using a simple La/I2/DIBAL‐Cl system via a selective C−F bond activation process. This versatile methodology provided homodienyl alcohols bearing a terminal CF2‐alkene with potential further applications, as shown by the dehydration to the first benzofulvenes carrying a difluorovinyl group. In addition, for certain electron‐poor aldehydes, unprecedented ipso substitution of the CF3 group in a diene was observed, which, according to DFT studies, is related to the presence of the large, Lewis‐acidic lanthanum metal. [ABSTRACT FROM AUTHOR]

A simple method was developed for the direct formation of unsaturated iminosugars starting from readily available [omega]-methanesulfonylglycononitriles. The nucleophilic addition/cyclization reaction with variation of the Grignard reagent allows for a range of different side chains to be incorporated to generate libraries of broussonetine analogues.

Nitromethylation of nitrones occurred efficiently in CH3NO2 in the presence of tetramethylammonium fluoride or triazabicyclodecene as promoters. The obtained adducts might be conveniently transformed into vicinal diamines. The process was extended to nitroethane and nitropropane affording mixtures of syn and anti stereoisomers with low diastereoselectivity. Comprehensive study of the addition of nitroalkanes to nitrones was conducted. The reaction proved efficient with TMAF or TBD as bases, in the presence of a large excess of R–NO2. Phase‐transfer catalysis gave also acceptable yields. Nitroethane or nitropropane afforded mixtures of isomerisable diastereomers. The reaction was applied to the synthesis of biologically relevant compounds. [ABSTRACT FROM AUTHOR]

The synthesis of the peracetylated ketonitrone 4 is described in four steps from l-sorbose. This cyclic nitrone is crystalline and proved to preferentially adopt a 4H3 conformation with all acetate groups in pseudo-axial orientation. Nitrone 4 undergoes regioselective cycloadditions with alkynes, affording tetra-O-acetyl-isoxazolines with good yields and stereoselectivities (4 : 1 to 9 : 1 diastereomeric ratio). Nitrone 4 and the obtained isoxazolines were smoothly deacetylated to produce the polyhydroxylated nitrone 5 and novel iminosugars containing an isoxazoline motif. Evaluation of their glycosidase inhibitory activity demonstrated their rather weak, but selective affinity for a variety of enzymes. [ABSTRACT FROM AUTHOR]

A 1,3‐dipolar cycloaddition reaction of carbohydrate‐derived five‐membered cyclic ketonitrones with alkynes and alkenes was developed as an efficient and regioselective process to access highly functionalised isoxazolines and isoxazolidines bearing a quaternary centre α to the nitrogen atom. The latter compounds were used as intermediates for the synthesis of unprecedented ring‐junction‐substituted polyhydroxylated pyrrolizidines and indolizidines. These compounds were evaluated against a panel of glycosidases, and showed moderate but selective inhibition of α‐glucosidases. [ABSTRACT FROM AUTHOR]

Two strategies based on kinetic resolution(s) of chiral alanes and providing enantioenriched syn homoallylamines are reported. The first implies a single kinetic resolution of the alane using camphor; the second requires two sequential kinetic resolutions using the synergistic combination of (-)-camphor/(R)-tert-butylsulfinamide-derived imines. This syn selectivity, specific to the use of allyaluminum, opens the way to the preparation of valuable building blocks as illustrated by the synthesis of (+)-epilupinamine. [ABSTRACT FROM AUTHOR]

Heavy metal on Lewis acid: The combination of lanthanide metals and AlCl3 has been employed for selective single C−F activation in benzofulvenes comprising an exocyclic CF3 substituent. Intermediate ϵ,ϵ-difluorinated metal-dienyl species react with a large variety of aldehydes in a highly regio- and diastereoselective fashion to afford 1,1-disubstituted indenes bearing a difluorovinyl group. These new building blocks have been further transformed through a hydrogenation-cyclization process into fluorinated heterocyclic spiro compounds. [ABSTRACT FROM AUTHOR]

Eleven compounds were isolated from Poraqueiba sericea stems and identified as niga-ichigoside-F1 (1), trachelosperoside B1 (2), 4-epi-niga-ichigoside (7), 19α-hydroxyasiatic acid (3), myrianthic acid (4), hyptatic acid (5), trachelosperogenin B (6), arjunolic acid (8), and trachelosperogenin E (9), secologanoside (10) and secoxyloganin (11). Compounds 1–11 were tested for their antileishmanial activities against Leishmania infantum promastigotes, 1–6 and 8–11 were tested for their cytotoxic activities on fibroblasts, 1–3, 5–6, 8–11 were evaluated for their anti-elastase and anti-acetylcholinesterase assays activities by a spectrophotometric method and 1–2, 5 and 7–10 were tested using bioautography for their β-glucosidase. No antileishmanial activity was detected; compounds 1, 2 and 11 showed a moderate cytotoxic activity with IC50 17.7, 20.5 and 10.9 μg/mL, respectively; compounds 2, 8, 9 and 10 gave a percentage of inhibition ranging from 13 to 16% (at 50 μg/mL) and compounds 1 and 2 showed an inhibition zone on β-glucosidase and anti-acetylcholinesterase assays. [ABSTRACT FROM AUTHOR]

An efficient (+)-camphor-mediated kinetic resolution of racemic cyclohex-2-en-1-ylalane is described. This approach provides an enantiomerically enriched form of the alane, in situ available for synthetic uses. Applied to the allylation of aldehydes, this protocol leads to the corresponding homoallylalcohols in a highly enantioselective manner. [ABSTRACT FROM AUTHOR]

Fucosidase inhibitors represent captivating targets for various biological applications. Iminosugars featuring a fluoroalkyl chain in the pseudoanomeric position were synthesized by nucleophilic addition of a perfluoroalkyl Grignard reagent to a nitrone. Reduction of the N-O bond of the hydroxylamine was achieved by treatment with an aqueous solution of sulfur dioxide. The p Ka = 4.5 of the target pyrrolidine reflected a strong electronic effect of the fluoroalkyl chain. Inhibitory potencies of the fluorinated iminosugars and their corresponding hydroxylamines were evaluated against α- L-fucosidase at various pH values. [ABSTRACT FROM AUTHOR]

[4Fe-4S] enzymes, fraudulent substrates, irreversible inhibition, IspG (GcpE), MEP pathway Cover Feature: Irreversible Inhibition of IspG, a Target for the Development of New Antimicrobials, by a 2-Vinyl Analogue of its MEcPP Substrate (Chem. Eur. J. 30/2022) Keywords: [4Fe-4S] enzymes; fraudulent substrates; irreversible inhibition; IspG (GcpE); MEP pathway EN [4Fe-4S] enzymes fraudulent substrates irreversible inhibition IspG (GcpE) MEP pathway 1 1 1 05/27/22 20220525 NES 220525 B The rational design b of a substrate analogue has afforded the first irreversible inhibitor of an IspG enzyme, a target for the development of new drugs to fight antimicrobial resistance. [Extracted from the article]

An unprecedented reactivity of CF3-TMS has been revealed, which exploits the basic character of the generated [CF3-] capable of delivering dichloromethide from dichloromethane with subsequent transfer to nitrones under smooth conditions. The proton-abstraction pathway was demonstrated through isotopic labeling experiments in CD2Cl2. The same reaction was achieved in acetonitrile with the introduction of a cyanomethyl group onto the nitrones. [ABSTRACT FROM AUTHOR]

Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L- fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking 3 E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100 % inhibition of the proliferation of MDA-MB-231 cancer cells at 50 μ M. [ABSTRACT FROM AUTHOR]

Abstract: 3,6-Anhydro-1-(aryl or alkylamino)-1-deoxy-d-sorbitol derivatives have been prepared in four steps from isosorbide, a by-product from the starch industry. The inhibitory activities of these new compounds have been evaluated towards 13 glycosidases. A first lead-compound was identified, which inhibited β-N-acetylglucosaminidase from bovine kidney (82% inhibition at 1mM). [Copyright &y& Elsevier]

Abstract: A short and practical procedure for the preparation of C-2 substituted polyhydroxypyrrolidines is described. The C-2 substituent is introduced by a stereoselective addition of a Grignard reagent to a 2,3,5-protected aldofuranose and the cyclization to the pyrrolidine ring system is performed through a bis-mesylation/double nucleophilic displacement sequence. The efficiency of the methodology was demonstrated by its application to the synthesis of HomoDMDP and DMDP. [Copyright &y& Elsevier]