Structural analysis of neomycin B and kanamycin A binding Aminoglycosides Modifying Enzymes (AME) and bacterial ribosomal RNA.

Aminoglycosides are crucial antibiotics facing challenges from bacterial resistance. This study addresses the importance of aminoglycoside modifying enzymes in the context of escalating resistance. Drawing upon over two decades of structural data in the Protein Data Bank, we focused on two key antibiotics, neomycin B and kanamycin A, to explore how the aminoglycoside structure is exploited by this family of enzymes. A systematic comparison across diverse enzymes and the RNA A-site target identified common characteristics in the recognition mode, while assessing the adaptability of neomycin B and kanamycin A in various environments.

A gold(i)-catalysed approach towards harmalidine an elusive alkaloid from Peganum harmala.

Upon gold catalysis, the 2,3-dihydropyrrolo[1,2-a]indole motif, encountered in few but interesting bioactive natural products, was efficiently obtained from N-aryl 2-alkynylazetidine derivatives. In an attempt to apply this methodology to the synthesis of harmalidine, isolated from the seeds of Peganum harmala, advanced amino 2,3-hydropyrrolo[1,2-a]indol(one) derivatives were readily obtained in only 11 steps from but-3-yn-1-ol. While the reported structure of harmalidine could not be reached from these intermediates, a surprising 12-membered diimino dimer was isolated. Extensive comparison of the reported harmalidine NMR data to the experimental and calculated data of our synthetic molecules, harmaline or the synthetised N-methylharmaline show discrepancies with the proposed natural product structure.

Rhazinilam-leuconolam family of natural products: a half century of total synthesis.

Covering: 1972 to 2021The rhazinilam family of natural products exhibits a main structure with a stereogenic quaternary carbon and a tetrahydroindolizine core imbedded within a 9-membered macrocycle, imposing axial chirality. This unique architecture combined with their taxol-like antimitotic activities have attracted various attention, especially from synthetic chemists, notably in the past decade. The present review describes the known total and formal syntheses of the members of the rhazinilam family (rhazinilam, rhazinal, leuconolam and kopsiyunnanines), according to the strategy developed.

trans-Dichlorobis(XPhos)palladium(II) Precatalyst for Suzuki-Miyaura Cross-Coupling Reactions of Aryl/Vinyl Sulfonates/Halides: Scope, Mechanistic Study, and Synthetic Applications.

Suzuki-Miyaura cross-coupling reactions of aryl/vinyl sulfonates/halides with various boron species were performed using an easily available trans-dichlorobis(XPhos)palladium(II) precatalyst. Under microwave assistance, more than 30 coupling products were obtained with yields ranging from 23 to 99%, including the synthesis of two bioactive compounds, dubamine and tamoxifen. A mechanistic investigation of the Suzuki-Miyaura reaction was conducted notably by nuclear magnetic resonance (NMR) and high-resolution mass spectroscopy, revealing the nature of the active Pd0 species and of the reducing entity.

Synthesis of Indolizine and Pyrrolo[1,2-a]azepine Derivatives via a Gold(I)-Catalyzed Three-Step Cascade.

Linear N-alkenyl or alkynyl N-sulfonyl 1-aminobut-3-yn-2-ones are converted into bicyclic indolizines and pyrrolo[1,2-a]azepine-type alkaloids upon gold(I) catalysis (17 examples, 10-85%). The reaction cascade allowed formation of C-N, O-S, and C-C bonds via a cycloisomerization/sulfonyl migration/cyclization process using 10 mol % of [(2-biphenyl)di-tert-butylphosphine]gold(I) triflimide complex in dichloromethane.

Borylation and rearrangement of alkynyloxiranes: a stereospecific route to substituted α-enynes.

1,3-Enynes are important building blocks in organic synthesis and also constitute the key motif in various bioactive natural products and functional materials. However, synthetic approaches to stereodefined substituted 1,3-enynes remain a challenge, as they are limited to Wittig and cross-coupling reactions. Herein, stereodefined 1,3-enynes, including tetrasubstituted ones, were straightforwardly synthesized from cis or trans-alkynylated oxiranes in good to excellent yields by a one-pot cascade process. The procedure relies on oxirane deprotonation, borylation and a stereospecific rearrangement of the so-formed alkynyloxiranyl borates. This stereospecific process overall transfers the cis or trans-stereochemistry of the starting alkynyloxiranes to the resulting 1,3-enynes.

Benzosultam Synthesis by Gold(I)-Catalyzed Ammonium Formation/Nucleophilic Substitution.

The synthesis of benzosultams has been achieved through a gold(I)-catalyzed ammonium formation strategy. Starting from easily available N-(2-alkynyl)phenylsulfonyl azetidine derivatives, a cyclization reaction generated a spiroammonium gold intermediate that was ring-opened by nucleophilic alcohol or indole. This new methodology is compatible with the large variation in the substrates and nucleophiles and allowed the formation of benzosultams in high yield (18-98%, 20 examples). This strategy also allowed the preparation of benzosultam analogs via iododeauration and subsequent cross-coupling reactions.

Total Synthesis of Rhazinilam through Gold-Catalyzed Cycloisomerization-Sulfonyl Migration and Palladium-Catalyzed Suzuki-Miyaura Coupling of Pyrrolyl Sulfonates.

We report the first general conditions for the challenging Suzuki-Miyaura reaction with pyrrole-related sulfonate coupling partners (24 examples, 60-97%). Bis(dichloro)bis(2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl)palladium(II) precatalyst ensures the high efficiency of the reaction. The total synthesis of rhazinilam, a monoterpenoid indole alkaloid, highlights such cross-coupling as well as the simple preparation of pyrrolyl sulfonates by N-to-O 1,5-sulfonyl migration catalyzed by gold(I) (15 examples, 54-93%).

Silver & gold-catalyzed routes to furans and benzofurans.

Silver and gold have become incredibly versatile and mild catalysts for numerous transformations, especially in heterocycle synthesis. For the most prominent of them, i.e. furans, silver and gold, with their unique reactivity and mildness, allow numerous possible routes to highly substituted and/or functionalized furans from a large variety of starting materials. Silver and gold catalysis provide thus the most flexible way to this important family of compounds. The present review describes these silver and gold-catalyzed routes, with some emphasis on mechanistic aspects, and proposes a comparison of both the silver and the gold-catalyzed syntheses of furans.

Gold(I)-Catalyzed N-Desulfonylative Amination versus N-to-O 1,5-Sulfonyl Migration: A Versatile Approach to 1-Azabicycloalkanes.

Valuable 1-azabicycloalkane derivatives have been synthesized through a novel gold(I)-catalyzed desulfonylative cyclization strategy. An ammoniumation reaction of ynones substituted at the 1-position with an N-sulfonyl azacycle took place in the presence of a gold cation by intramolecular cyclization of the disubstituted sulfonamide moiety onto the triple bond. Depending on the size of the heterocyclic ring and substitution of the substrates, two unprecedented forms of nucleophilic attack on the sulfonyl group were exploited, that is, a N-desulfonylation in the presence of an external protic O nucleophile (37-87 %, 10 examples) and a unique N-to-O 1,5-sulfonyl migration (60-98 %, 9 examples).

Gold(I)-Catalyzed Cyclization/Nucleophilic Substitution of 1-(N-Sulfonylazetidin-2-yl) Ynones into N-Sulfonylpyrrolin-4-ones.

Polysubstituted pyrrolin-4-ones have been efficiently synthesized from readily available 1-(N-sulfonylazetidin-2-yl) ynones via gold(I)-catalyzed cyclization/nucleophilic substitution in the presence of various nucleophiles, such as water, alcohols, or indoles. Additionally, 3-iodopyrrolin-4-one derivatives have also been obtained under the same reaction conditions upon addition of 1.2 equiv of N-iodosuccinimide.

Robust synthesis of N-sulfonylazetidine building blocks via ring contraction of α-bromo N-sulfonylpyrrolidinones.

A simple and robust one-pot nucleophilic addition-ring contraction of α-bromo N-sulfonylpyrrolidinones has been achieved toward α-carbonylated N-sulfonylazetidines. In the presence of potassium carbonate, various nucleophiles, such as alcohols, phenols or anilines, have been efficiently incorporated into the azetidine derivatives. Moreover, the α-bromopyrrolidinone precursors could be selectively obtained in good yields by monobromination of cheap and easily available N-sulfonyl-2-pyrrolidinone derivatives.

Gold(I)/(III)-catalyzed rearrangement of divinyl ketones and acyloxyalkynyloxiranes into cyclopentenones.

Multifaceted gold(I/III) catalysts with their carbophilic and oxophilic characters catalyzed very efficiently the formation of hydroxylated cyclopentenones from simple divinyl ketones or acyloxyalkynyloxiranes. The Nazarov reaction is rapidly performed in dichloroethane with 5 mol % of the simple gold(III) trichloride salt at 70 °C, while the rearrangement of alkynyloxiranes requires 5 mol % of a more stable NHC gold(III) triflimidate complex.

Gold(I)-catalyzed formation of furans from γ-acyloxyalkynyl ketones.

Various γ-acyloxyalkynyl ketones were efficiently converted into highly substituted furans with 2.5 mol % of triflimide (triphenylphosphine)gold(I) as a catalyst in dichloroethane at 70 °C.

Gold(I)-catalyzed rearrangement of N-aryl 2-alkynylazetidines to pyrrolo[1,2-a]indoles.

Various N-aryl-2-alkynylazetidines were very efficiently converted to pyrrolo[1,2-a]indoles with gold catalysts, especially the 2-biphenyl-dicyclohexylphosphino-gold(I) hexafluoroantimonate, in dichloromethane at room temperature. Additionally, two formal syntheses of bioactive non-natural compounds, i.e. 7-methoxymitosene and an 5-HT(2C) receptor agonist, have been achieved.

Silver(I)-catalyzed deprotection of p-methoxybenzyl ethers: a mild and chemoselective method.

The p-methoxybenzyl protecting group (PMB) on various alcohols and an acid was efficiently and selectively cleaved by the action of a catalytic amount of silver(I) hexafluoroantimonate combined with 0.5 equiv of 1,3,5-trimethoxybenzene in dichloromethane at 40 °C.

Coinage metals-catalyzed cascade reactions of aryl alkynylaziridines: silver(I)-single vs gold(I)-double cyclizations.

Alkynylaziridines carrying an aryl group could be efficiently converted into aminoallenylidene isochromans, isoquinolines, or tetrahydronaphtalenes with silver(I) salts and into 1-azaspiro[4.5]decane derivatives with gold(I) complexes. Mechanistic investigations revealed that both Ag- and Au-catalyzed reactions involved a Friedel-Crafts type intramolecular reaction leading to an allene and that Au also rapidly promoted a second intramolecular cyclization of the aminoallene intermediate to the corresponding spiro derivative. Stereochemical investigations suggested an anti-SN(2)'-type pathway for the first cyclization leading to a stereodefined allene, which could then be cyclized to the corresponding stereodefined spiro product. These results highlight the duality between oxo- or azaphilicity and alkynophilicity of Ag and Au as well as their complementarity in terms of reactivity.

Gold(I)-catalyzed rearrangement of aryl alkynylaziridines to spiro[isochroman-4,2'-pyrrolines].

Alkynylaziridines carrying an aryl group could be efficiently converted to spiro[isochroman-4,2'-pyrrolines] with gold salts as catalysts. This new rearrangement involved a Friedel-Crafts type intramolecular reaction followed by cyclization of the aminoallene intermediate, both initiated by the dual σ and π Lewis acidities of gold.

Amino-benzosuberone: a novel warhead for selective inhibition of human aminopeptidase-N/CD13.

This paper describes the design and synthesis of compounds belonging to a novel class of highly selective mammalian CD13 inhibitors. Racemic homologues of 3-amino-2-tetralone 1 were synthesised and evaluated for their ability to selectively inhibit the membrane-bound, zinc-dependent aminopeptidase-N/CD13 (EC 3.4.11.2). Some of these novel non-peptidic compounds are potent, competitive inhibitors of the mammalian enzyme, with K(i) values in the low micromolar range in spite of their minimal size (MW <200 Da). Moreover, they show an interesting selectivity profile against representative members of the aminopeptidase family, that is leucine aminopeptidase (EC 3.4.11.1), Aeromonas proteolytica aminopeptidase (EC 3.4.11.10) and the aminopeptidase activity of leukotriene A4 hydrolase (EC 3.3.2.6). The amino-benzosuberone derivative 4 is the most promising compound in terms of potency, stability and selectivity. A hypothetical binding mode of 4 to the catalytic zinc and several conserved active site residues is proposed, based on the observed structure-activity relationships, structural insights from aminopeptidase-N homologues of known three-dimensional structure.