RESUMO
Mastering of analytical methods for accurate quantitative determinations of enantiomeric excess is a crucial aspect in asymmetric catalysis, chiral synthesis, and pharmaceutical applications. In this context, the phenomenon of Self-Induced Diastereomeric Anisochronism (SIDA) can be exploited in NMR spectroscopy for accurate determinations of enantiomeric composition, without using a chiral auxiliary that could interfere with the spectroscopic investigation. This phenomenon can be particularly useful for improving the quantitative analysis of mixtures with low enantiomeric excesses, where direct integration of signals can be tricky. Here, we describe a novel analysis protocol to correctly determine the enantiomeric composition of scalemic mixtures and investigate the thermodynamic and stereochemical features at the basis of SIDA. Dipeptide derivatives were chosen as substrates for this study, given their central role in drug design. By integrating the experiments with a conformational stochastic search that includes entropic contributions, we provide valuable information on the dimerization thermodynamics, the nature of non-covalent interactions leading to self-association, and the differences in the chemical environment responsible for the anisochrony, highlighting the importance of different stereochemical arrangement and tight association for the distinction between homochiral and heterochiral adducts. An important role played by the counterion was pointed out by computational studies.
RESUMO
A copper(II)/HOBt-catalyzed procedure for the synthesis of dipeptides and "general" amides has been developed using microwave irradiation to considerably hasten the reaction. As an alternative to using traditional carboxylic acid activation, the method relies on the use of N-acyl imidazoles as activated amino partners. By doing so, a nonconventional way to reach dipeptides and amides has been proposed through the challenging and less studied N â C direction synthesis. A series of dipeptides and "general" amides have been successfully synthesized, and the applicability of the method has been illustrated in gram-scale syntheses. The mild reaction conditions proposed are completely adequate for couplings in the presence of sensitive amino acids, affording the products without detectable racemization. Furthermore, experimental observations prompted us to propose a plausible reaction pathway for the couplings.
Assuntos
Aminas , Dipeptídeos , Amidas/química , Aminoácidos/química , Ácidos Carboxílicos/química , Cobre/química , Dipeptídeos/química , ImidazóisRESUMO
As three-dimensional folding is prerequisite to biopolymer activity, complex functions may also be achieved through foldamer science. Because of the diversity of sizes, shapes and folding available with synthetic monomers, foldamer frameworks enable a numerous opportunities for designing new generations of catalysts. We herein demonstrate that heterocyclic γ-peptide scaffolds represent a versatile platform for enamine catalysis. One central feature was to determine how the catalytic activity and the transfer of chiral information might be under the control of the conformational behaviours of the oligomer.
RESUMO
A unified strategy for the construction of prevalent 1,3,5,... n (OH, Me) motifs based on consecutive copper-catalyzed asymmetric conjugate borylation (ACB) and methylation (ACA) reactions involving α,ß-unsaturated 2-acyl- N-methylimidazoles is described. Good yields and high diastereoselectivities have been obtained in ACA and ACB reactions for both matched and mismatched pairs as illustrated in the synthesis of syn/ anti and anti/ anti (Me, OTBS, Me) and (OH, OTBS, Me) motifs.
RESUMO
Growing resistance of pathogenic bacteria and shortage of antibiotic discovery platforms challenge the use of antibiotics in the clinic. This threat calls for exploration of unconventional sources of antibiotics and identification of inhibitors able to eradicate resistant bacteria. Here we describe a different class of antibiotics, odilorhabdins (ODLs), produced by the enzymes of the non-ribosomal peptide synthetase gene cluster of the nematode-symbiotic bacterium Xenorhabdus nematophila. ODLs show activity against Gram-positive and Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae, and can eradicate infections in animal models. We demonstrate that the bactericidal ODLs interfere with protein synthesis. Genetic and structural analyses reveal that ODLs bind to the small ribosomal subunit at a site not exploited by current antibiotics. ODLs induce miscoding and promote hungry codon readthrough, amino acid misincorporation, and premature stop codon bypass. We propose that ODLs' miscoding activity reflects their ability to increase the affinity of non-cognate aminoacyl-tRNAs to the ribosome.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Proteínas de Bactérias/biossíntese , DNA Bacteriano/genética , Infecções por Klebsiella/tratamento farmacológico , Subunidades Ribossômicas Menores/efeitos dos fármacos , Xenorhabdus/metabolismo , Aminoaciltransferases/genética , Aminoaciltransferases/metabolismo , Animais , Antibacterianos/metabolismo , Bactérias/genética , Bactérias/metabolismo , Proteínas de Bactérias/genética , Sítios de Ligação , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Masculino , Camundongos Endogâmicos ICR , Biossíntese de Proteínas/efeitos dos fármacos , Subunidades Ribossômicas Menores/genética , Subunidades Ribossômicas Menores/metabolismoRESUMO
The synthesis of cyclic imidazolidines via two N-C bond-forming sequences has been developed. The transformation goes through a (3 + 2)-cycloaddition reaction in the presence of catalytic amounts of palladium by combining several vinyl aziridines and cyclic N-sulfonyl imines. Interestingly, the use of LiCl as additive allowed the improvement of diastereoselectivities when less encumbered substrates were used. The imidazolidine derivatives that bear aminal cores are isolated in high yields (15 examples, up to 96% yield) and diastereoselectivities (up to >20:1).
RESUMO
After seminal Tsuji-Trost reactions (palladium catalyzed allylation of nucleophiles via π-allyl intermediates as electrophiles), the idea of reversal reactivity of π-allyl intermediates (i.e. π-allyl as nucleophiles) has been stated since the eighties. Thanks to different transition metal sources and the modification of their electronic environment through the use of additives and ligands, such 'reactivity switch' of π-allyl intermediates proved its powerfulness allowing high control in regio-, diastereo- and enantio-selectivities. These methodologies have thus emerged as efficient methods in the catalytic enantioselective allylation of carbonyl compounds and imines with a deep impact on natural product and/or drug elaboration. This tutorial review highlights the concept of 'umpoled' reactivity of π-allyl intermediates, relying on selected recent examples.
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A straightforward strategy for the syntheses of curcumene and ar-himachalene is reported. Synthetic highlights include a catalytic and asymmetric vinylogous Mukaiyama reaction and a stereospecific hydrogenolysis of a tertiary benzylic center using Pd/C or Ni/Raney catalysts. Notably, using Ni/Raney, the stereoselectivity outcome (inversion vs retention) of the hydrogenolysis depends on the tertiary benzylic alcohol substitution.
RESUMO
The present review offers an overview of nonclassical (e.g., with no pre- or in situ activation of a carboxylic acid partner) approaches for the construction of amide bonds. The review aims to comprehensively discuss relevant work, which was mainly done in the field in the last 20 years. Organization of the data follows a subdivision according to substrate classes: catalytic direct formation of amides from carboxylic and amines ( section 2 ); the use of carboxylic acid surrogates ( section 3 ); and the use of amine surrogates ( section 4 ). The ligation strategies (NCL, Staudinger, KAHA, KATs, etc.) that could involve both carboxylic acid and amine surrogates are treated separately in section 5 .
RESUMO
5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives were prepared by mechanochemistry from amino esters or dipeptides, via a 1,1'-carbonyldiimidazole-mediated one-pot/two-step cyclization reaction involving amino acid unsymmetrical urea A and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution were also performed. The successful preparation of an antibacterial agent precursor was also investigated.
RESUMO
The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and ß-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Fenitoína/química , Fenitoína/síntese química , Anticonvulsivantes/química , Ciclização , Ésteres , Hidantoínas/síntese química , Hidantoínas/química , Estrutura Molecular , SolventesRESUMO
An enantioselective cyclopropanation of alpha-substituted alpha,beta-unsaturated aldehydes with bromomalonate has been successfully developed through a domino Michael/alpha-alkylation strategy. The method allows the efficient formation of cyclopropanes bearing a quaternary carbon stereocenter at the alpha-position of the aldehydes by using iminium/enamine catalysis and gives a nice extension on the organocatalytic cyclopropanation of bromomalonate and alpha,beta-unsaturated aldehydes previously reported by other groups. Very good yields (up to 81%) and enantioselectivities (up to 97% ee) have been obtained. The optically active cyclopropane derivatives are of high synthetic interest as useful targets for further elaboration into more complex structures.
RESUMO
With the aim of creating new bisubstrate inhibitors of protein farnesyltransferase (FTase), new carboxylic farnesyl pyrophosphate analogues have been designed and synthesized. The original structures are built around three elements: a prenyl moiety, a 1,4-diacid motif and an imidazole ring. All the compounds were evaluated for their ability to inhibit FTase and compared with the corresponding derivatives lacking the imidazole ring, synthesized for that purpose. These new compounds are not bisubstrate inhibitors probably because the imidazole ring is not in the right position to interact with the zinc atom. However these derivatives display FPP competitive inhibition with a good activity in the carboxylic farnesyl pyrophosphate analogues series.
Assuntos
Inibidores Enzimáticos , Farnesiltranstransferase/antagonistas & inibidores , Imidazóis , Fosfatos de Poli-Isoprenil , Piranos , Sesquiterpenos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Fosfatos de Poli-Isoprenil/síntese química , Fosfatos de Poli-Isoprenil/química , Fosfatos de Poli-Isoprenil/farmacologia , Piranos/síntese química , Piranos/química , Piranos/farmacologia , Sesquiterpenos/síntese química , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Diaminations are a girl's best friend: New reactions in the field of transition-metal-catalyzed diamination of olefins provide a powerful tool for the elaboration of more complex molecules bearing the 1,2-diamine moiety. An overview of these methods, including asymmetric versions, is given.
Assuntos
Alcenos/química , Diaminas/química , Elementos de Transição/química , Catálise , Cobre/química , Estrutura Molecular , Paládio/química , EstereoisomerismoRESUMO
A novel series of compounds, derived from 2,5-functionalized imidazoles, have been synthesized as potential bisubstrate inhibitors of protein farnesyltransferase (FTase) using structure-based design. These compounds have a 1,4-diacid chain and a tripeptide connected by an imidazole ring. The synthetic strategy relies on the functionalization at the C-2 position of the heterocycle with the diacid side chain and peptide coupling at the C-5 position. Several new compounds were synthesized in good yields. Kinetic experiments on the most active compounds revealed different binding modes depending on the diacid chain length.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Inibidores Enzimáticos/síntese química , Imidazóis/síntese químicaRESUMO
Shuffling of two simple building blocks and a regioselective transfer hydrogenation allow for the rapid synthesis of a small collection of lepidopteran sex pheromones, e.g., 8E,10Z-tetradeca-8,10-dienal 5c, from the horse chestnut leafminer (Cameraria ohridella).
Assuntos
Lepidópteros/química , Atrativos Sexuais/síntese química , Aldeídos/química , Animais , Catálise , Cetonas/síntese química , Cetonas/química , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Sensibilidade e Especificidade , Atrativos Sexuais/química , EstereoisomerismoRESUMO
Amino alcohols are important synthons for N-heterocycles. We have developed an efficient method to activate hydroxyl groups, which avoids the use of toxic reagents and tolerates a wide variety of functional groups. Our strategy has been applied to the synthesis of functionalized p-methoxyphenyl-protected azetidines, pyrrolidines, and piperidines. The required amino alcohols were synthesized according to an optimized proline-catalyzed Mannich protocol. An azetidine analogue of ezetimibe was synthesized to demonstrate the potential for the synthesis of drug-like molecules.