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
We present here a stereoselective tandem reaction based on the asymmetric conjugate addition of dialkylzinc reagents to unsaturated acylimidazoles followed by trapping of the intermediate zinc enolate with carbocations. The use of a chiral NHC ligand provides chiral zinc enolates in high enantiomeric purities. These enolates are reacted with highly electrophilic onium compounds to afford densely substituted acylimidazoles. DFT calculations helped to understand the reactivity of the zinc enolates derived from acylimidazoles and allowed their comparison with metal enolates obtained by other conjugate addition reactions.
RESUMO
The present study describes an efficient access to enantioenriched pyrimidines' derivatives from readily available Boc-AA-NH2 and ß-enaminones. This strategy allows the synthesis of a large variety of chiral pyrimidines (18 examples) with good yields from the chiral pool. In the case of peptide isosteres, this procedure proved to be highly stereoretentive and paves the way to the construction of C-terminal modified peptidomimetics as illustrated in the synthesis of two original pyrimidines containing pseudo-dipeptides.
Assuntos
Peptídeos , Pirimidinas , Estereoisomerismo , DipeptídeosRESUMO
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
The configurational instability of allenyl copper reagents is unveiled. An experimental study highlights the crucial role of Li+ and of the reaction temperature in the control of the configurational stability of allenyl copper reagents. A judicious choice of the reaction conditions allows efficient dynamic kinetic resolution processes and gives a one-pot access to homopropargylic alcohols or amines bearing up to four contiguous defined stereogenic centers.
RESUMO
The reaction of a silyl dienolate, a Cu(II) salt and TBAT yielding the corresponding copper dienolate is addressed. A combined NMR and cyclic voltammetry analysis first highlight the role of TBAT in the Cu(II) to Cu(I) reduction and the structure of the precatalytic species. From these first results a second set of NMR and theoretical studies enable the determination of the structure and the mechanism of formation of the copper dienolate catalytic species. Finally, we showed that that the copper catalyst promote the E/Z s-cis/s-trans equilibration of the silyl dienolate precursor through a copper dienolate intermediate. All of these results unveil some peculiarities of the catalytic and asymmetric vinylogous Mukaiyama reaction.
RESUMO
While artificial cyclases hold great promise in chemical synthesis, this work presents the first example of a DNA-catalyzed inverse electron-demand hetero-Diels-Alder (IEDHDA) between dihydrofuran and various α,ß-unsaturated acyl imidazoles. The resulting fused bicyclic O,O-acetals containing three contiguous stereogenic centers are obtained in high yields (up to 99 %) and excellent diastereo- (up to >99:1 dr) and enantioselectivities (up to 95 % ee) using a low catalyst loading. Most importantly, these results show that the concept of DNA-based asymmetric catalysis can be expanded to new synthetic transformations offering an efficient, sustainable, and highly selective tool for the construction of chiral building blocks.
Assuntos
DNA/química , Catálise , Reação de Cicloadição , Elétrons , EstereoisomerismoRESUMO
A highly enantioselective iron-catalyzed Intramolecular Inverse Electron-Demand Hetero Diels-Alder (IIEDHDA) reaction is reported. By using a chiral semicorrin ligand in the presence of 2,6-lutidine, good isolated yields and excellent enantioselectivities were observed (up to 96% ee). Thanks to the versatile postfunctionalization of the acyl-imidazole moiety, this methodology represents a unique example of the straightforward construction of highly valuable enantioenriched bicyclic dihydropyran derivatives.
RESUMO
The popularity of NHCs in transition metal catalysis has prompted the development of chiral versions as electron-rich neutral stereodirecting ancillary ligands for enantioselective transformations. Herein we demonstrate that cyclic (alkyl)(amino)carbene (CAAC) ligands can also engage in asymmetric transformations, thereby expanding the toolbox of available chiral carbenes.
RESUMO
The studies culminating in the synthesis of two large subunits of tautomycetin are described. The first one, fragment C1-C12 that has an anti-1,3-dimethyl system and a terminal diene unit, was accomplished in 10 linear steps in 7.4% overall yield. The second one, fragment C13-C25 which bears the sensitive anhydride framework and the majority of the stereogenic centers, was prepared in 13 linear steps (longest sequence) in 8% overall yield. Among the key transformations used, a regioselective epoxide opening, a Pd-catalyzed addition of terminal alkyne to acceptor alkyne, a Mukaiyama aldol reaction, a Yamaguchi esterification, and a homemade mild di-esterification can be cited. The chosen strategies allowed good yields, stereoselectivity, reproducibility, and scalability for several important intermediates.
RESUMO
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
The spread of antibiotic-resistant pathogens is a growing concern, and new families of antibacterials are desperately needed. Odilorhabdins are a new class of antibacterial compounds that bind to the bacterial ribosome and kill bacteria through inhibition of the translation. NOSO-95C, one of the first member of this family, was synthesized for the first time, and then a structure-activity relationships study was performed to understand which groups are important for antibacterial activity and for inhibition of the bacterial translation. Based on this study an analogue showing improved properties compared to the parent compound was identified and showed promising in vitro and in vivo efficacy against Enterobacteriaceae.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , Subunidades Ribossômicas Menores/efeitos dos fármacos , Animais , Humanos , Infecções por Klebsiella/complicações , Infecções por Klebsiella/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Infecções Respiratórias/microbiologia , Relação Estrutura-Atividade , XenorhabdusRESUMO
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
Exchange of X (F, Cl, OMe) and a substituted enolate chain between SiMe3 and various CuI complexes was examined. Reaction mechanisms pass through a cyclic transition state in which the reaction coordinate is associated with rotation of the SiMe3 moiety. The dependence of the thermodynamic and kinetic features on the nature of the active and ancillary ligands was examined. Formation of copper enolate is shown to be favored when stabilized enolates are used. Replacement of F by Cl reverses the preference of the reaction. This is associated with the small difference between the Cu-Cl and Si-Cl bond energies, in contrast to other Si-X bonds, which are systematically stronger than their Cu-X analogues.
RESUMO
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.
RESUMO
The ubiquitous presence of spirooxindole architectures with several functionalities and stereogenic centers in bioactive molecules has been appealing for the development of novel methodologies seeking their preparation in high yields and selectivities. Expansion and refinement in the field of asymmetric organocatalysis have made possible the development of straightforward strategies that address these two requisites. In this review, we illustrate the current state-of-the-art in the field of spirooxindole synthesis through the use of non-covalent organocatalysis. We aim to provide a concise overview of very recent methods that allow to the isolation of unique, densely and diversified spirocyclic oxindole derivatives with high structural diversity via the use of cascade, tandem and domino processes.
Assuntos
Indóis/química , Compostos de Espiro/química , Catálise , Técnicas de Química Sintética , Alcaloides de Cinchona/química , Ligação de Hidrogênio , Indóis/síntese química , Estrutura Molecular , Oxindóis , Compostos de Espiro/síntese química , EstereoisomerismoRESUMO
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.