RESUMEN
Hydrogen peroxide (H2O2) is responsible for numerous damages when overproduced, and its detection is crucial for a better understanding of H2O2-mediated signaling in physiological and pathological processes. For this purpose, various "off-on" small fluorescent probes relying on a boronate trigger have been prepared, and this design has also been involved in the development of H2O2-activated prodrugs or theranostic tools. However, this design suffers from slow kinetics, preventing activation by H2O2 with a short response time. Therefore, faster H2O2-reactive groups are awaited. To address this issue, we have successfully developed and characterized a prototypic borinic-based fluorescent probe containing a coumarin scaffold. We determined its in vitro kinetic constants toward H2O2-promoted oxidation. We measured 1.9 × 104 m-1â s-1 as a second-order rate constant, which is 10,000-fold faster than its well-established boronic counterpart (1.8 m-1â s-1). This improved reactivity was also effective in a cellular context, rendering borinic acids an advantageous trigger for H2O2-mediated release of effectors such as fluorescent moieties.
RESUMEN
We give a full account of the total synthesis of tiacumicinâ B (Tcn-B), a natural glycosylated macrolide with remarkable antibiotic properties. Our strategy is based on our experience with the synthesis of the tiacumicinâ B aglycone and on unique 1,2-cis-glycosylation steps. We used sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors that allowed highly ß-selective rhamnosylation and noviosylation that rely on H-bond-mediated aglycone delivery. The rhamnosylated C1-C3 fragment was anchored to the C4-C19 aglycone fragment by a Suzuki-Miyaura cross-coupling. Ring-size-selective Shiina macrolactonization provided a semiglycosylated aglycone that was engaged directly in the noviolysation step with a virtually total ß-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethyl ether on a phenol, and efficient removal of all the protecting groups provided synthetic tiacumicinâ B.
RESUMEN
The synthesis of glycopyranosyl nucleosides modified in the sugar moiety has been less frequently explored, notably because of the lack of a reliable method to glycosylate pyrimidine bases. Herein we report a solution in the context of the synthesis of peptidonucleosides. They were obtained after glycosylation of different pyrimidine nucleobases with glucopyranosyl donors carrying an azide group at the C4 position. A methodological study involving different anomeric leaving groups (acetate, phenylsulfoxide and ortho-hexynylbenzoate) showed that a sulfoxide donor in combination with trimethylsilyl triflate as the promoter led to the best yields.
Asunto(s)
NucleósidosRESUMEN
A total synthesis of tiacumicinâ B, a natural macrolide whose remarkable antibiotic properties are used to treat severe intestinal infections, is reported. The strategy is in part based on the prior synthesis of the tiacumicinâ B aglycone, and on the decisive use of sulfoxides as anomeric leaving groups in hydrogen-bond-mediated aglycone delivery (HAD). This new HAD variant permitted highly ß-selective rhamnosylation and noviosylation. To increase convergence, the rhamnosylated C1-C3 fragment thus obtained was anchored to the C4-C19 aglycone fragment by adapting the Suzuki-Miyaura cross-coupling used for the aglycone synthesis. Ring-size-selective macrolactonization provided a compound engaged directly in the noviolysation step with virtually total ßâ selectivity. The final efficient removal of all the protecting groups provided synthetic tiacumicinâ B.
Asunto(s)
Fidaxomicina/síntesis química , Antibacterianos/síntesis química , Antibacterianos/química , Catálisis , Complejos de Coordinación/química , Fidaxomicina/química , Glicosilación , Enlace de Hidrógeno , Lactonas/químicaRESUMEN
Our study of the synthesis of the aglycone of tiacumicin B is discussed here. We imagined two possible strategies featuring a main retrosynthetic disconnection between C13 and C14. The first strategy was based on Suzuki-Miyaura cross-coupling of 1,1-dichloro-1-alkenes, but the failure of this pathway led us to use a Pd/Cu-dual-catalyzed cross-coupling of alkynes with allenes that had never been implemented before in a total synthesis context. We used density functional theory calculations to guide our strategic choices concerning a [2.3]-Wittig rearrangement step and the final ring-size selective Yamaguchi macrolactonization. This led to two syntheses of the aglycone of tiacumicin B, with one of last generation delivering ultimately an adequately protected and glycosylation-ready aglycone.
RESUMEN
The activation of aryl glycosyl sulfone donors has been achieved using scandium(iii) triflate and has led to the selective preparation of α-mannosides resulting from a post-glycosylation anomerization.
RESUMEN
One-step assembly of hexahydroisoindole scaffolds by a sequence that combines the Petasis (borono-Mannich) and Diels-Alder reactions is described. The unique selectivity observed experimentally was confirmed by quantum calculations. The current method is applicable to a broad range of substrates, including free sugars, and holds significant potential to efficiently and stereoselectively build new heterocyclic structures. This easy and fast entry to functionalized polycyclic compounds can be pursued by further transformations, for example, additional ring closure by a cross-metathesis/Michael addition domino sequence.
Asunto(s)
Aldehídos/química , Reacción de Cicloadición/métodos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
A regio- and stereocontrolled solution for a selective modification at the C-2 or C-4 position of N-acetylneuraminic acid involves the use of allylic substitution catalyzed by palladium. As illustrated in the scheme, regioselective malonylation is under the strict influence of the ligands associated with the allylpalladium complex.
Asunto(s)
Carbohidratos/química , Ácido N-Acetilneuramínico/química , Paladio/química , Compuestos Alílicos , Catálisis , Ligandos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Strigolactone (SL) plant hormones control plant architecture and are key players in both symbiotic and parasitic interactions. GR24, a synthetic SL analog, is the worldwide reference compound used in all bioassays for investigating the role of SLs in plant development and in rhizospheric interactions. In 2012, the first characterization of the SL receptor reported the detection of an unknown compound after incubation of GR24 samples with the SL receptor. We reveal here the origin of this compound (P270), which comes from a by-product formed during GR24 chemical synthesis. We present the identification of this by-product, named contalactone. A proposed chemical pathway for its formation is provided as well as an evaluation of its bioactivity on pea, Arabidopsis, root parasitic plant seeds and AM fungi, characterizing it as a SL mimic. Quality of GR24 samples can be easily checked by carrying out microscale hydrolysis in a basic aqueous medium to easily detect P270 as indicator of the presence of the contalactone impurity. In all cases, before being used for bioassays, GR24 must be careful purified by preparative HPLC.
Asunto(s)
Arabidopsis/química , Compuestos Heterocíclicos con 3 Anillos/análisis , Lactonas/análisis , Cromatografía Líquida de Alta Presión , Contaminación de Medicamentos , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Lactonas/síntesis química , Estructura MolecularRESUMEN
A highly effective method for the introduction of a formyl group at the anomeric position of pyranosides was developed via enolisation of beta-C-D-glycopyranosylpropan-2-one using thermodynamic conditions then oxidative cleavage of the more substituted double bond. This sequence affords the desired aldehydes that are conveniently protected as aminals for purification and storage and easily regenerated using Dowex resin H+. In this paper, the syntheses of nine differently protected aldehydes derived from d-glucose, d-galactose, lactose and N-acetyl-d-glucosamine are presented. Our strategy proved to be very efficient in most cases excepted in the D-mannose series.
Asunto(s)
Acetona/análogos & derivados , Formaldehído/análogos & derivados , Formaldehído/síntesis química , Glucosa/análogos & derivados , Glucosa/química , Acetilglucosamina/química , Galactosa/química , Lactosa/química , Oxidación-Reducción , TermodinámicaRESUMEN
Tiacumicin B is an antibiotic endowed with the remarkable ability to interact with a new biological target, giving it an inestimable potential in the context of the ever-growing and worrisome appearance of resistances of bacteria and mycobacteria to antibiotics. The synthesis of an aglycone of tiacumicin B ready for glycosylation is reported. The key steps of this approach are a [2,3]-Wittig rearrangement, a Pd/Cu-catalyzed allene-alkyne cross-coupling, a E-selective cross-metathesis, and a final ring-size selective macrolactonization.
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Antibacterianos/síntesis química , Fidaxomicina/síntesis química , Catálisis , Cobre/química , Diseño de Fármacos , Glicosilación , Estructura Molecular , Paladio/químicaRESUMEN
The three-component Petasis borono-Mannich reaction starting with easily accessible N-protected α-amino aldehydes produces efficiently and diastereoselectively 1,2-trans-diamines with an enantiomeric excess of up to 98%.
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Aldehídos/química , Boro/química , Diaminas/química , Diaminas/síntesis química , Técnicas de Química Sintética , EstereoisomerismoRESUMEN
Starting from methyl 6-bromo-4,6-dideoxy-alpha-D-threo-4-enopyranoside, 4-C-branched sugars have been prepared through indium-promoted Barbier-type allylation of various aldehydes in aqueous media followed by hydroboration of the resulting double bond. The intermediate unsaturated monosaccharides were shown to rearrange in acidic media to give 4-C-acetyl-5-C-alkyl pyranose compounds. From beta-1-formyl sugars the corresponding beta-(1-->4)-C-disaccharides were obtained.
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Compuestos Alílicos/síntesis química , Disacáridos/síntesis química , Indio/química , Monosacáridos/síntesis química , Compuestos Alílicos/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Datos de Secuencia Molecular , Monosacáridos/química , Agua/químicaRESUMEN
An unprecedented intramolecular Petasis condensation provides a novel approach to biologically important conduramines. The compounds are produced with an exclusive anti stereoselectivity for the newly created ß-amino alcohol motif. The stereochemical outcome of the reaction is opposite to the one usually observed in the intermolecular reaction.
Asunto(s)
Amino Alcoholes/síntesis química , Ciclohexilaminas/síntesis química , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
Iron(III) chloride hexahydrate promotes a cascade of transformations on a Petasis condensation product that sets up the right dihydropyran precursors of valuable Relenza congeners.
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Cloruros/química , Compuestos Férricos/química , Zanamivir/análogos & derivados , Zanamivir/síntesis química , Catálisis , Estructura Molecular , Zanamivir/químicaRESUMEN
A new series of 2,6-quinolinyl derivatives was prepared leading to potent low nanomolar VLA-4/VCAM-1 antagonists.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Integrina alfa4beta1/antagonistas & inhibidores , Quinolinas/química , Antiinflamatorios no Esteroideos/farmacología , Humanos , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
Palladium-catalysed carbonyl allylations can be effectively applied to the regio- and diastereoselective synthesis of 2-C- and 4-C-branched sugars from allylic esters or carbonates via the formation of pi-allylpalladium(II) intermediates and their reductive transmetalation with indium(I) bromide.
Asunto(s)
Compuestos Alílicos/química , Bromuros/química , Carbohidratos/química , Indio/química , Paladio/química , Catálisis , Estructura MolecularRESUMEN
Organolithium-induced deprotonation of terminal epoxides in the presence of appropriate diamine ligands allows trapping with a range of electrophiles, yielding functionalised di- and tri-substituted epoxides in good yields and with control of stereochemistry at the epoxide.