Gold(I)-catalysed one-pot synthesis of chromans using allylic alcohols and phenols

A gold(I)-catalysed reaction of allylic alcohols and phenols produces chromans regioselectively via a one-pot Friedel–Crafts allylation/intramolecular hydroalkoxylation sequence. The reaction is mild, practical and tolerant of a wide variety of substituents on the phenol

Synthèse d’imidazo[1,2-a]pyrazin-3(7H)-ones originales et leurs évaluations comme substrats de la luciférase mutée d’Oplophorus gracilirostris nanoKAZ

The large-scale use of marine luciferases as reporter systems is still very impeded by the prohibitive costs of their substrates. These imidazo[1,2-a]pyrazin-3(7H)-ones are difficult to synthesize, and their unstability make their storage and use cumbersome. In the course of this project, we have discovered a new synthesis of imidazo[1,2-a]pyrazin-3(7H)-ones in 5 to 10 steps, which allowed us to synthesize more than one hundred original potential substrates of these luciferases, alongside a derivatization method providing shelf-stable precursors of these molecules. The structure-luminescence relationships of these original substrates have been assessed with nanoKAZ, a mutated luciferase of the shrimp Oplophorus gracilirostris. This led us to identify original substrates endowed with greatly improved half-life (more than two hours) or with signal-over-noise ratios enhanced five to ten times versus the commercial furimazine/nanoKAZ system.L'utilisation massive des luciférases d'origine marine comme systèmes rapporteurs reste très limitée par le coût prohibitif de leurs substrats. Ces derniers sont constitués d'un noyau imidazo[1,2-a]pyrazin-3(7H)-one, dont les synthèses publiées sont difficiles et dont le stockage et l'utilisation nécessitent des précautions importantes. Nous avons découvert dans le cadre de ce projet une synthèse alternative originale d'imidazo[1,2-a]pyrazin-3(7H)-ones en 5 à 10 étapes ayant permis l'obtention au laboratoire de plus d'une centaine de nouveaux substrats potentiels, ainsi qu'une dérivatisation permettant le stockage de ces composés sans précaution particulière, à température ambiante, pour de longues périodes de temps. Ces luciférines originales ont ensuite été évaluées sur un mutant de la luciférase d'Oplophorus gracilirostris, nanoKAZ, afin d'étudier les relations structure-luminescence de ces substrats. Nous avons ainsi obtenu des substrats originaux avec des temps de demi-vie du signal bioluminescent largement accrus (plus de deux heures) ou des rapports signal/bruit cinq à dix fois supérieurs au couple commercial furimazine/nanoKAZ

Synthèse d’imidazo[1,2-a]pyrazin-3(7H)-ones originales et leurs évaluations comme substrats de la luciférase mutée d’Oplophorus gracilirostris nanoKAZ

The large-scale use of marine luciferases as reporter systems is still very impeded by the prohibitive costs of their substrates. These imidazo[1,2-a]pyrazin-3(7H)-ones are difficult to synthesize, and their unstability make their storage and use cumbersome. In the course of this project, we have discovered a new synthesis of imidazo[1,2-a]pyrazin-3(7H)-ones in 5 to 10 steps, which allowed us to synthesize more than one hundred original potential substrates of these luciferases, alongside a derivatization method providing shelf-stable precursors of these molecules. The structure-luminescence relationships of these original substrates have been assessed with nanoKAZ, a mutated luciferase of the shrimp Oplophorus gracilirostris. This led us to identify original substrates endowed with greatly improved half-life (more than two hours) or with signal-over-noise ratios enhanced five to ten times versus the commercial furimazine/nanoKAZ system.L'utilisation massive des luciférases d'origine marine comme systèmes rapporteurs reste très limitée par le coût prohibitif de leurs substrats. Ces derniers sont constitués d'un noyau imidazo[1,2-a]pyrazin-3(7H)-one, dont les synthèses publiées sont difficiles et dont le stockage et l'utilisation nécessitent des précautions importantes. Nous avons découvert dans le cadre de ce projet une synthèse alternative originale d'imidazo[1,2-a]pyrazin-3(7H)-ones en 5 à 10 étapes ayant permis l'obtention au laboratoire de plus d'une centaine de nouveaux substrats potentiels, ainsi qu'une dérivatisation permettant le stockage de ces composés sans précaution particulière, à température ambiante, pour de longues périodes de temps. Ces luciférines originales ont ensuite été évaluées sur un mutant de la luciférase d'Oplophorus gracilirostris, nanoKAZ, afin d'étudier les relations structure-luminescence de ces substrats. Nous avons ainsi obtenu des substrats originaux avec des temps de demi-vie du signal bioluminescent largement accrus (plus de deux heures) ou des rapports signal/bruit cinq à dix fois supérieurs au couple commercial furimazine/nanoKAZ

Design and optimization of original imidazo[1,2-a]pyrazin-3(7H)-ones and their assessment as substrates of the mutated Oplophorus gracilirostris luciferase nanoKAZ

L'utilisation massive des luciférases d'origine marine comme systèmes rapporteurs reste très limitée par le coût prohibitif de leurs substrats. Ces derniers sont constitués d'un noyau imidazo[1,2-a]pyrazin-3(7H)-one, dont les synthèses publiées sont difficiles et dont le stockage et l'utilisation nécessitent des précautions importantes. Nous avons découvert dans le cadre de ce projet une synthèse alternative originale d'imidazo[1,2-a]pyrazin-3(7H)-ones en 5 à 10 étapes ayant permis l'obtention au laboratoire de plus d'une centaine de nouveaux substrats potentiels, ainsi qu'une dérivatisation permettant le stockage de ces composés sans précaution particulière, à température ambiante, pour de longues périodes de temps. Ces luciférines originales ont ensuite été évaluées sur un mutant de la luciférase d'Oplophorus gracilirostris, nanoKAZ, afin d'étudier les relations structure-luminescence de ces substrats. Nous avons ainsi obtenu des substrats originaux avec des temps de demi-vie du signal bioluminescent largement accrus (plus de deux heures) ou des rapports signal/bruit cinq à dix fois supérieurs au couple commercial furimazine/nanoKAZ.The large-scale use of marine luciferases as reporter systems is still very impeded by the prohibitive costs of their substrates. These imidazo[1,2-a]pyrazin-3(7H)-ones are difficult to synthesize, and their unstability make their storage and use cumbersome. In the course of this project, we have discovered a new synthesis of imidazo[1,2-a]pyrazin-3(7H)-ones in 5 to 10 steps, which allowed us to synthesize more than one hundred original potential substrates of these luciferases, alongside a derivatization method providing shelf-stable precursors of these molecules. The structure-luminescence relationships of these original substrates have been assessed with nanoKAZ, a mutated luciferase of the shrimp Oplophorus gracilirostris. This led us to identify original substrates endowed with greatly improved half-life (more than two hours) or with signal-over-noise ratios enhanced five to ten times versus the commercial furimazine/nanoKAZ system

A Study of Negishi Cross-Coupling Reactions with Benzylzinc Halides To Prepare Original 3-Ethoxypyrazoles

International audienceThe Negishi palladium-catalyzed cross-coupling reaction between 3-ethoxy-4-iodo-1H-pyrazole and various benzylzinc halides was extensively studied. Using simplified, robust, and optimized reaction conditions, a series of electron-poor benzylzinc halides were prepared and used to synthesize 4-benzyl-3-ethoxy-1H-pyrazoles derivatives. From these, iodination on C5 of the pyrazole nucleus led to the corresponding 4-benzyl-3-ethoxy-5-iodo-1H-pyrazoles, these are original building blocks for the preparation of libraries of new chemical entitie

On the reliability of NMR relaxation data analyses: A Markov Chain Monte Carlo approach

none4The analysis of NMR relaxation data is revisited along the lines of a Bayesian approach. Using a Markov Chain Monte Carlo strategy of data fitting, we investigate conditions under which relaxation data can be effectively interpreted in terms of internal dynamics. The limitations to the extraction of kinetic parameters that characterize internal dynamics are analyzed, and we show that extracting characteristic time scales shorter than a few tens of ps is very unlikely. However, using MCMC methods, reliable estimates of the marginal probability distributions and estimators (average, standard deviations, etc.) can still be obtained for subsets of the model parameters. Thus, unlike more conventional strategies of data analysis, the method avoids a model selection process. In addition, it indicates what information may be extracted from the data, but also what cannot.noneDaniel Abergel;Andrea Volpato;Eloi P. Coutant;Antonino PolimenoDaniel, Abergel; Andrea, Volpato; Eloi P., Coutant; Polimeno, Antonin

Synthesis of α-Amino Esters via α-Nitro or α-Oxime Esters: A Review

International audienceThis review is an in-depth survey of the reported synthetic approaches for the preparation of racemic α-amino esters via the reduction of α-nitro or α-oxime ester intermediates. Accordingly, it describes the many pathways that have been designed to prepare such intermediates­. This includes synthesis starting with α-nitroacetates, dialkyl malonates, acetoacetates, diethyl oxalates as well as [2+3] or [2+4] cycloadditions using, respectively, alkyl carbonocyanidate N-oxides or alkyl 2-nitrosoacrylates. This review also contains the description of a myriad of side reactions which can occur when working with α-nitro esters­.1 Introduction2 α-Amino Esters from α-Nitroacetates via Condensation Reactions3 α-Amino Esters via C-Alkylation or C-Arylation of α-Nitroacetates4 α-Amino Esters from α-Nitroacetates Using Other Reactions5 Synthesis of α-Amino Esters via α-Oxime Esters6 Synthesis of α-Amino Esters via [2+3] Cycloadditions7 Synthesis of α-Amino Esters via [2+4] Cycloadditions8 On the Reduction of α-Oxime Esters9 Conclusio

Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

International audienceWe have explored here the scope of the age-old diethyl malonate-based accesses to α-amino esters involving Knoevenagel condensations of diethyl malonate on aldehydes, reductions of the resulting alkylidenemalonates, the preparation of the corresponding α-hydroxyimino esters and their final reduction. This synthetic pathway turned out to be general although some unexpected limitations were encountered. The synthetic modifications of some of the intermediates - using Suzuki-Miyaura coupling or cycloadditions - before undertaking the oximation step - provided accesses to further α-amino esters. Moreover, other pathways to α-hydroxyimino esters were explored including an attempt to improve the cycloadditions between ethyl β-bromo-α-hydroxyiminocarboxylate and various alkylfuranes

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

We report here on the use of ethyl nitroacetate as a glycine template to produce α-amino esters. This started with a study of its condensation with various arylacetals to give ethyl 3-aryl-2-nitroacrylates followed by a reduction (NaBH4 and then zinc/HCl) into α-amino esters. The scope of this method was explored as well as an alternative with arylacylals instead. We also focused on various [2 + 3] cycloadditions, one leading to a spiroacetal, which led to the undesired ethyl 5-(benzamidomethyl)isoxazole-3-carboxylate. The addition of ethyl nitroacetate on a 5-methylene-4,5-dihydrooxazole using cerium(IV) ammonium nitrate was also explored and the synthesis of other oxazole-bearing α-amino esters was achieved using gold(I) chemistry

Bioluminescence Profiling of NanoKAZ/NanoLuc Luciferase Using a Chemical Library of Coelenterazine Analogues

International audienceWe describe here an extensive structure-bioluminescence relationship study of a chemical library of analogues of coelenterazine, using nanoKAZ/NanoLuc, a mutated luciferase originated from the catalytic subunit of the deep-sea shrimp Oplophorus gracilirostris. Out of the 135 O-acetylated precursors that were prepared by using our recently reported synthesis and following their hydrolysis to give solutions of the corresponding luciferins, notable bioluminescence improvements were achieved in comparison with furimazine, which is currently amongst the best substrates of nanoKAZ/NanoLuc. For instance, the rather more lipophilic analogue 8-(2,3-difluorobenzyl)-2-((5-methylfuran-2-yl)methyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one provided a 1.5-fold improvement of the total light output over a 2 h period, a close to threefold increase of the initial signal intensity and a signal-to-background ratio five times greater than furimazine. The kinetic parameters for the enzymatic reaction were obtained for a selection of luciferin analogues and provided unexpected insights into the luciferase activity. Most prominently, along with a general substrate-dependent and irreversible inactivation of this enzyme, in the case of the optimized luciferin mentioned above, the consumption of 2664 molecules was found to be required for the detection of a single Relative Light Unit (RLU; a luminometer-dependent fraction of a photon)