Mechanistic Insights about the Ligand-Enabled Oxy-arylation/vinylation of Alkenes via Au(I)/Au(III) Catalysis

The mechanism of oxy-arylation/vinylation of alkenes catalyzed by the (MeDalphos)AuCl complex was comprehensively investigated by DFT. (P,N)Au(Ph)²⁺ and (P,N)Au(vinyl)²⁺ are key intermediates accounting for the activation of the alkenols and for their cyclization by outer-sphere nucleophilic attack of oxygen. The 5-exo and 6-endo paths have been computed and compared, reproducing the peculiar regioselectivity difference observed experimentally between 4-penten-1-ol, (E) and (Z)-4-hexen-1-ols. Examining the way the alkenol coordinates to gold (more η² or η¹) can offer, in some cases, a simple way to predict the favored path of cyclization.     

Hydrogen Peroxide-Responsive Triggers Based on Borinic Acids: Molecular Insights into the Control of Oxidative Rearrangement

Arylborinic acids represent new, efficient, and underexplored hydrogen peroxide-responsive triggers. In contrast to boronic acids, two concomitant oxidative rearrangements are involved in the complete oxidation of these species, which might represent a major limitation for an efficient effector (drug or fluorophore) release. Herein, a comprehensive study of H₂O₂-mediated unsymmetrical arylborinic acid oxidation to investigate the factors that could selectively guide their oxidative rearrangement is described. The o-CF₃ substituent was found to be an excellent directing group allowing a complete regioselectivity on borinic acid models. This result was successfully applied to synthesizing new borinic acid-based fluorogenic probes, which exclusively release the fluorescent moiety upon H₂O₂ treatment. These compounds maintained their superior kinetic properties compared to boronic acids, thus further enhancing the potential of arylborinic acids as valuable new H₂O₂-sensitive triggers.     

Marinobufagenin extraction from Rhinella marina toad glands: Alternative approaches for a systematized strategy

Marinobufagenin is a bufadienolide compound detected mainly in skin and parotoid gland secretions of Rhinella marina (L.) toad. Bufadienolides regulate the Na⁺/K⁺‐ATPase pump by inhibiting the cardiotonic steroid dependent‐site and act as cardiac inotropes with vasoconstrictive properties. Marinobufagenin and other bufadienolides, such as telocinobufagin and bufalin, are thought to be found endogenously in mammals in salt‐sensitive hypertensive states such as essential hypertension, congestive heart‐failure, and preeclampsia. The role of marinobufagenin as antimicrobial agent and its cytotoxic potential have also been recognized. The particular interest around marinobufagenin prompts us to consider the Rhinella marina toad venom as a possible source for molecules with pharmacological and/or diagnostic potential. In this article, two different approaches of extraction and purification of marinobufagenin from Rhinella marina (L.) venom are studied: (i) Preparative thin‐layer chromatography combined to mass spectrometry and/or ultraviolet detection and (ii) solid‐phase extraction coupled with fractionation on high‐performance liquid chromatography. Different chromatographic conditions are tested for each approach. The solid‐phase extraction combined with high‐performance liquid chromatography fractionation approach was preferred as it offered a greater yield, was less time‐consuming and allowed us to selectively isolate marinobufagenin. Both protocols aim to provide efficient and convenient methods for toad venom extraction, based on an easily automatable and systematized strategy.     

Expanding the Scope of Enantioselective FerroPHANE‐Promoted [3+2] Annulations with α,β‐Unsaturated Ketones

The planar chiral 2‐phospha[3]ferrocenophane I has been shown to be the first efficient nucleophilic organocatalyst for the enantioselective synthesis of cyclopentenylphosphonates, through [3+2] cyclizations between diethyl allenylphosphonate and α,β‐unsaturated ketones. The same catalyst has also been applied to the highly enantioselective [3+2] cyclizations of allenic esters with dibenzylideneacetone and analogous bis‐enones, leading to functionalised cyclopentenes with either monocyclic or spirocyclic structures (ee 84–95 %). It has been shown that the residual enone functions in the resulting cyclopentenes can be involved in subsequent cyclization steps to afford unprecedented C₂‐symmetric bis‐cyclopentenylketones. In order to provide insight into the behaviour of FerroPHANE I as a chiral catalyst in [3+2] cyclisations, the energetically most favoured isomers of the key phosphine‐allene adduct have been calculated by DFT methods. Factors likely to control the chiral induction process are highlighted.     

A progressive barrier derivative-free trust-region algorithm for constrained optimization

We study derivative-free constrained optimization problems and propose a trust-region method that builds linear or quadratic models around the best feasible and around the best infeasible solutions found so far. These models are optimized within a trust region, and the progressive barrier methodology handles the constraints by progressively pushing the infeasible solutions toward the feasible domain. Computational experiments on 40 smooth constrained problems indicate that the proposed method is competitive with COBYLA, and experiments on two nonsmooth multidisciplinary optimization problems from mechanical engineering show that it can be competitive with the NOMAD software.     

Impact of selective excitation on carbon longitudinal relaxation: Towards fast solid-state NMR techniques

The effect of selective pulses on the apparent carbon longitudinal relaxation is investigated in three fully ¹³C-labeled systems, histidine as a model system and two proteins MerP and YajG. It is shown that the longitudinal relaxation of a selectively excited carbon spin is greatly enhanced, mainly because of fast spin-diffusion. This relaxation enhancement allows reducing the time necessary for polarization recovery between two experiments. This effect can be exploited either to improve the sensitivity of NMR experiments or to reduce the experimental time. Using selective carbon excitation combined with fast pulsing on fully ¹³C-labeled proteins, a sensitivity improvement of 20–45% over standard cross-polarization methods is predicted from the measured relaxation times.     

Effects of Ulva sp. Extracts on the Growth,Biofilm Production,and Virulence of Skin Bacteria Microbiota: Staphylococcus aureus,Staphylococcus epidermidis,and Cutibacterium acnes Strains

Ulva sp. is known to be a source of bioactive compounds such as ulvans, but to date, their biological activity on skin commensal and/or opportunistic pathogen bacteria has not been reported. In this study, the effects of poly- and oligosaccharide fractions produced by enzyme-assisted extraction and depolymerization were investigated, for the first time in vitro, on cutaneous bacteria: Staphylococcus aureus, Staphylococcus epidermidis, and Cutibacterium acnes. At 1000 μg/mL, poly- and oligosaccharide fractions did not affect the growth of the bacteria regarding their generation time. Polysaccharide Ulva sp. fractions at 1000 μg/mL did not alter the bacterial biofilm formation, while oligosaccharide fractions modified S. epidermidis and C. acnes biofilm structures. None of the fractions at 1000 μg/mL significantly modified the cytotoxic potential of S. epidermidis and S. aureus towards keratinocytes. However, poly- and oligosaccharide fractions at 1000 μg/mL induced a decrease in the inflammatory potential of both acneic and non-acneic C. acnes strains on keratinocytes of up to 39.8%; the strongest and most significant effect occurred when the bacteria were grown in the presence of polysaccharide fractions. Our research shows that poly- and oligosaccharide Ulva sp. fractions present notable biological activities on cutaneous bacteria, especially towards C. acnes acneic and non-acneic strains, which supports their potential use for dermo-cosmetic applications.     

P450Jα: A New,Robust and α-Selective Fatty Acid Hydroxylase Displaying Unexpected 1-Alkene Formation

Oxyfunctionalization of fatty acids (FAs) is a key step in the design of novel synthetic pathways for biobased/biodegradable polymers, surfactants and fuels. Here, we show the isolation and characterization of a robust FA α-hydroxylase (P450_Jα) which catalyses the selective conversion of a broad range of FAs (C6:0-C16:0) and oleic acid (C18:1) with H₂O₂ as oxidant. Under optimized reaction conditions P450_Jα yields α-hydroxy acids all with >95 % regioselectivity, high specific activity (up to 15.2 U mg⁻¹) and efficient coupling of oxidant to product (up to 85 %). Lauric acid (C12:0) turned out to be an excellent substrate with respect to productivity (TON=394 min⁻¹). On preparative scale, conversion of C12:0 reached 83 % (0.9 g L⁻¹) when supplementing H₂O₂ in fed-batch mode. Under similar conditions P450_Jα allowed further the first biocatalytic α-hydroxylation of oleic acid (88 % conversion on 100 mL scale) at high selectivity and in good yields (1.1 g L⁻¹; 79 % isolated yield). Unexpectedly, P450_Jα displayed also 1-alkene formation from shorter chain FAs (≤C10:0) showing that oxidative decarboxylation is more widely distributed across this enzyme family than reported previously.