Green synthesis of (R)-3-hydroxy-decanoic acid and analogs from levoglucosenone: a novel access to the fatty acid moiety of rhamnolipids.

Rhamnolipids (RLs) are highly valuable molecules in the cosmetic, pharmaceutic, and agricultural sectors with outstanding biosurfactant properties. In agriculture, due to their potential to artificially stimulate the natural immune system of crops (also known as elicitation), they could represent a critical substitute to conventional pesticides. However, their current synthesis methods are complex and not aligned with green chemistry principles, posing a challenge for their industrial applications. In addition, their bioproduction is cumbersome with reproducibility issues and expensive downstream processing. This work offers a more straightforward and green access to RLs, crucial to decipher their mechanisms of action and design novel potent and eco-friendly elicitors. To achieve this, we propose an efficient seven-step synthetic pathway toward (R)-3-hydroxyfatty acid chains present in RLs, starting from cellulose-derived levoglucosenone, with Michael addition, Baeyer-Villiger oxidation, Bernet-Vasella reaction, and cross-metathesis homologation as key steps. This method allowed the production of (R)-3-hydroxyfatty acid chains and derivatives with an overall yield ranging from 24% to 36%.

An expeditive and green chemo-enzymatic route to diester sinapoyl-l-malate analogues: sustainable bioinspired and biosourced UV filters and molecular heaters.

Sinapoyl malate, naturally present in plants, has proved to be an exceptional UV filter and molecular heater for plants. Although there are nowadays industrially relevant sustainable synthetic routes to sinapoyl malate, its incorporation into certain cosmetic formulations, as well as its adsorption on plant leaves, is limited by its hydrophilicity. To overcome these obstacles, it is important to find a way to effectively control the hydrophilic-lipophilic balance of sinapoyl malate to make it readily compatible with the cosmetic formulations and stick on the waxy cuticle of leaves. To this end, herein, we describe a highly regioselective chemo-enzymatic synthesis of sinapoyl malate analogues possessing fatty aliphatic chains of variable length, enabling the lipophilicity of the compounds to be modulated. The potential toxicity (i.e., mutagenicity, carcinogenicity, endocrine disruption, acute and repeated-dose toxicity), bioaccumulation, persistence and biodegradability potential of these new analogues were evaluated in silico, along with the study of their transient absorption spectroscopy, their photostability as well as their photodegradation products.

Chemo-Enzymatic Synthesis and Biological Assessment of p-Coumarate Fatty Esters: New Antifungal Agents for Potential Plant Protection.

One trend in agriculture is the replacement of classical pesticides with more ecofriendly solutions, such as elicitation, which is a promising approach consisting of stimulating the natural immune system of a plant to improve its resistance to pathogens. In this fashion, a library of p-coumaric-based compounds were synthesized in accordance with as many principles of green chemistry as possible. Then, these molecules were tested for (1) the direct inhibition of mycelium growth of two pathogens, Botrytis cinerea and Sclerotinia sclerotiorum, and (2) plasma membrane destabilization in Arabidopsis and rapeseed. Finally, the protective effect was evaluated on an Arabidopsis/B. cinerea pathosystem. Total inhibition of the growth of both fungi could be achieved, and significant ion leakage was observed using dihydroxylated fatty p-coumarate esters. A direct effect on plants was also recorded as a ca. three-fold reduction in the necrosis area.

Optimization of DIC-Tripolium Ecofriendly Extraction Process: Recovery of Hesperidin from Orange Byproducts, Antioxidant and α-Amylase Inhibition of Extracts.

This study aimed to investigate the effect of an innovative ecofriendly process-instant controlled pressure drop technology, also known as "détente instantanée contrôlée" or DIC-coupled with Tripolium extraction (DIC-Tripolium), on the hesperidin recovery, and antioxidant and antidiabetic activities of orange byproduct extracts. A DIC pretreatment was applied to partially dried orange byproducts (~16% wet basis). A central composite rotatable design (CCRD), composed of 13 experimental trials (four factorial points, four-star points, and five repetitions for the central point), was followed by a Tripolium process consisting of successive intermittent extraction periods using ethanol/water solvent at 20 ± 1 °C, 5 kPa for 5 min and m/v ratio = 5 g/50 mL. The DIC pretreatment, coupled with the Tripolium process, increased the extractability of hesperidin (from 1.55- to 4.67-fold compared to untreated DIC orange byproducts). The radical scavenging activities of the extracts were also enhanced or preserved in different DIC-Tripolium extracts. The α-Amylase inhibition percentage varied between 55.6 ± 0.02 and 88.30 ± 0.01% according to DIC-Tripolium conditions. The multi-criteria optimized condition of DIC-Tripolium extraction, allowing for the maximization of the hesperidin content, radical scavenging activities, iron chelating activity, and α-amylase inhibition of extracts, corresponds to a DIC saturated steam pressure of 599.4 kPa and a DIC pretreatment time of 38 s.

Intensifying Effect of Instant Controlled Pressure Drop (DIC) Pre-Treatment on Hesperidin Recovery from Orange Byproducts: In Vitro Antioxidant and Antidiabetic Activities of the Extracts.

The orange byproduct is a widely accessible and valuable source of functional phenolic compounds, particularly hesperidin. Hesperidin extraction remains a challenging phase in its valorization chain due to its low solubility and limited extractability in solvents. This work aims to examine the effect of conventional solvent extraction (CSE) compared to emerging and innovative extraction methods: accelerated solvent extraction (ASE) and ultrasound-assisted extraction (UAE) when applied with or without a pretreatment process of instant controlled pressure drop (DIC) to intensify extraction, antioxidant, and antidiabetic activities. The total phenols, flavonoids, hesperidin contents, radical scavenging activities, iron chelating activity, and in vitro α-amylase inhibition of the extracts were determined for CSE (80%, 70 °C), UAE (ethanol 80%, 70 °C, 200 W), and ASE (ethanol 60%, 100 °C, 100 bars) with or without DIC pretreatment (pressure = 0.4 MPa, total thermal time = 30 s). The hesperidin amounts obtained were 0.771 ± 0.008 g/100 g DM, 0.823 ± 0.054 g/100 g DM, and 1.368 ± 0.058 g/100 g DM, for CSE, UAE, and ASE, respectively. DIC pretreatment of orange byproducts increased hesperidin recovery by 67%, 25.6%, and 141% for DIC-CSE, DIC-UAE, and DIC-ASE, respectively. The DPPH and ABTS radical scavenging and iron chelating activities of extracts were also significantly enhanced, and the in vitro antidiabetic activity of extracts was preserved.

Insight into the Photodynamics of Photostabilizer Molecules.

Solar exposure of avobenzone, one of the most widely used commercial UVA filters on the market, is known to cause significant degradation. This finding has fueled research into developing photostabilizer molecules. In an effort to provide insight into their stand-alone photoprotection properties, the excited state dynamics of the photostabilizer, 3-(3,4,5-trimethoxybenzylidene) pentane-2,4-dione (TMBP), and its phenolic derivative, 3-(4-hydroxy-3,5-dimethoxybenzylidene) pentane-2,4-dione (DMBP), were studied with ultrafast transient absorption spectroscopy. Solutions of TMPB and DMBP in ethanol and in an industry-standard emollient, as well as TMBP and DMBP deposited on synthetic skin mimic, were investigated. These experiments were allied with computational methods to aid interpretation of the experimental data. Upon photoexcitation, these photostabilizers repopulate the electronic ground state via nonradiative decay within a few picoseconds involving a twisted intramolecular charge transfer configuration in the excited state, followed by internal conversion and subsequent vibrational cooling in the ground state. This finding implies that, aside from acting as a photostabilizer to certain UV filters, TMBP and DMBP may offer additional photoprotection in a sunscreen formulation as a stand-alone UV filter. Finally, TMBP and DMBP could also find applications as molecular photon-to-heat converters.

Phenolic Compounds Extracted from Cherry Tree (Prunus avium) Branches: Impact of the Process on Cosmetic Properties.

Cherry tree branches (Prunus avium var burlat Rosaceae) are agricultural by-products that are often neglected, yet they are rich in phenolic compounds and highly appreciated for their numerous biological activities. Extracts of cherry tree branches were evaluated for their use in cosmetics, particularly for their antioxidant, anti-tyrosinase, and antimicrobial activities. Samples were obtained by accelerated solvent extraction (ASE) at different ethanol percentages and different temperatures. Fourteen phenolic compounds were identified in the extracts by mass spectrometry. Three major compounds were identified (catechin, genistin, and prunin) representing 84 wt% of the total phenolic compounds. Optimal operating conditions maximizing the content of phenolic compounds were determined using a one factor at a time (OFAT) approach (70% aqueous ethanol, 70 °C). The extract obtained under these conditions also showed the highest antioxidant and anti-tyrosinase activities, certainly due to a high catechin content. Although the antimicrobial activities of extracts are less versatile than those of synthetic molecules, they are nonetheless interesting. According to these results, the extracts of cherry tree branches could be used in cosmetics for their interesting properties.

Intensification of p-coumaric acid heterologous production using extractive biphasic fermentation.

p-coumaric acid (p-CA) can be produced from D-glucose by an engineered S. cerevisiae strain. p-CA has antimicrobial properties and retro-inhibition activity. Moreover, p-CA is a hydrophobic compound, limiting its accumulation in fermentation broth. To overcome these issues all at once, a liquid-liquid extraction in-situ product recovery process using oleyl alcohol as extractant has been implemented in order to continuously extract p-CA from the broth. Media and pH impacts on strain metabolism were assessed, highlighting p-CA decarboxylase endogenous activity. Biphasic fermentations allowed an increase in p-CA respiratory production rates at both pH assessed (13.65 and 9.45 mg L-1.h-1 at pH 6 and 4.5, respectively) compared to control ones (10.5 and 7.5 mg L-1.h-1 at pH 6 and 4.5, respectively). Biphasic fermentation effects on p-CA decarboxylation were studied showing that continuous removal of p-CA decreased its decarboxylation into 4-vinylphenol at pH 4.5 (57 mg L-1 in biphasic fermentation vs 173 mg L-1 in control one).

Synthesis of Biobased Phloretin Analogues: An Access to Antioxidant and Anti-Tyrosinase Compounds for Cosmetic Applications.

The current cosmetic and nutraceutical markets are characterized by a strong consumer demand for a return to natural products that are less harmful to both the consumers and the environment than current petrosourced products. Phloretin, a natural dihydrochalcone (DHC) found in apple, has been widely studied for many years and identified as a strong antioxidant and anti-tyrosinase ingredient for cosmetic formulations. Its low concentration in apples does not allow it to be obtained by direct extraction from biomass in large quantities to meet market volumes and prices. Moreover, its remarkable structure prevents its synthesis through a green process. To overcome these issues, the synthesis of phloretin analogs appears as an alternative to access valuable compounds that are potentially more active than phloretin itself. Under such considerations, 12 chalcones (CHs) and 12 dihydrochalcones (DHCs) were synthesized through a green Claisen-Schmidt condensation using bio-based reagents. In order to evaluate the potential of these molecules, radical scavenging DPPH and anti-tyrosinase tests have been conducted. Moreover, the UV filtering properties and the stability of these analogs towards UV-radiations have been evaluated. Some molecules showed competitive antioxidant and anti-tyrosinase activities regarding phloretin. Two compounds in particular showed EC50 lower than phloretin, one chalcone and one dihydrochalcone.

Sinapic Acid Esters: Octinoxate Substitutes Combining Suitable UV Protection and Antioxidant Activity.

In 2021, Hawaii will permanently ban the use and sale of octinoxate-based sunscreens as studies have shown serious impacts of such UV filters on the coral reef. This ban, which could be generalized to other countries, highlights the extreme need to offer alternative UV filters that are not only effective in terms of sun protection, but also healthy with regards to human health and the environment. In this context, a wide library of p-hydroxycinnamic esters deriving from naturally occurring sinapic acid has been synthesized using a Knoevenagel-Doebner condensation. The UV filtering activities as well as the antioxidant properties of these sinapic acid esters were then investigated. The results showed promising UVB protection and antioxidant efficacy. A Structure-Activity Relationship (SAR) study on the sinapic acid esters highlighted the need of a free phenol to, as expected, observe antioxidant activity, but also to obtain a higher intensity of protection. Moreover, the nature of the ester moiety also proved to be a key structural feature for the UV absorbance, as higher steric hindrance on the ester moiety leads to more active compounds. The judicious structural design of sinapic esters thus provides promising compounds combining UV protection and antioxidant activity.

Sustainable Straightforward Synthesis and Evaluation of the Antioxidant and Antimicrobial Activity of Sinapine and Analogues.

Naturally occurring sinapine was successfully synthesized through a proline-mediated Knoevenagel-Doebner condensation in ethanol. This synthetic process involving biobased syringaldehyde, Meldrum's acid, and choline chloride offers a sustainable alternative to the existing low-yield pathways. This two-step strategy gives access to sinapine in a 52% overall yield and has been implemented in the synthesis of sinapine analogues, using 4-hydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, and vanillin as precursors, giving target molecules with 34-61% overall isolated yields. The purity of synthetic sinapine and its analogues (ca. 95%) was assessed by NMR and high-performance liquid chromatography-mass spectrometry analyses. Furthermore, the antioxidant and antimicrobial activities were assessed, and the potential of this series of molecules was confirmed.

Innovative Bio-Based Organic UV-A and Blue Light Filters from Meldrum's Acid.

Faced with the ban of some organic UV filters such as octinoxate or avobenzone, especially in Hawaii, it became essential to offer new alternatives that are both renewable and safe for humans and the environment. In this context, a class of bio-based molecules displaying interesting UV filter properties and great (photo)stability has been developed from Meldrum's acid and bio-based and synthetic p-hydroxycinnamic acids, furans and pyrroles. Moreover, p-hydroxycinnamic acid-based Meldrum's derivatives possess valuable secondary activities sought by the cosmetic industry such as antioxidant and anti-tyrosinase properties. The evaluation of the properties of mixture of judiciously chosen Meldrum's acid derivatives highlighted the possibility to modulate secondary activity while maintaining excellent UV protection. Meldrum's acid derivatives are not only competitive when benchmarked against organic filters currently on the market (i.e., avobenzone), but they also do not exhibit any endocrine disruption activity.

Sustainable Synthesis of p-Hydroxycinnamic Diacids through Proline-Mediated Knoevenagel Condensation in Ethanol: An Access to Potent Phenolic UV Filters and Radical Scavengers.

p-Hydroxycinnamic diacids are reaction intermediates of the classical Knoevenagel-Doebner condensation between malonic acid and benzaldehydes. As they are generally obtained in low yields, they remain relatively under-studied and under-exploited. Herein, we developed and optimized a sustainable synthetic procedure allowing the production of these compounds in good to high yields (60-80%) using proline as the catalyst and ethanol as the solvent. Study of their antioxidant and anti-UV activities revealed that these p-hydroxycinnamic diacids were not only potent radical scavengers but also efficient UV filters exhibiting high photostability.

Lipase-Catalyzed Baeyer-Villiger Oxidation of Cellulose-Derived Levoglucosenone into (S)-γ-Hydroxymethyl-α,ß-Butenolide: Optimization by Response Surface Methodology.

Cellulose-derived levoglucosenone (LGO) has been efficiently converted into pure (S)-γ-hydroxymethyl-α,ß-butenolide (HBO), a chemical platform suited for the synthesis of drugs, flavors and antiviral agents. This process involves two-steps: a lipase-catalyzed Baeyer-Villiger oxidation of LGO followed by an acid hydrolysis of the reaction mixture to provide pure HBO. Response surface methodology (RSM), based on central composite face-centered (CCF) design, was employed to evaluate the factors effecting the enzyme-catalyzed reaction: pka of solid buffer (7.2-9.6), LGO concentration (0.5-1 M) and enzyme loading (55-285 PLU.mmol(-1)). Enzyme loading and pka of solid buffer were found to be important factors to the reaction efficiency (as measured by the conversion of LGO) while only the later had significant effects on the enzyme recyclability (as measured by the enzyme residual activity). LGO concentration influences both responses by its interaction with the enzyme loading and pka of solid buffer. The optimal conditions which allow to convert at least 80% of LGO in 2 h at 40°C and reuse the enzyme for a subsequent cycle were found to be: solid buffer pka = 7.5, [LGO] = 0.50 M and 113 PLU.mmol(-1) for the lipase. A good agreement between experimental and predicted values was obtained and the model validity confirmed (p < 0.05). Alternative optimal conditions were explored using Monte Carlo simulations for risk analysis, being estimated the experimental region where the LGO conversion higher than 80% is fulfilled at a specific risk of failure.