Hydroxyapatite: an Eco-Friendly Material for Enzyme Immobilization.

Biocatalysis has emerged in the last decade as a valuable and eco-friendly tool in chemical synthesis, allowing in several instances to reduce or eliminate the use of hazardous reagents, environmentally dangerous solvents and harsh reaction conditions. Enzymes are indeed able to catalyse chemical transformations on non-natural substrates under mild reaction conditions, still maintaining their high chemo-, regio-, and stereoselectivity. Enzyme immobilization, i.e. the grafting of enzymes on solid supports, can be viewed as an enabling technology, as it allows a better control of the reaction and the recycling of the biocatalyst, thus rendering economically viable the use of expensive enzymes also on a large scale. To pursue a sustainable approach, the supports for enzyme immobilization should be eco-friendly and possibly renewable. This review highlights the use of hydroxyapatite (HAP), an inorganic biomaterial able to confer strength and stiffness to the bone tissue in animals, as carrier for enzyme immobilization. HAP is a cheap, non-toxic and biocompatible material, with high surface area and protein affinity. Different enzyme classes, immobilization strategies, and the use of diverse HAP-based supports will be discussed, underlining the immobilization conditions and the properties of the obtained biocatalysts.

Synthesis of Tetrasubstituted Nitroalkenes and Preliminary Studies of Their Enantioselective Organocatalytic Reduction.

Starting from commercially available ketones, a reproducible and reliable strategy for the synthesis of tetrasubstituted nitroalkenes was successfully developed, using a two-step procedure; the HWE olefination of the ketone to form the corresponding α,ß-unsaturated esters is followed by a nitration reaction to introduce the nitro group in the α position of the ester group. The enantioselective organocatalytic reduction of these compounds has also been preliminarily studied, to access the functionalized enantioenriched nitroalkanes, which are useful starting materials for further synthetic elaborations. The absolute configuration of the reduction product was established by chemical correlation of the chiral nitroalkane with a known product; preliminary DFT calculations were also conducted to rationalize the stereochemical outcome of the organocatalytic enantioselective reduction.

Stereoselective [2 + 2] photodimerization: a viable strategy for the synthesis of enantiopure cyclobutane derivatives.

The [2 + 2] photodimerization of cinnamic acid derivatives to afford enantiopure cyclobutanes has been investigated. The use of a chiral auxiliary represents a convenient and straightforward method to exert enantiocontrol on the reaction. By exploiting Evans oxazolidinones, the stereoselective light-driven cyclisation affords a functionalised cyclobutane ring with up to 99% enantiocontrol after removing the chiral auxiliary. In-flow experiments allowed us to improve further the efficiency of the methodology, leading to high conversion and excellent enantioselectivity.

Bioengineered synthesis of phytochemical-adorned green silver oxide (Ag2O) nanoparticles via Mentha pulegium and Ficus carica extracts with high antioxidant, antibacterial, and antifungal activities.

Silver oxide nanoparticles have various biomedical and pharmaceutical applications. However, conventional nanofabrication of Ag2O is associated with the use of toxic chemicals and organic solvents. To circumvent this hurdle, herein silver oxide quantum dots (Ag2O-QDs) were synthesized quickly (3 min) via the use of ultrasonic irradiation and plant-extract. Additionally, due to ultrasonic irradiation's effect on cell-wall destruction and augmentation of extraction efficiency, ultrasonic was also used in the preparation of Mentha pulegium and Ficus carica extracts (10 min, r.t) as natural eco-friendly reducing/capping agents. The UV-Vis result indicated a broad absorption peak at 400-500 nm. TEM/SEM analysis showed that ultrasound introduced a uniform spherical particle and significantly reduced particle size compared to the conventional heating method (∼ 9 nm vs. ∼ 100 nm). Silver and oxygen elements were found in the bio-synthesized Ag2O by EDS. The FTIR and phenol/flavonoid tests revealed the presence of phenol and flavonoid associated with the nanoparticles. Moreover, nanoparticles exhibited antioxidant/antibacterial/antifungal activities. The MIC and MBC results showed the Ag2O QDs synthesized with M. pulegium extract have the highest antibacterial activity against E. coli (MBC = MIC:15.6 ppm), which were significantly different from uncoated nanoparticles (MBC = MIC:500 ppm). The data reflects the role of phyto-synthesized Ag2O-QDs using ultrasonic-irradiation to develop versatile and green biomedical products.

Catalytic Enantioselective Entry to Triflones Featuring a Quaternary Stereocenter.

A highly enantioselective one-pot synthesis of functionalized triflones, bearing a quaternary stereocenter, has been developed, exploiting the Michael reaction of α-(trifluoromethylsulfonyl) aryl acetic acid esters with N-acryloyl-1H-pyrazole catalyzed by commercially available Takemoto's catalyst, followed by nucleophilic acyl substitution with alcohols. Preliminary investigations highlighted the attractive potential of the triflinate anion as the leaving group for stereocontrolled postfunctionalizations.

Enantioselective Organophotocatalytic Telescoped Synthesis of a Chiral Privileged Active Pharmaceutical Ingredient.

The continuous flow, enantioselective, organophotoredox catalytic asymmetric alkylation of aldehydes was studied, by using a homemade, custom-designed photoreactor for reactions under cryogenic conditions. Going from microfluidic conditions up to a 10 mL mesofluidic reactor, an increase of productivity by almost 18000 % compared to the batch reaction was demonstrated. Finally, for the first time, a stereoselective photoredox organocatalytic continuous flow reaction in a fully telescoped process for an active pharmaceutical ingredient (API)synthesis was successfully achieved. The final process consists of four units of operation: visible light-driven asymmetric catalytic benzylation under continuous flow, inline continuous work-up, neutralisation and a final oxidative amidation step afforded the pharmaceutically active molecule in 95 % e.e.

Electrochemical Organic Synthesis of Electron-Rich Biaryl Scaffolds: An Update.

Biaryl scaffolds are widely spread in biologically important natural products, in numerous therapeutic agents, but they are also considered a privileged class of ligands and (organo)catalysts; therefore, the development of efficient alternative methodologies to prepare such compounds is always attracting much attention. The present review discusses the organic electrosynthesis of biaryls starting from phenols, anilines, naphthols, and naphthylamines. The most significant examples of the works reported in the last decade are presented and classified according to the single class of molecules: after the introduction, the first three sections relate to the reactions of phenols, naphthols, and anilines, respectively; the other two sections refer to cross-coupling and miscellaneous reactions.

Continuous Flow Synthesis of α-Trifluoromethylthiolated Esters and Amides from Carboxylic Acids: a Telescoped Approach.

A continuous flow approach to access α-trifluoromethylthiolated esters and amides using commercially available arylacetic acids and N-(trifluoromethylthio)phthalimide as the electrophilic reagent is described. The experimental protocol involves the in-flow conversion of the carboxylic acid into N-acylpyrazole followed by the α-trifluoromethylthiolation in a PTFE coil reactor and final reaction with primary or secondary amines, or alcohols, to afford in a telescoped process α-substituted SCF3 amides and esters, respectively, in good overall yield and short reaction times.

Nitroalkene reduction in deep eutectic solvents promoted by BH3NH3.

Deep eutectic solvents (DESs) have gained attention as green and safe as well as economically and environmentally sustainable alternative to the traditional organic solvents. Here, we report the combination of an atom-economic, very convenient and inexpensive reagent, such as BH3NH3, with bio-based eutectic mixtures as biorenewable solvents in the synthesis of nitroalkanes, valuable precursors of amines. A variety of nitrostyrenes and alkyl-substituted nitroalkenes, including α- and ß-substituted nitroolefins, were chemoselectively reduced to the nitroalkanes, with an atom economy-oriented, simple and convenient experimental procedure. A reliable and easily reproducible protocol to isolate the product without the use of any organic solvent was established, and the recyclability of the DES mixture was successfully investigated.

Metal-Free Deoxygenation of Chiral Nitroalkanes: An Easy Entry to α-Substituted Enantiomerically Enriched Nitriles.

A metal-free, mild and chemodivergent transformation involving nitroalkanes has been developed. Under optimized reaction conditions, in the presence of trichlorosilane and a tertiary amine, aliphatic nitroalkanes were selectively converted into amines or nitriles. Furthermore, when chiral ß-substituted nitro compounds were reacted, the stereochemical integrity of the stereocenter was maintained and α-functionalized nitriles were obtained with no loss of enantiomeric excess. The methodology was successfully applied to the synthesis of chiral ß-cyano esters, α-aryl alkylnitriles, and TBS-protected cyanohydrins, including direct precursors of four active pharmaceutical ingredients (ibuprofen, tembamide, aegeline and denopamine).

Ammonia borane as a reducing agent in organic synthesis.

Ammonia borane NH3·BH3 is considered a promising material for hydrogen storage and release, and is attracting increasing attention as a relatively inexpensive, atom economy-convenient and viable reagent for developing new green synthetic transformations. The present review offers a wide overview on the use of AB in the reduction of organic compounds, and highlights the versatility of this reagent, due to the possibility of modulating its activity employing different strategies, which include the use of transition metals, p-block species, organocatalysts and FLP systems.

Formal α-trifluoromethylthiolation of carboxylic acid derivatives via N-acyl pyrazoles.

Herein we disclosed a one-pot two-step protocol for the first direct, base-catalyzed α-trifluoromethylthiolation of carboxylic acid derivatives by using readily available N-acyl pyrazoles, N-(trifluoromethylthio)phthalimide and a nucleophile such as amines, alcohols and water. Straightforward elaboration of the products to alcohols and triflones expands further the synthetic utility of the process.

A one pot protocol to convert nitro-arenes into N-aryl amides.

A two-step one pot, experimentally simple protocol, based on readily available and inexpensive reagents allowed the conversion of nitro-arenes directly to N-aryl amides. A metal-free reduction of the nitro group, mediated by trichlorosilane, followed by the addition of an anhydride afforded the corresponding N-aryl carboxyamide, that was isolated after a simple aqueous work up in good-excellent yields. When the methodology was applied to the reaction with γ-butyrolactone, the desired N-aryl butanamide derivative was obtained, featuring a chlorine atom at the γ-position, a functionalized handle that can be used for further synthetic manipulation of the reaction product. Such an intermediate has already been employed as a key advanced precursor of pharmaceutically active compounds.

Organocatalytic Michael Addition to (D)-Mannitol-Derived Enantiopure Nitroalkenes: A Valuable Strategy for the Synthesis of Densely Functionalized Chiral Molecules.

Carbohydrates are abundant renewable resources and are a feedstock for green chemistry and sustainable synthesis of the future. Among the hexoses and the pentoses present in biomass, mannitol was selected in the present project as a valuable platform, directly available from the chiral pool, to build highly functionalized molecules. Starting from (R)-2,3-O-cyclohexylidene glyceraldehyde, which is easily prepared in a large scale from D-mannitol, an enantiopure chiral nitro alkene was prepared by reaction with nitromethane, and its reactivity studied. Organocatalytic Michael addition of dimethyl malonate, ß-keto esters, and other nucleophiles on the nitro alkene afforded high stereoselectivity and densely functionalized chiral molecules, which were further synthetically developed, leading to five-membered lactones and bicyclic lactams. Preliminary studies showed that the metal-free catalytic reaction on the chiral nitro alkene can be performed under continuous flow conditions, thus enabling the use of (micro)mesofluidic systems for the preparation of enantiomerically pure organic molecules from the chiral pool.

Set-Up of Bacterial Cellulose Production From the Genus Komagataeibacter and Its Use in a Gluten-Free Bakery Product as a Case Study.

The use of bacterial cellulose (BC) in food systems is still limited due to production costs. Nine clones belonging to Komagataeibacter hansenii, Komagataeibacter nataicola, Komagataeibacter rhaeticus, Komagataeibacter swingsii, and Komagataeibacter xylinus species were screened for cellulose productivity in growth tests with five different carbon sources and three nitrogen sources. The water-holding and rehydration capacities of the purified cellulose were determined. The structure of the polymer was investigated through nuclear magnetic resonance (NMR) spectroscopy, attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectroscopy and X-ray diffraction (XRD) analysis, and observed by scanning electron microscope (SEM). Natural mutants of K. rhaeticus LMG 22126T and K. swingsii LMG 22125T showed different productivity. The factors "bacterial isolate" and "nitrogen source" significantly affected the production of cellulose (p < 0.01) rather than the factor "carbon source" (p = 0.15). However, on average, the best conditions for increasing yield were found in medium containing glucose and peptone. Water-holding capacity (WHC) values ranged from 10.7 to 42.3 (g water/g cellulose) with significant differences among strains (p < 0.01), while the rehydration capacity varied from 4.2 to 9.3 (g water/g cellulose). A high crystallinity (64-80%) was detected in all samples with Iα fractions corresponding to 67-93%. The ATR-FT-IR spectra and the XRD patterns confirmed the expected structure. BC made by GVP isolate of K. rhaeticus LMG 22126T, which was the strain with the highest yield, was added to a gluten-free bread formulation. Results obtained from measurements of technological parameters in dough leavening and baking trials were promising for implementation in potential novel foods.

Evaluation of In-Batch and In-Flow Synthetic Strategies towards the Stereoselective Synthesis of a Fluorinated Analogue of Retro-Thiorphan.

A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch and afforded the target molecule in good yields and high diastereoselectivity. A crucial point of the synthetic sequence was the catalytic reduction of a fluorinated enamine with trichlorosilane as reducing agent in the presence of a chiral Lewis base. The absolute configuration of the key intermediate was unambiguously assigned by X-ray analysis. The synthesis was also investigated exploiting continuous flow reactions; that is, an advanced intermediate of the target molecule was synthesized in only two in-flow synthetic modules, avoiding isolation and purifications of intermediates, leading to the isolation of the target chiral fluorinated amine in up to an 87:13 diastereoisomeric ratio.

Stereoselective Catalytic Synthesis of Active Pharmaceutical Ingredients in Homemade 3D-Printed Mesoreactors.

3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.

A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin.

The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.

Novel Chiral Bis-Phosphoramides as Organocatalysts for Tetrachlorosilane-Mediated Reactions.

The formation of novel chiral bidentate phosphoroamides structures able to promote Lewis base-catalyzed Lewis acid-mediated reactions was investigated. Two different classes of phosphoroamides were synthetized: the first class presents a phthalic acid/primary diamine moiety, designed with the aim to perform a self-assembly recognition process through hydrogen bonds; the second one is characterized by the presence of two phosphoroamides as side arms connected to a central pyridine unit, able to chelate SiCl4 in a 2:1 adduct. These species were tested as organocatalysts in the stereoselective allylation of benzaldehyde and a few other aromatic aldehydes with allyl tributyltin in the presence of SiCl4 with good results. NMR studies confirm that only pyridine-based phosphoroamides effectively coordinate tetrachlorosilane and may lead to the generation of a self-assembled entity that would act as a promoter of the reaction. Although further work is necessary to clarify and confirm the formation of the hypothesized adduct, the study lays the foundation for the design and the synthesis of chiral supramolecular organocatalysts.

Stereoselective Reduction of Imines with Trichlorosilane Using Solid-Supported Chiral Picolinamides.

The stereoselective reduction of imines with trichlorosilane catalyzed by chiral Lewis bases is a well-established procedure for the synthesis of enantio-enriched amines. Five supported cinchona-based picolinamides have been prepared and their activity tested in a model reaction. The comparison of different supporting materials revealed that polystyrene gave better results than silica in terms of stereoselectivity. The applicability of the solid-supported catalyst of choice to the reduction of different imines was also demonstrated. Additionally, for the first time, a catalytic reactor containing a polymer-immobilized chiral picolinamide has been employed for the stereoselective reduction of imines with trichlorosilane under continuous flow conditions.