Concise syntheses of three ω-3 polyunsaturated fatty acids

The synthesis of the three ω-3 polyunsaturated fatty acids, eicosatetraenoic acid (3), docosapentaenoic acid (4), and stearidonic acid (5) has been achieved using eicosapentaenoic acid or docosahexaenoic acid as the starting materials.     

Production of ω-3 polyunsaturated fatty acids from cull potato using an algae culture process

Algal cultivation for converting cull potato to docosahexaenoic acid (DHA) was studied. Schizochytrium limacinum SR21 was selected as the better producing strain, compared with Thraustochytrium aureum because of higher cell density and DHA content. Used as both carbon and nitrogen source, an optimal ratio of hydrolyzed potato broth in the culture medium was determined as 50%, with which the highest production of 21.7 g/L dry algae biomass and 5.35 g/L DHA was obtained, with extra glucose supplemented. Repeat culture further improved the cell density but not fed batch culture, suggesting limited growth was most likely caused by metabolites inhibition.     

Synthesis of γ-keto carboxylic acids from γ-keto-α-chloro carboxylic acids via carbonylation—decarboxylation reactions catalysed by a palladium system

A palladium-based catalytic system is highly active in the synthesis of γ-keto acids of type ArCOCH₂CH₂COOH via carbonylation-decarboxylation of the corresponding α-chloride. Typical reaction conditions are: P(CO) = 20–30 atm; substrate/H₂O/Pd = 100–400/800–1000/1 (mol); temperature: 100–110 °C; [Pd]=0.25 × 10⁻²−1 × 1O⁻² M; solvent: acetone; reaction time: 1–2 h. A palladium(II) complex can be used as catalyst precursor. Under the reaction conditions above, reduction of the precursor to palladium metal occurs to a variable extent. High catalytic activity is observed when the precursor undergoes extensive decomposition to the metal. Pd/C is also highly active. Slightly higher yields are obtainable when the catalytic system is used in combination with a ligand such as PPh₃. A mechanism for the catalytic cycle is proposed: (i) The starting keto chloride undergoes oxidative addition to reduced palladium with formation of a catalytic intermediate having a Pd-[CH(COOH)CH₂COPh] moiety. The reduced palladium may be the metal coordinated by other atoms of palladium and/or by carbon monoxide and/or by a PPh₃ ligand when catalysis is carried out in the presence of this ligand. It is also proposed that the keto group in the β-position with respect to the carbon atom bonded to chlorine weakens the CCl bond, easing the oxidative addition step and enhancing the activity of the catalyst. (ii) Carbon monoxide ‘inserts’ into the PdC bond of the above intermediate to give an acyl catalytic intermediate having a Pd-[COCH(COOH)CH₂COPh] moiety. (iii) Nucleophilic attack of H₂O to the carbon atom of the carbonyl group bonded to the metal of the acyl intermediate yields a malonic acid derivative as product intermediate. This, upon decarboxylation, gives the final product. Alternatively, the desired product may form without the malonic acid derivative intermediate, through the following reaction pathway: the acyl intermediate undergoes decarboxylation with formation of a different acyl intermediate, having a Pd-[CO-CH₂CH₂COPh] moiety, which, upon nucleophilic attack of H₂O on the carbon atom of the carbonyl group bonded to the metal, yields the final product.     

Static–dynamic sequential superheated liquid extraction of phenols and fatty acids from alperujo

Superheated liquids of different polarity have been used for sequential extraction of fatty acids and phenols from alperujo. Multivariate methodology has been used to optimise the static–dynamic extraction. Forty-two minutes are required to complete extraction (20 mg/kg of fatty acids and up to 2,200 mg/kg of hydroxytyrosol in the raw material used). The efficacy of the extraction has been demonstrated and compared with that of conventional methods (Folch and stirring-based methods for fatty acids and phenols, respectively), which needed 4.5 and 24 h for the extraction of fatty acids and phenols, respectively. The non-polar and polar extracts were injected into GC–MS and HPLC–MS–MS equipment, respectively, for individual separation–quantification of the target compounds. The simplicity of the experimental setup and the low costs of the raw material make the proposed method advisable when extraction of both fractions is required.     

A general and efficient stereoselective synthesis of γ-azido-tetrahydrofuran carboxylic acids from glycals

An efficient, direct and general synthesis of enantiopure γ-azido-tetrahydrofuran carboxylic acid monomers (5-8) from commercially available glycals, suitable to design peptidomimetic oligomers with predisposed conformation, is described. The single crystal X-ray study of 8 showed that the compound crystallized in orthorhombic space group. The crystal-packing showed the presence of weak intermolecular C-H?O and aliphatic C-H?π interactions.     

Stereoselective synthesis of pinane-based β- and γ-amino acids via conjugate addition of lithium amides and nitromethane

Michael addition of dibenzylamine to (?)- and (+)-tert-butyl myrtenate, (?)-2 and (+)-2, derived from (?)- and (+)-myrtenal, furnished monoterpene-based β-amino acid derivatives in highly stereospecific reactions. The resultant amino esters (?)-3 and (+)-3 were transformed to unsubstituted, mono- and disubstituted and Fmoc-protected amino acids (?)-6-11 and (+)-6-11, which are promising building blocks for the synthesis of β-peptides and 1,3-heterocycles. The microwave-assisted conjugate addition of nitromethane to α,β-unsaturated esters (?)-12 and (+)-12 likewise resulted in nitro esters (?)-13 and (+)-13 in highly stereospecific reactions. Compounds (?)-13 and (+)-13 were successfully transformed into γ-amino acids (?)-16 and (+)-16 in two steps.     

Stereoselective Synthesis of γ-hydroxy-α-amino acids via intramolecular amidomercuration

A general method for the stereoselective conversion of homoallylic alcohols to erythro- or threo-β-hydroxy-α-amino acids is described. The key step is the stereoselective mercuric ion-initiated cyclofunctionalization of acylaminomethyl ether derivatives of the homoallylic alcohols (3 → 8). The stereochemistry of the products obtained from the cyclofunctionalization is controlled by the choice of reaction conditions. Reaction under conditions of kinetic control leads to predominant formation of cis 4,6-disubstituted tetrahydro-1,3-oxazines, while reaction under conditions which allow for equilibration of the organomercurial intermediates results in the formation of the trans stereoisomer with very high stereoselectivity. Oxidative demercuration and oxidation of the resulting alcohol produces a protected form of the title amino acids (8 → 9 → 10). Cleavage of the tetrahydrooxazine ring with hydrobromic acid then produces the amino acid products asγ-butyrolactone hydrobromides (11 and 12). This general method thus allows for stereoselective synthesis of either diastereomer of the amino acid product starting with a single homoallylic alcohol.     

Iron-catalyzed, highly regioselective synthesis of α-aryl carboxylic acids from styrene derivatives and CO2

The iron-catalyzed hydrocarboxylation of aryl alkenes has been developed using a highly active bench-stable iron(II) precatalyst to give α-aryl carboxylic acids in excellent yields and with near-perfect regioselectivity. Using just 1 mol % FeCl(2), bis(imino)pyridine 6 (1 mol %), CO(2) (atmospheric pressure), and a hydride source (EtMgBr, 1.2 equiv), a range of sterically and electronically differentiated aryl alkenes were transformed to the corresponding α-aryl carboxylic acids (up to 96% isolated yield). The catalyst was found to be equally active with a loading of 0.1 mol %. Preliminary mechanistic investigations show that an iron-catalyzed hydrometalation is followed by transmetalation and reaction with the electrophile (CO(2)).     

Simultaneous quantitative profiling of 20 isoprostanoids from omega-3 and omega-6 polyunsaturated fatty acids by LC–MS/MS in various biological samples

Isoprostanoids are a group of non-enzymatic oxygenated metabolites of polyunsaturated fatty acids. It belongs to oxylipins group, which are important lipid mediators in biological processes, such as tissue repair, blood clotting, blood vessel permeability, inflammation and immunity regulation. Recently, isoprostanoids from eicosapentaenoic, docosahexaenoic, adrenic and α-linolenic namely F₃-isoprostanes, F₄-neuroprostanes, F₂-dihomo-isoprostanes and F₁-phytoprostanes, respectively have attracted attention because of their putative contribution to health. Since isoprostanoids are derived from different substrate of PUFAs and can have similar or opposing biological consequences, a total isoprostanoids profile is essential to understand the overall effect in the testing model. However, the concentration of most isoprostanoids range from picogram to nanogram, therefore a sensitive method to quantify 20 isoprostanoids simultaneously was formulated and measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS). The lipid portion from various biological samples was extracted prior to LC–MS/MS evaluation. For all the isoprostanoids LOD and LOQ, and the method was validated on plasma samples for matrix effect, yield of extraction and reproducibility were determined. The methodology was further tested for the isoprostanoids profiles in brain and liver of LDLR^−/− mice with and without docosahexaenoic acid (DHA) supplementation. Our analysis showed similar levels of total F₂-isoprostanes and F₄-neuroprostanes in the liver and brain of non-supplemented LDLR^−/− mice. The distribution of different F₂-isoprostane isomers varied between tissues but not for F₄-neuroprostanes which were predominated by the 4(RS)-4-F_4t-neuroprostane isomer. DHA supplementation to LDLR^−/− mice concomitantly increased total F₄-neuroprostanes levels compared to F₂-isoprostanes but this effect was more pronounced in the liver than brain.     

DSC-studies of phospholipids containing iso-branched and ω-cyclohexane fatty acids

Differential Scanning Calorimetry (DSC) and Differential Scanning Densitometry (DSD) was employed to study the phase behavior of phospholipids with iso-branched and ω-cyclohexyl fatty acids. Phosphatidylcholines (PC) and phosphatidylethanolamines (PE) with iso-branched fatty acids show complicated phase behavior with several gel-gel transitions with odd-even effects. These odd-even effects are even more pronounced for phosphatidylcholines with ω-cyclohexyl fatty acids (cyPCs). Odd-numbered cyPCs show a large main transition with strong hysteresis while the even-numbered cyPCs have several transitions but show no hysteresis. These differences in thermotropic behavior are also reflected in their molecular volumes. The odd-numbered cyPCs display much tighter packing in the gel phase than the even-numbered analogues. Binary mixtures of cyPCs with either straight chain PCs or iso-branched PCs show eutectic behavior. This is also observed when cyPCs of different chain length are mixed.     

Synthesis of γ-keto alcohols and dihydrofurans from 2-furanpropanols

Summary A method was developed for the preparation of-keto alcohols and hence 2,3-dihydrofurans by the catalytic hydrogenation of 2-furanpropanols over platinized charcoal at 220° with formation of acetic esters of-keto alcohols, from which as a result of methanolysis-keto alcohols and dialkyldihydrofurans are formed.     

A facile synthesis of γ-butenolides via cyclization of 3-alkenoic acids with dimethyl sulfoxide and oxalyl bromide

The combination of dimethyl sulfoxide and oxalyl bromide was used to accomplish the cyclization of 3-alkenoic acids with the aid of a base to afford γ-butenolides, in which bromodimethylsulfonium salt generated in situ was proposed to serve as a Br⁺ source.     

Convenient synthesis of acetaminophen analogues containing α-amino acids and fatty acids via their mixed carbonic carboxylic anhydrides in aqueous organic solvent

Acetaminophen analogues containing α-amino acid and fatty acids were easily synthesized in 77–99% yields from the corresponding mixed carbonic carboxylic anhydrides of α-amino acid and fatty acids using aniline derivatives in aqueous MeCN.     

Inverse CO2/C2H2 Separation with MFU-4 and Selectivity Reversal via Postsynthetic Ligand Exchange

Although many porous materials, including metal–organic frameworks (MOFs), have been reported to selectively adsorb C₂H₂ in C₂H₂/CO₂ separation processes, CO₂-selective sorbents are much less common. Here, we report the remarkable performance of MFU-4 (Zn₅Cl₄(bbta)₃, bbta=benzo-1,2,4,5-bistriazolate) toward inverse CO₂/C₂H₂ separation. The MOF facilitates kinetic separation of CO₂ from C₂H₂, enabling the generation of high purity C₂H₂ (>98 %) with good productivity in dynamic breakthrough experiments. Adsorption kinetics measurements and computational studies show C₂H₂ is excluded from MFU-4 by narrow pore windows formed by Zn−Cl groups. Postsynthetic F⁻/Cl⁻ ligand exchange was used to synthesize an analogue ( MFU-4-F ) with expanded pore apertures, resulting in equilibrium C₂H₂/CO₂ separation with reversed selectivity compared to MFU-4 . MFU-4-F also exhibits a remarkably high C₂H₂ adsorption capacity (6.7 mmol g⁻¹), allowing fuel grade C₂H₂ (98 % purity) to be harvested from C₂H₂/CO₂ mixtures by room temperature desorption.     

Asymmetric synthesis of α,β-substituted γ-amino acids via conjugate addition

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected γ-nitrogen atom and an α-methyl group are present into α, β-unsaturated system is described. This reaction gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two contiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastereoselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral α, β-disubstituted γ-amino acids.     

Practical asymmetric synthesis of β-hydroxy γ-amino acids via complimentary aldol reactions

Orthogonally protected chiral β-hydroxy-γ-amino acids can be accessed in >100 g quantities from readily available starting materials and reagents in three to four steps. These chiral synthons contain two adjacent stereocenters along with suitably protected functional groups (O-TBS, N-Boc) for downstream reactivity. Implementation of two existing aldol technologies allows rapid access to all possible stereoisomers of 1. The guiding principles during reaction optimization were reaction scalability and operational efficiency. Conversion of the amino acids to a variety of chiral building blocks in one to two steps demonstrates their synthetic utility.     

An expedient synthesis of pyrrole-2-phosphonates via direct oxidative phosphorylation and γ-hydroxy-γ-butyrolactams from pyrroles

An expedient oxidative phosphorylation of pyrroles has been disclosed. The reaction of dialkyl phosphite and pyrrole in the presence of AgNO₃/K₂S₂O₈ in DMF/H₂O (8:1) produced pyrrole-2-phosphonates in good yields. In the absence of dialkyl phosphite, γ-hydroxy-γ-butyrolactam derivative was formed as a major product.     

Reaction of γ-dicarboxylic acids amides and imides with trifluoromethanesulfonamide and formaldehyde

Three-component condensation of trifluoromethanesulfonamide with paraformaldehyde and succinamide depending on the reaction conditions led alongside bis(trifluoromethanesulfonamido)methane to the formation of a substitution product, bis[(trifluoromethylsulfonyl)aminomethyl]succinamide, or to a cyclization product, N-[trifluoromethylsulfonyl)aminomethyl]succinimide. The attempt to obtain the latter by the reaction of the trifluoromethanesulfonamide sodium salt CF₃SO₂NHNa with N-chloromethylsuccinimide unexpectedly resulted in N,N-bis(succinimidomethyl)-trifluoromethanesulfonamide. Analogously the reaction of CF₃SO₂NHNa with N-chloromethyl-phthalimide gave N,N-bis(phthalimidomethyl)trifluoromethanesulfonamide. The reaction of CF₃SO₂NHNa with succinimide and phthalimide in water and alcohol solution resulted in the ring opening and further transformation of the formed monosubstituted N-(trifluoromethylsulfonyl)amides of succinic and phthalic acids.     

Enamines of 3-acyltetramic acids from β-enamino amides and amino acids

A novel approach for the synthesis of enamine derivatives of N-protected 3-acyltetramic acids is described. The synthetic procedure relies on α-C-acylation of β-enamino amides with N-protected α-amino acids and subsequent cyclisation of the obtained intermediates in refluxing TFA. The tetramic derivatives are obtained with very good enantiopurity (e.r. ≥95:5). Ring-enlarged analogues (piperidine-2,4-diones) can also be obtained from β-amino acids.