Reusable TsOH-H2SO4 Mixed Catalysis for Tandem Synthesis of Biodiesel and Oxygenated Fuel Additives, tert-Butyl Glycerol Ethers.

A mixture of p-toluenesulfonic acid and sulfuric acid (TsOH-H2SO4) was used as a catalyst with a good performance in transesterification of palm oil (PO) with methanol and etherification of crude glycerol with isobutylene (tandem synthesis). For TsOH-H2SO4 catalyzed biodiesel production, the reaction noticeably ran faster in comparison with TsOH or H2SO4 alone and also gave up to 99.9% of the conversion using MeOH/PO molar ratio 9:1 at 80℃, in the period of 4 h. After the whole transesterification process, the crude glycerol phase was separated and then reacted with isobutylene in the etherification process using isobutylene/glycerol molar ratio 9:1 at 80℃, in the period of 5 h reaction time, to give DTBG and TTBG (91.14%). In the case of the etherification in biodiesel, higher selectivity of DTBG and TTBG (99.39%) was obtained in comparison with an absence of biodiesel as the solvent. Furthermore, the catalyst could be reused for 6 cycles of tandem synthesis (transesterification and etherification). The TsOH-H2SO4 catalyst showed a good catalytic performance in tandem synthesis similar to TsOH and it could be recovered for reuse while TsOH could not be recovered. This process offers an attractive route for reuse homogeneous catalyst of tandem synthesis, the main by-product of biodiesel, to tert-butyl glycerol ethers - a value-added in applications as a valuable fuel additive.

Enantioselective Total Synthesis of the Archaeal Lipid Parallel GDGT-0 (Isocaldarchaeol)*.

Archaeal glycerol dibiphytanyl glycerol tetraethers (GDGT) are some of the most unusual membrane lipids identified in nature. These amphiphiles are the major constituents of the membranes of numerous Archaea, some of which are extremophilic organisms. Due to their unique structures, there has been significant interest in studying both the biophysical properties and the biosynthesis of these molecules. However, these studies have thus far been hampered by limited access to chemically pure samples. Herein, we report a concise and stereoselective synthesis of the archaeal tetraether lipid parallel GDGT-0 and the synthesis and self-assembly of derivatives bearing different polar groups.

Chemoenzymatic Synthesis of the New 3-((2,3-Diacetoxypropanoyl)oxy)propane-1,2-diyl Diacetate Using Immobilized Lipase B from Candida antarctica and Pyridinium Chlorochromate as an Oxidizing Agent.

To exploit the hydrolytic activity and high selectivity of immobilized lipase B from Candida antarctica on octyl agarose (CALB-OC) in the hydrolysis of triacetin and also to produce new value-added compounds from glycerol, this work describes a chemoenzymatic methodology for the synthesis of the new dimeric glycerol ester 3-((2,3-diacetoxypropanoyl)oxy)propane-1,2-diyl diacetate. According to this approach, triacetin was regioselectively hydrolyzed to 1,2-diacetin with CALB-OC. The diglyceride product was subsequently oxidized with pyridinium chlorochromate (PCC) and a dimeric ester was isolated as the only product. It was found that the medium acidity during the PCC treatment and a high 1,2-diacetin concentration favored the formation of the ester. The synthesized compounds were characterized using IR, MS, HR-MS, and NMR techniques. The obtained dimeric ester was evaluated at 100 ppm against seven bacterial strains and two Candida species to identify its antimicrobial activity. The compound has no inhibitory activity against the bacterial strains used but decreased C. albicans and C. parapsilosis growth by 49% and 68%, respectively. Hemolytic activity was evaluated, and the results obtained support the use of the dimeric ester to control C. albicans and C. parapsilosis growth in non-intravenous applications because the compound shows hemolytic activity.

Glycidol, a Valuable Substrate for the Synthesis of Monoalkyl Glyceryl Ethers: A Simplified Life Cycle Approach.

The disposal of any waste by recovering it within the production plant represents the ultimate goal of every biorefinery. In this scenario, the selective preparation of monoalkyl glyceryl ethers (MAGEs) starting from glycidol, obtained as byproduct in the epichlorohydrin production plant, represents a very promising strategy. Here, we report the synthesis of MAGEs through the reaction of glycidol with alcohols catalyzed by a green homogeneous Lewis acids catalyst, such as BiIII triflate, under very mild reaction conditions. To evaluate the green potential of the proposed alternative, a simplified life cycle assessment (LCA) approach was followed by comparing the environmental performance of the proposed innovative route to prepare MAGEs with that of the most investigated pathway from glycerol. A considerable reduction of all impact categories considered was observed in our experimental conditions, suggesting that the glycidol-to-MAGEs route can be a valuable integration to the glycerol-to-MAGEs chain. Thanks to the use of primary data within the LCA model, the results achieved are a very good approximation of the real case.

Synthesis of Monoalkyl Glyceryl Ethers by Ring Opening of Glycidol with Alcohols in the Presence of Lewis Acids.

The present work deals with the production of monoalkyl glyceryl ethers (MAGEs) through a new reaction pathway based on the reaction of glycidol and alcohols catalyzed by Lewis acid-based catalysts. Glycidol is quantitatively converted with high selectivity (99 %) into MAGEs under very mild reaction conditions (80 °C and 0.01 mol % catalyst loading) in only 1 h using Al(OTf)3 or Bi(OTf)3 as catalyst. The proposed method enhances the choice of possible green synthetic approaches for the production of value-added products such as MAGEs.

Selective preparation of monobenzyl glyceryl ethers by the condensation reaction of glycerol with benzyl alcohols in the presence of zeolite catalysts.

The selective preparation of monobenzyl glyceryl ethers, which are potential commodity chemicals with special functions, was explored to find new applications for glycerol. Among the acid catalysts investigated (sulfuric acid, heteropoly acid, Nafion(R), and zeolite), Zeolite Socony Mobil-5 (ZSM-5) afforded better results. The reaction of equimolar amounts of glycerol and benzyl alcohol at 150ºC for 7 h in the presence of 2 wt% ZSM-5 selectively afforded 3-(benzyloxy)propane-1,2-diol with a very small amount of the corresponding 2-benzyloxy isomer in 86% gas chromatography yield.

Niphatenones, glycerol ethers from the sponge Niphates digitalis block androgen receptor transcriptional activity in prostate cancer cells: structure elucidation, synthesis, and biological activity.

Extracts of the marine sponge Niphates digitalis collected in Dominica showed strong activity in a cell-based assay designed to detect antagonists of the androgen receptor (AR) that could act as lead compounds for the development of a new class of drugs to treat castration recurrent prostate cancer (CRPC). Assay-guided fractionation showed that niphatenones A (3) and B (4), two new glycerol ether lipids, were the active components of the extracts. The structures of 3 and 4 were elucidated by analysis of NMR and MS data and confimed via total synthesis. Biological evaluation of synthetic analogues of the niphatenones has shown that the enantiomers 7 and 8 are more potent than the natural products in the screening assay and defined preliminary SAR for the new AR antagonist pharmacophore, including the finding that the Michael acceptor enone functionality is not required for activity. Niphatenone B (4) and its enantiomer 8 blocked androgen-induced proliferation of LNCaP prostate cancer cells but had no effect on the proliferation of PC3 prostate cancer cells that do not express functional AR, consistent with activity as AR antagonists. Use of the propargyl ether 44 and Click chemistry showed that niphatenone B binds covalently to the activation function-1 (AF1) region of the AR N-terminus domain (NTD).

Effective production of the biodiesel additive STBE by a continuous flow process.

A new fuel additive, namely solketal tert-butyl ether (STBE), was developed and optimized under continuous flow conditions using a Corning® Advanced-Flow™ glass reactor. STBE was obtained in two steps from glycerol, a renewable building-block produced in large amount in the processing of biodiesel. The advantages of the highly engineered Corning glass reactor included high mixing and heat-exchange efficiency, chemical resistance under corrosive flow conditions and a small hold-up. A robust, continuous, green and safe industrial-scale process is described.

Ether lipids.

The naturally occurring 1-O-alkyl-sn-glycerols and their methoxylated congeners, 1-O-(2'-methoxyalkyl)-sn-glycerols, are biologically active compounds, ubiquitously found in nature as diacyl glyceryl ether lipids and phosphoether lipids. The chief objective of this article is to provide a comprehensive and up to date review on such ether lipids. The occurrence and distribution of these compounds in nature are extensively reviewed, their chemical structure and molecular variety, their biosynthesis and chemical synthesis and, finally, their various biological effects are described and discussed. An unprecedented biosynthesis of the 2'-methoxylated alkylglycerols is proposed. The first synthesis of enantiopure (Z)-(2'R)-1-O-(2'-methoxyhexadec-4'-enyl)-sn-glycerol, the most prevalent 2'-methoxylated type alkylglycerol present in cartilaginous fish, is described. It was accomplished by a highly convergent five step process.

Mechanistic study of the sPLA2-mediated hydrolysis of a thio-ester pro anticancer ether lipid.

Secretory phospholipase A(2) (sPLA(2)) is an interesting enzyme for triggered liposomal drug delivery to tumor tissue due the overexpression of sPLA(2) in cancerous tissue. A drug delivery system based on the triggered release of therapeutics from sPLA(2)-sensitive liposomes constituted of pro anticancer ether lipids, which become cytotoxic upon sPLA(2)-catalyzed hydrolysis has previously been established. To optimize the hydrolysis rate of the lipids and thereby optimizing the release profile of the drugs from the liposomes, we have synthesized a thio-ester pro anticancer ether lipid. Liposomes constituted of this lipid showed an altered rate of hydrolysis by sPLA(2). We have tested the cytotoxicity of the thio-ester pro anticancer ether lipids toward cancer cells, and the results showed that the cytotoxicity is indeed maintained upon sPLA(2) exposure. To further understand the origin for the observed different hydrolysis rates for the esters, we have applied molecular dynamics simulations and density functional theory. The combination of these theoretical methods has given valuable insight into the molecular mechanism for sPLA(2) action on sulfur-containing phospholipids. It appears that the enzyme-catalyzed hydrolysis of thio-esters follow a different pathway compared to the hydrolysis pathway of the free thio-ester.

Adjuvant potential of archaeal synthetic glycolipid mimetics critically depends on the glyco head group structure.

Subunit vaccines capable of providing protective immunity against the intracellular pathogens and cancers that kill millions of people annually require an adjuvant capable of directing a sufficiently potent cytotoxic T lymphocyte response to purified antigens, without toxicity issues. Archaeosome lipid vesicles, prepared from isoprenoid lipids extracted from archaea, are one such adjuvant in development. Here, the stability of an archaeal core lipid 2,3-di-O-phytanyl-sn-glycerol (archaeol) is used to advantage to synthesize a series of disaccharide archaeols and show that subtle variations in the carbohydrate head group alters the type and potency of immune responses mounted in a mammal. Critically, a glycosylarchaeol was required to elicit high cytotoxic CD8(+) T cell activity, with highest responses to the antigen entrapped in archaeosomes containing disaccharides of glucose in beta- or alpha1-6 linkage (beta-gentiobiose, beta-isomaltose), or of beta-lactose. This first study on synthetic archaeal lipid adjuvants reveals potential for this class of regulatory friendly, easily scalable, inexpensive, and potent glyco-adjuvant.

Archaeosomes based on synthetic tetraether-like lipids as novel versatile gene delivery systems.

Novel cationic liposomes, termed "archaeosomes", based on mixtures of neutral/cationic bilayer-forming lipids and archaeobacterial synthetic tetraether-type bipolar lipids show efficient in vitro gene transfection properties and represent a new approach for modulating the lipidic membrane fluidity of the complexes they form with DNA.

Synthesis and characterization of nonconventional surfactants of aromatic amino acid-glycerol ethers: effect of the amino acid moiety on the orientation and surface properties of these soap-type amphiphiles.

The synthesis, characterization, and surface properties of soap-type amphiphiles comprising alkyl chains of 10-16 carbon atoms linked through an ether group to a glycerol-amino acid hydrophilic head group is described. The surface properties of members of this series derived from histidine and tyrosine were compared with those of phenylalanine and tryptophan derivatives described previously and with those of conventional soaps. In all cases, the amino acid derivatives showed superior surface properties, and an interesting differentiation was discovered regarding the orientation of tryptophan derivatives.

Novel mutual pro-drugs of 2',3'-dideoxyinosine with 3-octadecyloxy-propane-1,2-diol by straightforward enzymatic regioselective synthesis in acetone.

Novel mutual pro-drugs in which 2',3'-dideoxyinosine anti-HIV (human immunodeficiency virus) drug and 3-octadecyloxy-propane-1,2-diol anti-inflammatory drug were attached to the same molecule via different biodegradable linkages, were synthesized through two-step enzymatic transesterification by a commercial lipase in acetone.

Synthesis and supramolecular assemblies of bipolar archaeal glycolipid analogues containing a cis-1,3-disubstituted cyclopentane ring.

Unsymmetrical archaeal tetraether glycolipid analogues 1-2 incorporating a 1,3-disubstituted cyclopentane ring into the bridging chain have been synthesized. The cyclopentane has been introduced with a totally controlled cis configuration, either into the middle of the aliphatic chain or at three methylene groups from the glycerol unit linked to the bulkier disaccharide residue. Freeze-fracture and cryotransmission electron microscopy experiments clearly demonstrated unprecedented glycolipid supramolecular organizations involving two-by-two monolayer associations coupled with interconnection and fusion phenomena. Furthermore, a significant difference in the hydration properties and in the lyotropic liquid crystalline behavior of bipolar lipids 1-2 was found depending on the position of the cyclopentane residue.

Supramolecular self-assembling properties of membrane-spanning archaeal tetraether glycolipid analogues.

The self-assembling properties of a new series of archaeal tetraether glycolipid analogues 1-6 that are characterized by a bipolar architecture with two similar or different glycosidic and/or phosphate polar heads and a lipid core possessing a cyclopentane unit and/or branched chains were studied by means of differential scanning calorimetry, optical microscopy, X-ray scattering, freeze-fracture electron microscopy and dynamic light scattering. Unsymmetrical phosphate derivatives 1 and 2 spontaneously formed thermostable multilamellar and unilamellar vesicles in which most of the bipolar lipids adopted a trans-membrane conformation, as revealed by freeze-fracture electron microscopy. Supramolecular aggregates of neutral glycolipids 3-6 were found to depend on both the saccharidic polar heads and the chain composition. The presence of one glycosidic residue with rather marked hydrophilic properties, such as the lactosyl moiety, was required to allow the formation of multilamellar vesicles. Surprisingly, the introduction of a cyclopentane unit in the bridging chain was able to induce an apparent two-by-two membrane association: this unusual behaviour might be the result of unsymmetrical interfacial properties of the lipid layer caused by the presence of the cyclopentane unit.

Membrane properties of archaeal macrocyclic diether phospholipids.

Several biophysical properties of four synthetic archaeal phospholipids [one polyprenyl macrocyclic lipid A and three polyprenyl double-chain lipids (B, C, D) bearing zero, one or four double bonds in each chain] were studied using differential scanning calorimetry, electron and optical microscopies, stopped-flow/light scattering and solid-state 2H-NMR techniques. These phospholipids gave a variety of self-organized structures in water, in particular vesicles and tubules. These assemblies change in response to simple thermal convection. Some specific membrane properties of these archaeal phospholipids were observed: They are in a liquid-crystalline state over a wide temperature range; the dynamics of their polyprenyl chains is higher than that of n-acyl chains; the water permeability of the membranes is lower than that of n-acyl phospholipid membranes. It was also found that macrocyclization remarkably improves the barrier properties to water and the membrane stability. This may be related to the adaptation of Methanococcus jannaschii to the extreme conditions of the deep-sea hydrothermal vents.

Synthesis of structured lipids and etherlipids with antioxidants: combination of a selena fatty acid and a selena fatty alcohol with a carotenoic acid in glyceride molecules.

Selenium and carotenoids show similar and complementary properties and protect against a variety of pathological processes. Mixtures of both compounds are found in nutritional supplements and are used to prevent several diseases. The synthetic connection of carotenoids with selenium in glycerols may increase the chemopreventive activity of the individual compounds. Beta-apo-8'-carotenoic acid and 7-selenacapryloic acid were esterified with glycerol to highly unsaturated stable di- and triglycerides. Intramolecular selenium:carotenoid ratios of 1:1, 2:1 and 1:2 were obtained for 1-(7-selenaoctanoyl)-3-(3beta-apo-8 -carotenoyl)-glycerol, 1,3-di-(beta-apo-8'-carotenoyl)-2-(7-selenaoctanoyl)-glycero l and 1,2-di-(7-selenaoctanoyl)-3-(beta-apo-8'-carotenoyl)-glycero l, respectively. The carotenoic acid was likewise connected to the pharmacologically interesting 11-selenalaurylglycerolether forming an alkyl-acylglyceride: 1-(11-selenadodecyl)-3-(beta-apo-8'-carotenoyl)-glycerol.

A comparison of the lytic properties of two ether-linked lipids, one with and one without antineoplastic activity.

We have synthesized two ether lipids: 2'-(trimethylammonio)ethyl 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (compound 1) with antineoplastic activity and a maltosyl derivative (compound 2) without antineoplastic activity. We have compared the antineoplastic activity of these two compounds against WEHI-3B cells with their ability to disrupt the membranes of erythrocytes or neutrophils. Since ether lipids are highly hydrophobic molecules, it is possible that they may exert their cytotoxic action by inducing the nonspecific perturbation of cellular membranes, causing lysis and cell death. Membrane disruption was monitored by the lysis of cells or the change in erythrocyte membrane microviscocity and compared with the effect of detergents (known nonspecific lytic agents). Both compounds 1 and 2 caused the lysis of erythrocytes and neutrophils. The rate of lysis of erythrocytes was comparable to the rate of change of erythrocyte membrane microviscosity caused by both compounds 1 and 2. Both compounds caused the lysis of erythrocytes via a noncolloid osmotic mechanism that displayed features of the lysis caused by detergents at high concentrations.