Unsaturated Derivatives Research Articles

Cinnamic acid derivatives as inhibitors for chorismatases and isochorismatases

Chorismatases and isochorismatases catalyse the hydrolysis of chorismate or isochorismate leading to unsaturated cyclohexenoic acid derivatives. Based on simplification of the physiological substrates, two cinnamic acid-derived compounds, differing in the saturation of the side chain, were developed. In contrast to earlier inhibitor studies, the compounds described here do not have an ether bond and therefore can be synthesised very easily in one or two steps without the need for protective groups. Both substances demonstrate inhibition of the isochorismatase EntB from Escherichia coli and the chorismatases FkbO and Hyg5 from Streptomyces. For chorismatases, the unsaturated compound shows IC50 values in the millimolar range, while the saturated compound is the better inhibitor with IC50 values in the micromolar/low millimolar range; for the isochorismatase tested both compounds inhibit in the micromolar range. Further, an analysis of the apparent Km values for FkbO and EntB was performed, showing that both inhibitors act in a competitive manner. Due to the ease of modifying these new inhibitors they are a suitable starting point for exploring further functionalised derivatives.

不飽和カルボン酸化合物の固相反応の機構解析と可視化

不飽和カルボン酸化合物の固相反応の機構解析と可視化

Systematic study on free radical hydrothiolation of unsaturated monosaccharide derivatives with exo- and endocyclic double bonds

Exo- and endocyclic double bonds of glycals and terminal double bonds of enoses were reacted with various thiols by irradiation with UV light in the presence of a cleavable photoinitiator. The photoinduced radical-mediated hydrothiolation reactions showed highly varying overall conversions depending not only on the substitution pattern and electron-density of the double bond but also on the nature and substitution pattern of the thiol partner. Out of the applied thiols thiophenol, producing the highly stabilized thiyl radical, exhibited the lowest reactivity toward each type of alkene. In most cases, the hydrothiolations took place with full regio- and stereoselectivities. Successful addition of 1,2 : 3,4-di-O-isopropylidene-6-thio-α-d-galactopyranose to a 2,3-unsaturated N-acetylneuraminic acid derivative, providing a (3 → 6)-S-linked pseudodisaccharide, demonstrated that the endocyclic double bond of Neu5Ac-2-ene, bearing an electron-withdrawing substituent, shows sufficient reactivity in the photoinduced thiol-ene coupling reaction.

BF3·OEt2/TMSN3 Mediated Regioselective Azidolysis of Vinylaziridines

An easy and general azidolysis of vinylepoxides mediated by BF3·OEt2 and TMSN3 recently reported by our group has been extended to vinylaziridines. The reaction affords unsaturated azido derivatives with complete stereoselectivity and regioselectivity, when in the presence of electron-poor olefins, regardless of the size of substituents on the heterocyclic ring.

Prospects for Three-Electron Donor Boronyl (BO) Ligands and Dioxodiborene (B2O2) Ligands as Bridging Groups in Binuclear Iron Carbonyl Derivatives

Recent experimental work (2010) on (Cy(3)P)(2)Pt(BO)Br indicates that the oxygen atom of the boronyl (BO) ligand is more basic than that in the ubiquitous CO ligand. This suggests that bridging BO ligands in unsaturated binuclear metal carbonyl derivatives should readily function as three-electron donor bridging ligands involving both the oxygen and the boron atoms. In this connection, density functional theory shows that three of the four lowest energy singlet Fe(2)(BO)(2)(CO)(7) structures have such a bridging η(2)-μ-BO group as well as a formal Fe-Fe single bond. In addition, all four of the lowest energy singlet Fe(2)(BO)(2)(CO)(6) structures have two bridging η(2)-μ-BO groups and formal Fe-Fe single bonds. Other Fe(2)(BO)(2)(CO)(n) (n = 7, 6) structures are found in which the two BO groups have coupled to form a bridging dioxodiborene (B(2)O(2)) ligand with B-B bonding distances of ~1.84 Å. All of these Fe(2)(μ-B(2)O(2))(CO)(n) structures have long Fe···Fe distances indicating a lack of direct iron-iron bonding. One of the singlet Fe(2)(BO)(2)(CO)(7) structures has such a bridging dioxodiborene ligand with cis stereochemistry functioning as a six-electron donor to the pair of iron atoms. In addition, the lowest energy triplet structures for both Fe(2)(BO)(2)(CO)(7) and Fe(2)(BO)(2)(CO)(6) have bridging dioxodiborene ligands with trans stereochemistry functioning as a four-electron donor to the pair of iron atoms.

Palladium(0)-catalyzed efficient synthesis of allylic N- and S-benzoheterocycles linked to unsaturated carbohydrate derivatives

An efficient strategy was developed to envisage the synthesis of new N- and S-benzoheterocycles attached to the C-4 position of pseudo-carbohydrates. The reaction was performed with unsaturated carbohydrates and benzoheterocycles as nucleophiles in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium(0) and chelating bidentate ligand dppb. This strategy allowed easy access to benzoheterocyclic sugars in moderate-to-good yields. A preliminary study for antioxidant activities of O-glycosides 2,3-unsaturated was evaluated based on the 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging and 2,2-azinobis 3-ethylbenzothiozoline-6-sulfonic acid (ABTS) radical cation decolorization assay, and showed low-to-moderate activities.

Coibacins A–D, Antileishmanial Marine Cyanobacterial Polyketides with Intriguing Biosynthetic Origins

Four unsaturated polyketide lactone derivatives, coibacins A-D, were isolated from a Panamanian marine cyanobacterium, cf. Oscillatoria sp. The two different types of termini observed in these co-occurring metabolites, either a methyl cyclopropyl ring as seen in curacin A or a methyl vinyl chloride similar to that observed in the jamaicamides, suggest an intriguing flexibility in the "beta branch" forming biosynthetic process. The coibacins possess selective antileishmanial activity as well as potent anti-inflammatory activity.

Syntheses of Isoxazoline-Based Amino Acids by Cycloaddition of Nitrile Oxides and Their Conversion into Highly Functionalized Bioactive Amino Acid Derivatives

The present account illustrates the syntheses of isoxazoline-based amino acids by the cycloaddition of 1,3-dipolar nitrile oxides to the C–C double bond of unsaturated amino acid derivatives, with focus on the regio- and stereoselectivities of the transformations. Emphasis is also placed on the syntheses of highly functionalized amino acids by means of isoxazoline ring opening. The syntheses of various pharmacologically active compounds and their analogues via the above strategies are described. 1 Introduction 2 1,3-Dipolar Cycloadditions of Nitrile Oxides 3 Syntheses of Isoxazoline-Based Amino Acids 3.1 Syntheses of Isoxazoline α-Amino Acids 3.2 Syntheses of Isoxazoline γ-Amino Acids and Their Transformation into Bioactive Derivatives 3.3 Syntheses of Isoxazoline β-Amino Acids 3.3.1 Syntheses of Highly Functionalized Cyclic β-Amino Acids by 1,3-Dipolar Cycloaddition of Nitrile Oxides 4 Cycloaddition of Nitrile Oxides to Amino Acid Precursors 5 Summary and Outlook

DABCO-catalyzed C–C bond formation reaction between electron-deficient alkynes and 1,3-dicarbonyl compounds

An excellent catalyst DABCO has been found to catalyze C–C bond formation reaction between activated methylenes and alkynes. The transformation has provided a facile route for the synthesis of 2H-pyran-2-ones or unsaturated alkenoic acid ester derivatives and explored the new possibilities of N-catalysts for Michael addition of nucleophiles with alkynoates.

Homogenous synthesis of 3-allyloxy-2-hydroxypropyl-cellulose in NaOH/urea aqueous system

3-Allyloxy-2-hydroxypropylcelluloses (AHP-celluloses), reactive unsaturated cellulose derivatives, were homogeneously synthesized by the reaction of cellulose with allyl glycidyl ether (AGE) in NaOH/urea aqueous solution. Water-soluble AHP-celluloses with DSNMR = 0.32–0.67 were prepared from microcrystalline cellulose. The degree of substitution (DS) of AHP-celluloses could be controlled by varying the molar ratio of AGE and NaOH to AGU and the reaction conditions. The structure of AHP-cellulose samples were characterized by means of FT-IR, NMR spectroscopy and size exclusion chromatography. The cellulose ether shows thermoreversible flocculation. Bromination reactions were carried out as subsequent functionalization both to illustrate the reactivity of the allyl function and to determine the DS values.

The cytoprotective effects of oleoylethanolamide in insulin‐secreting cells do not require activation of GPR119

β-cells express a range of fatty acid-responsive G protein-coupled receptors, including GPR119, which regulates insulin secretion and is seen as a potential therapeutic target in type 2 diabetes. The long-chain unsaturated fatty acid derivative oleoylethanolamide (OEA) is an endogenous agonist of GPR119 and, under certain conditions, some long-chain unsaturated fatty acids can promote β-cell cytoprotection. It is not known, however, if OEA is cytoprotective in β-cells. The present study has examined this and determined whether GPR119 is involved. Clonal rat insulin-secreting cell lines, BRIN-BD11 or INS-1E, were exposed to fatty acids complexed with BSA. cAMP levels, insulin release and cell viability were measured. Protein expression was studied by Western blotting and receptor expression by RT-PCR. GPR119 was expressed in both BRIN-BD11 and INS-1E cells and OEA was cytoprotective in these cells. However, cytoprotection was not reproduced by any of a range of selective, synthetic ligands of GPR119. The cytoprotective response to OEA was lost during exposure to inhibitors of fatty acid amide hydrolase (FAAH) suggesting that OEA per se is not the cytoprotective species but that release of free oleate is required. Similar data were obtained with anandamide, which was cytoprotective only under conditions favouring release of free arachidonate. Activation of GPR119 is not required to mediate the cytoprotective actions of OEA in BRIN-BD11 or INS-1E cells. Rather, OEA is internalised and subjected to hydrolysis by FAAH to release free oleate, which then mediates the cytoprotection.

Binuclear methylborole nickel carbonyls

The existence of the bis(borole) nickel sandwich compound (η5-C4H4BCH3)2Ni suggests the possibility of mixed methylborole nickel carbonyls. The structures and thermochemistry of the binuclear methylborole nickel carbonyls (C4H4BCH3)2Ni2(CO)n (n=3, 2, 1) have been compared with those of the isoelectronic cyclopentadienylcobalt derivatives (C5H5)2Co2(CO)n and cyclobutadiene nickel derivatives (C4H4)2Ni2(CO)3. For the tricarbonyls (n=3) the lowest energy structures in all three systems have two terminal carbonyl groups, one bridging carbonyl group, and metal–metal single bonds. However, for the unsaturated derivatives (C4H4BCH3)2Ni2(CO)n (n=2, 1) the pendant methyl groups are not “innocent bystanders”. Instead structures with one of the methyl hydrogens functioning as an agostic hydrogen to the nickel atom are competitive in energy with structures analogous to those of the (C5H5)2Co2(CO)n and (C4H4)2Ni2(CO)n analogues. Thus for (C4H4BCH3)2Ni2(CO)2 a structure with two bridging carbonyl groups and a formal NiNi double bond of length ∼2.37Å and a structure with one bridging carbonyl group, one terminal carbonyl group, a C–H–Ni agostic hydrogen atom, and a Ni–Ni single bond of length ∼2.48Å have essentially the same energies. For (C4H4BCH3)2Ni2(CO) the two lowest energy structures also have agostic C–H–Ni hydrogen atoms and Ni–Ni single bonds. The thermochemistry for the synthesis of (C4H4BCH3)2Ni2(CO)n derivatives from Ni(CO)4+(η5-C4H4BCH3)2Ni is not favorable since such reactions are endothermic requiring, for example, 13kcal/mol of energy for the reaction Ni(CO)4+(η5-C4H4BCH3)2Ni→(C4H4BCH3)2Ni2(CO)3+CO.

Unsaturated Fatty Alcohol Derivatives of Olive Oil Phenolic Compounds with Potential Low-Density Lipoprotein (LDL) Antioxidant and Antiobesity Properties

A new route for the synthesis of fatty alcohol derivatives of hydroxytyrosol and other olive oil phenolic compounds was developed to allow the preparation of unsaturated derivatives. The biological activity of synthesized compounds was evaluated. Most of the compounds presented a significant antioxidant activity on low-density lipoprotein (LDL) particles. The activity of the tested products was significantly influenced by the number and position of unsaturations as well as modifications on the polar head of the synthesized compounds. Some of them presented modulation of food intake in rats and, due to their molecular similarity with CB(1) endogenous ligands, the endocannabinoid system and PPAR-α were also evaluated as potential targets. The pharmacodynamics could not be totally explained by CB(1) and PPAR-α receptor interactions because only two of the four compounds with biological activity showed a CB(1) activity and all of them presented low PPAR-α affinity, not justifying its whole in vivo activity. The hydroxytyrosol linoleylether (7) increased LDL resistance to oxidation with a capacity similar to that of hydroxytyrosol and was the most active in vivo compound with a hypophagic effect comparable to that of oleoylethanolamine. We consider that this compound could be a good lead compound for future drug development in obesity treatments.

2,5-Diketopiperazines as Neuroprotective Agents

2,5-diketopiperazines are the simplest cyclic peptides found in nature, commonly biosynthesized from amino acids by different organisms, and represent a promising class of biologically active natural products. Their peculiar heterocyclic structure confers high stability against the proteolysis and constitutes a structural requirement for the active intestinal absorption. Furthermore, the diketopiperazine-based motif is considered as a novel brain shuttle for the delivery of drugs with limited ability to cross the blood-brain barrier (BBB) and can be proposed as an ideal candidate for the rational development of new therapeutic agents. Although these cyclic peptides have been known since the beginning of the 20th century, only recently have they attracted substantial interest with respect to the wide spectrum of their biological properties, including antitumor, antiviral, antifungal, antibacterial and antihyperglycemic activities. In addition to these, the most challenging function of the diketopiperazine derivatives is related with their remarkable neuroprotective and nootropic activity. The aim of the present paper is to provide an overview of the two major classes of diketopiperazines, the TRH-related and the unsaturated derivatives both characterized by a significant ability to protect against neurotoxicity in several experimental models. The neuroprotective profile of these compounds suggests that they may have a future utility in the therapy of neuronal degeneration in vivo, potentially through several different mechanisms.

Polyamide precursors from renewable 10-undecenenitrile and methyl acrylate via olefin cross-metathesis

The ruthenium-catalyzed cross-metathesis of the unsaturated fatty acid derivative 10-undecenenitrile 1 arising from castor oil with methyl acrylate produces a C12 nitrile ester with high turnover number. This product has potential as a new bio-sourced intermediate for the production of polyamides. This route competes favourably with the reverse cross-metathesis of methyl 10-undecenoate with acrylonitrile leading to the same C12 α,ω-amino ester 7 after hydrogenation of the carbon–carbon double bond and the nitrile functionality.

Synthetic Strategies Directed Towards 5a‐Carbahexopyranoses and Derivatives Based on 6‐endo‐trig Radical Cyclizations

AbstractSeveral synthetic strategies directed towards 5a‐carbahexopyranoses and based on 6‐endo‐trig radical cyclization of unsaturated carbohydrate derivatives have been devised. Three elements for regiocontrol to optimize the 6‐endo/5‐exo ratio have been incorporated, and their efficiencies in directing 6‐endo cyclizations have been evaluated. These elements – namely: i) the incorporation of a substituent at C‐5 (radical numbering), ii) the use of a vinyl (rather than alkyl) radical, and iii) the inclusion of ring strain in the system – have proved useful when used in combination. The simultaneous presence of two of them also results in 6‐endo selectivity. On another topic, the ozonation of the ensuing alkenylstananes to afford diols seems to be based on a tin‐oxygen rearrangement, similar to that reported for related vinylsilanes, rather than on remarkable stabilities of tin‐containing primary ozonides as we had previously suggested.

Phenylsulfanylation of 3′,4′-Unsaturated Adenosine Employing Thiophenol-N-Iodosuccinimide Leads to 4′-Phenylsulfanylcordycepin: Synthesis of 4′-Substituted Cordycepins on the Basis of Substitution of the Phenylsulfanyl Leaving Group

Upon reaction of the 3',4'-unsaturated adenosine derivative 2 with N-iodosuccinimide (NIS) and thiophenol, an unexpected electrophilic hydrophenylsulfanylation proceeded to provide 4'-phenylsulfanylcordycepin 7 in 79% yield with the ratio 7a/7b = 6.6/1. A study of the reaction mechanism revealed that hydrogen iodide (HI) generated from NIS and PhSH acted as an active species. On the basis of a deuterium experiment using PhSD, initial protonation occurred at the β face of the double bond to furnish the β-π complex III, which underwent anti addition of PhSH as a major pathway. Nucleophilic substitution of N(6)-pivaloylated 9 with various alcohols in the presence of N-bromosuccinimide (NBS) gave the respective 4'-α-alkoxycordycepins 15a-21a as the major stereoisomers. Use of DAST in place of an alcohol gave the 4'-α-fluoro analogue 23a stereoselectively. Radical-mediated carbon-carbon bond construction was also applicable to 7, giving 4'-α-allylcordycepin (24a) and 4'-α-cyanoethylcordycepin (25) derivatives.

Aryl and Acyclic Unsaturated Derivatives of Thioguanine and 6- Mercaptopurine: Synthesis and Cytotoxic Activity

Aryl and Acyclic Unsaturated Derivatives of Thioguanine and 6- Mercaptopurine: Synthesis and Cytotoxic Activity

ChemInform Abstract: A New Approach to Fused Furan Ring Systems and Benzofurans: Intramolecular Cyclization Reactions of Unsaturated Acyloxy Sulfone Derivatives.

AbstractThe LiN(Tms)2‐mediated intramolecular cyclization is followed by TosOH‐catalyzed dehydration and double bond isomerization.

ChemInform Abstract: Synthesis of New Unsaturated Derivatives of Functionally Substituted 2‐Imino‐2,5‐dihydrofurans.

5,5-Substituted 2-imino-4-methyl-2,5-dihydrofuran-3-carbonitriles reacted with aromatic aldehydes to give the corresponding 5,5-substituted 2-imino-4-(2-R-vinyl)-2,5-dihydrofuran-3-carbonitriles. The latter were converted into hydrochlorides which were hydrolyzed to 3-cyano-4-(2-R-vinyl)-2,5-dihydrofuran-2-ones whose condensation with malononitrile afforded dicyanomethylidene derivatives.