Studies on the Mass Spectra of N‐Aryl α,β‐Unsaturated γ‐Lactams

The mass spectra of a series of N‐aryl α,β‐unsaturated γ‐lactams were studied. Besides the molecular ion, the three characteristic fragments such as [M⁺‐29], [M⁺‐55], and [M⁺‐82] were commonly found in a series of N‐Aryl α,β‐unsaturated γ‐lactams in EI/MS. Further more the mechanism for the interpretation of these fragments is also de scribed.     

Enantioselective Syntheses of Substituted γ‐Butyrolactones

The previously described chiral 2‐acyloxathianes 5 (Scheme I) are used in two different enantioselective syntheses of γ‐butyrolactones. In one synthesis, Grignard addition, cleavage and reduction to carbinols RR'C(OH)CH₂OH is followed by tosylation, malonate homologation, lactonization, and removal of the carbomethoxy group to give optically active γ‐lactones. A modification of this synthesis (Scheme I) leads to optically active α‐methylene‐γ‐lactones. In the second synthesis, reaction of a bromomagnesium enolate with ketones 5 leads to β‐hydroxyesters, which, by appropriate sequences of reduction and cleavage (Scheme II) are converted to optically active α‐ or β‐hydroxy‐γ‐lactones.     

A New Route to N‐Aryl 2‐Alkenamides,N‐Allyl N‐Aryl 2‐Alkenamides,and N‐Aryl α,β‐Unsaturated γ‐Lactams from N‐Aryl 3‐(Phenylsulfonyl)propanamides

A series of N‐aryl 2‐alkenamides were produced efficiently by treating N‐aryl 3‐(phenylsulfonyl)‐propanamides with potassium tert‐butoxide in THF at 0°C. With out isolation, it was further treated with an additional equivalent of potassium tert‐butoxide and allyl bromide to give N‐allyl N‐aryl 2‐alkenamides in one pot in good yields. Followed by a ring‐closing metathesis reaction, these N‐allyl N‐aryl 2‐alkenamides were respectively converted into corresponding N‐aryl α,β‐unsaturated γ‐lactams in moderate yields.     

Synthesis of new optically active α,α′,β‐trisubstituted‐β‐lactones as monomers for stereoregular biopolyesters

Various optically active (4R)‐alkyloxycarbonyl‐3,3‐dialkyl‐2‐oxetanones as monomers were synthesized from L‐(S)‐malic acid in six steps to prepare a new family of stereopolyesters for biomedical applications. The synthesis began with an esterification followed of a dialkylation in the aim to introduce hydrophobic groups as methyl or reactive group as allyl. Then, a saponification has permitted to obtain the corresponding diacids that reacted with appropriate alcohols to furnish different monoesters. The last and most important step was activation of hydroxyl group of monoesters with the asymmetric carbon configuration inversion according to the Mitsunobu reaction. Thus, this reaction has provided lactones from monoesters with 100% enantiomeric excess which was confirmed by ¹H NMR and by the synthesis of corresponding isotactic and semicrystalline homopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2586–2597     

Ligand‐Enabled Arylation of γ‐C−H Bonds

Pd^II‐catalyzed arylation of γ‐C(sp³)?H bonds of aliphatic acid‐derived amides was developed by using quinoline‐based ligands. Various γ‐aryl‐α‐amino acids were prepared from natural amino acids using this method. The influence of ligand structure on reactivity was also systematically investigated.     

Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized 13C‐Labeled Molecular Probe

The γ‐glutamyl transpeptidase (GGT) enzyme plays a central role in glutathione homeostasis. Direct detection of GGT activity could provide critical information for the diagnosis of several pathologies. We propose a new molecular probe, γ‐Glu‐[1‐¹³C]Gly, for monitoring GGT activity in vivo by hyperpolarized (HP) ¹³C magnetic resonance (MR). The properties of γ‐Glu‐[1‐¹³C]Gly are suitable for in vivo HP ¹³C metabolic analysis since the chemical shift between γ‐Glu‐[1‐¹³C]Gly and its metabolic product, [1‐¹³C]Gly, is large (4.3 ppm) and the T₁ of both compounds is relatively long (30 s and 45 s, respectively, in H₂O at 9.4 T). We also demonstrate that γ‐Glu‐[1‐¹³C]Gly is highly sensitive to in vivo modulation of GGT activity induced by the inhibitor acivicin.     

Triphenylphosphine‐Mediated Reduction of Electron‐Deficient Propargyl Ethers to the Allylic Ethers

Semihydrogenation of α,β‐unsaturated ynoates and ‐ynones bearing a γ‐alkoxy group can be performed using triphenylphosphine and water. α,β‐Unsaturated ynoates were reduced to a mixture of cis and trans α,β‐unsaturated enoates, whereas, ynones were reduced to trans α,β‐unsaturated enones as the only products.     

A Novel Synthesis of γ,δ‐Unsaturated Aldehydes from α‐Formyl‐γ‐lactones

A preparatively useful one‐step transformation of γ,γ‐disubstituted α‐formyl‐γ‐lactones into trisubstituted γ,δ‐unsaturated aldehydes is described, by means of catalytic amounts of either AcOH or AcOEt in the vapor phase over a glass support. A mechanistic rationale is proposed.     

Phosphoryl group differentiating α‐amino acids from β‐ and γ‐amino acids in prebiotic peptide formation

In recent years β‐amino acids have increased their importance enormously in defining secondary structures of β‐peptides. Interest in β‐amino acids raises the question: Why and how did nature choose α‐amino acids for the central role in life? In this article we present experimental results of MS and ³¹P NMR methods on the chemical behavior of N‐phosphorylated α‐alanine, β‐alanine, and γ‐amino butyric acid in different solvents. N‐Phosphoryl α‐alanine can self‐assemble to N‐phosphopeptides either in water or in organic solvents, while no assembly was observed for β‐ or γ‐amino acids. An intramolecular carboxylic–phosphoric mixed anhydride (IMCPA) is the key structure responsible for their chemical behaviors. Relative energies and solvent effects of three isomers of IMCPA derived from α‐alanine (2a–c), with five‐membered ring, and five isomers of IMCPA derived from β‐alanine (4a–e), with six‐membered ring, were calculated with density functional theory at the B3LYP/6‐31G** level. The lower relative energy (3.2 kcal/mol in water) of 2b and lower energy barrier for its formation (16.7 kcal/mol in water) are responsible for the peptide formation from N‐phosphoryl α‐alanine. Both experimental and theoretical studies indicate that the structural difference among α‐, β‐, and γ‐amino acids can be recognized by formation of IMCPA after N‐phosphorylation. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 232–241, 2003     

A Minimal β‐Lactone Fragment for Selective β5c or β5i Proteasome Inhibitors

Broad‐spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here aimed at identifying minimal structural elements that confer β5c or β5i selectivity on proteasome inhibitors. Based on the natural product belactosin C, we synthesized two β‐lactones featuring a dimethoxybenzyl moiety and either a methylpropyl (pseudo‐isoleucin) or an isopropyl (pseudo‐valine) P1 side chain. Although the two compounds differ only by one methyl group, the isoleucine analogue is six times more potent for β5i (IC₅₀=14 nM ) than the valine counterpart. Cell culture experiments demonstrate the cell‐permeability of the compounds and X‐ray crystallography data highlight them as minimal fragments that occupy primed and non‐primed pockets of the active sites of the proteasome. Together, these results qualify β‐lactones as a promising lead‐structure motif for potent nonpeptidic proteasome inhibitors with diverse pharmaceutical applications.     

A Mild Isomerization Reaction for β,γ‐Unsaturated Ketone to α,β‐Unsaturated Ketone

A series of β,γ‐unsaturated ketones were isomerized to their corresponding α,β‐unsaturated ketones by the introduction of DABCO in iPrOH at room temperature. The endo‐cyclic double bond (β,γ‐position) on ketone was rearranged to exo‐cyclic double bond (α,β‐position) under the reaction conditions.     

One‐pot inimer promoted ROCP synthesis of branched copolyesters using α‐hydroxy‐γ‐butyrolactone as the branching reagent

An array of branched poly(?‐caprolactone)s was successfully synthesized using an one‐pot inimer promoted ring‐opening multibranching copolymerization (ROCP) reaction. The biorenewable, commercially available yet unexploited comonomer and initiator 2‐hydroxy‐γ‐butyrolactone was chosen as the inimer to extend the use of 5‐membered lactones to branched structures and simultaneously avoiding the typical tedious work involved in the inimer preparation. Reactions were carried out both in bulk and in solution using stannous octoate (Sn(Oct)₂) as the catalyst. Polymerizations with inimer equivalents varying from 0.01 to 0.2 were conducted which resulted in polymers with a degree of branching ranging from 0.049 to 0.124. Detailed ROCP kinetics of different inimer systems were compared to illustrate the branch formation mechanism. The resulting polymer structures were confirmed by ¹H, ¹³C, and ₁H‐₁₃C HSQC NMR and SEC (RI detector and triple detectors). The thermal properties of polymers with different degree of branching were investigated by DSC, confirming the branch formation. Through this work, we have extended the current use of the non‐homopolymerizable γ‐butyrolactone to the branched polymers and thoroughly examined its behaviors in ROCP. © 2016 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1908–1918     

Kinetics of Oxidation of L‐Cysteine by trans‐ and cis‐CoIII and FeIII Complexes based on α‐ and γ‐Diimine Schiff Base Ligands

Kinetics of oxidation of L ‐cysteine by Co^III and Fe^III complexes based on α‐ and γ‐diimine Schiff base ligands were studied in aqueous solution. Pairs of trans and cis isomers of the metal complexes were used in the studies. Kinetic measurements were performed at 25 °C and constant pH and ionic strength under pseudo‐first order condition, in which the concentration of cysteine was around two orders of magnitude greater than that of the metal complex. The observed rate constant was obtained by following the change in absorbance of the reaction mixture with time at a predetermined wavelength. The overall rate constant and order of the reaction with respect to cysteine and metal complex were determined. For both metal ions studied, the oxidation rate constant for the trans isomer was higher than that for the cis isomer. This was attributed to the contribution of the steric factor and the trans effect. The effects of substituents and the nature of the metal ion on the reaction rate are discussed.     

Synthesis and Structure of Low‐valent η4‐Cinnamaldehyde Cobalt Complexes

Three η⁴‐(C=C–C=O) coordination cobalt(I) complexes 1 – 3 were synthesized by the reactions of cinnamaldehyde, p‐fluorocinnamaldehyde, and p‐chlorocinnamaldehyde with CoMe(PMe₃)₄. Complex 4 as η²‐(C=C) coordination was prepared by the reaction of chalcone with Co(PMe₃)₄. The structures of complexes 1 – 4 were confirmed by single‐crystal X‐ray diffraction. Although the reactions didn't undergo C–H bond activation and decarbonylation, the formation of complexes 1 – 4 deepens our understanding of the reactions between α,β‐unsaturated aldehyde or ketone with low‐valent central cobalt atom.     

Synthesis of Phenanthrene Derivatives through the Reaction of an α,α‐Dicyanoolefin with α,β‐Unsaturated Carbonyl Compounds

Phenanthrene derivatives were prepared by reacting an α,α‐dicyanoolefin with different α,β‐unsaturated carbonyl compounds resulting from Wittig reaction of ninhydrin and phosphanylidene or condensation of barbituric acid and an aldehyde. The easy procedure, mild and metal‐catalyst free, reaction conditions, good yields, and no need for chromatographic purifications are important features of this protocol. The structures of the product of type 3 and 5 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS). A plausible mechanism for this type of reaction is proposed (Scheme 1).     

α‐methylene‐γ‐butyrolactones: versatile skin bioactive natural products

Natural products containing an α‐methylene‐γ‐butyrolactone moiety, mainly of the sesquiterpene type, are widely observed in plants, which upon coming into contact with skin, will induce major skin toxicological side effects or phytodermatitis. Indeed two main dermatological pathologies have been associated with a skin exposure to molecules containing an α‐methylene‐γ‐butyrolactone moiety: allergic contact dermatitis (ACD) and chronic actinic dermatitis (CAD). ACD is an immunologically based disease resulting from modifications of epidermal proteins by sensitizers or haptens. Indeed, α‐methylene‐γ‐butyrolactones are highly electrophilic structures that can act as Michael acceptors towards nucleophilic residues of proteins. Cysteine and lysine are the most modified residues leading, in the case of enantiomerically pure lactones, to the formation of diastereomeric adducts. This chemical enantioselectivity induces an enantiospecificity of the allergic reaction, i.e., an individual sensitized to one enantiomer will not develop clinical symptoms when exposed to the other enantiomer and vice versa. Sesquiterpene lactones have been also associated with another pathology that involves UV irradiation and DNA modifications. Interestingly, it was found that α‐methylene‐γ‐butyrolactones, in addition to their electrophilic properties, were highly photoreactive molecules able to react with thymine/thymidine to form [2 + 2] photoadducts in very high yields. In all cases a syn regioselectivity was observed, probably associated with the polarization of the exomethylenic bond. This high photoreactivity of α‐methylene‐γ‐butyrolactones towards thymidine could be an explanation of the progressive evolution of allergic contact dermatitis towards chronic actinic dermatitis. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 000–000; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.200900013     

Distal γ‐C(sp3)−H Olefination of Ketone Derivatives and Free Carboxylic Acids

Reported herein is the distal γ‐C(sp³)?H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino‐acid directing group and using the ligand combination of a mono‐N‐protected amino acid (MPAA) and an electron‐deficient 2‐pyridone were critical for the γ‐C(sp³)?H olefination of ketone substrates. In addition, MPAAs enabled the γ‐C(sp³)?H olefination of free carboxylic acids to form diverse six‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp³)?H bonds also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ‐C(sp³)?H olefinated products.     

Cu(II) immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe2O3@TiO2 (γ‐Fe2O3@TiO2‐EG‐Cu(II)): A highly efficient magnetically separable heterogeneous nanocatalyst for one‐pot synthesis of highly substituted imidazoles

A simple, efficient and eco‐friendly procedure has been developed using Cu(II) immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe₂O₃@TiO₂ (γ‐Fe₂O₃@TiO₂‐EG‐Cu(II)) for the synthesis of 2,4,5‐trisubstituted and 1,2,4,5‐tetrasubstituted imidazoles, via the condensation reactions of various aldehydes with benzil and ammonium acetate or ammonium acetate and amines, under solvent‐free conditions. High‐resolution transmission electron microscopy analysis of this catalyst clearly affirmed the formation of a γ‐Fe₂O₃ core and a TiO₂ shell, with mean sizes of about 10–20 and 5–10 nm, respectively. These data were in very good agreement with X‐ray crystallographic measurements (13 and 7 nm). Moreover, magnetization measurements revealed that both γ‐Fe₂O₃@TiO₂ and γ‐Fe₂O₃@TiO₂‐EG‐Cu(II) had superparamagnetic behaviour with saturation magnetization of 23.79 and 22.12 emu g^?1, respectively. γ‐Fe₂O₃@TiO₂‐EG‐Cu(II) was found to be a green and highly efficient nanocatalyst, which could be easily handled, recovered and reused several times without significant loss of its activity. The scope of the presented methodology is quite broad; a variety of aldehydes as well as amines have been shown to be viable substrates. A mechanism for the cyclocondensation reaction has also been proposed.     

Pharmacokinetics of 2,3,5,4′‐tetrahydroxystilbene‐2‐O‐β‐D‐glucoside in rat using ultra‐performance LC‐quadrupole TOF‐MS

2,3,5,4′‐Tetrahydroxystilbene‐2‐O‐β‐D‐glucoside (THSG) from Polygoni multiflori has been demonstrated to possess a variety of pharmacological activities, including antioxidant, anti‐inflammatory and hepatoprotective activities. Ultra‐performance LC‐quadrupole TOF‐MS with MS Elevated Energy data collection technique and rapid resolution LC with diode array detection and ESI multistage MSⁿ methods were developed for the pharmacokinetics, tissue distribution, metabolism, and excretion studies of THSG in rats following a single intravenous or oral dose. The three metabolites were identified by rapid resolution LC‐MSⁿ. The concentrations of the THSG in rat plasma, bile, urine, feces, or tissue samples were determined by ultra‐performance LC‐MS. The results showed that THSG was rapidly distributed and eliminated from rat plasma. After the intravenous administration, THSG was mainly distributing in the liver, heart, and lung. For the rat, the major distribution tissues after oral administration were heart, kidney, liver, and lung. There was no long‐term storage of THSG in rat tissues. Total recoveries of THSG within 24 h were low (0.1% in bile, 0.007% in urine, and 0.063% in feces) and THSG was excreted mainly in the forms of metabolites, which may resulted from biotransformation in the liver.     

Intermolecular Asymmetric Carboesterification of Alkenes by Using Chiral Amine Auxiliaries under O2: Synthesis of Enantioenriched α‐Methylene‐γ‐Lactones through Chloropalladation of Alkynes

Herein, the first example of chloropalladation‐initiated asymmetric intermolecular carboesterification of alkenes with alkynes by using chiral amine auxiliaries is reported. The use of (1S,2S)‐N¹,N¹‐dimethylcyclohexane‐1,2‐diamine auxiliaries is essential for providing α‐methylene‐γ‐lactones products in moderate to high yields and excellent enantioselectivities at room temperature. Moreover, the chiral amine auxiliaries can be readily removed by hydrolysis during the reaction process to keep the absolute configuration. This oxygen‐ and water‐promoted asymmetric reaction opens a new window to study asymmetric processes in halopalladation reactions.