Succinimide Derivatives Research Articles

Understanding the mechanism of the N-heterocyclic carbene-catalyzed ring-expansion of 4-formyl-β-lactams to succinimide derivatives

The mechanism of the N-heterocyclic carbene (NHC)-catalyzed ring-expansion of 4-formyl-β-lactams to succinimides has been studied using DFT methods at the B3LYP/6-31G ∗∗ level. The first step is the nucleophilic attack of NHC to the aldehyde to yield the zwitterionic intermediate, which by a proton-transfer process affords the Breslow intermediate. The lactam N–C breaking bond in this intermediate yields an enol-amidate, which by a keto–enol type equilibrium becomes the ketone form. The subsequent ring-closure achieved by the nucleophilic attack of the amidate to carbonyl carbon allows the formation of the five-membered ring. Finally, elimination of NHC affords the succinimide. Analysis of the nucleophilicity index correctly explains the behaviors of the NHCs and the Breslow intermediates in the umpolung reactivity of aldehydes.

Aqueous versus Neat Reaction Conditions: The Microwave-Assisted, Selective Conversion of a Fused Anhydride Ring with Amines in the Presence of a Keto Group

We describe the transformation of fused succinic anhydride derivatives of the bicyclo[2.2.2]oct-2-ene system with various amines under microwave-irradiation conditions. In aqueous suspensions, the reaction of an acetyl-containing derivative yielded chemoselectively succinimide derivatives with the acetyl group remaining unchanged. Conversely, the application of neat reaction conditions with a minor amount of a liquid additive (toluene) yielded succinimide derivatives with the acetyl moiety transformed into an imine group.

N-Heterocyclic Carbene Catalyzed Ring Expansion of 4-Formyl-β-lactams: Synthesis of Succinimide Derivatives

N-heterocyclic carbene (NHC) has been employed as an efficient catalyst for ring expansion of 4-formyl-beta-lactams, allowing the facile synthesis of succinimide derivatives. This organocatalytic process features readily availability of the catalyst, low catalyst loading, and mild reaction conditions.

The Thorpe-Ingold Effect in Cyclic Imides. Part III

- Reactivity of phenyllithium with a number of succinimide derivatives were studied. We have shown that the Thorpe-Ingold effect affected both the reaction products distribution and their structures. Regioselectivity of these reactions were rationalized. Structures were confirmed with NMR and crystallographic methods.

Thebaine Adducts with Maleimides. Synthesis and Transformations.

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Access to Tri‐ and Tetracyclic Structures by Thermally Promoted and High‐Pressure‐Promoted [4+2] Cycloadditions of 2‐, 3‐ or 4‐Vinyl‐Substituted Binuclear Heterocycles

AbstractA set of 3‐(2‐alkoxyvinyl)benzofurans, ‐furopyridines and‐indoles 5–8 have been tested in [4+2] cycloaddition reactions. The results indicate that they all behave as good dienes, even with only moderately activated dienophiles such as acrylates or MVK. The endo/exo selectivity observed in the adducts depends on the activation conditions: in general, thermal conditions tend to favour the exo isomers, while high pressures preferentially provide the endo isomers. Only the (E) isomers of these dienes proved reactive, the (Z) isomers generally being recovered unaltered. The [4.4.0] binuclear heterocycles such as the isochromene compound 13 and the isoquinolinones 14–16 tested here proved to be significantly less reactive. Finally, the resulting tricyclic adducts 19 were engaged in ene reactions with NPM. Additions involving solely the endo isomers of these adducts took place, stereoselectively affording the succinimide derivatives 29, although in low yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Organocatalytic Ring Expansion of β-Lactams to γ-Lactams through a Novel N1−C4 Bond Cleavage. Direct Synthesis of Enantiopure Succinimide Derivatives

Tetrabutylammonium cyanide (20 mol %) catalyzes ring expansion of 4-(arylimino)methylazetidin-2-ones 2 to 5-aryliminopyrrolidin-2-ones 3 through a novel N1-C4 bond cleavage of the beta-lactam nucleus. New, efficient one-pot protocols to enantiopure succinimide derivatives 3 and 4 from beta-lactam aldehydes 1 have also been developed. [reaction: see text]

Thebaine Adducts with Maleimides. Synthesis and Transformations

Diels-Alder reaction of thebaine with maleimides is structurally specific and yields [7,8,3′,4′ ]-succinimido-endo-ethenotetrahydrothebaines containing N′-alkyl, cycloalkyl, aralkyl or aryl substituents. N′-[1(S)-hydroxymethyl-2-methylpropyl]-succinimido-6,14-endo-ethenotetrahydrothebaine formed in reaction of S-valinol with (7α,8α)-anhydrido-6,14-endo-ethenotetrahydrothebaine. The reduction of the adducts by LiAlH4 afforded N′-substituted 7,8-pyrrolidino-endo-ethenotetrahydrothebaines. The reduction of fused succinimides by NaBH4 resulted in the corresponding 2′α-hydroxylactam derivatives. O-Demethylation of the tetrahydrothebaine pyrrolidine derivatives effected by BBr3 afforded compounds of the tetrahydrooripavine series. The O-demethylation of tetrahydrothebaine succinimide derivatives gave rise to the corresponding 6-demethyl-endo-ethenotetrahydrooripavines. Alkylation conditions were found for N′-(4-hydroxyphenethyl)-substituted tetrahydrothebaine succinimide derivatives.

NEPHROTOXICITY INDUCED BY C- AND N-ARYLSUCCINIMIDES

The succinimide ring is incorporated into hundreds of compounds that are widely used as agricultural, industrial, and pharmaceutical agents. Some succinimide derivatives that contain an aryl group on the ethylene bridge of the succinimide ring (C-arylsuccinimides) or on the nitrogen atom (N-arylsuccinimides) induce nephrotoxicity in humans and/or laboratory animals. Acute toxicity induced by this general class of compounds is typically characterized as polyuric renal failure, while chronic nephrotoxicity is seen as chronic interstitial nephritis. In this review, the structure–nephrotoxicity relationships, biotransformation, and mechanisms of nephrotoxicity for the C- and N-arylsuccinimides are examined.

Quantification of phosphoproteins with global internal standard technology

Global internal standard technology (GIST) is being developed for the quantification of all primary structure and post-translational variants of proteins in a proteome. This paper is directed at an analysis of phosphorylation, primarily of serine and threonine. Quantification was achieved by acylation of primary amino groups in peptide cleavage fragments of proteins with isotopically coded derivatizing agents. Peptides from controls were globally coded with an isotopically “light” form of the reagent while those from experimental samples were coded with a “heavy” form of the reagent. The two types coding reagents used in this work were N-hydroxyl succinimide derivatives of acetate and 4-trimethylammoniumbutyrate. Heavy isotope forms were produced by deuteration of methyl groups. Subsequent to coding and mixing, the two samples were passed through a Ga(III) immobilized metal affinity chromatography (IMAC) column and the selected peptide fraction was further resolved by reversed-phase chromatography (RPC) and analyzed by mass spectrometry (MS). Relative differences in phosphopeptide concentration between samples were derived from isotope ratio measurements of the peptide isoforms observed in mass spectra. The method was validated with model peptides.

Platinum(II)-based coordination compounds as nucleic acid labeling reagents: synthesis, reactivity, and applications in hybridization assays.

The synthesis, characterization, and molecular interactions of platinum(II) coordination compounds, which contain a distal nonradioactive reporter molecule, with mono- and polynucleotides are described. A [Pt(II)(en)(NH(2)(CH(2))(6)NH-tBoc)Cl](NO(3)) (en=ethylenediamine) entity has been coupled, after removal of the tBoc group, to a number of hapten and fluorophore molecules through succinimide derivatives. The influence of the various tethered reporter groups within these complexes on the reactivity towards guanosine 5'-monophosphate (5'-GMP), as a model for polynucleotide sequences, was investigated to shed light on the use of these reagents in hybridization assays. Reactivity turned out to be strongly dictated by the chemical nature of the distal reporter molecule present. At pH 7.0 the sequence of reactivity is cationic approximately aromatic (stacking) > neutral > anionic; there is approximately an order of magnitude difference between the fastest reacting complex (k=10.2 x 10(-2) M(-1) s(-1)) and the slowest reacting complex (k=0.93 x 10(-2) M(-1) s(-1)) under these conditions. Platination of an oligodeoxynucleotide (30-mer), dsDNA, or an RNA transcript, shows that a Pt/nucleotide ratio between 1:10 and 1:20 (established by using flameless atomic absorption spectroscopy) results in probes with excellent hybridization characteristics. In terms of applicability and detection limits these platinated nucleic acid probes perform equally well compared to conventionally generated nucleic acid probes, that is, through enzymatic incorporation of covalently labeled nucleotide triphosphates. Applications of these reagents to in situ hybridization assays and gene expression profiling on microarrays illustrate the potential of these monofunctional binding platinum triamine compounds.

N‐Acyl “Quat” Pyrrolidinone Auxiliary as a Chiral Amide Equivalent via Direct Aminolysis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Novel Method for Identifying PEGylation Sites of Protein Using Biotinylated PEG Derivatives

The identification of PEGylation sites is essential in the characterization of PEGylated therapeutic proteins. This report describes a simple and novel method of finding poly(ethylene glycol) (PEG) conjugation sites in PEGylated proteins by using a hetero-functional biotin-PEG-N-hydroxyl succinimide derivative. PEGylated lysozyme species having a biotin moiety at each PEG chain end were separated and digested by trypsin. Among the digested lysozyme fragments, biotin-terminated PEGylated peptide fragments were purified by a monomeric avidin immobilized column. Their mass was analyzed by matrix-assisted laser desorption ionization time of flight mass spectrometry, directly indicating that PEG was conjugated to lysine 33, 97, 116 residues. Reversed-phase high-pressure liquid chromatography results for the PEGylated peptide fragments exhibited that PEGylation occurred preferentially at lysine 33> lysine 97> lysine 116.

Modelling the hydrolysis of succinimide: formation of aspartate and reversible isomerization of aspartic acid via succinimide.

In the present study, we have modelled the nucleophilic attack of water and a hydroxyl anion on the carbonyl carbon of a succinimide derivative leading to aspartate and aspartic acid. Calculations have been carried out at the B3LYP/6-31 +G* level in a vacuum. The IEF-PCM methodology has been used to carry out single point calculations in solution. In neutral medium, hydrolysis is facilitated by the presence of a polar continuum, whereas in basic medium the polar environment hinders the hydrolysis of succinimide. The deltaH degrees and deltaS degrees values for the cyclization reactions of aspartic acid yielding succinimide are 29.2 kJ mol(-1) and 133.5 kJ mol(-1) K(-1) respectively in accordance with the experimental results on the isomerization of the Ac-Asp-Gly-NHMe dipeptide unit. In a neutral medium, the isoaspartate: aspartate is found to be 2.2:1 in a vacuum and 3.4:1 in solution, in line with the experimental findings based on the hydrolysis of a tetrapeptide (Ac-Gly-Asn-Gly-Gly-NHMe) and a hexapeptide (Val-Tyr-Pro-Asn-Gly-Ala) where this ratio was found to be 3.1:1.

Theoretical Study on the Alkaline and Neutral Hydrolysis of Succinimide Derivatives in Deamidation Reactions

The hydrolysis of a succinimide derivative in alkali and neutral media has been studied at the B3LYP/6-31+G* level. Stepwise and concerted mechanisms have been considered in a vacuum. Both mechanisms have been also studied in solution by means of integral equation formalism-polarizable continuum model with a single point calculation. In basic medium, the stepwise mechanism consists of a bond cleavage and a subsequent rotation of the hydroxyl group that require 8.6 and 3.0 kcal/mol, respectively. For the concerted hydrolysis in the same medium, the barrier is 9.8 kcal/mol. In neutral medium, the hydrolysis is facilitated by the presence of a polar continuum, whereas in basic medium, the polar environment hinders hydrolysis of succinimide.

Imide and isatin derivatives as γ-lactam mimics of ß-lactam antibiotics

Activated γ-lactams, which are derivatives of succinimide, phthalimide and isatin with suitable elements of molecular recognition, have been synthesised as mimics of the s-lactam antibiotics and their chemical and biological reactivity determined.

N-Acyl ‘Quat’ pyrrolidinone auxiliary as a chiral amide equivalent via direct aminolysis

A novel route to chiral amides through the efficient, non-racemising, cleavage of N-acyl side chains from a ‘Quat’ chiral auxiliary using N-centred nucleophiles is described. The synthetic utility of the procedure is then highlighted by the preparation of a range of succinamide and succinimide derivatives and through the synthesis of the natural product (S)-(+)-amphetamine via a stereospecific Hofman type degradation using a hypervalent iodine reagent.

The effect of polymer chain architecture on the adsorption properties of derivatised polyisobutylenes at the carbon/n-heptane interface

Adsorption isotherms for derivatised polyisobutylene (PIB) molecules from n-heptane onto activated carbon have been determined. Nine polyisobutylene samples were studied: three different molecular weight groups (1000, 2000 and 3000), with each molecular weight group having three different chain architectures, i.e. having one, two or three derivatised (azacarboxylate) terminal head groups. The adsorbed amounts of the various PIBs were found to be dependent not only on their structure, but also on their solubility in n-heptane. The difunctional PIB was found to adsorb the most strongly. The areas per molecule, particularly for the higher molecular weight samples, suggest that the PIBs adsorb at the surface in an aggregated form, resulting in multilayers at higher coverages. Furthermore, all the PIBs are highly solvated at the solid/solution interface. These two factors enable the polymer to confer good steric stabilisation effects on the carbon dispersions. Compared with previous studies of the adsorption of succinimide derivatives of PIBs onto carbon, the PIBs used in this work adsorb to a lesser extent, suggesting that the azo head group does not provide as effective an anchor to the particle surface as the corresponding succinimide.

Conformational Analysis of Peptides Containing Enantiomerically Pure α-Methylasparagine: Correspondence Between Computed and Solid State Structures

Asparagine has a high frequency of occurrence in β-turns. We have recently completed an asymmetric synthesis of α-methylasparagine suitably protected for incorporation into polypeptides, and report herein the synthesis and structure of dipeptide Ac-Ala-(Me)Asn-NHMe ( 1). The synthesis proceeds through the corresponding α-methylasparagine succinimide derivative. The three-dimensional structure of the dipeptide around the α,α-dialkylated α-amino acid is compared to that predicted for Ac-(Me)Asn-NHMe.

Effect of lysine residues on the deamidation reaction of asparagine side chains

The effect of lysine residues on the deamidation reaction of the asparagine side chain has been studied on the peptide and on its lysine-acetylated derivative in a wide range of pH values. The amino acid sequence of these peptides is similar to the local sequence flanking the labile Asn-67 in RNAse A. The experimental data show that Lys influences both the deamidation rate and the relative yield of the two reaction products, i.e., the aspartic acid and β-aspartic acid containing peptide. These effects are pH dependent and can be rationalized based on the mechanism previously proposed for the deamidation reaction via succinimide derivative. © 2000 John Wiley & Sons, Inc. Biopoly 53: 213–219, 2000