Lactam Ring Size Research Articles

Organocatalysts for the Asymmetric Neber reaction: Synthesis of Chiral 2‐(Tetrazol‐5‐yl)‐2H‐Azirines

Abstract‐ Several novel organocatalysts derived from β‐ and γ‐lactam‐fused thiazolidines and L‐phenylalanine‐based thiazolidines were efficiently synthetized. These organocatalysts, as well as other previously developed thiazolidine‐derived thioureas, were tested in the asymmetric one‐pot Neber reaction of β‐ketoxime‐1H‐tetrazoles towards chiral 2‐(tetrazol‐5‐yl)‐2H‐azirines. The results obtained when using thioureas only differing in the lactam ring size demonstrate that the presence of the 6β‐lactam ring in the catalysts is a requirement to achieve high enantioselectivity in the studied transformation. The new 6β‐aminopenicillanic acid‐derived thiourea afforded the R enantiomer of 3‐phenyl‐2‐(tetrazol‐5‐yl)‐2H‐azirine with >99 % ee.

Protein synthesis with conformationally constrained cyclic dipeptides

We have synthesized several conformationally constrained dipeptide analogues as possible substrates for incorporation into proteins. These have included three cyclic dipeptides formed from Boc derivatives of 2,4-diaminobutyric acid, ornithine and lysine, having 5-, 6-, and 7-membered lactam rings, respectively. These dipeptides were used to activate a suppressor tRNA transcript, the latter of which had been prepared by in vitro transcription. Using modified E. coli ribosomes described previously, these activated suppressor tRNAs enabled the incorporation of the three cyclic dipeptides into dihydrofolate reductase (DHFR) at positions 18 and 49. The suppression yields increased with increasing lactam ring size and were found to proceed in suppression yields ranging from 3.4 to 8.9% at two different protein sites for the 5-, 6- and 7-membered lactam dipeptides. The greater facility of incorporation of the 7-membered lactam prompted us to prepare two 7-membered cyclic acylhydrazides (4 and 5) by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)-mediated cyclization of amino acids having selectively protected hydrazine functional groups in their side chains. In common with the lactam dipeptides, acylhydrazide dipeptides 4 and 5 could be used to activate the same suppressor tRNA transcript and to incorporate the cyclic dipeptides into DHFR. They were incorporated into the same two DHFR sites in suppression yields ranging from 8.3 to 11.2%.

Molecular insights into the kinetic hydrate inhibition performance of Poly(N-vinyl lactam) polymers

The inhibition mechanism and the inhibition performance of four typical kinetic hydrate inhibitors (KHIs), poly(N-vinyl pyrrolidone) (PVP), poly(N-vinyl piperidone) (PVPip), poly(N-vinyl caprolactam) (PVCap) and poly(N-vinyl azacyclooctanone) (PVAco), have been studied using first-principle calculations and simulations. The results show that the inhibitors can disturb the local water structure, but also can adsorb onto the open hydrate cage, exhibiting the features of both the perturbation-inhibition and the adsorption-inhibition. By analyzing the molecular reactivity, KHI-water interactions, and adsorption ability of KHIs, it is found that the inhibition performance of the inhibitor increases with the increase of the lactam ring size, that is, PVP < PVPip < PVCap < PVAco. This study would be helpful to understand the inhibitor working mechanism as well as to promote the inhibitor screening.

Synthesis, molecular and crystal structure, and stereochemical non-rigidity of (O→Ge)-Bischelate bis[1-(2-oxoperhydroazepinyl)methyl]bromogermanium iodide and triflate

Reactions of (O→Ge)-bischelate dibromogermane (L7CH2)2GeBr2 (4c) with trimethyliodosilane and trimethylsilyl triflate proceed with the substitution of only one bromine atom and yield (O→Ge)-bischelate monobromogermanes (L7CH2)2Ge(Br)X (8c, X = I; 9c, X = OTf; LnCH2 = lactamomethyl C,O-chelate ligand; n = lactam ring size). According to X-ray crystal analysis data, triflate 9c is characterized by nearly ionic structure with the monodentate ligand and anion in trans-positions. The configuration of the germanium atom in the complex is intermediate between trigonal bipyramidal and square pyramidal. Quantum chemical calculations show the absence of additional coordinate bonding between the germanium atom and anion.Dynamic 1H NMR spectroscopy (1H DNMR) was used to study the stereochemical non-rigidity of monobromides 8c and 9c. Activation parameters for the inversion of the germanium atom configuration were calculated in various solvents. Based on the 1H DNMR data and quantum chemistry calculations, possible mechanisms of permutational isomerization are discussed.

Stimuli-Responsive Poly( N-Vinyllactams) with Glycidyl Side Groups: Synthesis, Characterization, and Conjugation with Enzymes.

Herein we report the synthesis of new reactive stimuli-responsive polymers by RAFT copolymerization of glycidyl methacrylate and three cyclic N-vinyllactam derivatives. The copolymerization process was thoroughly investigated and the influence of the steric hindrance originating from the monomer structure of cyclic N-vinyllactams on the polymerization process and the properties of obtained copolymers were studied. A series of water-soluble copolymers with variable chemical composition, controlled molecular weight and narrow dispersity ( Đ) were synthesized and their properties are systematically investigated. Experimentally determined cloud points for different copolymers in aqueous solutions indicate shift of lower critical solution temperature (LCST) to lower values with the increase of GMA content in copolymers and increase of the lactam ring size. The obtained reactive stimuli-responsive copolymers can be efficiently used for encapsulation of cellulase in water-in-oil emulsions forming biohybrid nanogels. The enzymes entrapped in nanogels demonstrated significantly improved resistance against harsh store conditions, chaotropic agents, and organic solvents.

Cleavages in stable tetrahedral intermediates' bonds and the role of water

AbstractUsing two‐dimensional energy diagrams, results on the formation and cleavage of detectable tetrahedral intermediates are used to predict the position of transition states involved in the cleavages of unstable and stable tetrahedral intermediates (STI). A late transition state (anti‐Hammond) for the former and synchronous cleavage for the latter are predicted and supported with experimental results. For instance, in the case of STI, intrinsic leaving abilities in the order CO &gt; CNHCO ≫ CNH were experimentally observed, confirming the departure of these groups without full heteroatom protonation. The STI designed herein mimics serine proteases enzymes due to the thermoneutral relationship between the enzyme substrate (ES) and enzyme‐acyl tetrahedral intermediate (EATI) analogs. In the STI models, a dramatic change in pKa is observed when changing the lactam ring size due to the strain in the 3‐fused‐ring system of the STI‐H2O complex formed and exo‐anomeric effect. A plot of ΔSo (STI formation) versus pKa provides evidence for the STI–water interaction. Since only one water molecule is required to produce the effect it is also detected when using ‘pure’ CDCl3 as the solvent and therefore may also play a role in the active sites of serine proteases. Copyright © 2010 John Wiley &amp; Sons, Ltd.

Parallel synthesis and spectroscopic analysis of a collection of heterocycles based on the diazabenz[ e]aceanthrylene core structure

A practical strategy for the synthesis of diazabenz[ e]aceanthrylene-based heterocycles is reported. The key step in this approach is a microwave-assisted condensation and cyclisation reaction between an anthranilic acid derivative and a 2′-carbomethoxy substituted N-aryl lactam. The scope of the reaction has been explored as a function of both the nature and position of substituents in both components and variations in lactam ring size. Interesting structural and spectroscopic variations observed across the compound collection are described and explored using NMR, X-ray crystallography and computational techniques.

A Samarium(II)-Mediated, Stereoselective Cyclization for the Synthesis of Azaspirocycles

Unsaturated keto-lactams undergo sequential conjugate reduction-aldol cyclization on treatment with SmI 2 to give syn-spirocyclic pyrrolidinones and piperidinones containing vicinal, fully substituted stereocenters with complete diastereocontrol. The substituent on nitrogen and the lactam ring size have a marked impact on the efficiency of the spirocyclization.

Serine Protease Mechanism-Based Mimics. Direct Evidence for a Transition State Bridge Proton in Stable Potentials

We have synthesized 1-(2-hydroxyacetyl)piperidine-2-one (2) and 1-(2-hydroxyacetyl)azepan-2-one (3). Equilibrium (K(f)) between the free alcohol (open form) and the tetrahedral intermediate (cyclol) is readily established, and both forms are observed in the D(2)O (1)H NMR spectra of 2 and 3. Therefore, their interconversion can be considered as an almost thermoneutral non-identical one. Pseudo-first-order rate constants (k(obs)) were obtained by simulating the AB (1)H NMR system observed for the cyclol. By best fitting the experimental points of a k(obs) versus pD profile to the equation k(obs) = 0.5k(0r) + 0.5k(r) K(ac)/(K(ac) + [D(+)]) + 0.5k(f)K(ao)/(K(ao)+ [D(+)]), the parameters involved were obtained: rate constants of rupture and formation (k(0r) and k(0f) = K(f)k(0r)) catalyzed by water, rate constants of rupture (k(r)) and formation (k(f)) from the conjugated bases of the cyclol form and the open form, and their acidity equilibrium constants K(ac) and K(ao). The system studied mimics the serine alcohol attack on the peptide bond and its reverse reaction in serine protease enzymes. In fact, the reaction rates are similar or perhaps even faster than the ones obtained for enzymatic reactions. The results also show the participation of water molecules forming catalytic proton bridges in stable potentials with the two interconverted forms. The position change of the bridged proton is sensitive to lactam ring size, and it is manifested by considerable change in the pKa values of both cyclol and open forms. Other evidence such as kinetics, DeltaS degrees , DeltaS, and proton inventory experiments and semiempirical molecular calculations support this proposal.

Targeting integrins: Insights into structure and activity of cyclic RGD pentapeptide mimics containing azabicycloalkane amino acids

A small library of cyclic RGD pentapeptide mimics incorporating stereoisomeric 5,6- and 5,7-fused bicyclic lactams was synthesized. This library was found to contain high-affinity ligands for the αvβ3 integrin. The aim of this study was to investigate activity, selectivity, and structure of these ligands in order to identify new specific αv-integrin antagonists that could be evaluated as tumor angiogenesis inhibitors. In vitro screening, including receptor-binding assays to purified αvβ3, αvβ5, and α5β1 integrins, and platelet aggregation assay, revealed ST1646 as a potent, highly selective αvβ3/αvβ5 integrin antagonist. Structure determination of the cyclic RGD pentapeptide mimics performed by a combination of NMR spectroscopy, and molecular mechanics and dynamics calculations showed a strong dependence of the RGD cyclopeptide conformation on lactam ring size and stereochemistry. ST1646 revealed the highest ability within the library to adopt the proper RGD orientation required for binding to the αvβ3 integrin, as deduced from the recently solved crystal structure of the extracellular segment of integrin αvβ3 in complex with a cyclic pentapeptide ligand.

The effect of structure on hydrogen bonding: Hydrogen bonded lactam dimers in CCl4Electronic Supplementary Information available. See http://www.rsc.org/suppdata/cp/b1/b108587e/

We have used both solution IR and NMR spectroscopies to investigate the hydrogen bonding of lactam dimers in CCl4. A series of lactam rings, from four- to eight-membered were investigated. Equilibrium constants for the formation of the cyclic hydrogen bonded dimer were obtained as a function of temperature in order to examine the effect of lactam ring size upon the enthalpy and entropy changes upon complexation. The resulting thermodynamic values for complexation do not follow the same trend with ring size as the equilibrium constants. It is also found that entropy plays an important role in determining the relative stability of a complex for a given ring size.

Conformational Analysis of Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer Dipeptide Mimics

In an effort to design structural mimics of protein and peptide reverse-turns, the conformations of 5,5-, 6,5-, and 7,5-fused 1-aza-2-oxobicycloalkane amino acids have been evaluated. The conformational preferences of these proline-derived bicyclic lactams have been studied by Monte Carlo molecular mechanics searches, and the reverse-turn inducing properties of the calculated structures have been quantitatively assessed using various geometrical parameters. All of the four possible diastereoisomers arising from two of the three stereogenic centres [C3 and bridgehead carbon atom; Pro Cα is (S) in all compounds] have been considered for each bicyclic scaffold. These studies have revealed that the (3S)-Pro Cα(S) configuration is an effective turn-inducer, although the torsion angles of the backbone do not always mimic those of classical β-turns. A dependence of the turn-inducing ability on lactam ring size and bridgehead stereochemistry has also been found. Reverse-turn mimetic bicyclic lactams have been shown to exhibit a tendency to form an inverse γ-turn or a type II′ β-turn. Experimental 1H-NMR and FT-IR spectroscopic data of model compounds in chloroform solutions have complemented our computer modelling studies and have confirmed our conclusions.

Conformational Analysis of Azabicycloalkane Amino Acid Scaffolds as Reverse-Turn Inducer Dipeptide Mimics

In an effort to design structural mimics of protein and peptide reverse-turns, the conformations of 5,5-, 6,5-, and 7,5-fused 1-aza-2-oxobicycloalkane amino acids have been evaluated. The conformational preferences of these proline-derived bicyclic lactams have been studied by Monte Carlo molecular mechanics searches, and the reverse-turn inducing properties of the calculated structures have been quantitatively assessed using various geometrical parameters. All of the four possible diastereoisomers arising from two of the three stereogenic centres [C3 and bridgehead carbon atom; Pro Cα is (S) in all compounds] have been considered for each bicyclic scaffold. These studies have revealed that the (3S)-Pro Cα(S) configuration is an effective turn-inducer, although the torsion angles of the backbone do not always mimic those of classical β-turns. A dependence of the turn-inducing ability on lactam ring size and bridgehead stereochemistry has also been found. Reverse-turn mimetic bicyclic lactams have been shown to exhibit a tendency to form an inverse γ-turn or a type II′ β-turn. Experimental 1H-NMR and FT-IR spectroscopic data of model compounds in chloroform solutions have complemented our computer modelling studies and have confirmed our conclusions.

Effects of lactam ring size on the thermodynamics of hydrogen bonding in CCl4 solutions: experimental and ab initio studies

The thermodynamic properties of hydrogen bonding among lactams with ring sizes n=4, 5 and 6 were investigated using infrared spectroscopy of the fundamental N–H stretching frequencies of both the monomer and dimer species. The results are consistent with a predominantly monomer–dimer equilibrium with the dimer having C2 symmetry. The thermodynamic properties (in CCl4) for the four-, five- and six-membered lactam rings are Kd (at 25°C)=12.4(9), 24(6) and 25(3), ΔHd (kJ mol-1)=-30(2), -30(1) and -28(2) and ΔSd (J mol-1 K-1)=-79(4), -74(3) and -67(5), respectively (precisions in parentheses). The experimentally determined thermodynamic properties are compared with abinitio calculations (6–31G** basis set) which represent gas-phase results. The comparison of these two approaches yields a picture which is consistent with the notion that the primary effect of ring size is an entropy of solvation effect and not the enthalpy of hydrogen bonding between the monomer units.

Conformational analysis of cyclic analogues of the Saccharomyces cerevisiae alpha-factor pheromone.

Analogues of the alpha-factor mating pheromone (WHWLQLKPGQPMY) from Saccharomyces cerevisiae in which the side chains of residues 7 and 10 were joined by lactam bonds were studied by nmr and molecular modeling. These investigations were carried out to discern the effect of lactam ring size on conformation and to ascertain whether the side chain i to i + 3 cyclized tetramers [H. R. Marepalli et al. (1996) Journal of the American Chemical Society, Vol. 118, pp. 6531-6539] can be considered as conformation-constraining building blocks when introduced into a long peptide chain. Nuclear Overhauser effect constraints, temperature coefficients, and backbone torsional angles were derived from 1H-nmr spectra measured in DMSO-d6. Modeling studies using the above constraints indicate that the lactam regions of the tridecapeptides assume various combinations of type II beta-turns, gamma-turns, and gamma 1-turns, but never type I beta-turns. These investigations provide evidence that the tetrapeptide building blocks retain their preferred conformations in larger molecules and can be used to control the architecture of regions of such peptides.

Physical properties and shrinkage of epoxy resins cured with lactams

In order to reduce the shrinkage of epoxy resin during the curing process, lactam is incorporated into epoxy in a copolymerization reaction. In this study, various amounts of lactams and BF3-MEA were added to epoxy, and the volume shrinkage of polymerization was investigated. It was found that shrinkage decreases with the increase of the lactam content and with the lactam ring size as well. Infrared spectroscopic analysis, scanning electronic microscopic analysis, and mechanical tests were used to investigate the structure and properties of the copolymers. The results show that the incorporation of caprolactam leads to an increase in tensile strength and elongation, but the Izod impact strength is not improved.

Thiophene systems. 14. Synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxythieno[3,2-b]pyrans and related compounds as new potassium channel activators.

The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.

The thermodynamic interaction of N-methyllactams with cyclohexane and methanol

The study deals with the dependence of thermodynamic interaction of the N-methylamine group in N-methyllactams with the acid hydrogen atom of methanol on the size of the lactam ring. The heats of mixing of N-methyl-4-butanelactam, N-methyl-6-hexanelactam, N-methyl-7-heptanelactam and N-methyl-8-octanelactam with methanol and cyclohexane were measured, and the data thus obtained were treated in terms of Barker’s quasichemical theory. In a series of N-methyllactam-cyclohexane systems the mixing is endothermic, and the heats of mixing decrease with increasing size of the lactam ring. On the contrary, the mixing of N-methyllactams with methanol proceeds exothermically; first, the heats of mixing decrease depending on the lactam ring size, but for N-methyl-8-octanelactam they are very close to values obtained for N-methyl-4-butanelactam. However, with increasing ring size the energy of interaction between the N-methylamide group and the acid hydrogen atom of methanol increases. Such apparent discrepancy may be explained, in particular, by an opposite effect of the interaction between this group and the alkyl hydrogen atom.

ChemInform Abstract: Synthesis and Antihypertensive Activity of 4‐(Cyclic Amido)‐2H‐1‐benzopyrans.

AbstractHydroxybromination of the benzopyrans (I), followed by cyclization, gives the epoxides (III) which are substituted by pyrrolidone (IV), yielding the derivatives (V).

Ruthenium tetroxide oxidation of N-alkyllactams.

Ruthenium tetroxide (RuO4) oxidation of N-alkyllactams proceeded regioselectively depending on the size of lactam ring, except for the seven-membered ring. Four- and eight-membered N-methyl- and N-ethyllactams were oxidized at the exocyclic α-carbon adjacent to nitrogen to produce the N-acyllactams and NH-lactams, while five- and six-membered lactams underwent endocyclic oxidation to yield the cyclic imides. Oxidation of seven-membered lactams yielded a mixture of products arising from both exocyclic and endocyclic oxidations. These regioselectivities were confirmed in the oxidation of substrates having a tertiary carbon at the oxidation position.