Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters with silyl nucleophiles

The Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters, which are easily prepared by the acetalization of β,γ-unsaturated α-keto esters, with silyl nucleophiles is presented. By employing trimethylsilyl enolate and allyltrimethylsilane as nucleophiles, the BF₃-promoted reactions of a series of β,γ-unsaturated α,α-dimethoxy esters bearing aromatic and aliphatic substituents proceeded at the γ-position in an SN2′ manner to furnish γ-substituted α,β-unsaturated α-methoxy esters in good yields with high regioselectivity. In contrast, the reaction using trimethylsilyl cyanide predominantly occurred at the α-position, and the reaction of silyl hydride resulted in a mixture of α- and γ-regioisomers in favor of the γ-substitution products.     

A solvent-dependent peptide spring unraveled by 2D-NMR

In this work, we introduce a 2D-NMR method to discriminate between the fully-extended and the 3₁₀-helical conformations for the C^α,α-diethylglycine homo-peptides in the solution phase. It is based on the observation of divergent cross-peak intensities in the NOESY spectra. In particular, any βCH₂(i-1)→NH(i) cross peak is more intense than the intraresidue βCH₂(i)→NH(i) cross peak when the peptide adopts the fully-extended conformation. In this 3D-structure a marked splitting of the chemical shifts of the two non-equivalent βCH₂ protons is also apparent. In contrast, an opposite trend of intensities of the same NOE cross-peaks indicates the occurrence of a 3₁₀-helical conformation. This 3D-structural shift is induced by a change in the nature of solvent.     

Amino acids and peptides—XIV : A simple and convenient method for preparation of α-substituted α-diazo esters

Treatment of 16 α-amino acid esters with isoamyl nitrite in the presence of a small amount of organic acid in chloroform or benzene, followed by chromatographic purification on alumina was found to afford the corresponding α-substituted-α-diazo esters (1) in fairly good yields.     

Enzymatic enantioselective reduction of α-ketoesters by a thermostable 7α-hydroxysteroid dehydrogenase from Bacteroides fragilis

A thermostable 7α-hydroxysteroid dehydrogenase (7-HSDH) from Bacteroides fragilis ATCC 25285 was cloned and over-expressed in E. coli, and its substrate specificity and stereoselectivity toward reduction of various ketones were examined. This alcohol dehydrogenase was active toward a series of aromatic and bulky aliphatic α-ketoesters. The substituents at the phenyl ring of aromatic α-ketoesters greatly affected the activity, but their effects on enantioselectivity were minimal. The synthetic application of this enzyme was then demonstrated through the preparation of a few α-hydroxy carboxylic acid esters of pharmaceutical interest.     

含柔性间隔链段的芳香共聚酯热致性液晶高分子的结构研究

本文用富里叶红外光谱方法研究了一系列柔性间隔链段长度不等的芳香共聚酯热致性液晶高分子。测定了它们的变温光谱和偏振性质。并将谱带的变温行为与液晶转变相关联。结果表明,芳香共聚酯热致性液晶中液晶基元之间的相互作用很强而柔性间隔链之间的相互作用很弱。柔性间隔链段主要是伸直的反式构象。从一些谱带的二向色性估算了体系的有序度参数以及取向角。分子链的取向程度随柔性间隔链段长度的增加而减小。     

α,α-Dialkylglycines obtained by solid phase Ugi reaction performed over isocyanide functionalized resins

The multicomponent Ugi reaction is a straightforward method that can be used for the synthesis of highly hindered C-tetrasubstituted amino acids by reacting an amine, a ketone or aldehyde, a carboxylic acid and an isocyanide. In the present work, the synthesis of several α,α-dialkylglycines (α,α-diethylglycine, Deg; α,α-dipropylglycine, Dpg; 1-amino-1-cyclohexanecarboxylic acid, Ac₆c) was achieved by solid phase Ugi reaction using resins functionalized with the isocyanide group. Since no resins with these features were available commercially, the functionalization of an aminomethylated resin started by the use of glycine (Gly), β-alanine (β-Ala) and γ-aminobutyric acid (GABA) as spacers. After spacer N-formylation, followed by dehydration, isocyanide functionalised resins were obtained. The resins were then used in solid phase Ugi reaction, using phenylacetic acid as the acid component, 4-methoxybenzylamine as the amine component and different ketones, to afford the desired N-acylated α,α-dialkylglycines in good overall yields (60–80%), after acidolytic cleavage from the resin, thus proving the feasibility of this approach.     

The gas-phase dipeptide analogue acetyl-phenylalanyl-amide: a model for the study of side chain/backbone interactions in proteins

The issue of the influence of the side chain/backbone interaction on the local conformational preferences of a phenylalanine residue in a peptide chain is addressed. A synergetic approach is used, which combines gas-phase UV spectroscopy as well as gas-phase IR/UV double-resonance experiments with DFT and post Hartree-Fock calculations. N-Acetyl-Phe-amide was chosen as a model system for which three different conformers were observed. The most stable conformer has been identified as an extended beta(L) conformation of the peptide backbone. It is stabilized by a weak but significant NH-pi interaction bridging the aromatic ring on the residue (i) with the NH group on residue (i+1), with the aromatic side chain being in an anti conformation. This stable conformation corresponds to the common NH(i+1)-aromatic(i) interaction encountered in proteins for the three aromatic residues (phenylalanine, tyrosine, and tryptophan), which illustrates the relevance of gas-phase investigations to structural biology issues. The two other less abundant conformers have been assigned to two gamma-folded backbone conformations that differ by the orientation of the side chain. In all cases, the IR data provided spectroscopic fingerprints of these interactions. Finally, the strong conformational dependence of the fluorescence yield found for N-acetyl-Phe-amide illustrates the role of the environment on the excited-state dynamics of these species, which is often exploited by biochemists to monitor protein structural changes from tryptophan lifetime measurements.     

Synchronous helicity control in zinc bilinone trimer

In order to develop an artificial signal transmission/amplification system triggered by chiral recognition, we synthesized a series of zinc bilinone (ZnBL) trimers bearing a tripodal spacer and investigated homohelicity induction by complexation with chiral α-amino esters. Controlling the length of the peripheral alkyl groups in ZnBL moieties led to preorganization of the trimer to homohelical conformers. In addition, complexation with chiral α-amino esters induced the formation of the chiral homohelical conformer in which three ZnBL moieties adopted the same helicity.     

Proline derivatives incorporating hydrophobic long-chain derived from natural and synthetic fatty acids

The α-hydrophobic long chain-α-amino esters are prepared by α-hydroxylation of a series of fatty acid esters [derived from oleic acid (OA), linoleic acid (LA), arachidonic acid (ARA) and docosahexaenoic acid (DHA)] followed by Mitsunobu reaction and hydrazinolysis of the phthalimide. These amino esters are mixed with aldehydes and electrophilic alkenes to give very good chemical yields and diastereoselectivities of prolinate derivatives incorporating a hydrophobic long chain at the α-position. This multicomponent 1,3-dipolar cycloaddition (1,3-DC) takes place at room temperature. The synthesis of the homologue hydrophobic chain of OA is performed by its oxidation to aldehyde/racemic N-tert-butylsulfinyl imine/Neff reaction. Final 1,3-DC with benzaldehyde and N-methylmaleimide affords homologue prolinate derivative in good yield.     

Raising the bar on-bead: Efficient on-resin synthesis of α-conotoxin LvIA

α4/7-Conotoxin LvIA is an isoform-selective inhibitor of the α3β2 nicotinic acetylcholine receptor. An efficient strategy for the synthesis of this toxin is critical to advancing its utility as a probe for receptor function and as a potential pharmaceutical lead target. On-resin methods for peptide synthesis offer potential synthetic advantages; however, strategies for on-resin formation of multiple disulfides have historically been low-yielding. Here, we harness the reactivity of the Allocam protecting group and employ a 3-amino acid spacer strategy to synthesize α4/7-conotoxin LvIA via three different on-resin strategies, each of which results in an isolated yield higher than previous fully on-resin approaches.     

Synthesis,thermal, and photocrosslinking studies of thermotropic liquid crystalline poly(benzylidene‐ether)esters containing α,β‐unsaturated ketone moiety in the main chain

A series of poly(benzylidene‐ether)esters containing a photoreactive benzylidene chromophore in the main chain were synthesized from 2,6‐bis(4‐hydroxy‐3‐methoxybenzylidene)cyclohexanone (BHMBCH) with various aliphatic and aromatic diacid chlorides by an interfacial polycondensation technique. The intrinsic viscosity of the synthesized homo and copolymers determined by Ubbelohde viscometer was found to be 0.12 to 0.17 dL/g. The molecular structure of the monomer and polymers was confirmed by FT‐IR, ¹H NMR, and ¹³C NMR spectral analyses. These polymers were studied for their thermal stability and photochemical properties. Thermal properties were evaluated by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). It was found that the polymers were stable up to 280 °C and start degrading thereafter. Increase in acid methylene spacer length decreased the thermal stability. The self‐extinguishing property of the synthesized polymers was studied by calculating the limiting oxygen index (LOI) value using a Van Krevelen's equation. The influence of the length of methylene spacer on phase transition was investigated using DSC and odd‐even effect has been observed. Hot‐stage optical polarizing microscopic (HOPM) study showed that most of the polymers exhibited birefringence and opalescence properties. The photolysis of liquid crystalline poly(benzylidene‐ether)esters revealed that α,β‐unsaturated ketone moiety in the main chain dimerises through 2π + 2π cycloaddition reaction to form a cyclobutane derivative and leads to crosslinking. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

On the conformational preferences of nylons-n: Analysis of the intramolecular interactions in even nylons-n

The relative stability between the fully-extended and quasi-extended conformations characteristic of the α and β forms of nylons, respectively, has been investigated for both even and odd nylons-n using ab initio quantum mechanical calculations. For nylon-2 the fully-extended is the most favored conformation and its stability clearly increases with the number of residues. On the other hand, for nylons-4 and -6 the quasi-extended conformation is slightly favored with respect to the fully-extended one, although the relative energy between the two conformations decreases with the number of residues. Thus, the fully-extended conformation is predicted as the most stable conformation in compounds with a larger number of residues for nylons-4 and -6. On the other hand, the quasi-extended conformation is the most favored for odd nylons-n and even nylons-n with n > 6. The results have been explained in terms of the intramolecular electrostatic interactions that appear in nylons-2, -4 and -6 between the N H and CO groups of a residue.     

Electroreductive acylation of aromatic imines with acylimidazoles

The intermolecular reductive coupling of aromatic imines with acylimidazoles was effected by electroreduction in the presence of chlorotrimethylsilane and gave α-amino-α-aryl ketones. This method was also effective for the synthesis of α-amino-α-aryl esters using methoxycarbonylimidazole as an electrophile.     

a,a,a,b-ZnT(o-BocThr)APP对咪唑衍生物和氨基酸酯的分子识别研究

Molecular Recognition of α,α,α,β-ZnT（o-BocThr）APP （1） toward a series of imidazole derivatives and amino acid esters was investigated. Association constants were determined in chloroform by means of UV-Vis titration method. The association constants of 1 with imidazole derivatives are larger than those of 1 with amino acid esters. 1H NMR spectra were investigated to describe the binding mode of the recognition system, showing that all the protons of the guests were shifted to upfield. The circular dichroism spectra of 1-L-/D-ValOMe showed a split cotton effect in Soret region, while those of 1-L-/D-PheOMe showed no split cotton effect. Molecular modeling was performed to understand chiral recognition on a molecular level. Quantum chemical calculation was carried out based on the stable conformations of these recognition systems, which gave a reasonable explanation for the behavior of molecular recognition. The results indicated that the conformation of 1-D-ValOMe was more stable than that of 1-L-ValOMe.     

Stapled Peptides as HIF-1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency

Protein–protein interactions (PPIs) control virtually all cellular processes and have thus emerged as potential targets for development of molecular therapeutics. Peptide-based inhibitors of PPIs are attractive given that they offer recognition potency and selectivity features that are ideal for function, yet, they do not predominantly populate the bioactive conformation, frequently suffer from poor cellular uptake and are easily degraded, for example, by proteases. The constraint of peptides in a bioactive conformation has emerged as a promising strategy to mitigate against these liabilities. In this work, using peptides derived from hypoxia-inducible factor 1 (HIF-1α) together with dibromomaleimide stapling, we identify constrained peptide inhibitors of the HIF-1α/p300 interaction that are more potent than their unconstrained sequences. Contrary to expectation, the increased potency does not correlate with an increased population of an α-helical conformation in the unbound state as demonstrated by experimental circular dichroism analysis. Rather, the ability of the peptide to adopt a bioactive α-helical conformation in the p300 bound state is better supported in the constrained variant as demonstrated by molecular dynamics simulations and circular dichroism difference spectra.     

On the aggregation of bilirubins using vapor pressure osmometry

Bilirubin and its analogs are carboxylic acids that engage in intramolecular hydrogen bonding and are thus thought to be monomelic in solution, although the evidence for the molecularity in solution is indirect. Contrastingly, the dimethyl esters favor intermolecular hydrogen bonding and are thought to be dimeric, yet they, like the bilirubin (acids), exhibit essentially no concentration dependence of their NH nmr chemical shifts upon dilution from 10^?2 to 10^?5 (or even 10^?6) M in chloroform‐d. Vapor phase osmometry (vpo) studies of chloroform solutions of eight bilirubins and their dimethyl esters clearly indicate that the former are monomelic, while the latter are dimeric — except when a β‐methyl group (but not an α*‐methyl) is present in each methyl propionate chain. Bilirubin mono‐esters might be monomelic or dimeric in solution. Using vpo to study some seven mono‐esters or mono acids, we found that the pigments were monomelic in chloroform.     

Supramolecular PEG-co-oligo(p-benzamide)s prepared on a peptide synthesizer

An automated synthesis protocol has been developed for the preparation of oligo(p-benzamide)s on solid support using a commercial peptide synthesizer employing a variation of standard Fmoc chemistry. Bis(trichloromethyl carbonate) in NMP was used to activate the aromatic carboxylic acids for acylation of secondary aromatic amines on solid support. N-Protected hepta(p-benzamide) was automatically prepared on solid support and manually converted to a solid supported block co-oligomer by attaching a poly(ethylene glycol) chain. Cleavage from the support could be achieved with minimal loss of the p-methoxybenzyl N-protective group. While the N-protected block co-oligomer was molecularly dissolved in nonpolar organic solvents, the N-deprotected block co-oligomer adopted a rod-coil conformation and showed strong aggregation as evidenced by gel permeation chromatography and transmission electron microscopy. Rigid rodlike aggregates could be observed in chloroform, toluene, as well as water.     

Reversed-phase HPLC of peptides: Assessing column and solvent selectivity on standard, polar-embedded and polar endcapped columns

We desired to evaluate the chromatographic selectivity for peptides of silica-based RP high-performance liquid chromatography stationary phases with various modifications (polar embedding and polar endcapping on C(18) columns; ether-linked phenyl column with polar endcapping) compared with n-alkyl (C(18), C(8)) and aromatic phenylhexyl columns. Thus, we have designed and synthesized two series of synthetic peptide standards with the sequence Gly-Gly-Leu-Gly-Gly-Ala-Leu-Gly-X-Leu-Lys-Lys-amide, where the N-terminal either contains a free α-amino group (AmC series) or is N(α)-acetylated (AcC series) and where position X is substituted by Gly, Ala, Val, Ile, Phe or Tyr. These represent series of peptides with single substitutions of n-alkyl (Gly相似文献   

A new method for the determination of the absolute stereochemistry of aromatic and heteroaromatic alkanols using Mosher's esters

A list of the ¹H NMR chemical shifts of the methoxy group of α-methoxy-α-(trifluoromethyl)phenylacetic acid (Mosher's) esters of α- and β-(hetero)aromatic secondary alkanols has been compiled. Methoxy groups which are orientated syn to the (hetero)aromatic group in Mosher's conformational model have lower chemical shift values than those in the anti-orientation.     

Effect of poly(ethylene glycol) (PEG) spacers on the conformational properties of small peptides: a molecular dynamics study

Poly(ethylene glycol) (PEG) is used as an inert spacer in a wide range of biotechnological applications such as to display peptides and proteins on surfaces for diagnostic purposes. In such applications it is critical that the peptide is accessible to solvent and that the PEG does not affect the conformational properties of the peptide to which it is attached. Using molecular dynamics (MD) simulation techniques, we have investigated the influence of a commonly used PEG spacer on the conformation properties of a series of five peptides with differing physical-chemical properties (YGSLPQ, VFVVFV, GSGGSG, EEGEEG, and KKGKKG). The conformational properties of the peptides were compared (a) free in solution, (b) attached to a PEG-11 spacer in solution, and (c) constrained to a two-dimensional lattice via a (PEG-11)(3) spacer, mimicking a peptide displayed on a surface as used in microarray techniques. The simulations suggest that the PEG spacer has little effect on the conformational properties of small neutral peptides but has a significant effect on the conformational properties of small highly charged peptides. When constrained to a two-dimensional surface at peptide densities similar to those used experimentally, it was found that the peptides, in particular the polar and nonpolar peptides, aggregated strongly. The peptides also partitioned into the PEG layer. Potentially, this means that at high packing densities only a small fraction of the peptide attached to the surface would in fact be accessible to a potential interaction partner.