Long‐Range Chemical Ligation from N→N Acyl Migrations in Tryptophan Peptides via Cyclic Transition States of 10‐ to 18‐Members

Chemical ligations to form native peptides from N→N acyl migrations in Trp‐containing peptides via 10‐ to 18‐membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. N→N acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the N?C bond distance in N‐acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.     

The antioxidant methyl 3‐(3,5‐di‐tert‐butyl‐4‐hydroxyphenyl)propionate

The title compound, C₁₈H₂₈O₃, was prepared by the reaction of 2,6‐di‐tert‐butylphenol with methyl acrylate under basic conditions using dimethyl sulfoxide as the promoter. The structure of this antioxidant indicates significant strain between the ortho tert‐butyl substituents and the phenolic OH group. In spite of the steric crowding of the OH group, it participates in intermolecular hydrogen bonding with the ester carbonyl O atom.     

Acyl guanidine functional poly(2‐oxazoline)s as reactive intermediates and stimuli‐responsive materials

The many postpolymerization modification opportunities of biocompatible poly(2‐alkyl/aryl‐2‐oxazoline)s (PAOx), such as thiol–ene/thiol–yne, azide–alkyne cycloadditions, amidation, and transesterification, are one of the most appealing features of this polymer class for its popularity in biomedicine. Inspired by recent reports on guanidine‐catalyzed transesterification and amidation reactions of methyl ester substrates, we explored the use of guanidines as a reactant for the modification of methyl ester functional PAOx, to obtain the respective acyl guanidines. The obtained acyl guanidines functional polymers display reactivity toward α‐haloketones, yielding imidazole functional PAOx. The obtained polymer structures are protonated in a broad pH range, and the acyl guanidine moiety is demonstrated to be a cleavable linker under basic conditions. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2616–2624     

Clionasterol Glucoside and Acylated Clionasterol Glucosides from Oplismenus burmannii

A new clionasterol glucoside, clionasterol‐[(1'→3α)‐O‐β‐D]‐glucopyranoside ( 1 ), a new acylated clionasterol glucoside, clionasterol‐[6'‐O‐acyl‐(1'→3β)‐O‐b‐D]‐glucopyranoside ( 2 ) and clionasterol ( 3 ) were isolated from the aerial parts of Oplismenus burmannii. The nature and length of fatty acid acyl chains in 2 was identified by alkaline methanolysis of compound 2 . The aglycone fraction on GC‐MS analysis showed three peaks in GC at t_R 49.86 (82.1%), 51.13 (13.3%) and 56.53 (4.6%) min, which were characterized as arachidic acid methyl ester ( a ) oleic acid methyl ester ( b ) and 12‐methyltetradecanoic acid methyl ester ( c ) respectively. Thus 2 was characterized as a mixture of three new compounds, clionasterol‐[6'‐O‐eicosanoyl‐(1'→3β)‐O‐β‐D]‐glucopyranoside ( 2a ), clionasterol‐[6'‐O‐(8Z)‐octa‐deca‐9‐enoyl‐(1'→3β)‐O‐β‐D]‐glucopyranoside ( 2b ) and clionasterol‐[6'‐O‐(12‐methyltetradecanoyl)‐(1'→3β)‐O‐β‐D]‐glucopyranoside ( 2c ).     

Total Synthesis of the Alkaloid (±)‐Aspidophytine Based on Carbonyl Ylide Cycloaddition Chemistry

The Rh^II‐catalyzed cycloaddition cascade of an indolyl‐substituted α‐diazo imide was used for the total synthesis of the complex pentacyclic alkaloid (±)‐aspidophytine. Treatment of the resulting dipolar cycloadduct with BF₃?OEt₂ induces a domino fragmentation cascade. The reaction proceeds by an initial cleavage of the oxabicyclic ring and formation of a transient N‐acyl iminium ion which reacts further with the adjacent tert‐butyl ester and sets the required lactone ring present in aspidophytine. A three‐step sequence was then used to remove both the ester and OH groups. Subsequent functional group manipulations allowed for the high‐yielding conversion to (±)‐aspidophytine.     

Asymmetric Synthesis of Hydrocarbazoles Catalyzed by an Octahedral Chiral‐at‐Rhodium Lewis Acid

A bis‐cyclometalated chiral‐at‐metal rhodium complex catalyzes the Diels–Alder reaction between N‐Boc‐protected 3‐vinylindoles (Boc=tert‐butyloxycarbonyl) and β‐carboxylic ester‐substituted α,β‐unsaturated 2‐acyl imidazoles with good‐to‐excellent regioselectivity (up to 99:1) and excellent diastereoselectivity (>50:1 d.r.) as well as enantioselectivity (92–99 % ee) under optimized conditions. The rhodium catalyst serves as a chiral Lewis acid to activate the 2‐acyl imidazole dienophile by two‐point binding and overrules the preferred regioselectivity of the uncatalyzed reaction.     

Study on the Selectivity of Benzoylation of Metal Chelates of Sucrose1

Abstract

A study of the selectivity of metal chelate-directed benzoylation of sucrose dianion, relative to unchelated sucrose anion, was conducted as part of a study on new synthetic approaches to the high-potency sweetener sucralose. Ionic complexes of sucrose with various metal ions were prepared in DMF and the resulting complexes reacted at low temperature with benzoic anhydride. Cobalt and manganese salts directed esterification mostly to the 3′-OH on the fructosyl portion. Unchelated sucrose anion and other metals favored esterification at the 2-OH of the glucosyl portion. Migration of the benzoate ester along the glucose portion was observed in the direction O-2 to O-6 at moderate temperature, but at higher temperature transannular migration was observed from the glucose to the fructose ring. Reaction mixtures were analyzed by HPLC and monobenzoates identified by retention times relative to standards. Six of eight possible monobenzoates of sucrose were isolated from mixtures and identified by their ¹H NMR spectra.     

Decomposition of 2‐Mercaptoethyl O‐Ester: SN2 Displacement or Acyl Transfer? A Theoretical Study

The mechanism for the decomposition of 2‐mercaptoethyl O‐ester was theoretically investigated. The mechanism that 2‐mercaptoethyl O‐ester undergoes an S_N2 displacement of the O atom by the S atom on α‐C is much favored over the mechanism of N‐to‐S acyl transfer. The length of the alcohol moiety has large effects on the decomposition efficiency of thiol‐substituted alkyl O‐esters. The reactivities of these esters are controlled by distortion energies. Only 2‐mercaptoethyl O‐ester can undergo the decomposition at room temperature due to the low distortion energy to achieve the transition state geometry. If the thiol group of 2‐mercaptoethyl O‐ester is replaced by an amino group, the N‐to‐N acyl transfer mechanism is more favored than the S_N2 displacement mechanism.     

New Monofunctionalized Fluorescein Derivatives for the Efficient High‐Throughput Screening of Lipases and Esterases in Aqueous Media

Monoalkylation or acylation of fluorescein ( 1 ) with various acyloxymethyl or acyl halides afforded, respectively, a series of ether‐ ( 2 ) and ester‐functionalized ( 3 ) fluorogenic probes. The highly reactive and water‐soluble substrates release fluorescein ( 1 ) upon reaction with lipases and esterases within seconds or minutes, both under fully aqueous conditions or in the presence of DMSO (20%) as a co‐solvent. The most‐reactive substrates in the two series were the octanoic acid derivatives 2f (= 2‐{6‐[(octanoyloxy)methoxy]‐3‐oxo‐3H‐xanthen‐9‐yl}benzoic acid) and 3a (= 2‐[6‐(octanoyloxy)‐3‐oxo‐3H‐xanthen‐9‐yl]benzoic acid). Esterases were found to generally react faster under aqueous conditions, while lipases were more reactive in the presence of DMSO as a co‐solvent.     

Acylglycerols (=Glycerides) from the Glandular Trichome Exudate on the Leaves of Paulownia tomentosa

Chemical investigations of the glandular trichome exudates on the leaves of Paulownia tomentosa (Scrophulariaceae) led to the identification of the thirty acylglycerols (=glycerides) 1 – 30 , including five known ones ( 2, 3, 6, 9 , and 15 ) (Fig. 1). Spectroscopic analysis combined with GC/MS studies of the glycerides and the liberated fatty acids, in the form of trimethylsilyl ether derivatives and trimethylsilylated methyl esters, respectively, established that the constituents belonged to 1,3‐di‐O‐acetyl‐2‐O‐(fatty acyl)glycerols, 1‐O‐acetyl‐2‐O‐(fatty acyl)‐sn‐glycerols, and 2‐O‐(fatty acyl)glycerols, wherein the fatty acyl moiety was either an eicosanoyl or an octadecanoyl group bearing OH and/or AcO groups at the 3‐, 3,6‐, 3,7‐, 3,8‐, or 3,9‐positions. The 1‐O‐acetyl‐2‐O‐[(3R,6S)‐3‐(acetyloxy)‐6‐hydroxyeicosanoyl]‐sn‐glycerol ( 12 ; 20% of the total glycerides), 2‐O‐[(3R,8R)‐3,8‐bis(acetyloxy)eicosanoyl]glycerol ( 17 ; 14%), 2‐O‐[(3R,9R)‐3,9‐bis(acetyloxy)eicosanoyl]glycerol ( 18 ; 12%), and 2‐O‐[(3R)‐3‐(acetyloxy)eicosanoyl]glycerol ( 10 ; 12%) were relatively abundant constituents. The configurations of the stereogenic centers of the fatty acyl moieties were determined by ¹H‐NMR analysis of the monoesters obtained from (R)‐ and (S)‐2‐(naphthalen‐2‐yl)‐2‐methoxyacetic acid ((R)‐ and (S)‐2NMA? OH and the hydroxy‐substituted fatty acid methyl esters (Fig. 2). The configuration at C(2) of the glycerol moiety of the 1‐O‐acetyl‐2‐O‐(fatty acyl)glycerols was determined to be (2S) by chemical conversion of, e.g., G‐2 (= 2 / 3 1 : 10) to (+)‐3‐O‐[tert‐butyl)diphenylsilyl]‐sn glycerol of known absolute configuration.     

In situ proton NMR study of acetyl and formyl group migration in mono‐O‐acyl D‐glucose

Acetyl and formyl group migration, mutarotation, and hydrolysis of mono‐O‐acylated glucose are studied by in situ 1D and 2D ¹H NMR spectroscopy. α‐D ‐Glucosyl‐1‐acetate and α‐D ‐glucosyl‐1‐formate serve as sole starting materials. They are generated in situ by configuration retaining glucosyltransfer from α‐D ‐glucosyl‐1‐phosphate to formate and acetate, which is catalyzed by the Glu‐237 → Gln mutant of Leuconostoc mesenteroides sucrose phosphorylase. Temporary accumulated regio‐isomeric mono‐O‐acyl D ‐glucoses are identified, characterized, and quantified directly from the reaction mixture. Time courses of the transformations give insight into pH dependence of acyl group migration and mutarotation as well as into the stability of various regioisomers. Copyright © 2009 John Wiley & Sons, Ltd.     

Regioselective Acylation of Ginsenosides by Novozyme 435 to Generate Molecular Diversity

Ginsenosides are major bioactive constituents of ginseng (Panax spp.; Araliaceae), a traditional Chinese medicinal herb. In order to increase the molecular diversity and broaden the potential usage of ginsenosides, ginsenosides Rd ( 1 ), Rg3 ( 2 ), (20R)‐Rg3 ( 3 ), Rh2 ( 4 ), Re ( 5 ), Rh1 ( 8 ), Rg2 ( 9 ), gypenoside XVII ( 6 ), and pseudoginsenoside F11 ( 7 ) were regioselectively acylated with vinyl acetate, catalyzed by Novozyme 435 (lipase B from Candida antarctica), in organic solvents to afford different mono‐acetyl ginsenosides. Ginsenoside Rd ( 1 ) was also acylated with vinyl decanoate or vinyl cinnamate to generate 1b and 1c , respectively. Acylation of glucosylated ginsenosides ( 1 – 4, 6, 8 ) occurred at the primary 6‐OH function of the terminal glucose (Glc) moiety of the sugar at C(3) or C(20) of the dammarane‐type aglycone. In contrast, ginsenosides 5, 7 , and 9 , containing mixed sugar moieties, resulted in acylation of both the rhamnose (Rha) and the glucose (Glc) moieties. In the case of ginsenoside Re ( 5 ) and pseudoginsenoside F11 ( 7 ), acylation at the secondary 4‐OH function of the terminal Rha moiety, attached at C(3) of the aglycone, is preferred. The structures of all acylated products were determined by extensive MALDI‐TOF‐MS and NMR analyses.     

Comparing Cyclophellitol N‐Alkyl and N‐Acyl Cyclophellitol Aziridines as Activity‐Based Glycosidase Probes

The synthesis and evaluation as activity‐based probes (ABPs) of three configurationally distinct, fluorescent N‐alkyl cyclophellitol aziridine isosteres for profiling GH1 β‐glucosidase (GBA), GH27 α‐galactosidase (GLA) and GH29 α‐fucosidase (FUCA) is described. In comparison with the corresponding acyl aziridine ABPs reported previously, the alkyl aziridine ABPs are synthesized easily and are more stable in mild acidic and basic media, and are thus easier to handle. The β‐glucose‐configured alkyl aziridine ABP proves equally effective in labeling GBA as its N‐acyl counterpart, whereas the N‐acyl aziridines targeting GLA and FUCA outperform their N‐alkyl counterparts. Alkyl aziridines can therefore be an attractive alternative in retaining glycosidase ABP design, but in targeting a new retaining glycosidase both N‐alkyl and N‐acyl aziridines are best considered at the onset of a new study.     

Benchmarking of DFT functionals for the kinetics and mechanisms of atmospheric addition reactions of OH radicals with phenyl and substituted phenyl‐based organic pollutants

^•OH addition reactions play a pivotal role in the atmospheric transformation of a number of phenyl and substituted phenyl‐based persistent and toxic organic pollutants. Here, we screened appropriate DFT functionals to predict reaction mechanisms and rate constants (k_OH) of the ^•OH additions by taking benzene and substituted benzenes (C₆H₅F, C₆H₅Cl, C₆H₅Br, C₆H₅CH₃, C₆H₅OH) as model compounds. By comparing the k_OH values calculated with DFT methods to experimental values, we found that the ωB97 functional is the best among the 18 functionals considered (using the basis sets 6‐31 + G(d,p) for optimizations and 6‐311++G(3df,2pd) for single point energy calculations) in the temperature range of 230‐330 K. In addition, we found that some other functionals performed well in specific conditions, e.g., BMKD3 is good for benzene, halogenated benzenes and C₆H₅CH₃, and CAM‐B3LYP is good for the reaction of C₆H₅OH at room temperature. Based on the diversity of the electronic structures of the selected model compounds and the frequent occurrence of certain substituents ( CH₃,  OH,  F,  Cl, and  Br) in the target compounds, the functionals recommended here can be used for future study of the reaction mechanisms and k_OH values for ^•OH addition to phenyl and substituted phenyl‐based persistent and toxic organic pollutants.     

A Comparison of Glucose‐ and Glucosamine‐Related Inhibitors: Probing the Interaction of the 2‐Hydroxy Group with Retaining β‐Glucosidases

The inhibition of the β‐glucosidases from sweet almonds and Caldocellum saccharolyticum at varying pH values by the glucosamine‐related inhibitors 1 – 7 has been compared to the inhibition by the known glucose analogues 8 – 14 . The amino derivatives 3 , 4 , 6 , and 7 were prepared in one step from the known 15 – 18 (Scheme 1), and the amino‐1,2,3‐triazole 5 by a variant of the synthesis leading to the glucose analogue 12 (Scheme 2). The key step for the preparation of the aminoimidazole 1 and of the amino‐1,2,4‐triazole 2 is the regioselective cleavage of the benzyloxy group at C(2) of the gluconolactam 35 and the mannonolactam 57 , respectively, by BCl₃ and Bu₄NBr (Schemes 3 and 4, resp.). The pH optimum for the inhibition by the amines is lower than their pK_HA values, evidencing that they are bound as ammonium salts and that H‐bonding between C(2)−NH and the cat. base B⁻ contributes more strongly to binding than any possible H‐bond to the NH₂−C(2) group. The influence of the ammonium group on the inhibitory strength correlates with the basicity of the `glycosidic heteroatom'. The strongest increase of the inhibitory strength is observed for the amines lacking a `glycosidic heteroatom' (ΔΔG(OH→NH)=−1.5 to −2.9 kcal/mol). The increase is less pronounced for the amino derivatives 3 – 4 , which possess a weakly basic `glycosidic heteroatom' (ΔΔG(OH→NH)=−0.6 to −1.1 kcal/mol); the amino compounds 1 and 2 , which possess a strongly basic `glycosidic heteroatom', are weaker inhibitors than the corresponding hydroxy compounds, as expressed by ΔΔG(OH→NH) between +4.3 and +4.7 kcal/mol for the amino‐imidazole 1 , and between +2.3 and 2.8 kcal/mol for the amino‐1,2,4‐triazole 2 , denoting the dominant detrimental influence of a C(2)−NH group on the H‐bond acceptor properties of a sufficiently basic `glycosidic heteroatom'.     

The Structure of a Novel Neutral Lipid A from the Lipopolysaccharide of Bradyrhizobium elkanii Containing Three Mannose Units in the Backbone

The chemical structure of the lipid A of the lipopolysaccharide (LPS) from Bradyrhizobium elkanii USDA 76 (a member of the group of slow‐growing rhizobia) has been established. It differed considerably from lipids A of other Gram‐negative bacteria, in that it completely lacks negatively charged groups (phosphate or uronic acid residues); the glucosamine (GlcpN) disaccharide backbone is replaced by one consisting of 2,3‐dideoxy‐2,3‐diamino‐D ‐glucopyranose (GlcpN3N) and it contains two long‐chain fatty acids, which is unusual among rhizobia. The GlcpN3N disaccharide was further substituted by three D ‐mannopyranose (D ‐Manp) residues, together forming a pentasaccharide. To establish the structural details of this molecule, 1D and 2D NMR spectroscopy, chemical composition analyses and high‐resolution mass spectrometry methods (electrospray ionisation Fourier‐transform ion cyclotron resonance mass spectrometry (ESI FT‐ICR MS) and tandem mass spectrometry (MS/MS)) were applied. By using 1D and 2D NMR spectroscopy experiments, it was confirmed that one D ‐Manp was linked to C‐1 of the reducing GlcpN3N and an α‐(1→6)‐linked D ‐Manp disaccharide was located at C‐4′ of the non‐reducing GlcpN3N (α‐linkage). Fatty acid analysis identified 12:0(3‐OH) and 14:0(3‐OH), which were amide‐linked to GlcpN3N. Other lipid A constituents were long (ω‐1)‐hydroxylated fatty acids with 26–33 carbon atoms, as well as their oxo forms (28:0(27‐oxo) and 30:0(29‐oxo)). The 28:0(27‐OH) was the most abundant acyl residue. As confirmed by high‐resolution mass spectrometry techniques, these long‐chain fatty acids created two acyloxyacyl residues with the 3‐hydroxy fatty acids. Thus, lipid A from B. elkanii comprised six acyl residues. It was also shown that one of the acyloxyacyl residues could be further acylated by 3‐hydroxybutyric acid (linked to the (ω‐1)‐hydroxy group).     

Sucrose-Branched Polymer Synthesized by Protease from Bacillus Subtilis

Summary: Vinyl sugar ester, 1′-O-vinyladipoyl-sucrose, was synthesized using sucrose and DVA (divinyl adipate) in organic medium (dimethylformamide), catalyzed by protease from Bacillus subtilis. Several reaction conditions were examined by means of qualitative analysis (TLC). The monomer obtained has undergone chemical polymerization with potassium persulfate and hydrogen peroxide to produce an amphiphilic polymer having sugar branches. The monomer was characterized by ¹³C-NMR and FTIR spectra. The IR analysis confirmed the synthesis of the poly (1′-O-vinyladipoyl-sucrose).     

Species‐Specific Hydrolysis Kinetics of N‐Methylated Heroin Derivatives

The hydroxide‐catalyzed hydrolysis of 3,6‐diacetylmorphine (heroin) was shown to take place predominantly via its positively charged form. N‐Methylated quaternary derivatives of heroin bearing a permanent positive charge were synthesized, and thus, hydrolysis kinetics of these cationic species could be studied over a wide pH range. Specific rate equations were introduced to characterize either the simultaneous or the consecutive decompositions. The kinetic constants determined for the diester are distinctive for the site of hydrolysis. The rate of 6‐acetyl‐N‐methylmorphine was quantified in terms of microscopic kinetic constants of hydrolysis, in which the protonation state of the phenolic OH group had also been taken into account. The site‐specific data indicate that the 3‐acetoxy moiety is hydrolyzed 6 – 12 times faster than the 6‐acetoxy function. The latter, previously ignored minor pathway was shown to represent a non‐negligible 10% of the overall decomposition process. Protonation of the 3‐O⁻ site accelerates the rate of hydrolysis of the 6‐acetoxy moiety by a factor of 4, and replacement of the adjacent OH group by MeO or AcO substituents slows the rate of hydrolysis slightly, presumably due to the increased local hydrophobicity caused by the alkyl or acyl moiety.     

Synthesis of 7,6‐Fused Bicyclic Lactams for Use as Beta‐Turn Mimics

An improved synthesis of the 7,6‐fused bicyclic lactam is presented starting from readily available chiral starting materials. (S)‐allylglycine is protected as the phthalimide derivative and coupled with (S)‐2‐amino‐6‐hydroxyhexanoic acid methyl ester. Oxidation of the hydroxyl group to the aldehyde followed by enamide synthesis and acyl iminium ion cyclization provide the bicyclic system as a single diastereomer in good overall yield.     

Axial Ligand and Spin‐State Influence on the Formation and Reactivity of Hydroperoxo–Iron(III) Porphyrin Complexes

The present study focuses on the formation and reactivity of hydroperoxo–iron(III) porphyrin complexes formed in the [Fe^III(tpfpp)X]/H₂O₂/HOO^? system (TPFPP=5,10,15,20‐tetrakis(pentafluorophenyl)‐21H,23H‐porphyrin; X=Cl^? or CF₃SO₃^?) in acetonitrile under basic conditions at ?15 °C. Depending on the selected reaction conditions and the active form of the catalyst, the formation of high‐spin [Fe^III(tpfpp)(OOH)] and low‐spin [Fe^III(tpfpp)(OH)(OOH)] could be observed with the application of a low‐temperature rapid‐scan UV/Vis spectroscopic technique. Axial ligation and the spin state of the iron(III) center control the mode of O? O bond cleavage in the corresponding hydroperoxo porphyrin species. A mechanistic changeover from homo‐ to heterolytic O? O bond cleavage is observed for high‐ [Fe^III(tpfpp)(OOH)] and low‐spin [Fe^III(tpfpp)(OH)(OOH)] complexes, respectively. In contrast to other iron(III) hydroperoxo complexes with electron‐rich porphyrin ligands, electron‐deficient [Fe^III(tpfpp)(OH)(OOH)] was stable under relatively mild conditions and could therefore be investigated directly in the oxygenation reactions of selected organic substrates. The very low reactivity of [Fe^III(tpfpp)(OH)(OOH)] towards organic substrates implied that the ferric hydroperoxo intermediate must be a very sluggish oxidant compared with the iron(IV)–oxo porphyrin π‐cation radical intermediate in the catalytic oxygenation reactions of cytochrome P450.