Effects of Active‐Site Modification and Quaternary Structure on the Regioselectivity of Catechol‐O‐Methyltransferase

Catechol‐O‐methyltransferase (COMT), an important therapeutic target in the treatment of Parkinson's disease, is also being developed for biocatalytic processes, including vanillin production, although lack of regioselectivity has precluded its more widespread application. By using structural and mechanistic information, regiocomplementary COMT variants were engineered that deliver either meta‐ or para‐methylated catechols. X‐ray crystallography further revealed how the active‐site residues and quaternary structure govern regioselectivity. Finally, analogues of AdoMet are accepted by the regiocomplementary COMT mutants and can be used to prepare alkylated catechols, including ethyl vanillin.     

Novel Selectivity in Carbohydrate Reactions Ii. Selective 6-O-Glycosylation of a Partially Protected Lactoside 1 2

Abstract

A novel regioselectivity was observed in the silver salt promoted glycosylation of 2-(trimethylsilyl)ethyl 3′-O-benzyl-β-D-lactoside using acetobromogalactose as the glycosyl donor. The resulting trisaccharide, obtained in 67% yield, was shown to have the newly formed β-glycosidic linkage at the O-6 position of the lactoside. This was confirmed by synthesis of the authentic product by an alternate route. The novel regioselectivity observed is attributed to the presence of the axially disposed 4′-OH group in the lactoside acceptor.

     

Regioselectively Modified Cellulose and Chitosan Derivatives for Mono- and Multilayer Surface Coatings of Hemocompatible Biomaterials

In this study different synthetic strategies were developed and applied to introduce solely or in combination heparin/heparansulfate-like functional groups such as N-sulfo, O-sulfo, N-acetyl, and N-carboxymethyl groups into chitosan and cellulose with highest possible regioselectivity and completeness and defined distribution along the polymer chain. Completely substituted 6-amino-6-deoxycellulose and related derivatives were prepared from tosylcellulose (DS 2.02; C₆ 1.0) by nucleophilic substitution with azido groups only in the 6-position at 50 °C with subsequent reduction to amino groups and completely removing tosyl groups in the 2,3-position. 2,6-Di-O-sulfocellulose was prepared using the reactivity difference between C-2, C-6 and C-3 of cellulose. The reactivity difference between amino groups and hydroxyl groups was used to prepare various N-substituted derivatives. Partially 2,6-di-O-sulfated cellulose was obtained from trimethylsilylcellulose by the insertion of sulfurtrioxide into the Si–O ether linkage. Partially 3-O-sulfocellulose was synthesized by protecting C-2 and C-6 with trifluoroacetyl groups. A copper–chitosan complex was used to synthesize 6-O-sulfochitosan with a DS of 1.0 at C-6 and various partially 6-O-desulfonated products are possible. Using the phthalimido group to increase the solubility of chitosan in DMF, the regioselectivity of 3-O-sulfo groups was improved by regioselective 6-O-desulfonation of nearly complete 3,6-O-disulfochitosan. The platelet adhesion properties of immobilized regioselectively modified water-soluble derivatives on membranes have been tested in vitro. Some regioselectively modified chitosan and cellulose derivatives are potential candidates for the surface coatings of biomaterials if the regioselective reactions are somewhat further optimized.     

Catalyst-Controlled Regiodivergent Synthesis of α/β-Dipeptide Derivatives via N-Allylic Alkylation of O-Alkyl Hydroxamates with MBH Carbonates

A controllable and regiodivergent N-allylation reaction involving readily available O-alkyl hydroxamates derived from natural α-amino acids has been developed, allowing regiospecific access to α/β-dipeptides containing α-unsaturated β-amino acids moieties in moderate to good yields. The regioselectivity could be conveniently switched by alternation of the catalysts and solvents.     

Regioselective Benzoylation of 6‐O‐Protected and 4,6‐O‐Diprotected Hexopyranosides as Promoted by Chiral and Achiral Ditertiary 1,2‐Diamines

Monobenzoylation of triols (6‐O‐silylated glycopyranosides) or diols (4,6‐O‐benzylidenated glycopyranosides) with benzoyl chloride and triethylamine at ?60° to 23° is promoted by catalytic amounts of ditertiary 1,2‐diamines. The regioselectivity depends mostly on the structure of the alcohols; it is modulated by the configuration and constitution of the diamines, as shown by comparing the effect of Oriyama's catalyst ((S)‐ 1 and (R)‐ 1 ), N,N,N′,N′‐tetramethylethylenediamine (TMEDA), N,N,N′,N′‐tetraethylethylenediamine (TEEDA), Et₃N, and EtNMe₂. The effect of the catalysts on the reactivity is impaired by their steric hindrance. In agreement with the modest enantioselectivity of the mono‐ and dibenzoylation of rac‐cyclohexane‐1,2‐diol in the presence of Oriyama's catalyst, the influence of these diamines on the regioselectivity is rather limited. While associated with procedural simplicity, these catalysts lead, in a few cases, to higher yields of a single benzoate than established methods, viz. in the preparation of the 3‐O‐benzoyl β‐D ‐glucopyranoside 4 , the 2‐O‐benzoyl α‐D ‐galactopyranoside 22 , the 3‐O‐benzoyl α‐D ‐galactopyranoside 23 , and the benzylidenated 2‐O‐benzoyl α‐D ‐galactopyranoside 44 . The regioselective benzoylation of the benzylidenated β‐D ‐mannopyranoside 47 , leading to 48 , appears to be new.     

Application of Site‐Directed Lipase Mutants on Regioselective Acylation of Monosaccharides

Mutants F344V and F345V of Candida rugosa lipase1 (CRL1) were tested in acylation reactions of monosaccharide derivatives 1–8, in order to study the regioselectivity, and the substrate specificity of lipase variants towards unnatural substrates, such as carbohydrates. Mutant F344V showed a better reaction kinetics and/or regioselectivity then the wild type enzyme with several substrates while mutant F345V was inefficient in most cases. With the aim of correlating experimental data with the structural features of the enzyme and substrates, the interaction of substrates methyl 4,6‐O‐benzylidene‐α‐d‐glucopyranoside (5a) and 4,6‐O‐benzylidene‐α‐d‐galactopyranoside (6a) with the wild type enzyme and the mutant F344V was investigated, using a molecular modelling approach.     

Regioselective Silylations of C-2 Hydroxyl Groups of Cyclodextrins Dependent on Reaction Temperature

Silylations of the C-2 hydroxyl group of cyclodextrins were carried out using t-butyldimethylsilyl imidazole in the presence of 4A molecular sieves in N,N-dimethylformamide. A unique aspect of this silylation method is the temperature dependence of the regioselectivity; silylation at 0 °C regioselectively favored the C-6 position to afford mono-6-O-t-butyldimehylsilyl-cyclodextrins, whereas silylation at 140 °C exhibited high regioselectivity on the C-2 hydroxyl group.     

Palladium-Catalyzed Hydrosilylation of Unactivated Alkenes and Conjugated Dienes with Tertiary Silanes Controlled by Hemilabile Hybrid P,O Ligand

Novel P,O-type ligands, N-disulfonyl bicyclic bridgehead phosphorus triamides, were synthesized and utilized in Pd-catalyzed hydrosilylation involving tertiary silanes, unactivated alkenes, and conjugated dienes. The ligand displayed a remarkable level of reactivity for alkene hydrosilylation with tertiary silanes and its use resulted in a significant improvement in the regioselectivity of diene hydrosilylation towards 1,2-hydrosilylation. X-ray crystallographic analysis confirmed the bidentate nature of the ligand, with coordination of phosphorus and oxygen. Control experiments provided evidence for the formation of Pd⁰ species and the reversibility of Pd−H insertion in the reaction mechanism. Density functional theory (DFT) computations supported the importance of the hemilabile P,O ligand in stabilizing both the rate-determining transition state of Pd−H insertion and the transition state of reductive elimination that determines the regioselectivity.     

Preparation of Regioselectively Protected Hydroquinones by Phosphorylation of p-Benzoquinones with Trialkyl Phosphites

The title reaction has been applied to 10 monosubstituted p-benzoquinones (Scheme 2, Table). The regioselectively of the O-phosphorylation is influenced by bulky substituents (t-butyl and trimethylsilyl) and, electronically, by the methoxy group. The regioselectivity, which is high in nonpolar media (benzene), is lower in polar solvents (CH₂Cl₂) and (CH₃CN). The synthetic potential of this transformation, exemplified by the preparation of compounds 29 (Scheme 3) and 32 (Scheme 4), is considerably extended by applying milder methods for the phosphate hydrolysis and by using the reagent couple P(OCH₃)₃/trimethylsilyl chloride, which gives clean access to p-hydroxyphenyl phosphates. p-Benzoquinones 4th and 4i with strong π-acceptor substituents react in a different way, giving phosphonates. The electronically induced regioselectivity of the O-phosphorylation is in according with the preferences expected for the attack by a nucleophilic phosphorylation agent.     

Mechanism of Copper(I)‐Catalyzed Allylic Alkylation of Phosphorothioate Esters: Influence of the Leaving Group on α Regioselectivity

The mechanism of Cu^I‐catalyzed allylic alkylation and the influence of the leaving groups (OPiv, SPiv, Cl, SPO(OiPr)₂; Piv: pivavloyl) on the regioselectivity of the reaction have been explored by using density functional theory (DFT). A comprehensive comparison of many possible reaction pathways shows that [(iPr)₂Cu]^? prefers to bind first oxidatively to the double bond of the allylic substrate at the anti position with respect to the leaving group, and this is followed by dissociation of the leaving group. If the leaving group is not taken into account, the reaction then undergoes an isomerization and a reductive elimination process to give the α‐ or γ‐selective product. If OPiv, SPiv, Cl, or SPO(OiPr)₂ groups are present, the optimal route for the formation of both α‐ and γ‐substituted products changes from the stepwise elimination to the direct process, in which the leaving group plays a stabilizing role for the reactant and destabilizes the transition state. The differences to the energy barrier for the α‐ and γ‐substituted products are 2.75 kcal mol^?1 with SPO(OiPr)₂, 2.44 kcal mol^?1 with SPiv, 2.33 kcal mol^?1 with OPiv, and 1.98 kcal mol^?1 with Cl, respectively; these values show that α regioselectivity in the allylic alkylation follows a SPO(OiPr)₂>SPiv>OPiv>Cl trend, which is in satisfactory agreement with the experimental findings. This trend mainly originates in the differences between the attractive electrostatic forces and the repelling steric interactions of the SPO(OiPr)₂, SPiv, OPiv, and Cl groups on the Cu group.     

Regioselectivity in 2-X-pyrazine aminations by O-mesitylenesulfonylhydroxylamine

The regioselectivity of 2-X-pyrazine aminations by O-mesitylenesulfonylhydroxylamine was studied experimentally and the results are discussed from the viewpoint of electronic and steric factors. DFT calculations are consistent with the reaction proceeding according to an S_N2 mechanism.     

Synthesis of Multi-O4-phospho-L-tyrosine-Containing Peptides

Multi-O⁴-phospho-L -tyrosine-containing peptides can be synthesized by the global as well as the buildingblock approach. Thus, we prepared by both strategies the triphosphorylated and the three regioisomeric diphosphorylated insulin-receptor-(1142–1153)-dodecapeptide derivatives 7 and 4–6 , respectively, of the parent Thr-Arg-Asp-Ile-Tyr-Glu-Thr-Asp-Tyr-Tyr-Arg-Lys ( 3 ). These phosphorylated peptides are valuable tools to study the regioselectivity of dephosphorylation by phosphatases.     

Visible Light Driven Copper(I) Catalyzed Oxyamination of Electron Deficient Alkenes†

A visible light driven Cu(I)‐catalyzed intermolecular oxyamination of electron‐deficient olefins has been achieved by using O‐benzoylhydroxylamines as donors both for amine and oxygen. The transformation properties afford mild conditions and a wide substrate scope, providing access to ester derivatives of β‐amino alcohols with good yields and high regioselectivity.     

Preparation of Primary and Secondary Azidosugars from Diols using the Dioxaphosphorane Methodology

ABSTRACT

Treatment of methyl 2,3-di-O-benzyl-α-D-glucopyranoside (1), methyl 2,3-di-O-acetyl-α-D-glucopyranoside (4), 3-O-benzyl-1,2-O-(1-methylethylidene)-α-D-glucofuranose (6), 3-O-acetyl-1,2-O-(1-methylethylidene)-α-D-glucofuranose (9), 1,2-O-(1-methylethylidene)-α-D-xylofuranose (11) and methyl 2,3-di-O-acetyl-α-D-galactopyranoside (15) with diisopropylazodicarboxylate-triphenylphosphine in tetrahydrofuran led to the corresponding dioxaphosphoranes, which were opened by trimethylsilyl azide affording the silylated primary azidodeoxysugars. When the same reaction was performed on methyl 2,3-di-O-benzyl-α-D-galactopyranoside (20), an inversion of the regioselectivity of the dioxaphosphorane opening was observed, leading mainly to the 4-azido-4-deoxy-α-D-glucopyranoside derivative 27.     

Enzymatic Synthesis of Acylphloroglucinol 3‐C‐Glucosides from 2‐O‐Glucosides using a C‐Glycosyltransferase from Mangifera indica

A green and cost‐effective process for the convenient synthesis of acylphloroglucinol 3‐C‐glucosides from 2‐O‐glucosides was exploited using a novel C‐glycosyltransferase (MiCGTb) from Mangifera indica. Compared with previously characterized CGTs, MiCGTb exhibited unique de‐O‐glucosylation promiscuity and high regioselectivity toward structurally diverse 2‐O‐glucosides of acylphloroglucinol and achieved high yields of C‐glucosides even with a catalytic amount of uridine 5′‐diphosphate (UDP). These findings demonstrate for the first time the significant potential of a single‐enzyme approach to the synthesis of bioactive C‐glucosides from both natural and unnatural acylphloroglucinol 2‐O‐glucosides.     

Hydrogen Peroxide-Responsive Triggers Based on Borinic Acids: Molecular Insights into the Control of Oxidative Rearrangement

Arylborinic acids represent new, efficient, and underexplored hydrogen peroxide-responsive triggers. In contrast to boronic acids, two concomitant oxidative rearrangements are involved in the complete oxidation of these species, which might represent a major limitation for an efficient effector (drug or fluorophore) release. Herein, a comprehensive study of H₂O₂-mediated unsymmetrical arylborinic acid oxidation to investigate the factors that could selectively guide their oxidative rearrangement is described. The o-CF₃ substituent was found to be an excellent directing group allowing a complete regioselectivity on borinic acid models. This result was successfully applied to synthesizing new borinic acid-based fluorogenic probes, which exclusively release the fluorescent moiety upon H₂O₂ treatment. These compounds maintained their superior kinetic properties compared to boronic acids, thus further enhancing the potential of arylborinic acids as valuable new H₂O₂-sensitive triggers.     

Cationic Ir/Me‐BIPAM‐Catalyzed Asymmetric Intramolecular Direct Hydroarylation of α‐Ketoamides

Asymmetric intramolecular direct hydroarylation of α‐ketoamides gives various types of optically active 3‐substituted 3‐hydroxy‐2‐oxindoles in high yields with complete regioselectivity and high enantioselectivities (84–98 % ee). This is realized by the use of the cationic iridium complex [Ir(cod)₂](BAr^F₄) and the chiral O‐linked bidentate phosphoramidite (R,R)‐Me‐BIPAM.     

Origins of regioselectivity in radical arylation of aniline: A computational study

The radical arylation of the para‐substituted anilines under three different conditions (A: arylhydrazines as the radical precursors and MnO₂ as the oxidant in acetonitrile; B: arylhydrazine hydrochlorides as the radical precursors and O₂ as the oxidant in aqueous sodium hydroxide solution; C: arenediazonium salts as the radical precursors and TiCl₃ as the reductant in aqueous hydrochloric acid solution) has been theoretically studied and the origins of the ortho/meta regioselectivity have been explored. The arylation process is suggested to contain three steps: radical generation, radical addition, and rearomatization. Calculations show that the arylation of the neutral anilines is kinetically controlled under conditions A and B, and the regioselectivity is determined by the radical addition. As a directing group, ? NH₂ plays an important role in these cases with the assistance of Mn(OH)₂ (the reduced product of MnO₂ under condition A) and Na⁺ (condition B). As for the arylation of the protonated anilines under condition C, the regioselectivity is affected by the substituents in the para‐position of anilines. Electron‐donating groups support meta‐addition and the selectivity is decided by the radical addition. Conversely, electron‐withdrawing groups favor ortho‐addition, and in this situation the arylation process is thermodynamically controlled and the regioselectivity is determined by the radical addition and rearomatization. © 2015 Wiley Periodicals, Inc.     

Synthesis of Novel Pyrazole–sucrose Derivatives by 1,3‐dipolar Cycloaddition

The syntheses of an important class of enantiopure five‐membered glyconjucates containing furan unit are described. The regioselective synthesis of a series of sugar‐fused pyrazole heterocycles was achieved by the Huisgen cyclization of aryl diazomethanes with propargyl O‐glycoside derivatives in good yields. The cycloaddition regioselectivity was confirmed by NMR.     

Quinoline and ferrocene conjugates: Synthesis,computational study and biological evaluations

Novel O‐alkylated quinoline and N‐alkylated 4‐quinolone derivatives attached to the ferrocene moiety through 4,1‐ ( 7a–d , 8a–d and 12a–d ) and 1,4‐disubstituted ( 9a , 9b , 10a and 10b ) 1,2,3‐triazole moiety were synthesized. The observed regioselectivity of O‐ vs. N‐alkylation was explored by the use of NMR and computational techniques. Among the N‐alkylated derivatives, the quinolone‐ferrocene conjugate 9a displayed marked activities against chronic myeloid leukemia in blast crisis (K562) and Burkitt lymphoma (Raji). The 6‐chloroquinolone‐ferrocene conjugate 12c , with selective inhibitory activity on Raji cells and no cytostatic effect on normal MDCK1 cells was highlighted as the most promising anticancer organometallic complex in a group of O‐alkylated quinolines.