取代硼酸与羟乙基胺化合物间的相互作用研究

取代硼酸与顺式二羟基化合物间的可逆的共价相互作用为糖蛋白和糖等重要生物分子的识别和分离提供了独特的亲和作用.为了获得良好的选择性,以β-激动剂与β-阻断剂这两类典型的羟乙基胺化合物为研究对象,利用核磁共振和高效液相色谱研究了它们与苯硼酸间的相互作用.研究结果表明,在高pH值条件下,羟乙基胺化合物与苯硼酸间存在强亲和作用,而在低pH值条件下,该亲和作用变弱甚至消失.这种pH值调控的相互作用表观上与顺式二羟基和苯硼酸间的硼亲和作用很相似.但是,与硼亲和作用机理不同,质子化溶剂的存在能加强这种相互作用,而非质子化溶剂的存在会破坏相互作用.本研究为深入认识硼亲和作用和获得可靠的应用提供了新依据,同时也为利用取代硼酸和羟乙基胺化合物之间的相互作用奠定了基础.     

Synthesis of a (β-acetamido-α-acetoxyethyl)boronic ester via azido boronic esters

(Azidomethyl)boronic esters of 1,2-dicyclohexyl-1,2-ethanediol (“DICHED”) and pinanediol have been prepared from the corresponding (bromomethyl)boronic esters. Conversion to (2-azido-1-chloro- or bromoethyl)boronic esters by reaction with a (dihalomethyl)lithium followed. Attempted displacement of halide from DICHED (2-azido-1-haloethyl)boronates with alkoxides failed. Reaction of either pinanediol or DICHED (2-azido-1-chloromethyl)boronate with sodium acetate in acetic acid yielded the 1-acetoxy derivative as a ∼1:1 mixture of diastereomers, indicating probable involvement of an α-boryl carbocation intermediate. Hydrogenation of the pinanediol azido boronic ester over platinum in a solution of hydrogen chloride in dioxane was accompanied by deacetylation to form the impure (2-amino-1-hydroxyethyl)boronic ester hydrochloride. Attempted purification of this material resulted in deboronation to ethanolamine. Acetylation yielded pinanediol (2-acetamido-1-acetoxyethyl)boronate.     

Enantiospecific Synthesis of ortho‐Substituted 1,1‐Diarylalkanes by a 1,2‐Metalate Rearrangement/anti‐SN2′ Elimination/Rearomatizing Allylic Suzuki–Miyaura Reaction Sequence

The one‐pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N‐activator, the boronate complex formed from an ortho‐lithiated benzylamine and a boronic ester undergoes stereospecific 1,2‐metalate rearrangement/anti‐S_N2′ elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ‐selective allylic Suzuki–Miyaura cross‐coupling to generate 1,1‐diarylalkanes. When enantioenriched α‐substituted benzylamines are employed, the corresponding 1,1‐diarylalkanes are formed with high stereospecificity.     

Influence of the boron atom on the solvatochromic properties of 4-nitroaniline-functionalized boronate esters

Para-nitroaniline derivatives with peripheral 1,2- and 1,3-diol functionalities [O(2)N-C(6)H(4)-NR(1)-CH(2)CH(OH)CH(2)OH; O(2)N-C(6)H(4)-NR(1)-CH(CH(2)OH)(2); R(1) = -H, -CH(3)] covalently bonded to the amino group are esterified with various para-substituted phenylboronic acids [R(2)-C(6)H(4)-B(OH)(2); R(2) = -OCH(3), -CH(3), -H, -Br, -CHO, -NO(2), -B(OH)(2)], and the solvatochromic properties of these esters are investigated in 33 solvents of different polarity. To interpret the solvent effects, the established linear solvation energy (LSE) multiparameter equations of Kamlet-Taft and the improved Catalán scales are used. Although the boron atom is separated by two or three sp(3)-hybridized carbon atoms from the actual chromophore, solvation effects have a significant positive solvatochromic effect on the nitroaniline unit (R(1) = -CH(3)) as result of the solvent acting as a donor at the boron atom. The influence of the substituent R(2) on the coefficient b of the LSE relationship according to Kamlet-Taft and Catalán, which reflects the quantitative influence of the hydrogen-bonding acceptor or the electron-pair donor capacity of the solvent on the position of the UV-vis absorption maximum, can be determined via a linear Hammett relationship [b = f(σ(p))]. The interpretation of the effects is based on the electronic influence of the solvated boronic acid ester unit on the 4-nitroaniline group, predominantly through inductive interactions.     

Cyclization of peptoids by formation of boronate esters

Introduction of conformational constraints into peptoids (N-substituted oligoglycines) will enable new applications in molecular recognition and self-assembly. Peptoids that contain both a phenylboronic acid side chain and a vicinal diol cyclize by intramolecular condensation to form boronate esters. A fluorescent indicator of free boronic acid was used to assay esterification. A galactose moiety 2 to 5 monomer units away from a boronic acid side chain in a peptoid reacts with the boronic acid in competition with the indicator. The intramolecular reaction predominates in each case, with 80-90% of the peptoid cyclized. When the diol is a simple 2,3-dihydroxypropyl group, esterification is less favored but still appreciable.     

Diverse reactivity of dialkylaluminum dimesitylboryloxides [(mu-Mes2BO)AlR2]2. Synthetic and structural study

Several stable dimeric dialkylaluminum boryloxides of the formula [(mu-Mes2BO)AlR2]2 (R = Me (1), Et (2), iBu) have been prepared from dimesitylborinic acid Mes2BOH and trialkylaluminums R3Al. Compound 1 has been characterized by X-ray diffraction. These compounds exhibit diverse reactivity toward protonolytic reagents depending on the bulkiness of these reagents. Treatment of 1 with tert-butyl alcohol afforded crystalline species trans-[mu-tBuO)(Mes2BO)AlMe]2 (3), which is the first example of a mixed system containing boryloxide and alkoxide ligands together. Most surprisingly, Mes2BOH was found to undergo catalytic decomposition in the presence of [(mu-Mes2BO)AlR2]2 via the unexpected cleavage of one boron-carbon bond. The molecular structure of the decomposition product, i.e., trimesitylboroxin [MesBO]3 (4) is reported.     

Asymmetric synthesis of 1-acyl-3,4-disubstituted pyrrolidine-2-boronic acid derivatives

An analogue of N-acetylkainic acid having a cyano group and a boronic acid group in place of the two carboxyl groups has been synthesized with high stereocontrol via a series of chain extensions of pinanediol [(trityloxy)methyl]boronate with (dihalomethyl)lithium followed by appropriate nucleophilic substitution of the resulting chloro or bromo boronic ester. Substituents were introduced in the order isopropenyl, cyanomethyl, and bis(trimethylsilyl)amino. The last of these was converted to acetamido, the hydroxyl function was unmasked and mesylated, and the pyrrolidine ring was closed. Attempts to carry out further chain extension on the boronic ester resulted in low yields, evidently the highly polar amido substituent interferes with the (dichloromethyl)lithium insertion process.     

Synthesis of 3′-deoxy-3′-iminodiacetic acid and 3′-deoxy-3′-aminodiethanol thymidine analogues and NMR study of their complexation with boronic acids

The iminodiacetic acid and aminodiethanol moieties are known for their ability to generate with boronic acids bicyclic structures having a strong intramolecular NB coordination. We describe here the convergent synthesis of 3′-deoxy-3′-iminodiacetic acid and 3′-deoxy-3′-aminodiethanol thymidine analogues. The abilities of these compounds to form boronate complexes with aliphatic or aromatic boronic acids were established by 1D and 2D ¹H and ¹³C NMR. Moreover, conformational analysis of the newly synthesized compounds revealed a marked preference for an N-type sugar puckering.     

Controlling deposition and release of polyol-stabilized latex on boronic acid-derivatized cellulose

Poly(glycerol monomethacrylate)-stabilized polystyrene (PGMA-PS) latex particles undergo specific, pH-dependent adsorption onto regenerated cellulose film bearing surface phenylboronic acid groups (cellulose-PBA). Deposition occurs at pH 10 and is driven by the boronate ester formation with the polyol latex surface coating. In contrast, no deposition occurs at pH 4, and previously deposited particles can be readily desorbed at this lower pH. In control experiments, conventional anionic sulfate-stabilized polystyrene latex did not deposit onto the hydrophilic cellulose surface. The distribution of boronate groups in the cellulose was determined by exposure to Alizarin Red S dye, which forms a fluorescent complex with phenylboronic acid; confocal microscopy was used to determine a surface density of 3 nm(2) per boronic acid group on the cellulose surface. Although the boronic acid binding constant with PGMA is relatively low (5.4 L/mol), the cooperative interactions between multiple PBA surface sites and the many PGMA chains per latex particle are sufficient to induce specific latex adsorption, providing a convenient new tool for controlling nanoparticle deposition on surfaces.     

Deprotection of pinacolyl boronate esters by transesterification with polystyrene-boronic acid

Mild deprotection of pinacolyl boronate esters to the corresponding boronic acids was achieved in the presence of excess polystyrene-boronic acid via a transesterification process. The procedure allows for the cleavage of pinacolyl boronate esters in the presence of sensitive functional groups.     

A Wulff-type boronate for boronate affinity capture of cis-diol compounds at medium acidic pH condition

A new Wulff-type boronate was designed and synthesized. Upon immobilization on a polymeric monolith and acidified as boronic acid, the ligand exhibited specific boronate affinity to cis-diol compounds at medium acidic pH condition.     

Synthesis,characterization, and star polymer assembly of boronic acid end‐functionalized polycaprolactone

Boronic acid end‐functionalized polycaprolactone (PCL) polymers were synthesized by ring‐opening polymerization using a pinacol boronate ester‐containing (Bpin) initiator. The polymerization provides access to boron‐terminated polymers (i.e. Bpin‐PCL‐OH) with narrow molecular weight distributions (PDI = 1.09). Postsynthetic manipulation of the polymer's terminal hydroxyl group by copper‐catalyzed azide‐alkyne cycloaddition chemistry provides a series of bis end‐functionalized polymers with significant structural diversity at the termini. Deprotection of the boronate ester end group was accomplished with an acidic solid phase DOWEX resin. The boronate ester deprotection methodology does not result in hydrolysis of the polymeric backbone. The boronic acid‐tipped polymers were converted into star polymer assemblies using thermal dehydration and ligand‐facilitated trimerization. Thermal dehydration of (HO)₂B‐PCL‐OAc to the corresponding boroxine‐based star polymer assembly was inefficient and lead to degradation products. Ligand‐facilitated trimerization using either pyridine or 7‐azaindole as the Lewis base was efficient and mild. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

An Exploratory Study of Silylated Amino Boronic Ester Chemistry

Diisopropyl [bis(trimethylsilylamino)methyl]-boronate, the analogous pinacol boronic ester ( 3 ), andpinacol [(2,2,5,5-tetramethyl-2,5,1-disilazol-1-yl)-methyl]boronate ( 8 ) were prepared from the corresponding (bromomethyl)boronic ester 1 or 2 and silylated lithium amide. Reaction of 3 or 8 with (dichloromethyl)lithium yielded the corresponding [1-chloro-2-(silylated amino)ethyl]boronate 4 or 9 . Further transformations of 4 to methylthio derivative 5 and dimethylamino derivative 7 as well as conversion of 5 to ureido derivatives 6 are described. (S,S)-1,2-Dicyclohexylethanediol [1-chloro-2-(trityloxy)-ethyl]boronate ( 13 ) has been converted to bis(tri-methylsilyl)amino derivative 14 and formamido derivative 15 as well as to N-benzyl analogs 18 and 19 . Attempted chain extensions of 14, silylated 15, or 19 with (dichloromethyl)lithium indicated that the alkyl migration from boron to carbon is slow and incomplete. © 1997 John Wiley & Sons, Inc. Heteroatom Chem 8: 487–494, 1997     

Copper-mediated sequential cyanation of aryl C-B and arene C-H bonds using ammonium iodide and DMF

The cyanation of aromatic boronic acids, boronate esters, and borate salts was developed under copper-mediated oxidative conditions using ammonium iodide and DMF as the source of nitrogen and carbon atom of the cyano unit, respectively. The procedure was successfully extended to the cyanation of electron-rich benzenes, and regioselective introduction of a cyano group at the arene C-H bonds was also achieved. The observation that the reaction proceeds via a two-step process, initial iodination and then cyanation, led us to propose that ammonium iodide plays a dual role to provide iodide and nitrogen atom of the cyano moiety.     

Enantioselective installation of adjacent tertiary benzylic stereocentres using lithiation–borylation–protodeboronation methodology. Application to the synthesis of bifluranol and fluorohexestrol

1,2-Diaryl ethanes bearing 1,2-stereogenic centres show interesting biological activity but their stereocontrolled synthesis has not been reported forcing a reliance of methods involving diastereomer and enantiomer separation. We have found that this class of molecules can be prepared with very high stereocontrol using lithiation–borylation methodology. The reaction of an enantioenriched benzylic lithiated carbamate with an enantioenriched benzylic secondary pinacol boronic ester gave a tertiary boronic ester with complete diastereo- and enantiocontrol. It was essential to use MgBr₂/MeOH after formation of the boronate complex, both to promote the 1,2-migration and to trap any lithiated carbamate/benzylic anion that formed from fragmentation of the ate complex, anions that would otherwise racemise and re-form the boronate complex eroding both er and dr of the product. When the benzylic lithiated carbamate and benzylic secondary pinacol boronic ester were too hindered, boronate complex did not even form. In these cases, it was found that the use of the less hindered neopentyl boronic esters enabled successful homologation to take place even for the most hindered reaction partners, with high stereocontrol and without the need for additives. Protodeboronation of the product boronic esters with TBAF gave the target 1,2-diaryl ethanes bearing 1,2-stereogenic centres. The methodology was applied to the stereocontrolled synthesis of bifluranol and fluorohexestrol in just 7 and 5 steps, respectively.     

Separation and analysis of cis-diol-containing compounds by boronate affinity-assisted micellar electrokinetic chromatography

Cis-diol-containing compounds (CDCCs) are usually highly hydrophilic compounds and are therefore difficult to separate by conventional reversed-phase-based micellar electrokinetic chromatography (MEKC) due to poor selectivity. Here, we report a new method, called boronate affinity-assisted micellar electrokinetic chromatography (BAA-MEKC), to solve this issue. A boronic acid with a hydrophobic alkyl chain was added to the background electrolyte, which acted as a modifier to adjust the selectivity. CDCCs can covalently react with the boronic acid to form negatively charged surfactant-like complexes, which can partition into micelles formed with a cationic surfactant. Thus, CDCCs can be separated according to the differential partition constants of their boronic acid complexes between the micellar phase and the surrounding aqueous phase. To verify this method, eight nucleosides were employed as the test compounds and their separation confirmed that the combination of boronate affinity interaction with MEKC can effectively enhance the separation of CDCCs. The effects of experimental conditions on the separation were investigated. Finally, the BAA-MEKC method was applied to the separation and analysis of nucleosides extracted from human urine. BAA-MEKC exhibited better selectivity and improved separation as compared with conventional MEKC and CZE. Successful quantitative analysis of urinary nucleosides by BAA-MEKC was demonstrated.     

Which is reactive in alkaline solution, boronate ion or boronic acid? Kinetic evidence for reactive trigonal boronic acid in an alkaline solution

That boronic acid is a reactive species toward a diol moiety even in an alkaline solution and that the boronate ion is not very reactive were demonstrated by the estimated upper limit of the rate constants for the reactions of some boronic acids with 2,2'-biphenol and 2,3-dihydroxynaphthalene in a neutral-alkaline solution, which will correct a common misunderstanding in boron chemistry and would renew the idea of effective boronic acid sensor design for carbohydrates.     

Diols and anions can control the formation of an exciplex between a pyridinium boronic acid with an aryl group connected via a propylene linker

The exciplex formation between a pyridinium boronic acid and phenyl group connected via a propylene linker can be monitored using fluorescence. Addition of pinacol affords a cyclic boronate ester with enhanced Lewis acidity that increases the strength of its cation-π stacking interaction causing a four-fold fluorescence enhancement.     

Thermodynamic and structural study of complexation of phenylboronic acid with salicylhydroxamic acid and related ligands

Stability constants of boronate complexes with a highly efficient bioconjugation ligand salicylhydroxamic acid, its derivatives and some structurally related compounds were determined by potentiometric and spectroscopic titrations at variable pH allowing one to obtain detailed stability – pH profiles and to identify the optimum pH for complexation with each ligand. The N,O‐binding of salicylhydroxamic acid via condensation of boronic acid with phenolic OH and hydroxamic NH groups was established by crystal structure determination of isolated complexes with phenylboronic and 4‐nitrophenylboronic acids. Although this type of binding is impossible for N‐methylated salicylhydroxamic acid it still forms stable boronate complexes supposedly involving unusual 7‐membered –O‐B‐O‐ cycle supported by ¹H NMR studies. Hydroxamic acids lacking ortho‐OH group and salicyloyl hydrazide form less stable boronate complexes, which nevertheless possess stabilities similar to those of catechole complexes and may be useful for conjugation applications. In contrast to other ligands, which form tetrahedral anionic complexes, salicylamidoxime forms tetrahedral, but neutral boronate complex with high stability in weakly acid solutions. The highest affinity in neutral and acid solutions surpassing that of salicylhydroxamic acid is observed with 2,6‐dihydroxybenzhydroxamic acid (K_obs = 5.2 × 10⁴ at pH 7.4). Fairly stable mono‐ and bisboronate complexes are formed with 2,5‐dihydroxy‐1,4‐benzdihydroxamic acid, which also possesses intense fluorescence and may serve as a boronic acid sensor with detection limit 4 μM. Results presented in this study provide quantitative basis for rational applications of hydroxamic acid derivatives in bioconjugation and sensing.     

Multicomponent assembly of boron-based dendritic nanostructures

A new synthetic strategy for the construction of boron-based macrocycles and dendrimers is described. Condensation of aryl- and alkylboronic acids with 3,4-dihydroxypyridine is shown to give pentameric macrocycles in which five boronate esters are connected by dative B-N bonds. Three macrocycles have been characterized crystallographically. The boron atoms of these assemblies represent chiral centers, and the assembly process is highly diastereoselective. Attachment of amino or aldehyde groups in the meta position of the arylboronic acid building blocks does not interfere with macrocyclization. This allows performing multicomponent assembly reactions between functionalized boronic acids, dihydroxypyridine ligands, and amines or aldehydes, respectively. Reaction of 3,5-diformylphenylboronic acid, 3,4-dihydroxypyridine, and a primary amine R-NH2 (R=Ph, Bn) gives dendritic nanostructures having a pentameric macrocyclic core and 10 amine-derived R groups in their periphery. Combination of 3,5-diformylphenylboronic acid with 2,3-dihydroxypyridine and the dendron 3,5-(benzyloxy)benzylamine, on the other hand, results in formation of a dendrimer with a tetrameric macrocyclic core and eight dendrons in its periphery.