Formation with Boronic Acid Derivatives

Complex Formation with Boronic Acid Derivatives 

Boronic acid derivatives are able to form ring structures with other molecules having neighboring functional groups consisting of 1,2- or 1,3-diols, 1,2- or 1,3-hydroxy acids, 1,2- or 1,3-hydroxylamines, 1-2- or 1,3-hydroxyamide, 1,2- or 1,3-hydroxyoxime, as well as various 

Typically, the boronic acid group is part of an aminophenyl boronic acid derivative, and this group has been used for bioconjugation and affinity chromatography purposes (Burnett et al., 1980 O Shannessy and Quarles, 1987). A common partner for a phenyl boronic acid group in bioconjugation is the salicylhydroxamic acid (SHA) group (Chapter 17, Section 3) (Reaction 59). 

Click Chemistry Cu1-promoted Azide—Alkyne [3 + 2] Cycloaddition 

Click chemistry refers to the reaction between an azido functional group and an alkyne to form a [3 + 2] cycloaddition product, a 5-membered triazole ring. This reaction has been used for many years in organic synthesis to form heterocyclic rings. Normally, the click reaction requires high temperatures, and this was the main reason that it was not used as a bioconjugation tool. However, it was discovered that in aqueous solutions and in the presence of Cu(I), the reaction kinetics are dramatically accelerated to provide high yields even at room temperature and ambient pressures (Rostovtsev et al., 2002 Tornoe et al., 2002 Sharpless et al., 2005). 

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Complex Formation with Boronic Acid Derivatives... 

Facile synthesis of simple 3-arylpyrroles from pyrroline by tandem Suzuki dehydrogenation reaction is depicted in Scheme 229. Thus, treatment of l-benzyl-2,5-dihydro-l//-pyrrol-3-yl trifluoromethanesulfonate 1195 (prepared in 55% yield from l-benzyl-3-pyrrolidinone 1194 by trapping the enolate with a triflating reagent), with boronic acid derivatives leads to the formation of 3-arylpyrroles 1196 in good yields (65-74%) <2000TL3423>. 

At first it was believed that enzyme inhibition by boronic acid derivatives was due to reversible covalent bond formation between boron and His-57 [151, 156]. Then several studies showed that with some inhibitors. 

However, the application of these classical procedures for 1-alkenylboronic acid or ester synthesis may suffer from the formation of small amounts of the opposite stereoisomers, or from bis-alkenylation leading to the boronic acid derivatives. Also, formation of trialkylboranes may occur. A recent useful variant utilizes organolithium reagents and triisopropyl borate, followed by acidification with HCl to give directly alkyl-, aryl-, 1-alkynyl-, and 1-alkenylboronic esters in high yields, often over 90% (Scheme 2-6) [27]. Triisopropyl borate was shown to be the best of the available alkyl borates to avoid multiple alkylation of the borates. 

Similar concepts describing the formation of novel C-C bonds in the cleavage step were introduced by Holmes et al. [96] and Park et al. [97] Both groups utilized aryl sulfonyloxy linkers that were cleaved by reaction with boronic acids or Grignard reagents to give biphenyl derivatives. Wustrow et al. introduced a... 

There are interesting studies, although formally lying beyond the scope of this review, on extraction and membrane transport of saccharides assisted by the formation of covalent bonds. For this purpose Shinbo and co-workers [204] introduced phenylboronic acid. It forms esters with vid-nal-diol compounds, and the resulting anion may be transported across a nonpolar membrane in the presence of, e.g., trioctylmethylammonium counterion. Even ribonucleosides were successfully transported using this technique, with a remarkable and easily understandable 200-fold preference over deoxynucleosides [205]. Some other reports have appeared on the use of boronic acid derivatives in binding [206,207] and transport [208,209] of saccharides and related compounds. 

The Suzuki-Miyaura cross-coupling reaction is a standard method for carbon-carbon bond formation between an aryl halide or triflate and a boronic acid derivative, catalyzed by a palladium-metal complex. As with the Mizoroki-Heck reaction, this cross-coupling reaction has been developed in ionic liquids in order to recycle and reuse the catalyst. In 2000, the first cross-coupling of a halide derivative with phenylboronic acid in [bmim] [BF4] was described. As expected, the reaction proceeded much faster with bromobenzene and iodobenzene, whereas almost no biphenyl 91 was obtained using the chloride derivative (Scheme 36). The ionic liquid allowed the reactivity to be increased, with a turnover number between 72 and 78. Furthermore, the catalyst could be reused repeatedly without loss of activity, even when the reaction was performed under air. Cross-coupling with chlorobenzene was later achieved - although with only a moderate yield (42%) - using ultrasound activation. 

A detailed stndy of the combination of flnorescein boronic acid with diol-appended quenchers a-c and comparison with the fluorescence outputs of nonboron or nondiol-containing systems (i.e., fluorescein or methyl red were employed directly) revealed that the boronate ester formation results in enhanced quenching in each case, and that compound c is the best overall quencher. Nncle-osides were also shown to bind to the same fluorescein boronic acid derivative. While the quenching ability of each nucleoside tested was different, the same ratiometric quenching enhancement was observed in each case, sng-gesting similar binding affinities. 

Boronic acid derivatives of proteases have recently been shown to combine with active-site nucleophiles in the manner shown below, both by X-ray and infrared spectroscopy. The pH dependence of binding is also consistent with this view, according to which these analogs are considered to resemble tetrahedral intermediates in the formation and breakdown of covalent acyl-enzyme intermediates in double displacement. ... 

Boronic acids bearing strong electron-poor aromatic groups (such as pyridinyl) were reported to lack reactivity in the Petasis-Akritopoulou reaction, using standard conditions (dichloromethane, room temperature) [54]. Boronic esters were also studied [57] and the authors reported that the mechanism of formation of the boronate species was different from that with phenylboronic acid derivatives. Piettre and coworkers considered the use of hexafluoro-iso-propyl alcohol (HFIP), which is an alcohol with higher ionizing power, as the solvent in the Petasis-Akritopoulou reaction with boronic esters (Scheme 6.43). Compared to the use of methanol as solvent and microwave-assisted irradiation (MW), the yields were much higher (a maximum of 99% yield was obtained ) [58]. 

Formation of Boron Esters. Esterification of boronic acid derivatives occurs readily with (1), and has been used in many hydroboration reaction sequencesThe six-membered ring boronates are more stable than the corresponding five-membered ring or acyclic products made from 1,2-diols or alcohols. The title reagent has been used to regenerate carbohydrates from boronate derivatives. ... 

Unsubstituted 20-ketones undergo exchange dioxolanation nearly with the same ease as saturated 3-ketones although preferential ketalization at C-3 can be achieved under these conditions. " 20,20-Cycloethylenedioxy derivatives are readily prepared by acid-catalyzed reaction with ethylene glycol. The presence of a 12-ketone inhibits formation of 20-ketals. Selective removal of 20-ketals in the presence of a 3-ketal is effected with boron trifluoride at room temperature. Hemithioketals and thioketals " are obtained by conventional procedures. However, the 20-thioketal does not form under mild conditions (dilution technique). ... 

In contrast, highly stereoselective aldol reactions are feasible when the boron etiolates of the mandelic acid derived ketones (/ )- and (5,)-l- t,r -butyldimethylsiloxy-l-cyclohexyl-2-butanone react with aldehydes33. When these ketones are treated with dialkylboryl triflate, there is exclusive formation of the (Z)-enolates. Subsequent addition to aldehydes leads to the formation of the iyn-adducts whose ratio is 100 1 in optimized cases. 

The second synthetic route consists of the coupling of hexa(4-iodophenyl)ben-zene (34) with an alkylated oligophenylboronic acid to produce a hexa(oligo-phenyl)benzene by extending the aromatic chain [52]. This route is illustrated by the reaction of hexa(4-iodophenyl)benzene (34) with an alkylated terphenyl boronic acid with formation of the hexa(quaterphenyl)benzene derivative 33. Once again, the aliphatic substituents serve to guarantee sufficient solubility. 

An alternative approach to reduce the levels of impurity (VII) would be to have a "transient" existence of the lithio species, so that it reacts instantaneously with trialkyl borate to form the aryl boronate, prior to being quenched by any extraneous proton source to form (VII). Thus, the preparation of boronic acid (II) was improved by changing the order of the reagents. The slow addition of n-butvl lithium also controls the exotherm of the reaction. There was no reaction observed between n-butyl lithium and triisopropyl borate (to form any butyl boronic acid), nor was there any formation of 2-butyl derivative of (VII) formed by reaction between butyl bromide and the lithio species. The reaction is veiy fast and as soon as the addition of n-butyl lithium is completed the reaction is finished. This indicates a rapid transmetallation and instantaneous boronation of the lithio species. The reaction is very much a... 

The interaction of PBA derivatives with molecular species having the above functional groups occurs optimally in the pH range of 8-9, but it is typically reversible at acid pH or in the presence of a high concentration of competing ligand. However, the heterocyclic boronic acid complex is relatively stable under optimal conditions of formation. 

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