Boronate 1,2-diol formation

Boronic ester formation is an alternative process suitable for dynamic covalent chemistry. Nishimura and Kobayashi made use of the reversible condensation between an aryl-boronic acid and catechol in the development of dynamic hemicarcerand 42. Heating a 2 4 mixture of a tetra-boronic acid cavitand and biscatechol 43 resulted in the quantitative formation of 42. Again, the high efficiency is a result of the proper choice of the building blocks. Biscatechol 43, which in its lowest energy conformation is a perfect 120° ditopic bis-l,2-diol unit, is complementary to the orientation of the boronic acids in the cavitand building block to yield 42 with little or no strain. 

A fluorescein boronic acid derivative was prepared to function as the fluorescent partner and a series of methyl-red-inspired diols were synthesized as qnencher partners to probe the FOrster resonance energy transfer (FRET) quenching sensing regime based on boronate ester formation (Fignre 11). ... 

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. 

Similar to borax, boronic acid-containing polymers can also be used to crosslink polyhydroxy polymers, such as PVA. Kitano et al. reported the first example of an interpolymer complex based on boronate-diol interactions. The complex was formed by mixing a PVA solution and an alkali solution of poly(AI-vinyl-pyrrolidone-co-3-acrylamidophenylboronic acid). Complex formation leads to an increase in solution viscosity. Above a critical polymer concentration, the complex solution loses its fluidity to become a transparent gel. The authors later increased the solubility of the polymer under physiological and acidic aqueous conditions by incorporation a third comonomer, Af,Af-dimethylaminopropylacrylamide (DMAPAA). Therefore, an interpolymer complex can form at physiological pH. 

Figurel.lO Specific examples of boronic ester formation with cyclic diols.

As discussed in the Introduction, boronic ester formation is a readily reversible process. Therefore, most of the inhibitors are used in their free acid form. However, if one uses a diol that can form a very tight covalent adduct with a boronic acid, one can make an ester inhibitor that is stable enough to hydrolysis on the time scale needed for the inhibitory activities. 

Scheme 7 The equilibria for boronate ester formation couple to generate a thermodynamic cycle. The formation of the diol boronate anion complex is defined as Ktet and the formation of the diol boronic acid complex is defined as K,rig, where it is observed that > K ig. The acidity constant of the unbourid complex is defined as Ka and the acidity constant of the bound complex is defined as Kf, where it is observed that pKa > pKj.

FIGURE 5. Bis-diol functionalized porphyrins assemble into macrocycles based on boronate ester formation coupled with metal ligation to a Lewis basic pyridine. 

FIGURE 12. Coordinative linear polymers based on boronate ester formation result from (a) ditopic coordination of pyridyl boronic acids to bis-diol functionalized porphyrins and (b) through coordinative interactions between rhodoximes and 3-aminoboronic acid. 

FIGURE 16. (a) When phenylene-l,3-diboronic acid was coupled with the bis-l,3-diol, pentaerythritol, traditional cyclic boronate ester formation resulted in macrocyclic structures, (b) The bis-l,2-diol 1,2,4,5-tetrahydroxybenzene forms similar structures. 

Growing from simple polymeric assemblies, more complex structures arise from the interactions between polyvalent boronic acids interacting with poly-functional diols. These products may be dynamic, highly cross-linked polymer networks, analogous to slime. Alternatively, these assemblies have taken the form of highly ordered frameworks with persistent pores. Regardless of the degree of order inherent in these systems, the key assembly motif still relies on boronate ester formation. 

The synthesis of the polyol glycoside subunit 7 commences with an asymmetric aldol condensation between the boron enolate derived from imide 21 and a-(benzyloxy)acetaldehyde (24) to give syn adduct 39 in 87 % yield and in greater than 99 % diastereomeric purity (see Scheme 8a). Treatment of the Weinreb amide,20 derived in one step through transamination of 39, with 2-lithiopropene furnishes enone 23 in an overall yield of 92 %. To accomplish the formation of the syn 1,3-diol, enone 23 is reduced in a chemo- and... 

It should be noted that one of these diols, the hydroquinone, did not provide any oligomer in the first step. This was due to the formation of the quinone structure which made it impossible to use hydroquinone directly in the substitution reaction. An alternate method was used to overcome this problem which involved the use of 4-methoxyphenol to obtain the sulfone product, followed by cleavage of the methyl ether to the diol (VIII) with boron tribromide. This set of reactions is outlined in Figure 5. 

The protected diol side-chain of 456 is introduced by asymmetric dihydroxylation and directs diastereoselectivity in the formation of 457 and 458 by lithiation. The most acidic position of 456, between the two methoxy groups, is first protected by silylation. Suzuki coupling of 459 with the boronic acid 460 gives the kinetic product 461—the more severe hindrance to bond rotation in this compound does not allow equilibration to the more stable atropisomer of the biaryl under the conditions of the reaction. 

The reaction follows the mechanism shown in 8-24 until formation of the borepoxide 74. In the presence of water the third boron — carbon migration does not take place, because the water hydrolyzes 74 to the diol 77. 

Boronic acids can be reversibly esterified with resin-bound diols (Figure 3.15). The resulting boronic esters are stable under the standard conditions of amide bond formation, but can be cleaved by treatment with water under acidic or neutral conditions to yield boronic acids. Treatment of the resin-bound boronic esters with alcohols yields the corresponding boronic esters [197]. Resin-bound boronic esters are suitable intermediates for the Suzuki reaction [198], Treatment with H202 leads to the formation of alcohols (Entry 8, Table 3.36), while treatment of resin-bound aryl boronates with silver ammonium nitrate leads to the conversion of the C-B bond into a C-H bond (Entry 14, Table 3.46). 

Isotope labeling experiments indicate that the B—O bond is broken and not the C—O bond in the formation of the diol-boric acid complexes (18). This indicates that the initial step in the mechanism may be an attack on the boron atom by an oxygen of the diol, followed by the release of water. This could occur without developing any charge separation. If such a mechanism were correct, it would seem that an attack on the boron atom would be easier for trigonal boric acid than for the tetrahedral borate anion (Figure 1). 

An alternative method of hydroboration is to use diisopinocampheylborane (12) (Scheme 4). This reaction is particularly useful for sterically hindered alkenes. Diisopinocampheylborane (12) is prepared from borane-dimethyl sulfide and (+)-pinene.[23-24] Treatment of 4-meth-ylenecyclohexanone ethylene ketal with diisopinocampheylborane (12) gives the borane 13.[25] Further treatment with 2 equivalents of an aldehyde results in the elimination of pinene and the formation of a new dialkyl boronate, e.g. treatment of 13 with acetaldehyde gives the diethyl cyclohexylmethylboronate 14J261 The dialkyl boronates thus produced can be transesterified with pinanediol to give 15[26] or with other cyclic diols. 

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