Pinanediol boronic esters

In this section, the boronate esters have been named throughout as pinanediol boronic esters. The correct Chemical Abstracts name of, for example, 3, is 3a.S,[2(R ),3aa,4/ ,6/ .7aa] -2-(l-chloroalkyl)-hexahydro-3a,5,5-trimethyl-4,6-methano-l,3,2-benzodioxaborole. 

S)-Pinanediol boronic esters 2 with (dichloromethyl)lithium produce (aS)-a-chloro boronic esters 3. The first experiments provided diastereomerie ratios in the range 75 25 to 98 2. The best results (>94 6) were obtained with phenyl, ethenyl, or 1-phenylethyl attached to the boron atom39 40. The diastereomerie ratios were estimated from the rotations of esters of derived secondary alcohols. It was subsequently found that zinc chloride catalysis of the rearrangement of the intermediate borate complexes 2 improved the yields, usually to 85-95%, with diastereo-meric ratios often >99 1 when R1 = alkyl, as shown by NMR measurements15,43. 

Table 2. Reaction of Pinanediol Boronic Esters 1 with (Dichloro-methyljlithium With and Without Zinc Chloride...

Addition of a wide range of boronic acids [RB(OH)2] or esters [RB(OR )2] to the pinanediols gives the very stable pinanediol boronic esters. For example, propylboronic acid (available from the addition of propylmagnesium bromide to trimethyl borate followed by acid hydrolysis) and the (s) pinanediol combine to give a homochiral boronic ester as shown in Equation B6.3. 

Figure B6.1 depicts the construction of a chiral centre on an (s) pinanediol boronic ester. Initially LiCHCl2 is added to the substrate A to give a...

A second peptide coupling employing 2-pyrazine carboxylic acid (24) and TBTU affords 25. Finally the boronic ester moiety is removed under acidic conditions using isobutyl boronic acid. This regenerates pinanediol boronic ester 16, which can be used in another batch run of the process. Crystallization from ethyl acetate gives bortezomib in its anhydride (boroxine) form 26. The overall yield for the route is 35% with a typical purity of > 99% w/w. 

The two contiguous stereocenters present in the aldehyde 155 were installed in a straightforward manner and with an extremely high stereoselectivity using the dihalomethyllithium insertion method of Matteson (Scheme 3) [157]. The (-i-)-pinanediol boronic ester derivative... 

Scheme 8.3 General assembly of asymmetric carbon chains via pinanediol boronic esters. Structures 13-20 are drawn as slightly distorted planar projections of a three-dimensional computer model of the rigid terpenoid unit. For detailed reaction conditions, see Scheme 8.1.

A limitation of pinanediol boronic esters (15) results from the difference between the two diastereotopic faces of the trigonal boron atom. The sequential double di-astereodifferentiation observed with chiral directors having C2-symmetry is not possible. Borate anion 16 derived from 15 rearranges to (a-chloroalkyl)boronic esters 17 and 18 in a ratio that usually exceeds 50 1 (Scheme 8.3) [12]. Alkylmetallic reagents attack 17 from the less hindered side to form 19, in which the chloride to be displaced is not in a comparable steric environment to that in 16 (28). The major diastereomer 20 is produced in about the same proportion as its precursor 17 (Scheme 8.3). 

One of the limitations of (a-chloroalkyl)boronic ester chemistry has been that the chiral directors are difficult to cleave from boron, and boronic esters are inert in some of the useful transformations of trialkylboranes and alkyldihaloboranes. The vigorous conditions that will remove pinanediol from any pinanediol boronic ester, treatment with boron trichloride [12], leave the pinanediol as tarry ruins and with it any sensitive functionality on the boronic ester. The much milder cleavage by transfer of pinanediol or other chiral diol to phenylboronic acid in a two-phase system works well if the boronic acid to be isolated is water soluble [26]. Other cleavage methods include reduction of pinanediol boronic esters with lithium aluminum hydride or alkylation to borinic ester intermediates [73]. 

Boronic esters (3) can be homologated to a-chloroboronic esters (4) (Scheme 2) replacement of the chlorine atom by carbon nucleophiles, such as Grignard reagents, and oxidation of the carbon-boron bond gives a new route to alcohols/ If the sequence is performed with (+)- or (-)-pinanediol boronic esters it can be made into a directed chiral synthesis of alcohols, as illustrated in Scheme 3 from phenyl boronic acid the homologation steps were found to occur with diastereoselectivities in excess of 90%, the chlorine replacement proceeds with inversion, and the oxidative step with retention of configuration. 

Matteson et al have studied the homologation of boronic esters with dichloromethyl lithium. The stereoselectivity of the reaction involving pinanediol boronic esters is decreased due to epimerization of the homologated product by co-produced lithium chloride. Assembling the proposed intermediate by the reaction of the dichloromethyl boronic ester with an alkyl lithium does not give the same enantioselectivity as with the previous procedure. This was thought to be associated with kinetic selectivity in the attack by the nucleophiles R and CHClJ. 

Matteson DS, Sadhu KM, Peterson ML. 99% ChiraUy selective synthesis via pinanediol boronic esters insect pheromones, diols, and an amino alcohol. J. Am. Chem. Soc. 1986 108 81(R819. 

Boronic esters are easily prepared from a diol and the boronic acid with removal of water, either chemically or azeotropically. (See Chapter 2 on the protection of diols.) Sterically hindered boronic esters, such as those of pinacol, can be prepared in the presence of water. Boronic esters of simple unhindered diols are quite sensitive to water and hydrolyze readily. On the other hand, very hindered esters, such as the pinacol and pinanediol derivatives, are exceedingly difficult to hydrolyze and often require rather harsh conditions to achieve cleavage. 

If the pKa of the corresponding acid R1 - H from the stabilized carbanion is smaller than 35, the migration of R1 fails in (dichloromethyl)borate complexes. Failure to convert pinanediol [(phenylthio)methyl]boronate to an a-chloro boronic ester has been reported15. Reaction of (dichloromethyl)lithium with an acetylenic boronic ester resulted in loss of the acetylenic group to form the (dichloromethyl)boronate, and various attempts to react (dichloromethyl)boronic esters with lithium enolates have failed17. Dissociation of the carbanion is suspected as the cause, but in most cases the products have not been rigorously identified. 

The most advanced synthetic methods involve chiral directors that have C2 symmetry. These are discussed first for x-chloro boronic esters (Section 1.1.2.1.2.1.) and then for the bromo analogs, which are better in reactions involving enolates (Section 1.1.2.1.2.2.). The first syntheses of secondary alcohols utilized pinanediol as chiral director (Section 1.1.2.1.2.3.). The method is marginally successful for some tertiary alcohols (Section 1.1.2.1.2.4.). 

The first useful asymmetric synthesis with a-halo boronic esters utilized (S)-pinanediol [1S-(la,2/1.3//,5a)]-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol as the chiral director39,40. This diol is easily prepared from ( + )-a-pinene by a catalytic hydroxylation with osmium tetroxide, and its enantiomer (i )-pinanediol is available from (-)-(a)-pinene41,42. Pinanediol esters remain useful in view of their excellent stability as well as the ease of preparation of the diol. and their stereoselectivity is very high even though it is no longer the state of the art. 

A)-Pinanediol ethylboronate with (l,l-dichloroelhyl)lithium yields the (S)-a-chloro boronic ester (89 11 d.r.), which is converted by phenylmagnesium bromide to the (S)-tert-alkylboronate, the same isomer obtained from (S )-pinanediol phenylboronate. The enantiomeric excess of the derived (R)-2-phenyl-2-butanol is 70%. 

A number of other a-amido boronic esters or adds have been synthesized similarly and are of interest as enzyme inhibitors45,63,64. It is noteworthy that the substitution of an (S)-pinanediol (1-chloro-2-propenyl)boronic ester with lithium hexamethyldisilazanide to form the (S)-pinanediol [l-bis(trimethylsilyl)amino-2-propenyl]boronic ester proceeds without difficulty, in contrast to the unsuccessful attempts to react (S)-pinanediol (l-chloro-2-propenyl)boronic esters with alkoxides (Section 1.1.2.1.3.4.)16. 

Boronic esters of (R,R)-l,2-dicyclohexyl-l,2-ethanediol or pinanediol react with thionyl chloride and excess imidazole in acetonitrile on a borosilicate glass surface to form the corresponding cyclic sulfites of diols <20010M2920>. Similarly, cyclic sulfites and sulfates have been prepared from silicates of diols <1997TL4841>. 

Many boronic ester homologation reactions have been performed using pinanediols as chiral auxiliaries. These are readily available from (+)- and (-)-a-pinene by osmium tetroxide-catalyzed oxidation reactions (Equations B6.1 and B6.2). 

In a subsequent investigation by the author with others (2) (+)-pinanediol 4-bromo-(R)-aminobutane boronate hydrochloride and other cr-bromo boronic esters have been used as intermediates in the preparation of peptide derivatives (2). 

Boronic ester homologation. (R,R)-2,3-Butanediol- and (-(- )-pinanediol have been used as the chiral adjuncts in a diastereoselective homologation of dichloromethaneboronic esters (1) to the (aS)-a-chloroboronic esters (2). Reaction of 1 with an alkyllithium produces a borate complex (a), which rearranges diastereoselectively in the presence of ZnCl, to 2 with introduction of a chiral center adjacent to boron. The reaction permits... 

Boronic esters are not as reactive as triorganylboranes towards nucleophiles however, rearrangement does take place if the boronic ester is treated with an a-halocarbanion (equation 54). In this case, the I-chloroethylboronate (36) can be obtained in 95% de due to the diastereofacial influence of the chiral pinanediol. Similarly, chloro- or bromo-alkylboronic esters react with Grignards reagents, alkyllithiums and enolates leading to rearranged products. ... 

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