Pinanediol boronate, reaction

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

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.

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. 

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.). 

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. 

A number of biological studies have been conducted with the pinacol or pinanediol esters of boronic acid. At physiological pH these esters have biological activity equivalent to the free boronic acid. 6 This is due to the equilibrium of the ester with water as shown in Scheme 6. The pinanediol esters of boronic acids 16 are rapidly hydrolyzed in aqueous solution while the pinacol esters, though less stable, are hydrolyzed more slowly. In general, it is sufficient to incubate pinacol esters for 30 minutes in phosphate buffer, pH 7.5, prior to running biological reactions.16 ... 

Pinanediol esters cannot be readily displaced by treating with diethanolamine. A convenient method of removing either pinanediol esters or pinacol esters for boronic acids that are insoluble in ethers and are readily soluble in water has been developed. 34 The boronic acid ester, e.g. 21, is incubated with a hydrophobic boronic acid such as phenylboronic acid 34 in a rapidly stirred mixture of water and ether (Scheme 8). After 3 hours, the phases are separated and the aqueous phase is concentrated to give the free boronic acid 22. In this case the reaction is driven to completion by the greater solubility of the free boronic acid in the aqueous phase and the greater solubility of the pinacol ester of phenylboronate in the ether phase. This procedure has also been used to remove the pinanediol ester from Ac-D-Phe-Pro-boroArg-pinanediol 34 (see Section 15.1.7.5). 

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). 

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... 

Chain extensions using an insertion reaction of dichloromethyllithium or dibromomethyllithium with (5 )-pinanediol [(benzyloxy)methyl]boronate 26 has been used to generate L-C3-, L-C4-and L-Cs-aldoses [51]. In order to obtain 2,3-di-O-benzyl-L-glyceraldehyde 27, the insertion reaction has to be applied twice (Scheme 13.20). By repeating the process two more times, L-ribose has been prepared with high enantiomeric purity [51]. 

The use of chiral boronic esters in the Petasis borono-Mannich reaction has been reported to result in low levels of enantioselectivity of the adducts at room temperature (6-15% ee) [48]. Auxiliaries used in this study by Scobie and co-workers included pinanediol and tartaric acid derived alkenylboronates. Morpholine was the only secondary amine used, with the primary amine ethyl glycinate failing to react. 

The first synthesis of an (a-haloalkyl)boronic ester [8], a free radical addition of a tetrahalomethane, was followed by mechanistic studies that indicated the potential for stereospecific alkylation with Grignard reagents via borate intermediates [9], if only there had been a way to obtain asymmetric examples. The discovery of the efficient reaction of (dichloromethyl)lithium with boronic esters to form (a-chloroalkyl)boron-ic esters by insertion of a CHCl group into the B-C bond opened a new opportunity [10]. Boronic esters of pinanediol, prepared from (+)-a-pinene by osmium tetroxide catalyzed oxidation, were soon found to undergo the insertion reaction with a strong asymmetric bias, with diastereomeric selectivities frequently in the 90-95% range [llj. It was subsequently found that anhydrous zinc chloride promotes the reaction and increases diastereoselectivity to as high as 99.5% in some cases [12]. 

Scheme 8.4 Lack of diastereoselectivity in reactions of pinanediol (a-chloroalkyl)boronates.

Pinanediol (lR)-(l-benzyloxypentyl)boronate (48) prepared from chloroboronic ester 47 provided a model for the reaction conditions needed (Scheme 8.11) [29]. Rearrangement of the benzyloxy group from boron to carbon tended to be sluggish, and best results were obtained when about 1 mol of dimethyl sulfoxide was added as a promoter. The reactants are customarily mixed at -78 °C and allowed to warm to room temperature afterward, though there is no evidence that the cold mixing is necessary. 

Trityloxy is a useful blocking group for terminal hydroxyl. The reaction of lithium or sodium trityloxide with pinacol (bromomethyl)boronate (63) proceeds efficiently in anhydrous dimethyl sulfoxide to provide 64. Transesterification of 64 with (R,R)-1,2-dicyclohexyl-1,2-ethanediol ["(J )-DICHED ] yields (J )-DICHED (trityloxyme-thyl)boronate (65) (Scheme 8.15) [43]. Both 64 and 65 are crystalline and their X-ray structures have been determined. Pinanediol (trityloxymethyl)boronate has been prepared in a similar manner and its X-ray structure determined [43]. These are useful starting points for several synthetic sequences. 

The reaction of (a-chloroalkyl)boronic esters with silicon tetrachloride does not epimerize (a-chloroalkyl)boron groups. As a test, (S)-DICHED (1-chloropentyl)-boronate (142) with potassium bifluoride was converted into potassium (1-chloro-pentyl)trifluoroborate (143), which was treated with silicon tetrachloride in THF to form (l-chloropentyl)dichloroborane (144). The dichloroborane was converted into the stable pinacol ester 145, which was transesterified to the (R)- and (5)-pinanediol esters 146 and 147, respectively (Scheme 8.33). H NMR spectra of these two di-astereomers differ sufficiently to show that each was pure and free from more than 1-2% of the other. Compound 144 was shown to react readily with diethylzinc followed by base and finally hydrogen peroxide to yield the expected (S)-3-heptanol, but this chemistry awaits further development to achieve efficient synthetic procedures. 

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