Pinanediol reaction with

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]. 

Borate esters are hydrolyzed with aqueous acid or base. More sterically hindered borates such as pinanediol derivatives are quite stable to hydrolysis. Borates are stable to anhydrous acid and base, HBr/BzOOBz, NaH, and Wittig reactions. ... 

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. 

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

A solution of lithium benzyloxide is prepared by addition of 56 mL (90 mmol) of 1.6 M butyllithium in hexane to 9.2 mL (88 mmol) of benzenemethanol in 100 mL of THF at — 78 C, followed by the addition of rigorously anhyd DMSO. This solution is added to a solution of 16.38 g (71.7 mmol) of (S)-pinanediol (chloromethyl)boronatc in 60 mL of THF stirred at — 78 °C. The mixture is allowed to warm to r.t. and then heated at 45-50rC for 3 h, at which time TLC indicates the reaction is complete. The mixture is worked up by acidificalion with 0.5 M aq hydrochloric acid followed by diethyl ether extraction. The diethyl ether, DMSO, and benzenemethanol are distilled under vacuum and the residue is chromatographed on silica gel with 10% ethyl acetate in hexane. The product is distilled, and solidifies on cooling vield 19.8 g (92%) bp 158-162 °C (0.2 Torr) mp 25-27°C. 

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). 

Dichloromethane is first deprotonated with "BuLi in tetrah>drofur-an at -10U C. The reaction of dichloromethane with "BuLi represents a competition between deprotonation and halogen-metal exchange. When reaction is carried out at very low temperature only deprotonation occurs. The at complex 16 forms after addition of the methanohoronic acid pinanediol ester 15.10 Upon introduction ofZnCl2 this complex rearranges to compound 3.11... 

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]. 

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