Pinanediol esters

The heterocyclic scaffolds are prepared from pyroglutamic acid [154, 155]. 1-aminoalkyl boronic acid pinanediol esters are readily available through a diastereoselective homologation with dichloromethyllithium, providing (5)-a-chloroboronic esters. Aminolysis of the chloride yielded... 

This section includes a discussion of various mechanistic details which need to be understood in order to achieve optimal utilization of the synthetic method. This information is especially relevant to any modification or extension of the procedures that might be attempted. Included here are the reasons for ultrahigh diastereoselection with chiral directors of C2 symmetry (Section 1.1.2.1.1.1.), the epimerization problem (Section 1.1.2.1.1.2.), various elimination problems (Section 1.1.2.1.1.3.), and consequences of the lack of C2 symmetry in pinanediol esters (Section 1.1.2.1.1.4.). 

II-NMR analysis of derived pinanediol ester. b By 13C-NMR and GC analyses of derived 4-methyl-3-heptanol see text. c 1H-NMR analysis of derived symmetrical diol. The construction of R3 (Section 1.1.2.1.6.) was not totally stcrcospecific and may have been the source of the 12% diastercomeric contaminant. d From the ee of the homoallylic alcohol derivative formed by reaclion with benzaldchyde, measured by GC on a chiral column. 

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 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 ... 

Scheme 6 Cleavage of Pinanediol Esters of Boronic Acids by Hydrolysis with Water...

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). 

Bromo-l-chlorobutylboronic Add Pinanediol Ester (25) Using Dichloromethane/Butyllitbium/ Zinc(II) Chloride 14 ... 

Bromo-l-[bis(trimethylsilyl)amino]butylboronic acid pinanediol ester (26) was prepared by first dissolving hexamethyldisilazane (16.9 mL, 80.0 mmol), in THF (30 mL), cooling the soln to —78 °C, and adding 1.62 M BuLi in hexane (49.4 mL, 80.0 mmol). The soln was allowed to slowly warm to rt. It was recooled to —78°C and 4-bromo-l-chlorobutylboronic acid pinanediol ester (25 28.0 g, 80.0 mmol), was added in THF (20 mL). The mixture was allowed to slowly warm to rt and to stir overnight. The solvent was removed by concentration and dry hexane (400 mL) was added to yield a precipitate, which was removed by filtration under N2. The filtrate was cooled to —78 °C and 4 M anhyd HC1 in dioxane (60 mL, 240 mmol) was added. The reaction was allowed to slowly warm to rt and stirred for 2h. Additional hexane can be added to aid in precipitation. The product was isolated as a solid (20 g) by filtration. After drying in vacuo, the crude product was dissolved in CHC13 and insoluble material was removed by filtration. The filtrate was concentrated and the residue dissolved in EtOAc. The product 27 was crystallized (EtOAc) yield 15.1 g (51%) mp 142-144°C. 

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... 

S, 4S)-4-Methylheptan-3-ol is a component of the aggregation pheromone of the elm bark beetle Scolytus multistriatus. It is readily synthesized from the (s) pinanediol ester of propylboronic acid as shown in Figure B6.2. 

There are several situations where cleavage of a 1,3,2-dioxaborolane to the boronic acid and diol is useful. One of these is for removal of a chiral director and replacement by its enantiomer. The first time we encountered this problem, a pinanediol ester was converted to the boronic acid via destructive cleavage of the pinanediol with boron trichloride (14). More recently, it has proved possible to convert an (R)-DICHED a-benzyloxy boronate (20) to the free bororric acid (23) with the aid of sodium hydroxide and a tris(hydroxymethyl)methane to form water soluble derivative 21 (R = CH2OH or NH(CHi)3S03 ) plus water insoluble (R)-DICHED (22). Treatment of 23 with (S)-DICHED (24) then yielded diastereomer 25 (76%, 97-98% diastereomeric purity). Further chain extension and alkylation led to 26 and 27, and deboronation yielded 28, all of which are stereoisomers that could not be accessed directly with a single chiral director (Scheme 6). 

The chemistry of boronic esters that have cyano substituents closely resembles that of boronic esters with carboxylic ester substituents. The same rules apply to the requirements for separation between the boron atom and the substituent. Lithioace-tonitrile reacts with (a-haloalkyl)boronic esters in the same maimer as does tert-butyl lithioacetate, but the less bulky nitrile function encounters fewer steric obstacles. Some examples of sterically hindered compounds that can be made in this way include pinanediol ester 97 [46], (J )-DICHED ester 98 [54], and the (a,a-dimethyl-P-cyanoethyl)boronic ester 99 (Scheme 8.22) [37]. 

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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