Pinanediol

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. ... 

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. 

This method was only partially successful with the pinanediol boroanate ... 

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.). 

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. 

Pinanediol (Dichloromethyl)boronate Effects of Lack of C2 Symmetry... 

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.). 

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. 

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. 

Pinanediol (S)-[Chloro(phenyl)methyl]boronate Special Procedure12 ... 

The procedure is similar to that described in the preceding paragraph for the preparation of the (1S)-(1-chloropentyl)boronate, but with (,5)-pinanediol (phenyl)boronate in place of (S(-pinanediol (butyl)boronate as the substrate. An essential difference is that after the zinc chloride is added the mixture is kept at —45 CC to — 25 rC for only 45 min, then immediately concentrated under vacuum with the heating bath kept at — 10 C or below. Further workup, as described in the preceding paragraph, is followed by chromatography on silica gel with light petroleum ether (bp 30-60 C) yield 84% 94 6 d.r. as determined by the ratio of H-NMR absorptions mp 63-64 C (hexane) [or]246 —43.7 (c = 1.25. THF). 

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

After discovery of the higher stereoselectivities made possible by the zinc chloride catalysis, the synthesis was applied to several secondary alcohols having two or more stereocenters15. The first of these (35,4S)-4-methyl-3-heptanol, was first made with (S)-pinanediol as the chiral director, but has since been made more stereoselectively with (R,R)-2,5-dimethyl-3,4-hexanedi-ol (Section 1.1,2.1.2.1.). Another insect pheromone, eldanolide, requires the use of (R)-pinane-diol in order to obtain the natural enantiomer, and introduces the use of an enolate as well as an allylic Grignard reagent for C-C bond formation15. 

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%. 

The insect pheromone exo-brevicomin is a masked diol derivative. The route to the natural enantiomer utilized (7 )-pinanediol as the chiral director15. 

S)-Pinanediol (chloromethyl)boronate is prepared by stirring 48.3 g (0.27 mol) of diisopropyl (chloro-methyl)boronate with 46.1 g (0.27 mol) of (S)-pinanediol in 200 mL of diethyl ether overnight. The solution is concentrated and the product is chromatographed on a short column of silica gel and distilled yield 58.8 g (95%) bp 95-100T (0.2 Torr). 

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. 

Pinanediol (2-Bcnzyloxy-l-bromoalkyl)boronate General Procedure5 ... 

By the general procedure, 10.91 g (36.3 mmol) of (S (-pinanediol [(benzyloxy)methyl]boronatc is converted to (S)-pinanediol [(l.S)-2-(benzyloxy)-l-bromo-ethyl]boronate containing 6% unconverted [(benzyloxy)-methyljboronate. An analytical sample may be obtained by chromatography, but with considerable loss. 

S)-Pinanediol l,2-Bis(benzyloxy)alkyl]boronate General Procedure ... 

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. 

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