Of -pinanediol

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

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

A stirred soln. of pinanediol in THF under an inert atmosphere treated via syringe with ca. 1 eq. lithium triethylborohydride at 0°, stirred at the same temp, for 5 min then at room temp, for 1 h, quenched with water, and stirring continued for a further 30 min product. Y 85%. The reaction fails with catechols, the corresponding lithium salts being formed. F.e. incl. 5cc-butyl and /-amyl derivs. s. L. Garlaschelli et al.. Tetrahedron Letters 30, 597-600 (1989). 

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]. 

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). 

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

The first test of pinanediol (a-chloroalkyl)boronic ester chemistry included syntheses of (2S,3S)- and (2J ,3S)-3-phenyl-2-butanol, each in 94-96% diastereopurity and, assuming independent stereoselection for installation of each of the two adjacent stereocenters, >99% enantiopurity [11]. These targets were chosen because their absolute configurations had been estabhshed by Cram s classic work [30]. Zinc chloride catalysis had not been discovered, and other features of the syntheses are also ob-... 

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]. 

The homologation of phenylboronic esters of pinanediol with dichloromethyl-lithium proceeds via a lithium borate intermediate, leading to a synthesis of either the threo- or ery//tro-alcohols (70), depending on the enantiomer of pinanediol used in the second step. " ... 

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. 

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. 

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). 

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%. 

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. 

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