Asymmetric synthesis, with boronic esters

Recent Progress in Asymmetric Synthesis with Boronic Esters... 

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 earlier work, we had shown that a-azido boronic esters are surprisingly stable and will undergo the reaction with (dichloromethyl)lithium, albeit with some complications caused by azide reactivity (1). We have also used azido boronic esters as intermediates in an asymmetric amino acid synthesis (21). It now appears that azido boronic esters may be the best general protected amine functionality for synthetic purposes, and we will report new flndings in this area shortly (22). Older findings with azido boronic esters as well as the compatibility or incompatibility of other polar functionality with boronic ester chemistry have been reviewed elsewhere recently in considerable detail (23). 

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]. 

The reaction of boronic esters with (dihalomethyl)lithium is particularly well suited to the building of asymmetric structures in which there are no functional substituents. At the end of the synthesis, the boronic ester group can be replaced by reaction with hydrogen peroxide to form the corresponding asymmetric secondary alcohol [11,12, 29]. 

The use of a-halo(alkyl) boronic esters in asymmetric synthesis provides state of the art stereoselection1-3. The diastereomeric ratio of the a-halo boronic esters synthesized as intermediates is routinely in the 100 1 range. However, with the proper choice of chiral director, displacement of the oc-halogen provides a second stcrcodifferentiation step, after which diastereomeric ratios may exceed 1000 1 4. 

In the initial discovery of the asymmetric synthesis of a-chloro boronic esters 3, the diastereomeric ratios of 3 were estimated by reaction with Grignard reagents to form secondary alkyl boronic esters 5 and deboronation with hydrogen peroxide to secondary alcohols of known absolute configuration and rotation40. 

These difficulties of asymmetric synthesis of a-alkoxy boronic eslers are disappointing inasmuch as these esters are particularly useful in the chirality transfer reaction with aldehydes, reviewed in Section D.1.3.3.3.3. 

The quinoline portion of the target alkaloids was prepared by condensing p-anisidine 9 with ethyl propiolate, followed by bromination. Coupling of 10 with the boronic ester 8 proceeded to give 11, the intermediate for the synthesis of both 1 and 2. Selective direct epoxidation of 11 using the usual reagents failed, but Sharpless asymmetric dihydroxylation was successful, providing the diol in > 96 4... 

This iterative procedure has been utilized with great effect in asymmetric synthesis via chiral boronic esters derived from chiral alcohols. ... 

It is dear that boron is the most common metal for attaching chiral ligands, and this is mainly due to ease of preparation. However, chiral ligands on titanium can also promote enantioselective aidol reactions. Duthaler s reagent 56 leads to good levels of asymmetric induction with acetate aidol reactions [39] and has been used with ester 57 to give 58, an important intermediate in the total synthesis of tautomycin (Scheme 9-19) [40]. 

Oppolzer has developed a method of asymmetric synthesis based on the use of the chiral auxiliaries 39A and 39B derived respectively from (+ )-camphor [(+ )-40] and (- )-camphor [(- )-40]. Crotonylation of 39A gave the ester that was attacked by 4-methyl-3-pentenyllithium in the presence of copper iodide tributylphosphine and boron trifluoride from only one side of the molecule, the product 41 having the (S)-configuration (enantioselectivity 98.5%). The ester 42—similarly obtainable from 39B—was methylated under similar conditions, also yielding 41 with 92% enantioselectivity. (S)-Citronellic acid [(S)-36] or (S)-citronellol [(S)-33] were then obtained from 41 by the action of sodium hydroxide or lithium aluminum hydride (Scheme 6). Reduction of potassium... 

A general synthesis of a-chiral ketones with essentially 100% ee is based on the utilization of boronic esters. These esters can be prepared by asymmetric hydroboration of prostereogenic olefins and subsequent removal of the chiral auxiliary. Two approaches to a-chiral ketone formation are known ... 

The utility of (a-haloalkyl)boronic esters in asymmetric synthesis results from a unique combination of several features of their chemistry. A wide variety of products can be obtained in very high stereopurity, and the reactions are compatible with a considerable variety of functional substituents, provided that OH and NH groups are masked. Stereospecific displacement of halide from an (a-haloalkyl)boronic ester with a nucleophile yields an asymmetric boronic ester, which can either be converted stereospecifically into another product such as an alcohol or put into another cycle of reaction with (dihalomethyl)lithium to install additional stereocenters. The general synthetic utility of these boronic esters can best be understood from a detailed outline of the general processes involved. 

The stability of a-azido substituents in boronic esters was first observed in exploratory studies [29]. Azido groups are compatible with several standard reactions of boronic esters, including chain extension with (dichloromethyl)lithium and substitution of the resulting a-chloro substituent. After peroxidic deboronation, reduction of the azido group with lithium aluminum hydride led to an asymmetric amino alcohol, (5S,6S)-BuCH(NH2)CH(OH)Bu, in 98% diastereopurity [29]. Details ofa more recent amino alcohol synthesis are shown below in Scheme 8.31. 

Once this information had been obtained, a simple asymmetric synthesis of amino acids (130) followed (Scheme 8.30) [67]. Reactions with azide ion were sluggish, and (a-bromoalkyl)boronic esters (126) were preferred. These reactions were carried out... 

A simple extension of the foregoing synthesis was also shown to be usefrd for making phenylalanine asymmetrically deuterated in the CHD group [68], Azido substituted boronic esters have been mentioned in passing in Section 8.3.5 in conjunction with another synthesis (Scheme 8.22) [54]. 

Several types of replacement of halide by metals are known. The only one that appears to have direct utility in asymmetric synthesis is the reaction of (tributylstan-nyl)lithium with (a-chloroalkyl)boronic esters. The replacement is stereospecific and provides a route to a-lithioethers having high enantiopurity [88]. This chemistry is illustrated by the conversion of (S)-DIPED (R)-(l-chloro-2-methylpropyl)boronate (157) into the (S)-tributylstannyl derivative 158 (Scheme 8.38). The displacement is unusually sluggish and was promoted with zinc chloride. Peroxidic deboronation yielded... 

The utility of (a-haloalkyl)boronic esters as reagents for asymmetric synthesis is well established. A wide variety of products can be made in high stereopurity. This fundamental research has been supported for many years by the National Science Foim-dation, with periods of additional support from the National Institutes of Health. The discovery of the useful anticancer pharmaceutical Velcade , which is derived from an (a-aminoalkyl)boronic ester made from an (a-haloaIkyl)boronic ester, provides an example of the practical long-range benefits of support for fundamental research. 

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