Pure auxiliary functions

In the second category, a functional site adjacent to that at which an asymmetric reaction is to be effected is reacted with an optically pure reagent (the chiral auxiliary or chiral adjuvant) to give an optically pure modified reactant. In the subsequent reaction to form the new chiral site, two diastereoisomers would be formed in unequal proportions (the reaction is then said to be diastereo-selective). When the chiral auxiliary is then subsequently removed, one of the enantiomers would be present in a greater proportion [e.g. (c), where the optically pure auxiliary reacts with the carboxyl group, and the subsequent reaction is controlled by the chirality of the auxiliary]. A further point to note is that frequently the mixture of diastereoisomers may be separated readily by one of the latest chromatographic techniques (Section 2.31), in which case removal of the auxiliary leads to the isolation of the pure enantiomers. 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

Trace amounts of complexes 3 and 20 promote the synthesis of optically pure, multiply functionalized, versatile intermediates such as pyrones or lactones from activated, acid-labile siloxydienes with aldehydes. The reagents typically work under mild conditions and therefore promote the survival of valuable functionality in the dienophile, the diene, and cycloadduct [105-107]. As a consequence this procedure is applied in the total synthesis of various natural products, often requiring an intramolecular Diels-Alder approach [106]. Specific interactivity of the chiral precatalyst Eu(hfc)3 (hfc = 3-(heptafluorpropylhydroxymethylene)-D-camphorate with Danishefsky s diene bearing a chiral auxiliary resulted in cycloaddition products of high diastereofacial excess (95 % eq. (8)) [105]. 

After reduction of the carbonyl group with sodium borohydride and protective silylation of the resulting hydroxy group, the auxiliary is removed by ozonolysis of the alkenylphos-phonamide group. By this method, or other obvious sequences, the primary products are converted into a series of enantiomerically pure, interestingly functionalized cyclopropane derivatives (Scheme 4), which should find applications as synthetic building blocks. 

In y-alkoxyfuranones the acetal functionality is ideally suited for the introduction of a chiral auxiliary simultaneously high 71-face selectivity may be obtained due to the relatively rigid structure that is present. With ( + )- or (—(-menthol as auxiliaries it is possible to obtain both (5S)- or (5/ )-y-menthyloxy-2(5//)-furanones in an enantiomerically pure form293. When the auxiliary acts as a bulky substituent, as in the case with the 1-menthyloxy group, the addition of enolates occurs trans to the y-alkoxy substituent. The chiral auxiliary is readily removed by hydrolysis and various optically active lactones, protected amino acids and hydroxy acids are accessible in this way294-29s-400. 

The auxiliary electrolyte is generally an alkali metal or an alkaline earth metal halide or a mixture of these. Such halides have high decomposition potentials, relatively low vapor pressures at the operating bath temperatures, good electrolytic conductivities, and high solubilities for metal salts, or in other words, for the functional component of the electrolyte that acts as the source of the metal in the electrolytic process. Between the alkali metal halides and the alkaline earth metal halides, the former are preferred because the latter are difficult to obtain in a pure anhydrous state. In situations where a metal oxide is used as the functional electrolyte, fluorides are preferable as auxiliary electrolytes because they have high solubilities for oxide compounds. The physical properties of some of the salts used as electrolytes are given in Table 6.17. 

The use of the glucose chiral auxiliary by Lubineau et al. led to moderate asymmetric induction in the Claisen rearrangement (20% de) (Eq. 12.75).159 Since it could be removed easily, glucose functioned here as a chiral auxiliary. After separation of the diastereomers, enan-tiomerically pure substances could be obtained. 

Chiral amines were always considered important targets for synthetic chemists, and attempts to prepare such compounds enantioselectively date back to quite early times. Selected milestones for the development of enantioselective catalysts for the reduction of C = N functions are listed in Table 34.1. At first, only heterogeneous hydrogenation catalysts such as Pt black, Pd/C or Raney nickel were applied. These were modified with chiral auxiliaries in the hope that some induction - that is, transfer of chirality from the auxiliary to the reactant -might occur. These efforts were undertaken on a purely empirical basis, without any understanding of what might influence the desired selectivity. Only very few substrate types were studied and, not surprisingly, enantioselectivities were... 

Recently, Schaumann et al. 153,154 an(j Bienz et tf/.155,156 have developed dependable routes for the resolution of racemic functionalized organosilanes with Si-centered chirality using chiral auxiliaries, such as binaphthol (BINOL), 2-aminobutanol, and phenylethane-l,2-diol (Scheme 2). For instance, the successive reaction of BINOL with butyllithium and the chiral triorganochlorosilanes RPhMeSiCl (R = /-Pr, -Bu, /-Bu) affords the BINOL monosilyl ethers 9-11, which can be resolved into the pure enantiomers (A)-9-ll and (7 )-9-11, respectively. Reduction with LiAlFF produces the enantiomerically pure triorgano-H-silanes (A)- and (R)-RPhMeSiH (12, R = /-Pr 13, -Bu 14, /-Bu), respectively (Scheme 2). Tamao et al. have used chiral amines to prepare optically active organosilanes.157... 

The focus in this section is the electrophilic a-functionalization of 2,2-dimethyl-l,3-dioxan-5-one. Various reactions have been carried out, such as alkylations, aldol additions, Mannich reactions, and transition metal-catalyzed reactions. Conditions were described for diastereoselective transformations, or auxiliary controlled diastereoselective transformations, providing enantiomerically pure products, and enantioselectively catalyzed reactions using organo-catalysts. 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

Thus, the N,N-dibenzyl-protected aminonitrile 55 was prepared via Swern oxidation of N,N-dibenzylaminoethanol 54 followed by treatment with the enantio-pure amine auxiliary (S,S)-53 and HCN, resulting in the formation of a 3 2 epimeric mixture of the aminonitriles 55 in 55% yield, from which the single dia-stereomers could be isolated by chromatography. After lithiation with LDA, addition to the requisite (E)-a, P-unsaturated esters and hydrolysis of the aminonitrile moiety with silver nitrate, the desired a-amino keto esters R)-S6 were obtained with yields of 65-81% and enantiomeric excesses ee of 78-98%, which could be improved to ee > 98% by a simple recrystallization. Since the amino ketone functionality can be cleaved oxidatively, the 5-amino-4-oxo-esters 56 could be transformed to the corresponding succinic half-esters 57 with hydrogen peroxide in methanol in good to excellent yields (68-90%) (Scheme 1.1.15). 

In the second approach the carbonyl function is incorporated in a chiral adjuvant (or auxiliary) which then stereoselectively directs a preferred attack of the organometallic reagent on the si- or re-faces of the carbonyl group, as determined by steric and electronic interactions. This results in two diastereoisomeric products in a ratio dependent on the relative free energies of activation. One such auxiliary is (12), derived from the readily available and optically pure ( + )-pulegone. 

We also introduced an alternative purification method which makes use of functionalization of the isomer mixture, followed by HPLC separation and final removal of the functional groups [71], Since the functional group attached as an auxiliary is chiral, the method is similar to the one described above for C76. It offers the advantage of not only providing pure constitutional isomers but also enantiomers - when these exist [71]. A conceptually similar approach was... 

For time-dependent systems again the purely exponential time-dependence of the correlation function allows the derivation of a set of differential equations for the auxiliary operators... 

As we shall see, the only restriction as to where the carboxylic acid functional group can be located in the reactant is that it should not make it chiral. It is not necessary for the carboxylic acid group (and hence the chiral auxiliary) to be situated near the site of reaction the role of the chiral auxiliary is simply to insure a chiral space group. A final point is that an amine functional group can serve equally well as the point of attachment of the chiral auxiliary to the reactant. In this case the ionic chiral auxiliary would be an optically pure carboxylate or sulfonate anion. 

---