Chiral adjuvants

Posner and coworkers have published a series of papers in which they described a successful application of the Michael reaction between a variety of carbanionic reagents and chiral cycloalkenone sulphoxides 557 to the synthesis of chiral organic compounds (for reviews see References 257, 649, 650). In several cases products of very high optical purity can be obtained. Subsequent removal of the sulphinyl group, serving as a chiral adjuvant, leads to optically active 3-substituted cycloalkenones 558 (equation 356 Table 27). 

Mukaiyama et al. developed a rather general and versatile method for the preparation of optically active a-hydroxyaldehydes by using the diamine (99) as chiral adjuvant. Thus, one Grignard reagent (R MgX) is reacted with the aminal (102) of methyl glyoxylate. In the next step a second kind of Grignard reagent (R2-MgX) is diastereoselectively added to the ketoaminal, and the desired chiral a-hydroxy-aldehyde (103) is obtained by hydrolysis 117-1I8). 

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. 

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. 

The most important development of this useful procedure has been the incorporation of an optically active amino alcohol, to provide a chiral adjuvant (or auxilliary), in the resulting oxazoline. The amino alcohol employed was (1S.2S)-... 

Chiral 4-substituted Pybox derivatives (1) were synthesized as chiral adjuvants to study remote electronic effects of the substituents in the asymmetric hydrosilylation. The 4-Cl-Pybox-(5,5)-ip-Rh catalyst afforded the highest result (80% ee (5)) for the reduction of 2-octanone to 2-octanol in 88% yield. 

A special class of acyclic diastereoselective reactions involves the use of chiral auxiliaries to control the absolute stereochemistry of nucleophilic additions at carbonyl centers. This process takes advantage of steric and/or electronic factors within the chiral adjuvant to promote nucleophilic addition from one face of the molecule, and thereby generate one predictable diastereomer. Removal of the auxiliary, in the best cases, generates enantiomerically pure products, as well as the recyclable chiral adjuvant. The end result of this process is the synthesis of enantiomerically pure products via diastereoselective reactions. 

Allylic t ganranetallics modified at the metal center by chiral adjuvants add to aldehydes and ketones to provide optically active hranoallylic alcohols. This process has been described for reagents containing boron, tin and chromium metd centers. Gore and coworkers have shown that a chrranium-medi-ated addition reaction of allylic brranides to simple aldehydes that uses a complex of lithium N-methyl-nt ephedrine and chromium(Il) chloride occurs with modest (6-16% ee) enantioselectivity (equation 61, Table 8). 

Advantages of this chiral auxiliary include the ready availability of either enantiomer and its ease of removal, as well as the dual utility of the chiral acetal as both chiral auxiliary, and carbonyl-protectirig group. A published synthesis of optically pure (-)-7-deoxydaunomycinone exemplifies the utility of this chiral adjuvant. ... 

Diastereoselective halogenations using removable chiral auxiliaries have been the purpose of recent significant developments. a-Halo aldehydes, a-halo ketones and a-halo carboxylic acid derivatives are very useful precursors involved for total syntheses of pharmaceutical drugs and phytochemicals. In most cases, the biological activity is associated with one of the two enantiomers. So, diastereoselective halogenation of carbonyl compounds and carboxylic acid derivatives has attracted considerable attention in recent years, as a tool for the production of enantiomerically pure substances. The numerous examples of diastereoselective halogenation of compounds with non removable chiral adjuvants are outside the scope of this review. 

If a chiral adjuvcuit (chiral auxiliary reagent) is built into the starting material, the chiral center (or other chiral element) created in the asymmetric synthesis must be readily separable from the chiral adjuvant without racemization ... 

The chiral adjuvant itself must be recoverable in good yield and without loss of encuitiomeric purity. 

The chiral adjuvant should be readily (cheaply) available in enantiomerically pure form. 

In order to examine the steric course proposed by Mitsui et al., we have performed asymmetric syntheses of alanine, a-aminobutyric acid, phenylglycine, phenylalanine and glutamic acid from the corresponding a-keto acids using (S)-a-methylbenzylamine [Me(-)], ( )-a-ethylbenzylamine [Et(-)] and (R)-a-(1-naphthyl)ethyl-amine [Naph(-)] as the chiral adjuvant. The results are shown in Table... 

Addition of Chiral Ligands. If a chiral adjuvant is used to achieve asymmetric induction, it should preferentially be inexpensive, easily removed, efficiently recovered, and capable of inducing high stereoselectivity. Of these, 1,3-oxathianes based on (-l-)-camphor or (-l-)-pulegone, and proline-derived 1,3-diamines, have been accorded the greatest attention. 

D-(-)-diethyl- or L-(+)-diethyl tartrates as chiral adjuvants. Treatment of the neryl epoxide (150) with titanium tetraisoprop-... 

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