Imides, enolates

Chiral amide and imide enolates are amongst the most effective reagents providing. yv -3-hy-droxycarboxylic acids in both high simple diastereoselectivity and induced stereoselectivity, e.g., the amides 1 and 2, and especially, the imides 3 and 4 (derived from (S(-valine and (l/ ,2S)-norephedrine, respectively)93 and the C2-symmetric amide 594 are highly effective systems ... 

A few a/j/r -selective amide and imide enolates which arc able to provide high induced diastereo-selectivity have been uncovered very recently. The /V-propionylsultam 1 w hich opens a way to sryn-aldols as described in Section D.1.4.3.2.3.1. also allows the synthesis of r/nh-adducls. For this purpose. 1 is converted into the silyl-iV.O-ketene acetal 2 and subsequently added to aldehydes in a Mukaiyama-type aldol reaction106 to give awi-adducts 310<>f. 

STEREOSELECTIVE ALDOL CONDENSATIONS 3. Chiral Amide and Imide Enolates... 

The chiral auxiliaries H-A developed by Evans et al. 176) were derivatives of naturally occurring amino acids. The (S)-proline-derived amide enolates (164) as well as the (S)-valine-derived amide enolates (166) and imide enolates (165) have proven to be exceptionally versatile chiral nucleophiles. 

The metallation should proceed via the formation of a chelated tetrahedral magnesium enolate complex, with a (Z)-geometry. The conformational rigidity would be enforced by chelation of both the imide enolate and bis(sulfonamide) ligand to the tetrahedral magnesium ion. 

The enantioselective amination of iV-acyl oxazolidinones has been studied as part of a general approach to the synthesis of arylglycines. In this case, the enolization is initiated by a chiral magnesium bis(sulfonamide) complex. The oxazolidinone imide enolates are generated using catalytic conditions (10 mol% of magnesium complex) and treated in situ with BocN=NBoc to provide the corresponding hydrazide. 20 mol% of iV-methyl-p-toluensulfonamide are added to accelerate the reaction (equation 117). 

The electrophilic introduction of azide with chiral imide enolates has also been used to prepare a-amino acids with high diastereoselection (Scheme 2.6). The reaction can be performed with... 

Diastereoselective acylation of the imide enolates of 107 proceeded smoothly, and the corresponding P-keto carboximides were obtained in good yield and excellent >96% de. The acylated products could be converted to P-hydroxy carboximides in high syn anti selectivity (96 4 in the... 

The reaction of 1-iodonaphthalene with chiral-assisted imide enolate ion 3 provides an interesting example of the stereoselective coupling of an aromatic radical with a nucleophile. In this reaction, the diastereomeric isomers of the substitution compound are formed (43-64%), while the seledivity observed is highly dependent on the metal counterion used and its chelation properties (Scheme 10.11). All of the ions studied (Li, Na, K, Cs, Ti(IV)) are seledive however, the highest stereoseledivity... 

Electrophilic Azidation of Chiral Imide Enolates to Give at-Ami no Acids... 

A further investigation was carried out to determine whether the trends observed during the azidation studies of imide enolates (see previous section) were applicable to other types of enolates. Consequently dihydrocinnamate 1 was chosen as a typical ester enolate2. 

The best results are obtained with trisyl azide, which again leads to high yields of the azide transfer product 2, especially if the enolate 1 is added to trisyl azide (see entries 1 and 2). Interestingly, the best chemoselectivity and, in addition, identical yields of azide (73%) result from the reaction of the lithium enolate with trisyl azide (entry 3). The reaction of the ester enolate 1 with trisyl azide is less sensitive to the nature of the enolate metal than is the corresponding imide enolate reaction (see Section 7.1.1.). Acetic acid quench, on the other hand, again proved to be useful. Unfortunately, bis-azidation to 3 and diazo transfer to 4 are also observed. 

The lower stereoselectivity compared with the azidation of the imide enolate 6 (see Section 7.1.1.) is surprising in view of the much higher selectivity (>96%) observed in the alkylation reactions of 610. 

Electrophilic Azidation of a Chiral, Cyclic Imide Enolate... 

Nitta, Hatanaka and Ishimura11 started their synthesis of cephalosporin precursors from L-aspartic acid. The key intermediate is the lactone 1. The azidation resembles the general preparation procedure given for open-chain imide enolates in Section 7.1.1. The main differences are the generation of a dianion with lithium diisopropylamide and the application of tosyl azide. 

In summary, although the azidation of phosphorus-stabilized carbanions at the present time is not yet as stereoselective as azidation, especially of chiral imide enolates (see Section 7.1.1.), the Evans reagents2 also provide a promising methodology for the preparation of optically active a-aminophosphonic acids12. 

In contrast, molybdenum and iron diene complexes undergo the same type of reaction with chiral lithium imide enolates, with moderate to good induction at the p-position (eq 16). ... 

Michael Addition. Titanium imide enolates are excellent nucleophiles in Michael reactions. Michael acceptors such as ethyl vinyl ketone, Methyl Acrylate, Acrylonitrile, and f-butyl acrylate react with excellent diastereoselection (eq 21 ). - Enolate chirality transfer is predicted by inspection of the chelated (Z)-enolate. For the less reactive unsaturated esters and nitriles, enolates generated from TiCl3(0-j-Pr) afford superior yields, albeit with slightly lower selectivities. The scope of the reaction fails to encompass p-substituted, a,p-unsaturated ketones which demonstrate essentially no induction at the prochiral center. Furthermore, substimted unsamrated esters do not act as competent Michael acceptors at all under these conditions. 

Various chelated lithium imide enolates have also served as nucleophiles in Michael additions to 3-trifluoromethyl acrylate, favoring the anti isomer (eq 22). ... 

Aldol Reactions. The dibutyl boryl enolates of chiral acylox-azolidinones react to afford the syn-aldol adducts with virtually complete stereocontrol (eq 32). 14,43.61-64 Notably, the sense of induction in these reactions is opposite to that predicted from the analogous alkylation reactions. This reaction is general for a wide range of aldehydes and imide enolates. - Enolate control overrides induction inherent to the aldehyde reaction partner. 

Synthesis of Cyclopropanes. Chiral imide enolates which contain y-halide substituents undergo intramolecular displacement to form cyclopropanes. Halogenation of y,5-unsamrated acyl imides occurs at the y-position in 85% yield with modest stereoinduction. The (Z) sodium enolates of these compounds then cyclize through an intramolecular double stereodifferentiating reaction (eq 61). 

Oxazolidinone auxiliaries were also employed for stereoselective acylation reactions of imide enolates with acid halides [158]. For example, the lithium enolate of the imide 223 reacted... 

Evans, D. A., Ennis, M. D., Mathre, D. J. Asymmetric alkylation reactions of chiral imide enolates. A practical approach to the enantioselective synthesis of a-substituted carboxylic acid derivatives. J. Am. Chem. Soc. 1982, 104, 1737-1739. 

In order to overcome the problems associated with acid hydrolysis of amides of prolinol, the Evans research group has investigated the diastereoselectivity of the alkylation of imides derived from chiral 2-oxazolidones. Imide enolates are somewhat less nucleophilic than amide enolates, but they have the advantage that their diastereomeric alkylation products are easily separated and the imide linkage is cleaved with a variety of reagents under mild conditions. As shown in Scheme 64, alkylation of the chelated (Z)-enolate of the propionimide derived from (S)-valinol (135) with benzyl bromide occurred in high chemical yield and with high si-face diastereoselectivity. In addition to oxazolidones, imidazoli-diones have proved to be useful chiral auxiliaries for diastereoselective enolate alkylations. ... 

Jacobson, I. C. and Reddy, G. P. (1996) Asymmetric reactions of chiral imide enolates with a-keto esters. Tetrahedron Letters, 37, 8263-8266. 

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