Imide enolates, chiral

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 ... 

Reagent control This involves the addition of a chiral enolate or allyl metal reagent to an achiral aldehyde. Chiral enolates are most commonly formed through the incorporation of chiral auxiliaries in the form of esters, acyl amides (oxazolines), imides (oxazolidinones) or boron enolates. Chiral allyl metal reagents are also typically joined with chiral ligands. 

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 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... 

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... 

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

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. 

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). 

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. 

Following the same strategy, further improvements in similar catalytic asymmetric [4 + 2] cycloaddition reaction have been made by Lectka group. The cyclic 1,4-benzoxazinones 3 (Scheme 10.4) that rely on the highly enantioselective [4 + 2] cycloaddition of o-benzoquinone imides with chiral ketene enolates were efficiently constructed, which can be derivatized in situ to provide a-amino acid derivatives in good to excellent yields and with virtual enantiopurity [9]. 

Optically active 2-alkylbutanedioates are also available from the stereoselective alkylation of chiral imide enolates. Thus, prepared by means of nondestructive and reusable chiral auxiliaries (e.g. chiral oxazolidinones ), dimethyl (7 )-2-terr-butylbutanedioate (>99 /oee)... 

A different approach to enantioselective electrophilic fluorination is the use of chiral auxiliary groups on the substrate this converts the problem into a diastereo-selective fluorination. The ground-breaking work in this field was done since 1992 by the Davis group [207], by fluorination of imide enolates modified by Evans oxazolidinone chiral auxiliary [208] using N-fluoro-o-benzenedisulfonimide (NFTh) as the electrophilic fluorination agent (Scheme 2.94). 

Amide and imide enolates. Scheme 5.31 illustrates several examples of asymmetric Michael additions of chiral amide and imide enolates. Yamaguchi [163] investigated the addition of amide lithium enolates to -ethyl crotonate, but found no consistent topicity trend for achiral amides. The three chiral amides tested are illustrated in Scheme 5.31a-c. The highest diastereoselectivity found was with the C2-symmetric amide shown in Scheme 5.3Ic. Evans s imides, as their titanium enolates, afforded the results shown in Scheme 5.31d and e [164,165]. The yields and selectivities for the reaction with acrylates and vinyl ketones are excellent, but the reaction is limited to P-unsubstituted Michael acceptors P-substituted esters and nitriles do not react, and 3-substituted enones add with no selectivity [165]. 

Diastereoselective trifluoromethylation of chiral imide enolate with iodotri-fluoromethane was performed at -78 °C to produce a-trifluoromethyl carboximide... 

Scheme 8. Diastereoselective trifluoromethylation of chiral imide enolates...

Imide enolates derived from (5)-valinol and (15,2/f)-norephe-drine and obtained by either LDA or Sodium Hexamethyldisi-lazide deprotonation (eq 24) exhibit complementary and highly diastereoselective alkylation properties. Mild and nondestructive removal of the chiral auxiliary to yield carboxylic acids, esters, or alcohols contributes to the significance of this protocol in small-and large-scale synthesis. ... 

The enantioselective introduction of fluorine has been accom plished by the use of chiral imide enolates derived from Evans... 

The most general protocol (eq 10) has therefore been based on potassium hexamethyldisilazide (KHMDS) as the base addition of trisyl azide at —78 °C and then acetic acid at the same temperature. Excellent levels of diastereoselectivity are ohsCTved with most substrates and the method has been used widely in the enantioselective synthesis of a-amino acids from chiral iniides. Chemoselective azidation of an imide enolate in the presence of an ester function has been demonstrated (eq 11). The product distribution is nevertheless finely balanced, as discovered with the respective dimethyl and dihenzyl ethers of the 3,5-substituted phenylacetyl imide (3) (eq 12). ... 

General Synlliesis.— An enantioselective synthesis of a-substituted carboxylic acids and their derivatives has been described involving the asymmetric alkylation of chiral imide enolates. Yields are good, and the optical purity of the purified products is >99% for each case. The method (Scheme 1) has been... 

The enantioselective introduction of fluorine has been accomplished by the use of chiral imide enolates derived from Evans ox-azohdone chiral auxihary (eq 13). This approach has been utilized to prepare o -lluoroaldehyde, a-lluoroketone, a-fluoroacid, and 2-deoxy-2-fluoropentose derivatives. 2 Fluorination of )8-keto amides can be used as a method to prepare 3-lluoroazetidinones. ... 

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