Amide and Imide 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... 

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]. 

Scheme 5.31. Asymmetric Michael addition of amide and imide enolates. (a-c) [163]. (d)...

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

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 acetylation of amines with isopropenyl acetate appears to be a transition between the highly exothermic reactions of acyl halides and anhydrides with amines on the one hand and the reaction of amines with more conventional esters on the other. While this reagent is of particular value in the preparation of enol acetate, it has been used for the preparation of amides. One interesting aspect of its use is that acetone forms as a coproduct which may distill off as the reaction proceeds. Isopropenyl acetate and other isopropenyl esters may also be used to Y-acylate amides and imides. By the judicious selection of starting amides and isopropenyl esters, tertiary amides with three different acyl groups may be synthesized. This may very well be one of very few reaction systems which permits the synthesis of this rare group of tertiary amides. 

Thus, jyn-adducts arise predominantly, as expected, according to the Zimmerman-Traxier model. Provided that either boron or zirconium is the enolate-metal atom, high syn selectivity is achieved. The total amount of anti-adducts is lower than 2% in the case of amides 1 and 2, and it approaches zero when the other reagents arc used94 . The induced stereoselectivities are impressive for the amides and remarkable in the case of the imides. 

Our research group developed catalytic enantioselective protonations of preformed enolates of simple ketones with (S,S)-imide 23 or chiral imides 25 and 26 based on a similar concept [29]. For catalytic protonation of a lithium eno-late of 2-methylcyclohexanone, chiral imide 26, which possesses a chiral amide moiety, was superior to (S.S)-imide 23 as a chiral acid and the enolate was pro-tonated with up to 82% ee. 

The utility of /f-enaminones (vinylogous amides) and / -enamidones (vinylogous imides) has been successfully demonstrated in both inter- and intramolecular [2 + 2] photocycloaddition reactions. The vinylogous amide, which reacts as a /Mieteroatom substituted enone, serves as the nitrogen analogue of the enol form of a / -diketone in the de Mayo reaction24. 

The superior nucleophilicity and excellent thermal stability of pseudoephedrine amide enolates make possible alkylation reactions with substrates that are ordinarily unreactive with the corresponding ester and imide-derived enolates, such as (3-branched primary alkyl iodides. Also, alkylation reactions of pseudoephedrine amide enolates with chiral (J-branched primary alkyl iodides proceed with high diastereoselectivity for both the matched and mismatched cases (Table 3). ... 

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. ... 

Chiral amides (222) and (223) and imides (224) and (225) have also been studied as reagents for asymmetric aldol reactions. These reagents show excellent diastereofacial preferences as their boron and zirconium enolates, but generally show poor selectivity as their lithium enolates. The reader is referred to other chapters in this volume for a discussion of these and related reagents. 

These four examples do not seem to comply with a consistent mechanistic model. The dilithioprolinol amide enolate in Scheme 5.31a is attacked on the enolate Si face, in accord with the sense of asymmetric induction observed in alkylations of this enolate [166,167]. On the other hand, the structurally similar dilithiovalinol amide enolate, while being attacked on the same face (as expected), reverses top-icity. Furthermore, the S,S-pyrrolidine enolate in Scheme 5.31c is attacked from the Si face by Michael acceptors, but from the Re face by alkyl halides [168] and acid chlorides [169]. The titanium imide enolate in Scheme 5.31d adds Michael acceptors from the Si face, consistent with the precedent of aldol additions of titanium enolates (c/. Table 5.4, entry 2, [88]). An intramolecular addition (Scheme 5.3le) seems to follow a clear mechanistic path [165] the Si face is attacked by the electrophile, and the cis geometry of the product implicates intramolecular complexation of the acceptor carbonyl. This coordination of the acceptor carbonyl is probably a function of the metal recall the lithium ester enolates illustrated in Scheme 5.30c and d, but also metal chelation in titanium aldol additions (Table 5.4, entry 2). 

Heterocyclic analogues of BINAP, such a< 2,2, 5,5 -tetramethyl-4,4 -bis(dipheny Iphosph and tested in the Heck reaction. Incorporaut sulfinyl group to a double bond elicits enj intramolecular Heck reaction. Optically ai ides are produced from (/ )-l-f-butylsulfinylcy Palladacycle (109) and its analogues ind rearrangement of allylic imidates. - For a thioamides, it is convenient to allylate thi dine. This process involves a thio-Claisen n Enantioselective deprotonation of ketones slum bis[yV-benzyl-N-(a-phenethyl)]amide.-- tonation of enolates. ... 

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. ... 

Problem 4.—Write the enolic or "aci formulas corresponding to the formulas given above for imides, I and II nitro compounds, sulfone amides, and enols. Note that all of the acidic groups may be considered as possessing an hydro.xyl group united to an unsaturated atom. 

Lithium enolates from esters, amides, and ketones may be fluorinated with A-fluorobis[(trifluoromethyl)sulfonyl]imide (Eq. 6.58) [91],... 

---