Enolates amide-derived

Carbonylation of enol triflates derived from ketones and aldehydes affords Q,/)-unsaturated esters[332]. Steroidal esters are produced via their aryl and enol triflates[328]. The enol triflate in 477 is more reactive than the aryl tritlate and the carbonylation proceeds stepwise. First, carbonylation of the enol triflate affords the amide 478 and then the ester 479 is obtained in DMSO using dppp[333]. 

Figure 3.11 Woodward s reagent K undergoes a rearrangement in alkaline solution to form a reactive ketoket-enimine. This active species can react with a carboxylate group to create another active group, an enol ester derivative. In the presence of amine nucleophiles, amide bond formation takes place.

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

Note that we can write a similar resonance picture for esters, and we shall actually need to invoke this when we discuss enolate anions (see Section 10.7). However, electron donation from oxygen is not as effective as from the less electronegative nitrogen. We shall also see that this resonance effect in amides has other consequences, such as increased acidity of the amide hydrogens (see Section 10.7) and stereochemical aspects of peptides and proteins (see Section 13.3). In addition, the amide derivatives have... 

Alkylation of the enolates of the amides derived from these chiral auxiliaries is a very useful method for the enantioselective preparation of chiral 2-alkylalkanoic acid derivatives. 

One of the key steps in building the fused ring involves the reaction of the activated acetoacetate methylene group in that compound with toluenesulfonyl azide to give the diazo intemediate (12-1). Treatment of that product with rhodium acetate leads to a loss of nitrogen with the consequent formation of carbene (12-2) this inserts into the adjacent amide N—H bond to form a five-membered ring and thus the carbapenem (12-3) [15]. The first step in the incorporation of the thioenol function consists in the conversion of the ketone to the enol phosphate derivative... 

With regards to studies on the stereoselective functionalization of prochiral glydne Dpm amide derivative 22, Maruoka and coworkers found that chiral ammonium enolate generated from lg and 22 had an ability to recognize the chirality of P-branched primary alkyl halides, which provides impressive levels of kinetic resolution during the alkylation with racemic halide 29, allowing for two a- and y-stereocenters of 30 to be controlled, as exemplified in Scheme 5.16 [22]. 

Recent progress on the use of hypervalent iodine reagents for the construction of carbon-het-eroatom (N, O, P, S, Se, Te, X) bonds is reviewed. Reactions of aryl-A3-iodanes with organic substrates are considered first and are loosely organized by functional group, separate sections being devoted to carbon-azide and carbon-fluorine bond formation. Arylations and alkenyla-tions of nucleophilic species with diaryliodonium and alkenyl(aryl)iodonium salts, and a variety of transformations of alkynyl(aryl)iodonium salts with heteroatom nucleophiles are then detailed. Finally, the use of sulfonyliminoiodanes as aziridination and amidation reagents, and reactions of iodonium enolates formally derived from monoketones are summarized. 

The addition of an alkaline earth metal enolate A to a carbonyl compound is always an exer-gonic process irrespective of whether the enolate is derived from a ketone, an ester, or an amide and whether the carbonyl compound is an aldehyde or a ketone (Figure 13.44, top). One of the reasons for this exergonicity hes in the fact that the alkaline earth metal ion is part of a chelate in the alkoxide B of the aldol addition product. The driving forces for the additions of alkaline earth metal enolates of esters and amides to carbonyl compounds are further increased because the aldol adducts B are resonance-stabilized, whereas the enolates are not. 

The Merck group has applied the electrophilic amination using lithium terf-butyl N-(tosyloxy)carbamate 9a to the chiral amide derived from (lS,2/ )-cw-amino-indanol [10] (Scheme 4). Treatment of 10 with n-Buli in THF at -78 °C gave the lithium enolate which was reacted with CuCN. The resulting amide cuprate was allowed to react with 9a. The authors found that a single diastereomer of a-Boc-protected amino amide 11 was formed. The sense of asymmetric induction observed was consistent with preferential approach of 9a from the least hindered face of the enolate. The removal of the chiral auxiliary with refluxing 6N HC1 afforded a-amino acids 12 in good yields and optical purities. 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

New bases have also been proposed to extend the arsenal presented in Scheme 16. In particular, conformational constraints have been introduced on the amide. It was shown, for instance, that e.e. values up to 81% can be returned for the deprotonation of 4-f-butylcyclohexanone in a THF/HMPA mixture by a lithium amide derived from a tetrahydroquinoline bearing a heterocycle at C3102. Note that the same ketone can be converted in its (S)-enolate in 90% e.e. resorting to the bulky lithium A-trityl-A-(/ )-l-phenethylamide79. Interestingly, chiral lithium amides on polymeric solid support have also been successfully employed to deprotonate bridged cycloheptanones103. 

The direct fluorination with elemental fluorine at — 78 "C of trimethylsilyl enol ethers derived from diketones results in the formation of the corresponding monofluoro diketones 11 in moderate yield. The trimethylsilyl ethers from cyclic diketones undergo smooth fluorination to give the enol forms, c.g. 12, and not the keto forms.Higher yields are generally observed for the analogous reactions of silyl derivatives of esters, carboxylic acids, malonates, dimethyl amides and lactones (Table 4). ... 

Asynunetric Deprotonation/Protonation of Ketones. Lithium amides of chiral amines have been used for performing asymmetric deprotonations of symmetrically substituted (prochiral) ketones. The resulting optically active enols orenol derivatives (most frequently enol silanes) are highly versatile synthetic intermediates. Particularly useful for this purpose are chiral amines possessing Cj symmetry, such as (1). For example, reaction of 4-r-butylcyclohexanone with the lithium amide of (R,R)-(1) (readily prepared in situ by treatment of (1) with n-Butyllithium) is highly stereoselective the resulting enol silyl ether possesses an 88% ee (eq 4). ... 

A similar conformational analysis has been done with formamide derivatives, with secondary amides, and for hydroxamide acids. It is known that thioformamide has a larger rotational barrier than formamide, which can be explained by a traditional picture of amide resonance that is more appropriate for the thioformamide than formamide itself. Torsional barriers in a-keto amides have been reported, and the C—N bond of acetamides, thioa-mides, enamides carbamates (R2N—C02R), and enolate anions derived... 

In the strictest sense, the aldol reaction involves the condensation of an enolate derived from an aldehyde or a ketone with another aldehyde or ketone to give a (3-hydroxyaldehyde or a (3-hydroxyketone, respectively. In a broader sense, the aldol reaction encompasses reactions of enolates—usually derived from ketones, esters, or amides—with an aldehyde or a ketone. 

The lithium enol e derived from N/ -dimethylcycloheptatrienecarboxamide (172) crystallizes as the bis-THF-solvated dimer (173). Neither the amide nitrogens nor the extended ir-system participates in complexation to the lithium atoms in this complex. 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

Myers et al. found that silyl enolates derived from amides undergo a facile non-catalyzed aldol addition to aldehydes at or below ambient temperature [90]. In particular, the use of cyclic silyl enolate 27, derived from (S)-prolinol propionamide, realizes high levels of diastereoface-selection and simple diastereoselection (anti selectivity) (Scheme 10.27). It has been proposed that this non-catalyzed highly stereoselective reaction proceeds via attack of an aldehyde on 27 to produce a trigonal bipyramidal intermediate 29 in which the aldehyde is apically bound 29 then turns to another isomer 30 by pseudorotation and 30 is then converted into 28 through a six-membered boat-like transition state (rate-determining step). 

Under more equilibrating conditions such as alkoxide bases in alcohol solution or amide bases in liquid ammonia, enolisation occurs to give the extended enolate 83 which is then alkylated in the a-position by alkyl halides. At first this seems the most difficult combination to achieve thermodynamic enolisation followed by kinetically controlled addition of an electrophile, but it is in fact a common result achieved with a variety of bases. Examples include the synthesis of pentethylcyclanone 100, an anti-tussive drug, by alkylation of the enone 103, the aldol dimer of cyclopentanone. Disconnection at the branchpoint to the available alkyl halide 102 X = Cl requires a-alkylation of the extended enolate 101 derived from the cyclopentanone aldol dimer27 103. This is easily achieved by sodium amide in toluene.28... 

The development of the asymmetric aldol reaction [2] has been dominated by the stereo-controlled addition of chiral, amide-derived enolates to, mainly, aldehydes. This constitutes an excellent method for the first step of many NARC processes. The pamamycins [3] and the nactins [4] are two groups of naturally-occurring ionophores. They contain tetrahydrofuran sub-units which have proved to be suitable targets for the application of the NARC process. 

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