Enantioselective preformed enolates

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. 

Among the methodologies listed in the introduction to generate the key enol/enolate intermediate, the enantioselective protonations of metal enolates, the so-called preformed enolates, or of their substitutes such as enamines or enol ethers have known, by far, the most intensive research development (Scheme 7.2). 

Our research group independently found a catalytic enantioselective proto-nation of preformed enolate 47 with (S,S)-imide 30 founded on a similar concept (Scheme 5) [51]. The chiral imide 30, which has an asymmetric 2-oxazoline ring and is easily prepared from Kemp s triacid and optically active amino alcohol, is an efficient chiral proton source for asymmetric transformation of simple metal enolates into the corresponding optically active ketones [50]. When the lithium enolate 47 was treated with a stoichiometric amount of the imide 30, (K)-en-riched ketone 48 was produced with 87% ee. By a H-NMR experiment of a mixture of (S,S)-imide 30 and lithium bromide, the chiral imide 30 was found to form a complex rapidly with the lithium salt. We envisaged that a catalytic asym-... 

The reaction, if not controlled, can give a very complicated mixture of products due to reactivity, chemoselectivity, regioselectivity, and stereoselectivity issues. The synthesis of aldols with defined stereocenters in an efficient diastereo- and enantio-controlled fashion can be achieved with nature s aldolaze enzymes [2]. Their ability to control the enantioselectivity of the direct aldol reaction led chemists to the development of one of the most important C-C bond formation reactions. In the modem aldol reaction, a preformed enolate is added to a carbonyl compound even though the direct cross-aldol reaction is a more attractive approach [3]. 

Preformed enolates of hthium have been used in enantioselective, albeit not catalytic, aldol additions based upon chiral additives that are used in stoichiometric amounts. In early approaches that may be considered the first enantioselective aldol-type addition, the groups of Seebach [80], Shioiri [81], and Tomioka [82] reported aldol additions of lithium enolates that were mediated by... 

In the context of catalytic enantioselective conjugate additions, preformed enolates play two different roles as enolates, mainly those of silicon, they add to Michael acceptors under activation by a catalyst. On the other hand, enolates are involved in a second different function as intermediates, if any nucleophile reacts with a,P-unsaturated carbonyl compounds they may be quenched by protonation or reaction with different electrophiles in a stereoselective manner. 

Sodeoka and co-workers have reported enantioselective aldol and Mannich reactions (Equations (106) and (J07)) 464,464a 464e Involvement of palladium enolates was confirmed by 111 NMR and ESI-MS spectrometry. /3-Keto esters (pronucleophiles) directly add to imines with high selectivity without preformation of silicon enolates (Equation (108)). 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

The aldol reaction is well established in organic chemistry as a remarkably useful synthetic tool, providing access to p-hydroxycarbonyl compounds and related building blocks. Intensive efforts have raised this classic process to a highly enantioselective transformation employing only catalytic amounts of chiral promoters, as reviewed in the previous section (Chap. 29.1). While some effective applications have been reported, most of the methodologies necessarily involve the preformation of latent enolates 2, such as ketene silyl acetals, using... 

The imines 12 (X = 4-CH3-QH4-SO2 (Ts), Ar, C02R, COR, etc.) preformed or generated in situ from N,0- or N,N-acetals or hemiacetals are another important class of Mannich reagents frequently used for diastereo- and/or enantioselective aminoalkylation reactions catalyzed by chiral Lewis acids (usually copper or palladium BINAP complexes such as 13). Among other things excellent results were obtained in the aminoalkylation of silyl enol ethers or ketene acetals [24], A typical example is the synthesis of Mannich bases 14 depicted in Scheme 5 [24b], Because of their comparatively high electrophilicity imines 12 could even be used successfully for the asymmetric aminoalkylation of unactivated alkenes 15 (ene reactions, see Scheme 5) [24h, 25], and the diastereo- and/or enantioselective aminoalkyla-... 

Later, the same group showed that an asymmetric protonation of preformed lithium enolate was possible by a catalytic amount of chiral proton source 23 and stoichiometric amount of an achiral proton source [45]. For instance, when hthium enolate 44, generated from ketene 41 and -BuLi, was treated with 0.2 equiv of 23 followed by slow addition of 0.85 equiv of phenylpropanone, (S)-enriched ketone 45 was obtained with 94% ee (Scheme 4). In this reaction, various achiral proton sources including thiophenol, 2,6-di-ferf-butyl-4-methylphenol, H2O, and pivalic acid were used to provide enantioselectivity higher than 90% ee. The value of the achiral acid must be smaller than that of 45 to accomplish a high level of asymmetric induction. The catalytic cycle shown in Scheme 2 is the possible mechanism of this reaction. 

Various methods using a stoichiometric amount of chiral proton sources or chiral ligands are available for enantioselective protonation of metal enolates e.g., protonation of metal enolates preformed by deprotonation of the corresponding ketones or by allylation of ketenes [6,7,8,9,10,11,13,17,18,19,21,22,25,26, 29,30,31,32,37,40,41,42,43,49,50,53,54,55,56,57,59,60,63], the Birch reduction of a, 3-unsaturated acids in the presence of a sugar-derived alcohol 2... 

The catalytic enantioselective direct alkylation reaction of enolates is a less developed field. Early research from Evans group demonstrated that preformed titanium enolates derived from chiral Af-acyloxazolidinones reacted with orthoesters to provide the alkylated adducts with high levels of diastereo-control. In2005, the same group reported the enantioselective nickel-catalysed... 

In this chapter, the enantioselective protonation of preformed and a-stabilized carbanions is disclosed. A second part is devoted to the asymmetric protonation of enolate species obtained in situ through a first chemical transformation with activated double bonds (i.e., ketenes or Michael acceptors). Herein, among all the advances made using these two main approaches, methodologies that have been used in total synthesis of natural and pharmacologically active products are emphasized. 

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