Metal enolates, asymmetric protonation

A new chiral proton source (111), based on an asymmetric 2-oxazoline ring, has been found to be capable of effecting asymmetric protonation of simple prochiral metal enolates (112) to give corresponding ketones (113) which need not bear polar groups. 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

The chemistry of asymmetric protonation of enols or enolates has further developed since the original review in Comprehensive Asymmetric Catalysis [1], Numbers of literature reports of new chiral proton sources have emerged and several reviews [2-6] cover the topics up to early 2001. This chapter concentrates on new examples of catalytic enantioselective protonation of prochiral metal enolates (Scheme 1). Compounds 1-41 [7-45] shown in Fig. 1 are the chiral proton sources or chiral catalysts reported since 1998 which have been employed for the asymmetric protonation of metal enolates. Some of these have been successfully utilized in the catalytic version. 

Several new methods for the asymmetric protonation of metal enolates have appeared however, the catalytic mechanisms are fundamentally the same as that described in Scheme 2 of the 1st edition. 

Several new catalytic asymmetric protonations of metal enolates under basic conditions have been published to date. In those processes, reactive metal enolates such as lithium enolates are usually protonated by a catalytic amount of chiral proton source and a stoichiometric amount of achiral proton source. Vedejs et al. reported a catalytic enantioselective protonation of amide enolates [35]. For example, when lithium enolate 43, generated from racemic amide 42 and s-BuLi, was treated with 0.1 equivalents of chiral aniline 31 followed by slow addition of 2 equivalents of ferf-butyl phenylacetate, (K)-enriched amide 42 was obtained with 94% ee (Scheme 2). In this reaction, various achiral acids were... 

The asymmetric synthesis of a-hydroxymethyl carbonyl compounds is currently the subject of considerable interest because of their versatility as dual-function chiral synthons. There have been no reports of successful enantioselective hydroxymethylations of prochiral metal enolates with formaldehyde because of the instability and small steric size of gaseous formaldehyde. The author and Yamamoto et al. developed the enantioselective alkoxymethylation of silyl enol ethers by introducing suitable carbon-electrophiles in place of the activated-protons of LBA [142]. 

Asymmetric protonation of a metal enolate basically proceeds catalytically if a coexisting achiral acid A-H reacts with the deprotonated chiral acid A -M faster than with the metal enolate, a concept first described by Fehr et al. [44]. A hypothesis for the catalytic cycle is illustrated in Scheme 2. Reaction of the metal enolate with the chiral acid A -H produces (R)- or (S)-ketone and the deprotonated chiral acid A -M. The chiral acid A -H is then reproduced by proton transfer from the achiral acid A-H to A -M. Higher reactivity of A -M toward A-H than that of the metal enolate makes the catalytic cycle possible. When the achiral acid A-H protonates the enolate rapidly at low temperature, selective deprotonation of one enantiomer of the resulting ketone by the metallated chiral acid A -M is seen as an alternative possible mechanism. 

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-... 

Asymmetric protonations of prochiral ketenes, metal enolates or enamines are performed with chiral alcohols, amines or amine salts [552], Recently, good enantiomeric excesses ( 80%) have been obtained in ketene protonations with the following a-hydroxyesters methyl (R)- or ([Pg.88]

All of the above methods introduce the aryl group during the enantiodetermining step. An alternative strategy would be to already have the aryl group in place and to generate the tertiary stereocentre via an asymmetric protonation of an enolate complex. This was first reahsed by the pioneering work of Yamamoto in this area with the use of Lewis acid assisted chiral Bronsted acid (LBA) catalysts in the enantioselective synthesis of a-aryl cyclohexanones ((2), Scheme 4.34). Initially developed with the use of stoichiometric quantities of a BlNOL-SnCLi catalyst for the asymmetric protonation of silyl enol ethers, [63] the extensive development of this reaction has resulted in a catalytic variant with an achiral proton donor [64] and expansion of the scope to include tertiary a-aryl carboxylic acids. [65] Further improvement was made with the development of a metal free IV-triflyl thiophos-phoramide BINOL derived proton source (126) [66] and more recently a Lewis base-tolerant chiral LBA [67]. 

Carbon-carbon bond formation by using metal enolates as synthons in organic chemistry and the protonation, alkylation, arylation, and vinylation of enolates have been reviewed. " The stereoselective carbon-carbon formation of bond through Mannich reaction has been detailed according to the type of Mannich base produced. Phosphine-catalysed asymmetric additions of malonate esters to y-substituted allenoates and aUenamides have been reported. ... 

The postulated catalytic cycle of the asymmetric epoxidation reaction is shown in Figure 13.10. A lanthanide metal alkoxide moiety changes to a rare earth metal-peroxide through proton exchange (I). In this step, lanthanide metal alkoxide moiety functions as a Bronsted base. The rare earth metal-BINOL complex also functions as a Lewis acid to activate electron-deficient olefins through monoden-tate coordination (II). Enantioselective 1,4-addition of rare earth metal-peroxide gives intermediate enolate (III), followed by epoxide formation to regenerate the catalyst (IV). 

However, despite the considerable efforts devoted to address the fundamental issues toward the development of asymmetric protonation, its applications to natural or bioactive synthesis remain sporadic. Herein, two main strategies, namely the enantioselective protonation of metal enolates, especially silicon enolates and the protonation of polar double bonds, i.e., Michael acceptors, were depicted trough the most relevant synthetic applications. These two strategies led to the synthesis of fragrance, natural products, ° bioactive compoundsand... 

Thereafter, Yamamoto reported the first metal-free Bronsted add catalyzed asymmetric protonahon reachons of silyl enol ethers using chiral Bronsted acid 13c in the presence of achiral Bronsted add media (Scheme 5.34) [61]. Importantly, replacement of sulfur and selenium into the N-triflyl phosphoramide increases both reactivihes and enanhoselectivihes for the protonation reaction. 

It is well established that the reaction of carbenoids with At-alkylindoles delivers zwitterionic intermediates. The reason why this scenario is favored can be ascribed to the fact that the positive charge of the intermediate is stabilized by the electron-rich indole while the negative charge is stabilized by the carbenoid component. In other words, the site of C3 is highly reactive in metal carbenoid insertion reactions. In 2010, Lian and Davies described such a process in their seminal work on Rh-catalyzed [3 + 2] annulation of indoles. In the presence of 1,2-dimethylindole 53, Rh2(S-DOSP)4 induced the decomposition of methyl a-phenyl-a-diazoacetate la and C—H bond insertion of indole, providing the C3 functionalization product 54 in 95% yield but negligible asymmetric induction (<5% ee). It is proposed that the poor chiral induction in the formation of C—H bond insertion product 54 can be attributed to the rapid proton transfer from the zwitterionic intermediate A to the achiral enol B, which can further tautomerize into the observed C—H bond insertion product 54 (Scheme 1.18). 

As an essential component to asymmetric organocatalysis, chiral, metal-free Bron-sted bases have mediated several types of C-C and C-X bond-forming reactions mediated by enamine and enolates. Brmsted bases (Figure 13.1) have the functional capacity to accept a hydrogen (or proton) from an acidic source or equivalent activated species. This proton transfer forms the basis of the key activation component to new-bond formation reactions. 

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