Enantioselective metal enolates

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

Enantioselective protonation of ketone metal enolates constitutes an important method for the preparation of optically active ketones. Fuji and coworkers have shown interest in the magnesium countercation in the enantioselective protonation of such enolates. Pertinent results are obtained with protonation of Mg(II) enolates of 2-alkyltetralones and carbamates derived from l,l -binaphtalene-2,2 -diol as chiral proton sources, as indicated in equation 82 and Table 11. 

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 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 most smdied O-bonded transition metal enolates are titanium enolates . The reason for their success has beeu recognized in the fact that titanium enolates show an enhanced stereochemical control in C—C bond-forming reactions over simple lithium enolates and the possibility of incorporating chiral ligands at the titanium centre, a possibility which has lead to enantioselective aldol reactions with excellent enantiomeric excess. Moreover, titanium euolates have been used in oxidation reactions with remarkable diastereoselectivity. 

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]. 

The metal enolate of (/ )-/V./V-dimethyl-a-(p-tolylsulfinyl)acetamide (92) reacts with an aldehyde to afford a diastereomeric mixture of adduct (93). which undergoes desulfurization with 10% Na(Hg) in MeOH (NaH2P04> to give an optically active 3-hydroxyamide (94). By the use of Li" as a countercation, low to medium levels of enantioselection are achieved. However, the magnesium enolate of (92) realizes a high enantioselectivity, as summarized in Table 4. A rigid chelation model, shown in Scheme 26, is suggested for the transition state of this addition. 

This chapter will provide coverage of the scope and limitations of alkylations of metal enolates of saturated and unsaturated ketones, aldehydes and carboxylic acid derivatives, together with a discussion of alkylations of various enols and enolate equivalents. Where applicable, the utility of these reactions for the diastereoselective and enantioselective synthesis of a-substituted carbonyl compounds will be described. Inevitably, the coverage of a vast research area such as this will be incomplete and in part will reflect the author s interests. However, it is hoped that most of the useful methods of carbon-carbon o-bond formation by alkylations of enolates and enols will be included. 

In recent years, investigations of the diastereoselectivity and enantioselectivity of alkylations of metal enolates of carboxylic acid derivatives have become one of the most active areas of research in synthetic organic chemistry. Intraannular, extraannular and chelate-enforced intraannular chirality transfer may be involved in determining the stereochemistry of these alkylations. 

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). 

Catalytic enantioselective protonations of metal enolates already published can be roughly classified into two methods carried out under basic conditions and acidic conditions. The process under basic conditions is, for example, the protonation of reactive metal enolates such as lithium enolates with a catalytic amount of chiral acid and an excess of achiral acid. The process under acidic conditions employs silyl enol ethers or ketene silyl acetals as substrates. Under the influence... 

The first example of catalytic enantioselective protonation of metal enolates was achieved by Fehr and coworkers (Scheme 3) [44]. They found the enantioselective addition of a lithium thiolate to ketene 41 in the presence of an equimolar amount of (-)-iV-isopropylephedrine (23) with up to 97% ee. Based on the results, they attempted the catalytic version for example, slow addition of p-chlo-rothiophenol to a mixture of ketene 41 (1 equiv) and lithium alkoxide of (-)-N-isopropylephedrine 23-Li (0.05 equiv) gave thiol ester 43 with 90% ee. First, the thiol is deprotonated by 23-Li to generate lithium p-chlorothiophenoxide and 23. The thiophenoxide adds to the ketene 41 leading to Z-thiol ester enolate which is presumed to react with the chiral amino alcohol 23 via a four-membered cyclic transition state 42 to form the product 43 and 23-Li. The hthium alkoxide 23-Li is reused in the catalytic cycle. The key to success in the catalytic process is that the rate of introduction of thiophenol to a mixture of the ketene 41 and 23-Li is kept low, avoiding the reaction of the thiol with the intermediate hthium enolate. 

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-... 

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 reaction of a-ketoesters with the tin (II) enolate of IV-acetyl-thiazolidinethione 1.123 (R=R1=H, X = S) has been earned out with an excellent enantioselectivity in the presence of chiral amine 2.13 (Figure 6.88). The reactions of a- or P-alkoxyaldehydes with metal enolates may or not be under chelation control (Cram cyclic model, 1.4.2). Reetz has shown that triisopropoxy- or tris-diethylaminotitanium enolates display a sufficiently weak Lewis acidity so as to avoid chelation control [408],... 

The aldol reactions of titanium enolates have been the best studied of all the transition metal enol-ates."- In many cases they show higher stereoselectivity and chemoselectivity in their reactions than lithium enolates and are easily prepared using inexpensive reagents. They also promote high levels of diastereofacial selectivity in reactions of chiral reactants. The Lewis acidity of the titanium metal center can be easily manipulated by variation of the ligands (chloro, alkoxy, amino, cyclopentadienyl, etc.) attached to titanium, which leads to enhanced selectivity in appropriate cases. Moreover, the incorporation of chiral ligands on titanium makes possible efficient enantioselective aldol reactions. 

The use of chiral Lewis acids for enantioselective Diels-Alder and hetero Diels-Alder reactions and for other processes of C—C bond formation has recently received great attention. Reetz and coworkers reported that a stoichiometric amount of the chiral Lewis acid (137) effectively promotes the reaction of silyl ketene acetal (98) to give the aldol product in 57% yield and 90% ee (equation 48, R = Me2CHCH2—). When a catalytic amount (5 mol %) of the chiral rhodium perchlorate (138) is used, the aldol product is obtained in >75% yield and 12% ee (equation 48 R = Ph). ° Both reactions probably proceed through the corresponding metal enolates. - The development of new efficient chiral catalysts for the Mukaiyama reaction is certainly one of the challenges of the 1990s. 

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