Ketones chiral enolates

Asymmetric hydrogenolysis of epoxides has received relatively little attention despite the utility such processes might hold for the preparation of chiral secondary alcohol products. Chan et al. showed that epoxysuccinate disodium salt was reduced by use of a rhodium norbornadiene catalyst in methanol/water at room temperature to give the corresponding secondary alcohol in 62% ee (Scheme 7.31) [58]. Reduction with D2 afforded a labeled product consistent with direct epoxide C-O bond cleavage and no isomerization to the ketone or enol before reduction. 

Aldol reactions of a-substituted iron-acetyl enolates such as 1 generate a stcrcogenic center at the a-carbon, which engenders the possibility of two diastereomeric aldol adducts 2 and 3 on reaction with symmetrical ketones, and the possibility of four diastereomeric aldol adducts 4, 5, 6, and 7 on reaction with aldehydes or unsymmetrical ketones. The following sections describe the asymmetric aldol reactions of chiral enolate species such as 1. 

Thus, in the above reactions of cither enantiomer of chiral aldehydes with the ketone enolate, as well as with the amide enolate, the stereochemical outcome in each case is largely determined by the inherent selectivity of the chiral enolate reagent. 

The application of auxiliary control in the asymmetric Michael addition of chiral enolates derived from ketones is rare the only example known is the use of (27 ,37 )-2,3-butancdiol as an auxiliary. The ketal of (27 ,37 )-2,3-butanediol with 3-methyl-l,2-cyclohexanedione reacts with 3-buten-2-one using as base a catalytic amount of sodium ethoxide in ethanol195. 

Camell, A.J., Swain, S.A. and Bickley, J.E., Chiral enol acetates derived from prochiral oxabi-cyclic ketones using enz3mies. Tetrahedron Lett., 1999, 40, 8633. 

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

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. 

These reactions can also be made enantioselective (in which case only one of the four isomers predominates) by using539 chiral enol derivatives,540 chiral aldehydes or ketones,541 or both.542 Since both new chiral centers are formed enantioselectively, this kind of process is called double asymmetric synthesis.543 A single one of the four stereoisomers has also been produced where both the enolate derivative and substrate were achiral, by carrying out the reaction in the presence of an optically active boron compound544 or a diamine coordinated with a tin compound.545... 

Promising examples of the catalytic asymmetric Darzens condensation, which yields an epoxide product via carbon-carbon and carbon-oxygen bond formation, have been reported recently by two groups (Scheme 10.11). Toke and co-workers used crown ether 24 in the reaction to form the a,P-unsaturated ketone 78 [38b] with 64% ee, whereas the Shioiri group used the cinchona-derived salt 3a [52], which resulted in 78 with 69% ee. The latter authors propose a catalytic cycle involving generation of a chiral enolate in situ from an achiral inorganic base... 

J. Park, Practical ruthenium/lipase-catalyzed asymmetric transformations of ketones and enol acetates to chiral acetates,... 

The absolute configuration and enantiomeric excess of amino ketones 20 were evaluated by gas chromatography (GC) and, 3C NMR studies after conversion into the diastereomeric acetals 21. The reaction proceeds via addition of the nitrene 18 to the double-bond of 19. The yield and diastereoselectivity of this reaction were significantly enhanced when using chiral enol ethers 23, generated from C2 symmetric 22. The best result (36 % yield and 50 % ee) was obtained using a fivefold excess of reagent 6e and equimolar amount of triethylamine [12d] (Scheme 9). 

SCHEME 59. Various types of solid-state mixed aggregates involving ketone lithium enolates (A) pinacolone enolate/lithium amide [LiHMDS/CH2C(OLi)Bu-i, 2 DME]230 (B) pentan-3-one enolate/2 chiral lithium amide232 (C) pinacolone enolate/lithium amide/LiBr [LiHMDS/2 Cl HCtOI.ijBu-f/LiBr, 2 TMEDA]235... 

Although chiral nonracemic enolates of type 21 and 22 are expected to exist under particular conditions, their half-lives to racemization are usually too short to effect actual asymmetric reactions. To realize an asymmetric transformation via a chiral enolate of type 21, chiral ketone 23 was designed that would generate a chiral enolate with a significantly long half-life to racemization (Scheme 3.8). Steric interactions of C(2)-OMe with C(2,)-OEt and C(8 )-H in the enolate would prevent free rotation of the C(l)-C(l ) bond as well as coplanarity of the enolate double bond with the naphthalene ring. Thus the enolate was expected not to exist as an achiral planar enolate, but it could be a chiral enolate with a chiral C(1)-C(T) axis. The rotational barrier about the C(1)-C(T) bond may be estimated by analogy with 2,2/-disubstituted biphenys because of similarity of the local steric environment around the chiral axes. The half-life to racemization was assumed to be about a few years at —78°C from the reported rotational barrier of various 2,2/-disubstituted biphenys ( 80 kJ/mol).16... 

Aldol coupling of chiral acetals.6 The acetals (2) prepared from an aldehyde and (2R,4R)-pentanediol react with a-silyl ketones or enol silyl ethers in the presence of TiCl4 to form aldol ethers 3 and 4 with high diastereoselectivity (>95 5). Removal of the chiral auxiliary usually results in decomposition of the aldol, but can be effected after reduction... 

Enol acetates and corresponding derivatives constitute another class of unsaturated compounds that can advantageously be hydrogenated with high enantiomeric excess. This reaction is related to the enantioselective reduction of ketones. Acylated enol carboxy-lates (as an equivalent of a-keto carboxylic acid) can likewise be successfully reduced with rhodium(I) catalysts based on (5,5)-ethyl-DuPHOS (eq 8). Subsequent deprotection of the hydroxyl group or reduction of the carboxylic acid derivatives so obtained deliver chiral a-hydroxy carboxylates and 1,2-diols, respectively. 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

These reactions can also be made enantioselective (in which case only one of the four isomers predominates) ° ° by using chiral enol derivatives, chiral aldehydes or ketones, or both. ° " Chiral bases can be used, such as prohne, ° prohne derivatives, or chiral additives, used in conjunction with the base. ° A chiral binaphthol dianion has been used to catalyze the reaction. Chiral auxiharies ° ° have been developed that can be used in conjunction with the aldol condensation, as well as chiral catalysts and chiral ligands " ... 

The method is also successful for carboxyhc esters , and A,A-disubstituted amides, and can be made enantioselective by the use of a chiral oxaziridine. Dimethyldioxirane also oxidizes ketones (through their enolate forms) to a-hydroxy ketones. Titanium enolates can be oxidized with tert-butyl hydroperoxide or with dimethyl dioxirane and hydrolyzed with aqueous ammonium fluoride to give the a-hydroxy ketone. Ketones are converted to the a-oxamino derivative (0=C CH2- 0=C CHONHPh) with excellent enantioselectivity using... 

In all three cases the starting materials are already chiral. If the allylic alcohol or the cycx. ammonium salt were prepared, by resolution or by asymmetric synthesis, as a single enantiomer, then A too would be a single enantiomer. However, the ketone used in the first route, though aJK chiral, has an achiral enolate so asymmetry could be introduced at that point. It isn t possible to u-se the chiral enolates described in the chapter (p. 1230). Probably the easiest approach is to make thf aUylic alcohol by asymmetric reduction, say by the CBS reducing agent (p. 1234). 

Boron reagents such as ( + )- or (-)-(Ipc)2BOTf are chiral promoters in aldol condensations. " Enolization of an achiral ketone with (Ipc)2BOTf forms a chiral enolate and thus imparts diastereofacial selectivity (DS) for condensation with a chiral aldehyde. If the ketone is chiral, the DS of the reagent may be matched or mismatched with the... 

Azodicarboxylate esters are the reagents of choice for electrophilic N-amino amination leading to hydrazine derivatives. Besides Grignard reagents and alkyl or aryl lithium compounds,enolates and silyl enol ethersderived from ketones have been aminated by this method. In particular, di-r-butyl azodicarboxylate has been reacted with a variety of chiral enolates (Scheme I9)i03->o and chiral silyl ketene acetds (Schemes 20 and to afford a-hydrazino acid derivatives with high dia-... 

Reddy, D. R., Thornton, E. R. A very mild, catalytic and versatile procedure for a-oxidation of ketone silyl enol ethers using (salen)manganese(lll) complexes a new, chiral complex giving asymmetric induction. A possible model for selective biochemical oxidative reactions through enol formation. J. Chem. Soc., Chem. Commun. 1992, 172-173. 

The Patemo-Buchi reaction is the photocycloaddition of an alkene with an aldehyde or ketone to form oxetanes. This transformation has been shown to proceed through a biradical intermediate, and up to three new stereocenters can be formed as a result of this reaction. A general mechanism for the reaction between an aldehyde and a chiral enol silyl ether is shown in Eq. (13.7) [18]. Allylic 1,3-strain is cited as the control element in reactions of this type, and diastereomeric ratios of >95 5 are reported for products 30 containing four contiguous stereocenters. Examples of photocyclizations of amino acid derivatives proceeding through biradical intermediates have been repotted [19]. 

In this section are discussed aldol reactions of achiral aldehydes with chiral enolates. In previous sections, many such examples have already been given for enolates derived from rigid cyclic ketones, lactones and lactams. The emphasis here is on reactions of the enolates of conformationally flexible, achiral ketones, esters and amides. 

Six-membered chiral acetals, derived from aliphatic aldehydes, undergo aldol-type coupling reactions with a-silyl ketones, silyl enol ethers," and with silyl ketene acetals " in the presence of titanium tetrachloride with high diastereoselectivities (equation 41) significant results are reported in Table 20. This procedure, in combination with oxidative destructive elimination of the chiral auxiliary, has been applied... 

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