Prochiral enolate

Following their success with chiral ketone-mediated asymmetric epoxidation of unfunctionalized olefins, Zhu et al.113 further extended this chemistry to prochiral enol silyl ethers or prochiral enol esters. As the resultant compounds can easily be converted to the corresponding a-hydroxyl ketones, this method may also be regarded as a kind of a-hydroxylation method for carbonyl substrates. Thus, as shown in Scheme 4-58, the asymmetric epoxidation of enol silyl... 

The reactivity of lithium enolates has been explored in a theoretical study of the isomers of C2H30Li, such as the lithium enolate, the acyl lithium, and the a-lithio enol. Imides containing a chiral 2-oxazolidine have been employed for enantioselective protonation of prochiral enolates.A degree of kinetic control of the product E/Z-enolate ratio has been reported for the lithiation of 3,3-diphenylpropiomesitylene, using lithium amides/alkyls. " °... 

Larry Overman also used (J. Am. Chem. Soc. 2004,126, 14043) a chiral pool starting material, but in a different way. The prochiral enolate 12 showed substantial diastereoselectivity in its reaction with the bis-triflate 13, almost 10 1. Through the power of algebra, it followed that the three diastereomers of 14 were formed in a ratio of 90 9 1. The crystalline 14 was easily isolated in diastereomerically-pure form, and carried on to phenserine 15. This is a new method for the stereocontrolled construction of chiral quaternary centers. 

Significant progress has been made on the asymmetric Pd-catalyzed aliylic alkylation of prochiral enolates, with a number of ligands now available that provide products with high ee. Trost was the first to demonstrate that high enantiomeric excesses were capable with ketoester substrates [29] now asymmetric aliylic alkylation of ketoesters and simple ketone substrates has been achieved in several more cases. Table 4 summarizes the ligands, substrates, and ee for recent examples. 

Recently it has been reported that the catalytic isomerization of allylic alcohols is promoted by [Rh(diphosphine)(solvent)2]+ at 25°C yields synthetically useful quantities of the corresponding simple enols and that the transformation of allylic alcohols to enols and thereby to ketonic products proceeds catalytically via hydrido-7t-allylic and hydrido-7t-oxy-allylic intermediates, respectively [20]. Consistently observed, enantioselection has been in the process of conversion of a prochiral enol to a chiral aldehyde. Thus, the prochiral substrate 32 is transformed to the optically active aldehyde 34 with 18% ee by using [Rh(BINAP)]+ catalyst (eq 3.13). Accordingly, this isomerization proceeds via a different mechanism from that of the isomerization of allylamine. For the reaction mechanism of the... 

The use of nucleophiles, which can coordinate to a transition metal, provides an opportunity to control the orientation of a prochiral enolate (Eq. 8E, 19). With a-cyanoesters as substrate,... 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

The asymmetric alkylation of other prochiral enolates has also been studied, and good results have been obtained provided that the intermediate enolate is stabilised by conjugation. For example, the extended enolate derived from 15 has been trapped with a range of alkylating agents to give a-alkylated esters such as 16 in 98% ee (Scheme 5) [12]. 

Muzart and coworkers have reported a new catalytic enantioselective protonation of prochiral enolic species generated by palladium-induced cleavage of p-ketoesters or enol carbonates of a-alkylated 1-indanones and 1-tetralones [21 ]. Among the various (S)-p-aminocycloalkanols examined, 17 and 18 were effective chiral catalysts for the asymmetric reaction and (J )-enriched a-alkylated 1-indanones and 1-tetralones were obtained with up to 72% ee. In some cases, the reaction temperature affected the ee. 

In the following, the stereofacial differentiation will be considered in a classical way (Figure 1). Thus, if the direct precursor of the prochiral enolate and/or the reacting electrophile is covalently linked to the source of asymmetry, we will classify the transformation in the category of the diastereospecific reactions. In contrast, if achiral (or racemic) structures are employed and the asymmetry is introduced via the use of non-covalently bonded chiral ligands, we will refer to enantiospecific reactions. 

SCHEME 98. Metal and temperature effects on the C-arylation of prochiral enolates by photostimulated SKW1 reaction (Ar = 1-naphthyl)484... 

Chiral bis(oxazolines) 51 with an oxalylic acid backbone were used for the Ru-catalyzed enantioselective epoxidation of tran5-stilbene yielding franx-l,2-diphenyloxirane in up to 69% ee [24]. The asymmetric addition of diethylzinc to several aldehydes has been examined with ferrocene-based oxazoline ligand 52 [25], resulting in optical yields from 78-93% ec. The imide 53 derived from Kemp s triacid containing a chiral oxazoline moiety was used for the asymmetric protonation of prochiral enolates [26]. Starting from racemic cyclopentanone- and cyclohexanone derivatives, the enantioenriched isomers were obtained in 77-98 % ee. 

Reaction of a chiral a-alkoxyaldehydc with a prochiral enol silyl ether catalyzed by SnCh results in a single diastereomer with additional. vvn-selectivity (equation II). 

Asymmetric a-amination of enolates has also been described. For example, treatment of a-silyl ketone 109 with LDA followed by addition of oxaziridine 65a gave the A -BOC-amino ketone 110 in 29% yield and 88% de <1998TA3709>. Asymmetric amination of the prochiral enolate of 111 with chiral nonracemic oxaziridine 112 afforded amino ester 113 in 51% yield and 21% de <2001TA535>. 

Asymmetric a-Hydroxylation of Enolates. a-Hydroxy lation of enolates represents one of the simplest and most direct methods for the synthesis of a-hydroxy carbonyl compounds, a key structural unit found in many natural products. Enolate oxidations using (+)- and (—)-(l) and their derivatives generally effect this transformation in good to excellent yields with a minimum of side reactions (e.g. over-oxidation). Furthermore, these reagents are the only aprotic oxidants developed to date for the direct asymmetric hydroxylation of prochiral enolates to optically active a-hydroxy carbonyl compounds. 

The lithium amide of (,S S)-(1) has been used to convert racemic a-substituted ketones into optically active ketones via sequential deprotonation/asymmetric protonation of rigid prochiral enolates. Enantiomeric enrichment may occur during the protonation step as a result of the tight coordination between the enolate and the lithium amide in the form of diastereomeric complexes (eq 7). ... 

Stereoselective Alkylation of Prochiral Enolates. A limited amount of work has demonstrated the potential use of chiral amines in inducing stereoselectivity in the alkyla-tion/carboxylation of prochiral enolates. The selectivity of these reactions, like those described above, is highly dependent on solvent and temperature conditions. The use of ether at — 196°C provides optimal results in a particular system (eq 10). ... 

Of particular concern with a-hydroxy carbonyl compounds is the stereochemistry of the hydroxy group attached to the stereogenic carbon because biological activity is often critically dependent on its orientation. A-Sulfonyloxaziridines have played a prominent role in the stereoselective synthesis of this key structural element (Scheme 25). Enantiomerically and diastereomerically enriched materials have been prepared by (1) the hydroxylation of chiral nonracemic enolates with racemic A-sulfonyloxaziridines, for example (63a) (2) the asymmetric hydroxylation of prochiral enolates with enantiopure A-sulfonyloxaziridines and (3) a combination of the first two, double stereodifferentiation. 

Birch reduction of chiral benzamide (181) followed by oxidation of the resulting enolate with (+)-(114) afforded dienol (182) in 86% de, but in only 16% yield <92JOC2973>. The yield improves to 57%, (80% based on recovered starting material) if ammonia is removed prior to the oxidation (Scheme 33). Asymmetric hydroxylation of the prochiral enolate derived from the Birch reduction of methyl 2-methoxybenzoate with ( + )-(114) gave the corresponding dienol in 50-60% yield and 30% ee. 

The nucleophilic addition on substituted ketenes is a well-known method to generate a prochiral enolate that can be further protonated by a chiral source of proton. Metallic nucleophiles are used under anhydrous conditions therefore, the optically pure source of proton must be added then (often in a stoichiometric amount) to control the protonation. In the case of a protic nucleophile, an alcohol, a thiol, or an amine, the chiral inductor is usually present at the beginning of the reaction since it also catalyzes the addition of the heteroatomic nucleophile before mediating the enantioselective protonation (Scheme 7.5). The use of a chiral tertiary amine as catalyst generates a zwitterionic intermediate B by nucleophilic addition on ketene A, followed by a rapid diastereoselective protonation of the enolate to acylammonium C, and then the release of the catalyst via its substitution by the nucleophile ends this reaction sequence. 

The research group of Muzart and Henin studied extensively the palladium-catalyzed EDP of allyl- or benzyl-carboxylated compounds. Mainly two types of substrates, prochiral enol carbonates A and racemic (3-keto esters B, were used to afford enols C as transient species [25]. In the presence of a chiral proton source, asymmetric protonation/tautomerization of enols led to enantioenriched ketones D... 

Enantioselective protonation of prochiral enols or enolates, which provides synthetic access to optically active carbonyl compounds, is an elegantly simple test reaction for enantioselective reagents and catalysts, for which a number of examples have been described [80]. The only reaction described with alkyl enol ethers concerns the highly enantioselective protonation of enol ethers such as 55 by catalytic antibody 14D9, an antibody raised against hapten 10 [81]. Antibody 14D9 has a practical turnover of /c-at = 0.4 for substrate 55 and produces... 

A newer approach toward the enantioselective electrophilic fluorination of jS-ketoesters is based on enolization of the substrate under neutral conditions by coordination to a chiral titanium catalyst [211]. The catalyst, a chiral titanium TADDOLato complex (TADDOL = a,a,a, a -tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol) [212, 213], coordinates to the -ketoester, enolizes it, and thus renders it susceptible to electrophilic fluorination (Scheme 2.95). One face of the prochiral enolate substructure is covered by a bulky naphthyl substituent from the TADDOL ligand, impeding electrophilic attack of F-TEDA. 

Controlling enantioselectivity at the enol centre alone can be achieved with special reagents and a very complex catalyst. An allylic carbonate with a fluorinated esterifying group allylates a prochiral enolate derived from i-propyl cyanopropionate catalysed by Pd, Rh, and the chiral Fe TRAP ligand 257, gives excellent results. The explanations for these last two examples are complicated and you are referred to the papers if you want to know more.60... 

The enantioface selective protonation of prochiral enol derivatives is a simple and attractive route for the preparation of optically active carbonyl derivatives. Reports of stoichiometric protonation of metal enolates by a chiral proton source at low temperature leads to optical yields from 20 to 85% ee and yeast esterase catalyzes the hydrolysis of 1-acetoxycycloalkenes with enantioselectivi-ties between 41 and 96% for enol protonation [17,18]. These reactions involve enolates under basic conditions. Hydrolysis of enol ethers under acidic conditions proceeds via a rate-determining carbon protonation and is catalyzed by carboxylic acids [19,20]. Raymond et al. [21] reasoned that a complementary... 

Asymmetric protonations of prochiral enolates or enaroines by enantiopure carboxylic acids typically occur with low enantioselectivity, but there are some exceptions. P. Duhamel, L. Duhamel and coworkers accomplished the " deracemi-zation of Schiff bases of a-aminoesters [552], The best selectivities (ee 70%) are obtained when the substrates are deprotonated by Li (ify-A -ethylphene-thylamide, and then reprotonated at -70°C by (fy )-diacyltartaric add 2.2 (R = fert-BuCO) [154] (Figure 4.4). In another successful application, asymmetric protonation of the potassium enolale of racemic benzoin 4.7 by (RJR) 2.2 (R = terf-BuCO) gjves the (S)-enantiomer with a good enantiomeric excess [552] (Figure 4.4). 

The principal factor that was responsible for the rebirth of the venerable aldol reaction as a modem method of synthesis was the discovery that its stereochemistry can be controlled quite effectively through the use of preformed enolates. In this section is discussed simple diastereoselection, reactions between prochiral enolates and prochiral aldehydes (equation 37) the synJanti stereochemical notation is employed. ... 

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