Enolate asymmetric

Another example is the asymmetric synthesis of ( )-pinidine 208 and its isomers. These syntheses are achieved via asymmetric enolization, stereoselective cyclopropanation, and oxidative ring cleavage of the resulting cyclopropanol system (Scheme 5-68).123... 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

A similar sequence was reported where the asymmetry was introduced by the reaction of weio-3-substituted glutanc anhydrides and (S)-methylbenzylamines to give diastereomeric hemiamides that could be separated by recrystallization The asymmetnc desymmetrization of certain 4-aryl substituted glutanmides has also been accomplished with high levels of selectivity (up to 97% ee) by enolization with a chiral bis-lithium amide base. The selectivity of the reaction was shown to be the result of asymmetric enolization, followed by a kinetic resolution." ... 

Asymmetric enolates of meso-ketones.1 The ketal 1, formed from 4-ethyl-cyclohexanone and (2R,4R)-2,4-pentanediol, when treated with triisobutylalu-minum in CH2C12 at -78° gives the enol ethers (S)-2 and (R)-2 in the ratio 6 1. Somewhat superior selectivity obtains by use of a dialkylaluminum amide such as 3.8... 

Recently, a stereoselective synthesis of carbon-linked analogues of a- and 0-ga-lactoserine glycoconjugates has been reported using asymmetric enolate methodology [19]. The key step involved the electrophilic animation of a chiral oxazolidinone enolate with DTBAD. 

Only recently, Shibasaki et al. reported on the application of a Sm-Na-(R)-BINOL-complex as catalyst in a reaction cascade consisting of an a.symmetric Michael addition of thiols to a,fS- xn-saturated carbonyl compounds followed by an asymmetric enolate protonation [20]. 

Arya, P Qin, H. Advances in Asymmetric Enolate Methodology, Tetrahedron 2000,56, 917-947. 

S) -( — )-2-Methyl-2-hydroxy-y-butyrolactone (176a) is a useful synthon for the asymmetric construction of acyclic tertiary a-hydroxy acids found in natural products such as the pheromone frontalin and mevalonolactone, the biosynthetic precursor of terpenoids and steroids. This compound is readily prepared from lactone (175) using the asymmetric enolate oxidation protocol and dimethoxy oxaziridine ( + )-(158) <95JOC6l48>. The a-hydroxy lactone (176b), isolated as the benzoate, was obtained in 84% ee and 70% yield. A single crystallization from ethyl acetate improved the ee to >94% (Equation (41)). 

Later in the book, when we deal with asymmetric enolate reactions, boron enolates will be very important. A simple example20 of an aldol reaction with a boron enolate, prepared from the ester 149 and a boron triflate using an amine as base, shows why. The boron enolate 150 could be prepared with a weak base and reacts with the aldehyde without catalysis to give essentially one diastereoisomer of the aldol 151 in good yield. If the titanium enolate (prepared with TiCI4 and an amine) was used, both the yield and the stereoselectivity were worse. In other circumstances enolates of titanium and other metals are very successful. 

Scheme 3.16. Early examples of asymmetric enolate alkylations (a) Meyers s oxazolines [77-79] (b) Evans s [81,82] and Sonnet s [80] proline amide alkylations. ...

The aldol addition reaction, and the related crotyl metal additions (section 5.1), have figured prominently in the total synthesis of a number of complex natural products (reviews [48,140-142]). Figure 5.8 illustrates those mentioned in the preceding discussion, along with others selected from the recent literature, with the stereocenters formed by stereoselective aldol addition indicated ( ). For the Prelog-Djerassi lactone and ionomycin, recall (Figure 3.8) that most of the other stereo-centers were formed by asymmetric enolate alkylation. 

Enol silylations. With the superhindered iithium t-butyl(trityl)amide (and related tritylamides) ketones give more ( )-siloxyalkenes than lithium 2,2,6,6-tetramethyl-piperidide. Asymmetric enolization is possible using chiral V-(l-phenethyl) analogue. ... 

A number of other asymmetric enolate protonation reactions have been described using chiral proton sources in the synthesis of a-aryl cyclohexanones. These include the stoichiometric use of chiral diols [68] and a-sulfinyl alcohols [69]. Other catalytic approaches involve the use of a BlNAP-AgF complex with MeOH as the achiral proton source, [70] a chiral sulfonamide/achiral sulfonic acid system [71,72] and a cationic BINAP-Au complex which also was extended to acyclic tertiary a-aryl ketones [73]. Enantioenriched 2-aryl-cyclohexanones have also been accessed by oxidative kinetic resolution of secondary alcohols, kinetic resolution of racemic 2-arylcyclohexanones via an asymmetric Bayer-Villiger oxidation [74] and by arylation with diaryhodonium salts and desymmetrisation with a chiral Li-base [75]. 

Scheme 8.21 Selective reaction of one enantiomer of an (a-haloall(yl)boronic ester with an asymmetric enolate.

The final example of asymmetric enolates concerns the iron acyl complexes developed by the Davies group. t O] These complexes give excellent enantioselectivity in a wide variety of asymmetric reactions but unfortunately the auxiliary can only be obtained by a tedious resolution procedure, is very expensive and cannot readily be recycled. 

The Prelog-Djerassi lactone is a degradation product of the macrolide antibiotics methy my cin and narbomycin. Evans uses it here to illustrate his asymmetric enolate methodology (see section 5.3.2). Of the many syntheses of tnis popular target molecule, this is one of the best in terms of diastereo- and enantioselectivity. 

The text starts with a brief historic overview and then describes in great detail the various ways of enolate generation and the structural properties of metallated enolates (Chapters 1-3). This sets the stage for asymmetric enolate reactions. In Chapter 4, diastereoselective auxiliary-controlled enolate alkylations and aldol additions are presented with main focus on Evans type auxiliaries, without, however, neglecting alternative auxiliaries. The largest chapter (Chapter 5) is devoted... 

As a single example of asymmetric enolate Claisen rearrangement assisted by a chiral ligand, Kazmaier and Krebs reported that the treatment of allyl aminoac-etatesa with LiHMDS in the presence of Al(Oi-Pr)3 and quinine gives the Claisen product with excellent diastereo- and enantioselectivity (Scheme 6.165) [195]. 

Arya P, Qin H. Advances in asymmetric enolate methodology. Tetrahedron 2000 56 917 947. 

SCHEME 13.44. Asymmetric enolate alkylation in the synthesis of cyanthiwigin F. 

The first three sections of this chapter describe diastereoselective alkylations of chiral enolates including heteroatom-substituted enolates [15, 20]. Section 3.4 deals with the class of enolate alkylations that have typically been included under the rubric of chiral-auxiliary-controlled processes. As suggested by the term, the auxiliary is only transiently utilized and, following alkylation, is subsequently excised. The facile use of chiral auxiliaries in asymmetric enolate alkylations has played and continues to play a pivotal role in the stereoselective formation of new C-C bonds. After a brief survey of the relatively few developments in catalytic enantioselective enolate alkylations (Section 3.5) [21, 22], selected examples of enolate a-hydroxylations (Section 3.6) [23-25] and a-halogenations (Section 3.7) [26, 27] are covered. The corresponding a-aminations of enolates are discussed in Chapter 10, describing stereoselective formation of a-amino acids. 

Asymmetric Enolate Alkylations Using Chiral Auxiliaries... 

The investigations of Enders, Evans, and others have demonstrated the versatility of chiral auxiliaries based on the proline skeleton [80]. Katsuki designed and utilized a C2-symmetric, 2,5-disubstituted pyrrolidine auxiliary for asymmetric enolate alkylations (Equation 10) [81]. Enolates prepared from 112 generally undergo alkylations with superb diastereoselectivity dr >95 5). However, in contrast to the prolinol amide-derived systems described above, accessibility of the chiral auxiliary hinged upon a multi-step synthetic preparation involving resolution, and the hydrolytic removal of the auxiliary necessitated considerably harsher reaction conditions. 

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