A-substituted enolates

Analogous to the closely related aldol reactions, reactions of achiral a-substituted enolates and imines lead to mixtures of syn- and rwd-diastereomers. The following diagram shows the postulated pericyclic transition states involved in enolate-iminc condensations10. 

The importance of the (Z)-enolate substitution has been noted elsewhere in this chapter (see Table 32). A practical solution to the generation of a useful chiral acetate enolate synthon has been to employ a substituted enolate where the ligand Rj may be removed after the aldol condensation. Enolate 149b (Rj = SMe) serves this purpose adequately (eq. [102]). The resultant alddl adducts 151b... 

Interestingly, treatment of the allylic carbonate 23, which had proven problematic in the previous study, under analogous reaction conditions with the copper enolate derived from 24 furnished the a,/9-disubstituted ketone. Subsequent ring-closing metathesis furnished the 1,2-cyclohexenes 25a/25b in 75% overall yield favoring the trans-dia-stereomer 25a (2° 1°=30 1, ds=10 l) [14]. Overall, this reaction provides an alternative approach to an exo-selective Diels-Alder cycloaddition, and indicates that a-substituted enolates are even more tolerant nucleophiles than the unsubstituted derivatives. 

Lactols and their acetals can be transformed easily into their 2-arylsulfonyl derivatives 337 by reaction with a sulfinic acid under Lewis acid activation. The corresponding organolithiums are prepared by deprotonation with n-BuLi or LDA and, after reaction with electrophiles, a /(-elimination of sulfinic acid afforded a cyclic a-substituted enol ether514,547,548. 2-Lithio-2-(arylsulfonyl)tetrahydropyrans equilibrated to give mainly the anomer with the lithium atom at the equatorial position549. 

Therefore, the isomerization reaction was also performed starting from the a-substituted enol ether 119 (Scheme 52). By using the tandem allylic C-H activation-elimination reactions, Z-120c is initially formed and by a transmetalation reaction into organocopper with a stoichiometric amount of CuCI/ 2LiCl, followed by heating at +50 °C for 1 h and reaction with allyl chloride, the resulting ( , )-diene 122 is obtained with an isomeric ratio of 90 10 but in a low 40% yield as described in Scheme 52. 

Lithium enolates having a-methyl substituents, such as (33b) and the related species (37b), derived from S-t-butylcyclohexanone, show a somewhat greater stereoselectivity of axial alkylation than the corresponding a-unsubstituted compounds. For example, the enolate (37a) gave the products (38a) and (39a) in a 68 32 ratio upon treatment with methyl iodide in THF, while the 2-methyl-substituted derivative (37b) gave an 83 17 mixture of (38b) and (39b) upon reaction with trideuteriomethyl iodide in DME (Scheme 18). Similarly, a greater stereoselectivity for axial alkylation has been observed for other a-substituted enolates compared with their counterparts lacking a-substituents. - ... 

They can ben rationalized using conjugated hydrocarbons as models (fig. 11). In this way, vinyl alcohol CH2=CH-OH is seen as allyl anion CH2=CH-CH2 The 7r molecular orbitals system is then filled with not 3 but 4 electrons. In the similar way, for a substituted enol, for instance CFH=CHOH, the model will be a butadiene with 2 extra electrons. Additional electrons in formerly empty molecular orbitals are, in our model, grounds for the structural changes. 

Reaction of an a-substituted enolate with an aldehyde or ketone can give two pairs of aldol dia-stereomers, which are conveniently designated as the syn form (17) and the anti form (18), where is part of the parent chain in lUPAC nomenclature (equation 29). For simplicity, only one enantiomer of each pair will usually be shown throughout this section. The syn/anti notation for aldol diastereomers has been described in detail by Heathcock. ... 

All the depsipeptides contain a common /3-hydroxy acid, which can be disconnected by an aldol reaction. However, it is an example of an acetate aldol that suffers from poor facial selectivity of the acetate enolate. Many of the auxiliaries and reagent-based conditions that work for propionate and other a-substituted enolates are unsuitable for acetate aldols. In the event, each depsipeptide total synthesis has featured a different route for the synthesis of this /3-hydroxy acid fragment. 

The equilibrium between a-silyl alkoxides and silojq carbanions can be shifted toward the carbanion side by introduction of a conjugating group into either or both the acylsilane and the nucleophile. In 1980, Reich et al. reported that treatment of all l-substituted acylsilanes with vinyllithium followed by a variety of electrophiles affords a-substituted enol silyl ethers 22 via a siloxy allyllithium intermediate 21 fScheme 8.1Similar reactions using phenyllithium give products in which electrophilic quenching occurred at the benzylic position. 

Scheme 6.14 Stereoselective formation of a-substituted enol silyl ethers from acylsilanes and vinyllithium.

A soln. of 4-hydroxy-2-butanone in THF added slowly dropwise to 2.2 eqs. /-PrjNLi in the same solvent at —78°, and quenched with 2.5 eqs. of trimethylchlorosilane - product. Y 81%. The least substituted enolate anion is generated, with improved regioselectivity over ketones lacking a P-hydroxy group in the case of sym. a-substitution, enolization distal to the P-oxido substituent is favoured thermodynamically. F.e., also p,p-dihydroxyketones from aldehydes, s. V.A. Martin, K.F. Albizati, J. Org. Chem. 53, 5986-8 (1988). 

When, in reactions 1-3, the enolate does not have an a-substituent, e.g. 29 (R = H), induced stereoselectivity is highly desirable. In addition, the corresponding reaction of a-substituted enolates 29 (R H) should not only provide induced stereoselectivity but also simple diastereoselectivity. In this chapter we will not use induced diastereoselectivity as a subdivision applicable to reactions 1 and 2 and induced enantioselectivity for reaction 3 (leading to enantiomeric aldol products), because, irrespective of the stereochemical relationship of the products (diastereomers or enantiomers), the transition states leading to the different stereoisomeric compounds are always diastereotopic, even if the products are enantiomers (reaction 3). The term induced stereoselectivity , which includes the different variants 1-3, is therefore used here [57, 61]. 

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