Stereoselective reactions enolate formation

The regio- and stereoselectivity of enolate formation are essential for the control of alkylation reactions. The regioselectivity of ketone deprotonation has been extensively investigated and this important step in alkylation reactions has been discussed in many reviews (e.g., refs 1-4, 71) and textbooks (e.g., refs 5, 6). Therefore, this topic will be discussed here only in general terms. 

Aldol reactions Enolate formation from ketones and subsequent aldol reaction give yyn-aldols stereoselectively. 

The (Z)/( ) stereoselectivity of enolate formation is dictated by the structure of the starting carbonyl compound and the base used for deprotonation. Compared to LDA, Lithium 2,2,6,6-Tetra-methylpiperidide usually favors ( )-enolates whereas Lithium Hexamethyldisilazide preferentially leads to (Z)-enolates (eq 10). With a caveat for any generalization, enolate configuration usually determines the stereochemical result in the product for example, using a hindered ester and a bulky aldehyde combination, excellent stereoselectivities in aldol reactions are observed (eq 11). ... 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

An example of such a rearrangement, in which the intermediate enolate has been further treated with alkylation agents29, is shown for enolate 12. The intermediate enolate can also undergo an aldol reaction. Thus, trapping the enolate with benzaldehyde provides an indication that the Z-enolate is the predominating species29. Further systematic studies are needed in order to assess the applicability of this method of stereoselective enolate formation. However, the potential for the use of this method in asymmetric synthesis appears to be good29. 

The cis stereoselectivity can be explained by a six-membered chair-like transition state model (19) resulting from the interaction of an ( )-enolate with an imine in its trans configuration (Scheme 20). Conditions favoring ( )-enolate formation (LDA, THF) predominantly yield cis -lac-tams. 55,156,158 Addition of HMPA or reactions at higher temperature favor the forma-... 

The first reaction is a conjugate addition that evidently goes ivithout any worthier stereoselectivity. The stereochemistry is not fixed in the addition but in the protonation of. enolate in the work-up. Equilibration of the mixture by reversible enolate formation gives me -. -the all-equatorial compound. 

A stereoselective reaction leads to the exclusive or predominant formation of one of several possible stereoisomeric products. Thus, one reaction pathway from a given substrate is favored over the other (as in nucleophilic additions to cyclic ketones or alkylations of enolate ions). 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

The stereoselectivity of the formation of the ( )-lithium enolate and thus of the entire rearrangonent can be significantly increased by a change in the reaction solvent from 23% HMPA/THF to 45% DMPU/THF (Scheme 22). ... 

It is also important to note that several factors influence both the stereoselectivity of hydrogen exchange and enolate formation in base-promoted reactions. Houk, Ando and co-workers found that differing conju-gative stabilization by CH p-orbital overlap does not directly influence stereoselectivity.205 Steric effects only dominate is exceptionally crowded transition structures, but torsional strain involving vicinal bonds contributes significantly to the stereoselectivity of all cases studied. 

The treatment of an ester (or lactone) with a base and a silyl halide or trillate gives rise to a particular type of sUyl enol ether normally referred to as a silyl ketene acetal. The extent of O- versus C-silylation depends on the structure of the ester and the reaction conditions. The less-bulky methyl or ethyl (or 5-tert-butyl) esters are normally good substrates for O-silylation using LDA as the base. Acyclic esters can give rise to two geometrical isomers of the silyl ketene acetal. Good control of the ratio of these isomers is often possible by careful choice of the conditions. The f-isomer is favoured with LDA in THF, whereas the Z-isomer is formed exclusively by using THF/HMPA (1.24). Methods to effect stereoselective silyl enol ether formation from acyclic ketones are less well documented. ... 

We postulated a mechanism for the CRI reaction of 34 to rationalize this stereochemical outcome (Scheme 9). Reduction of the azide group with BU3P followed by hydrolysis triggers ring-opening and intermediate formation (35-36). Further, nucleophilic attack (36-37), enol formation (37-38), and stereoselective [1,3]-H migration (38-30) produce cis isomer 30 tmder kinetic control. 

Stereoselective aldol reactions are limited by their ability to obtain stereoisomerically pure ( )- or (Z)-enolates separately, and it has been suggested that equilibration may be occurring to erode the enolate selectivities. However, it would appear that the measured rate of enolate equilibration appears to be too low to be much of an influence.It was suggested by Ireland in 1976 that LDA-mediated enolizations may proceed by cycUc transition states via disolvated LDA monomers. Tbis mecbanism bas since been widely cited for its predictive power. Ireland proposed that the deprotonation process may be proceeding via one of two proposed transition states, where proton transfer is synchronous with metal ion transfer. Non-bonded interactions between amide alkyl groups and the enolate alkyl group cause a preference for E-enolate formation (Scheme 1, refs 124,136). 

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