Enolates stereoselective formation

Regioselectivity and Stereoselectivity in Enolate Formation from Ketones and Esters... 

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... 

Among the most useful carbonyl derivatives are (V-acyloxazolidinones, and as we shall see in Section 2.3.4, they provide facial selectivity in aldol addition reactions. l,3-Thiazoline-2-thiones constitute another useful type of chiral auxiliary, and they can be used in conjunction with Bu2B03SCF3,44 Sn(03SCF3)2,45 or TiCl446 for generation of enolates. The stereoselectivity of the reactions is consistent with formation of a Z-enolate and reaction through a cyclic TS. 

In studies not yet published (66), the A/-acyl-oxazolidine-2-one 62 has been found to exhibit exceptionally high levels of (Z)-enolization stereoselection with either amide bases (LDA, THF, -78°C) or boryl triflates [(n-C4H9)2BOTf, CH2CI2, -78°C] in the presence of diiso-propylethylamine (DPEA). Upon aldol condensation, the enolates 63a and 63b afford the aldolates 64 (Scheme 11), which react readily with nucleophiles at the carbonyl function (Table 22). As discussed earlier, the large preference for (Z)-enolate formation in this system can be attributed to allylic strain considerations (37)... 

Stereoselective addition of cuprates to y-alkoxy enoates of type 49 [17] (see Schemes 6.8 and 6.9) has been used in the construction of polypropionate-type structures. Thus, a sequence of diastereoselective cuprate addition, enolate formation, and diastereoselective oxygenation with Davis s reagent has been applied iteratively to provide a C19-C28 segment of Rifamycin S (60) [17c, d]. 

For many ketones, stereoisomeric as well as regioisomeric enolates can be formed, as is illustrated by entries 6, 7, and 8 of Scheme 1.3. The stereoselectivity of enolate formation, under conditions of either kinetic or thermodynamic control, can also be controlled to some extent. We will return to this topic in more detail in Chapter 2. 

Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.5.2), there has been a good deal of interest in the factors that control the stereoselectivity of enolate formation from esters. For simple esters such as ethyl propanoate, the /r-enolate is preferred under kinetic conditions using a strong base such as LDA in THF solution. Inclusion of a strong cation solvating co-solvent, such as HMPA or tetrahydro-1,3 -dimethyl-2(1 Z/)p y r i m i d o nc (DMPU) favors the Z-enolate.13... 

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. 

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 addition of acetate-derived, achiral lithium enolates to monoprotected a-amino aldehydes is controlled by chelation, and leads to a modest stereochemical preference in favor of the 3,4-syn configuration (Table 1, entry a). 18 The formation of the 3, A-syn-product is enhanced by the use of acetate-derived silyl ketene acetals and the addition of titanium(IV) chloride or tin(IV) chloride to the reaction mixture (Table 1, entries b and c). 22-23 The same enolates add stereoselectively to A2 A-dibenzyl a-amino aldehydes but with diastereomeric ratios in favor of the Felkin-Ahn 3,4-anti-product (Table 1, compare entries a and d, and b and f). 22-24 Reverse stereocontrol is observed in the presence of a Lewis acid such as tita-nium(IV) chloride, but the yield is low (Table 1, entry e). 24 ... 

The effect of the steric and electronic nature of lithium amide bases (71-74) on highly stereoselective kinetic enolate formation from six ketones (70a-f) in THF has been investigated. The results in general can be rationalized with respect to the cyclic... 

Silyl ketene acetals from esters.1 Ireland has examined various factors in the enolization and silylation of ethyl propionate (1) as a model system. As expected from previous work (6, 276-277), use of LDA (1 equiv.) in THF at —78 -+ 25° results mainly in (E)-2, formed from the (Z)-enolate. The stereoselectivity is markedly affected by the solvent. Addition of TMEDA results in a 60 40 ratio of (Z)- and (E)-2 and lowers the yield significantly. Use of THF/23% HMPA provides (Z)- and (E)-2 in the ratio of 85 15 with no decrease in yield. This system has been widely used for (E)-selective lithium enolate formation from esters and ketones. Highest stereoselectivity is observed by addition of DMPU, recently introduced as a noncar-... 

The regio- and stereoselectivity of enolate formation has been discussed in many reviews . In general, the stereo- and regioselectivity of ketone deprotonation can be thermodynamically or kinetically controlled. Conditions for the kinetic control of enolate formation are achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent at low temperature. In this case the deprotonation occurs directly, irreversibly and with high regioselectivity (equation 1). By using a proton donor (solvent or excess of ketone) or a weaker base, an equilibration between the enolates formed may... 

TABLE 2. Conditions for the stereoselective enolate formation of acyclic ketones according to equation 2... 

Better inductions by a vicinal amino acid were observed by Ojima and coworkers in the benzylation of chiral /3-lactam ester enolates (255, equation 67) °. Interestingly, the enolate formation occurred at an uncommonly high temperature (0°C) to form the thermodynamic Li-chelated enolate 256, which allowed a stereoselective attack of the electrophile, while the diastereoselectivity with the nonchelated kinetic enolate 259 was significantly lower. Subsequent hydrogenolytic cleavage of lactam 257 delivered S)-a-methylphenylalanine derivative 258 in nearly quantitative yield and high diastereoselectivity. 

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-... 

Ireland, R E, Mueller, R H, Willard, A K, Ester enolate Claisen rearrangement — stereochemical control through stereoselective enolate formation, J. Am. Chem. Soc., 98, 2868-2877, 1976. 

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. 

---