Alkylation enolate

Mechanism of Enolate Alkylation SN2 reaction, inversion of electrophile stereochemistry... 

One of the general features of the reactivity of enolate anions is the sensitivity of both the reaction rate and the ratio of C- versus O-alkylation to the degree of aggregation of the enolate. For example, addition of HMPA fiequently increases the rate of enolate alkylation... 

In general, the stereoselectivity of enolate alkylation can be predicted and interpreted on the basis of the stereoelectronic requirement for approximately perpendicular approach to the enolate in combination with selection between the two faces on the basis of steric factors. 

Chiral oxazolines were the first ehiral auxiliaries used for asymmetrie enolate alkylations. Subsequent studies led to the development of a number of other ehiral auxiliaries (34-38) ineluding those reported by Evans, Myers, Enders, Sehollkopf, and others, whieh are now widely used in asymmetrie synthesis. Although these new auxiliaries frequently provide higher yields and enantioseleetivities than the oxazolines originally developed by Meyers, the pioneering work of Meyers laid the groundwork for these later studies. 

When the cyclic enone is unsubstituted, but the resulting enolate is quenched with an electrophile under conditions of kinetic control the irons adduct is formed exclusively303. Particularly successful is the sequential Michael addition/enolate alkylation in diastereoselective routes to frans-a,/j-difunctionalized cycloalkanones and lactones304-308. The key steps in the synthesis of methyl ( + )-jasmonate (3)309-310 (syn/anti diastereoselection) and (-)-khushimone (4) (syn/anti and induced diastereoselection) illustrate this sequence311 (see also Section D. 1.1.1.3.). 

ENONE REDUCTION-ENOLATE ALKYLATION SEQUENCE 2 - ALLYL- 3-METH YLC Y CLOHEX AN ONE... 

For general reviews of enolate alkylation, see D. Caine, in Carbon-Carbon Bond Formation, Vol. 1, R. L. Augustine, ed., Marcel Dekker, New York, 1979, Chap. 2 C. H. Heathcock, Modem Synthetic Methods, 6, 1 (1992). 

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... 

The cis product must be formed through a TS with a twistlike conformation to adhere to the requirements of stereoelectronic control. The fact that this pathway is not disfavored is consistent with other evidence that the TS in enolate alkylations occurs early and reflects primarily the structural features of the reactant, not the product. A late TS would disfavor the formation of the cis isomer because of the strain associated with the nonchair conformation of the product. 

Houk and co-workers examined the role of torsional effects in the stereoselectivity of enolate alkylation in five-membered rings, and their interpretation can explain the preference for C(5) alkylation syn to the 2-methyl group in trans-2,3-dimethylcyclopentanone.59... 

In acyclic systems, the enolate conformation comes into play. p,(3-Disubstituted enolates prefer a conformation with the hydrogen eclipsed with the enolate double bond. In unfunctionalized enolates, alkylation usually takes place anti to the larger substituent, but with very modest stereoselectivity. 

These examples illustrate the issues that must be considered in analyzing the stereoselectivity of enolate alkylation. The major factors are the conformation of the enolate, the stereoelectronic requirement for an approximately perpendicular trajectory, the steric preference for the least hindered path of approach, and minimization of torsional strain. In cyclic systems the ring geometry and positioning of substituents are often the dominant factors. For acyclic enolates, the conformation and the degree of steric discrimination govern the stereoselectivity. 

Scheme 1.8 shows some intramolecular enolate alkylations. The reactions in Section A involve alkylation of ketone enolates. Entry 1 is a case of a-alkylation of a conjugated dienolate. In this case, the a-alkylation is also favored by ring strain effects because y-alkylation would lead to a four-membered ring. The intramolecular alkylation in Entry 2 was used in the synthesis of the terpene seychellene. 

Entries 3 to 6 are examples of ester enolate alkylations. These reactions show stereoselectivity consistent with cyclic TSs in which the hydrogen is eclipsed with the enolate and the larger substituent is pseudoequatorial. Entries 4 and 5 involve SN2 substitutions of allylic halides. The formation of the six- and five-membered rings, respectively, is the result of ring size preferences with 5 > 7 and 6 > 8. In Entry 4, reaction occurs through a chairlike TS with the tertiary C(5) substituent controlling the conformation. The cyclic TS results in a trans relationship between the ester and vinylic substituents. 

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

A number of other types of chiral auxiliaries have been employed in enolate alkylation. Excellent results are obtained using amides of pseudoephedrine. Alkylation occurs anti to the a-oxybenzyl group.93 The reactions involve the Z-enolate and there is likely bridging between the two lithium cations, perhaps by di-(isopropyl)amine.94... 

Scheme 1.9 gives some examples of diastereoselective enolate alkylations. Entries 1 to 6 show the use of various IV-acyloxazolidinones and demonstrate the... 

Scheme 1.9. Diastereoselective Enolate Alkylation Using Chiral Auxiliaries...

Intramolecular alkylation of enolates can be used to synthesize bi- and tricyclic compounds. Identify all the bonds in the following compounds that could be formed by intramolecular enolate alkylation. Select the one that you think is most likely to succeed and suggest reasonable reactants and reaction conditions for cyclization. 

Enantioselectivity can also be based on structural features present in the reactants. A silyl substituent has been used to control stereochemistry in both cyclic and acyclic systems. The silyl substituent can then be removed by TBAF.326 As with enolate alkylation (see p. 32), the steric effect of the silyl substituent directs the approach of the acceptor to the opposite face. 

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