Enantioselective Enolate Alkylations

Any comparison between enantioselective enolate alkylations and related processes and methods based on the use of chiral auxiliaries reveals that the former area remains much less well developed. Nevertheless, a number of impressive approaches have emerged, as discussed below [21, 22]. 

Enantioselective alkylation of achiral enolates can provide an alternative to desymmetrization processes for the preparation of optically active Ca-substituted ketones. Alkylation of enolate 190 thus furnishes ketone 193 in 96 % ee and 76 % yield in the presence of chiral tetraamine 191 (Equation 14) (107). The reaction protocol prescribes the use of MeLi-LiBr for the generation of enolate 190 from enolsilane 189. The presence of lithium bromide was important, as it had a pronounced effect both on the subsequent rate of alkylation and on the stereoselectivity. Interestingly, the use of LiBr in combination with excess N,N,N, N -tetramethylpropylenediamine (192) enables the use of substoichiometric amounts of the chiral tetramine 191 (5mol%) (108). It has been suggested that diamine 192 functions as a trapping agent for LiBr, which otherwise complexes with and deactivates 191 in the course of the reaction. 

There are only scattered reports of catalytic enantioselective processes for the alkylation of enolates. Most notably in this respect, Jacobsen has reported that Cr-salen complex 195 mediates the alkylation of a range of tributyltin enolates. Thus, treatment of 194 with 2.5 mol % of catalyst 195 and benzyl bromide affords 196 in 91 % yield and 93% ee (Equation 15) [22, 109]. 

In addition to the alkylations described in the preceding sections, stereoselective reactions with heteroatom electrophiles - including oxygen, nitrogen, and halogen derivatives - have also been developed. Selected examples of a-hydroxylations are discussed in this section [23-25], and a-halogenations are considered in Section 3.7, while a-aminations of enolates are showcased in Chapter 10, Section 10.5. 

The corresponding a-hydroxylation of aldehydes is often complicated by undesired self-condensation of the enolates and instability of the hydroxy-lated products [24]. However, for substrates such as 203, the -hydroxylated aldehyde 204 can be prepared in 96% yield as a single stereoisomer (Equation 17) [114], 

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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... 

E. J. Corey, F. Xu, M. C. Noe, A Rational Approach to Catalytic Enantioselective Enolate Alkylation Using a Structurally Rigidified and Defined Chiral Quaternary Ammonium Salt under Phase Transfer Conditions , J. Am. Chem. Soc, 1997,119,12414-12415. 

Acyclic a,a-disubstituted tin enolates 6 inevitably form as cis/trans-mixtures. Nevertheless, application of the chromium alkylation protocol with the modified salen complex 7 provides fair enantioselectivity with various alkylating agents R CH2X hke allyl bromide, benzyl bromide, allyl iodide, and ethyl iodoacetate, as outlined in Scheme 5.5. A plausible explanation is based on the assumption of a rapid cis/trans-isomerization of the tin enolates 6 through the C-bound tautomer and the postulate that one of the enolate diastereomers reacts distinctly faster than the other. The role of the additive BugSnOMe, which has a beneficial effect on the enantioselectivity, might be to catalyze the cis/trans-isomerization of the enolate. Several models have been proposed for the mechanisms of the enantioselective enolate alkylation like transmetallation of tin into a chromium enolate, formation of a stannate by iodine transfer from chromium to tin, as well as activation of the alkyl halide by chromium [5]. 

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. 

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. 

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

Enantioselective a-alkylation of the enolates of synthetic equivalents for glycine (R3 = H) and several other a-amino acids (R3 4= H) equivalents can be accomplished via 4-imidazolidinone derivatives of type 11,4,<5,7,8,1°-12. Both of the pure enantiomers of the glycine equivalent are readily available. Alkylation of these ultimately furnishes enantiomerically pure a-amino adds with a a-hydrogen11,12, whereas if R3 =t= H in the starting 4-imidazolidinones 1 then a-alkyl-a-amino acids 2 are obtained4,7 8,10-12. 

Inter- and intramolecular reactions between a propargyiic carbocation equivalent stabilized by Co2(CO)6-coordination and enol derivatives also provide a good method for the carbon-carbon bond formation at the propargyiic carbon of propargyiic alcohols and their derivatives. Many diastereoselective and enantioselective propargyiic alkylation reactions at the propargyiic position take place between chiral propargyiic cation equivalents and enol derivatives. 

The same strategy has been used by Williams (90JA808) in his synthesis of brevianamide B. The aldehyde (82), prepared enantioselectively from L-proline, was converted to the silyl ether. Acylation of this (BuLi, ClC02Me) gave the carbomethoxy derivative as a mixture of diastereo-mers, which was alkylated by gramine. As before, an enolate alkylation (Sn2 ) on an allyl chloride derived from the above gave the tricyclic compound, which could be transformed to brevianamide B (Scheme 24). 

The oxazolidinones have been used as chiral auxiharies for enolate alkylation and aldol reactions in enantioselective and total syntheses The interest in these substrates is largely known for iyw-diastereoselective aldol reactions with chlorotitanium or diaUcylboron oxazilidinone enolates (equation 114). 

In recent years, investigations of the diastereoselectivity and enantioselectivity of alkylations of metal enolates of carboxylic acid derivatives have become one of the most active areas of research in synthetic organic chemistry. Intraannular, extraannular and chelate-enforced intraannular chirality transfer may be involved in determining the stereochemistry of these alkylations. 

Enantioselection can be controlled much more effectively with the appropriate chiral copper, rhodium, and cobalt catalyst.The first major breakthrough in this area was achieved by copper complexes with chiral salicylaldimine ligands that were obtained from salicylaldehyde and amino alcohols derived from a-amino acids (Aratani catalysts ). With bulky diazo esters, both the diastereoselectivity (transicis ratio) and the enantioselectivity can be increased. These facts have been used, inter alia, for the diastereo- and enantioselective synthesis of chrysan-themic and permethrinic acids which are components of pyrethroid insecticides (Table 10). 0-Trimethylsilyl enols can also be cyclopropanated enantioselectively with alkyl diazoacetates in the presence of Aratani catalysts. In detailed studies,the influence of various parameters, such as metal ligands in the catalyst, catalyst concentration, solvent, and alkene structure, on the enantioselectivity has been recorded. Enantiomeric excesses of up to 88% were obtained with catalyst 7 (R = Bz = 2-MeOCgH4). 

Very strong uncharged polyaminophosphazene bases with good chemical and thermal stability, their pKa ranging from 24 to 47 in the absolute MeCN scale and relatively non-nucleophilic. Useful in alkylation of enolates, in enantioselective a-alkylation of amino acids, in Ullmann synthesis. 

While the a-allylation of enolates occurs with high ee using palladium catalysts (see Section 10.2) there have been few reports on the enantioselective metal-catalysed enolate alkylation. The best results to date have been achieved by Doyle and lacobsen using the chromium(salen) complex (12.42) in the alkylation of cyclic tin enolates with a range of alkyl halides, including propargyl and benzylic hahdes... 

An aldol reaction is the addition of an enolate to an electrophile, where the electrophile is an aldehyde or a ketone. You have already seen earlier in this chapter how enolates can be used to make new C-C bonds enantioselectively when we explained how to control enolate alkylation with Evans chiral auxiliaries. Evans auxiliaries also provide one of the most straightforward ways of carrying out asymmetric aldol reactions, and we will start with an example before explaining how asymmetric aldol reactions can be done using catalytic methods. 

Enolate alkylations can be carried out stereoselectively to give enantiomerically enriched a-alkyl carbonyl compounds. Particular success has been achieved with the aid of chiral auxiliaries, enantiomerically pure chiral compounds that can be attached to the carbonyl group to control the direction of substitution at the a carbon, then removed to leave the desired a-alkyl carbonyl compound with high enantioselectivity. 

In 2005 Trost reported a similar system using enol carbonate substrates for the enantioselective allyUc alkylation of cyclic ketones (Scheme 4.17) [39]. The best ligand for the transformation was (/ ,/ )-ANDEN-Trost ligand (L2) which provided... 

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