Enolate alkylation stereochemistry

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

The prediction and interpretation of alkylation stereochemistry requires consideration of conformational effects in the enolate. The decalone enolate 3 was found to have a strong preference for alkylation to give the cis ring junction, with alkylation occurring cis to the f-butyl substituent.58... 

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... 

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. 

The synthesis in Scheme 13.13 leads diastereospecifically to the erythro stereoisomer. An intramolecular enolate alkylation in Step B gave a bicyclic intermediate. The relative configuration of C(4) and C(7) was established by the hydrogenation in Step C. The hydrogen is added from the less hindered exo face of the bicyclic enone. This reaction is an example of the use of geometric constraints of a ring system to control relative stereochemistry. 

The stereochemistry of the C(3) hydroxy was established in Step D. The Baeyer-Villiger oxidation proceeds with retention of configuration of the migrating group (see Section 12.5.2), so the correct stereochemistry is established for the C—O bond. The final stereocenter for which configuration must be established is the methyl group at C(6) that was introduced by an enolate alkylation in Step E, but this reaction was not very stereoselective. However, since this center is adjacent to the lactone carbonyl, it can be epimerized through the enolate. The enolate was formed and quenched with acid. The kinetically preferred protonation from the axial direction provides the correct stereochemistry at C(6). 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

The relative stereochemistry indicated in the product structures in Table 13 are as predicted from earlier enolate alkylation studies4,22 and from knowledge of a favored syn intermediate haloalkylated species (vide infra). Presumably, conformations adopted by the intermediates are such that cyclization is favored only for a limited range of ring sizes. 

The Kishi group developed a second synthesis of 3,6-epidithia-2,5-piperazine-diones that is particularly useful for the synthesis of simpler systems on a large scale [Scheme 5,41 ] 77 The route benefits from the stereochemistry of the double 5-alkylation of 41.1 to give the cis-product 41.2 A second double enolate alkylation was again stereoselective, giving 413 in 83% yield. Finally treatment of the bis(0,5-acetal) 413 with trichloroborane gave the 3,6-epidithia-2,5-piper-azinedione 41,4 in 77% yield. 

In addition, the lithium enolate derived from pseudoephedrine propionamide has been shown to undergo highly diastereoselective Mannich reactions with p-(methoxy)phenyl aldimines to form enantiomerically enriched a,p-disubstituted p-amino acids (Table 10). As observed in alkylation reactions using alkyl halides as electrophiles, lithium chloride is necessary for the reaction of aldimines. With respect to the enolate, the stereochemistry of the alkylation reactions is the same as that observed with... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

The stereochemistry of enolate alkylation follows the general rule governing the stereochemistry of reactions an achiral starting material yields an achiral or racemic product. For example, when cyclohexanone (an achiral starting material) is converted to 2-ethylcyclohexanone by treatment with base and CH3CH2I, a new stereogenic center is introduced, and both enantiomers of the product are formed in equal amounts—that is, a racemic mixture. 

An important strategy for achieving substrate control is the use of chiral auxiliaries, which are structures incorporated into reactants for the purpose of influencing the stereochemistry. Two of the most widely used systems are oxazolidinones " derived from amino acids and sultams derived from camphorsulfonic acid. These groups are most often used as carboxylic acid amides. They can control facial stereoselectivity in reactions such as enolate alkylation, aldol addition, and Diels-Alder cycloadditions, among others. The substituents on the chiral auxiliary determine the preferred direction of approach. 

The stereochemistry of enolate alkylations has been studied by determining the stereochemistry of products from alkylation of cyclic ketones. The stereochemistry of alkylation of the enolates 1 and 2 has been determined. While 1 shows no... 

Aldehyde 73 was prepared from aldehyde 70 using a Brown Allylation to control absolute stereochemistry in the preparation of 72. Bromide 68 was prepared using a Sharpless epoxidation to control absolute stereochemistry. Conversion of 73 to the corresponding enolate, alkylation with 68, and addition of more LDA to generate a new enolate (74) gave a reasonable yield of 75 (see Histrionicotoxin-8/9). 

In the synthesis in Scheme 13.34, the first configuration that is established after construction of the decalin system is the one at C-8 in step A. An enolate alkylation is carried out with methallyl iodide. The observed, and desired, stereochemistry is governed by the C-10 methyl group, which blocks attack from the top side of the molecule. In step B, the five-membered ring is formed by intramolecular aldol condensation. The reduction of the enone (step C) establishes the configuration at C-13, and this chirality is subsequently transferred to C-9 by the intramolecular Claisen rearrangement in step D. 

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