Alkylations, asymmetric ester

The use of a-halo(alkyl) boronic esters in asymmetric synthesis provides state of the art stereoselection1-3. The diastereomeric ratio of the a-halo boronic esters synthesized as intermediates is routinely in the 100 1 range. However, with the proper choice of chiral director, displacement of the oc-halogen provides a second stcrcodifferentiation step, after which diastereomeric ratios may exceed 1000 1 4. 

In the initial discovery of the asymmetric synthesis of a-chloro boronic esters 3, the diastereomeric ratios of 3 were estimated by reaction with Grignard reagents to form secondary alkyl boronic esters 5 and deboronation with hydrogen peroxide to secondary alcohols of known absolute configuration and rotation40. 

S. Rodriguez, K. T. Schroeder, M. M. Kayser, and J. D. Stewart, Asymmetric synthesis of I-hydroxy esters and a-alkyl-/ -hydroxy esters by recombinant Escherichia coli expressing enzymes from baker s yeast, J. Org. Chem. 2000, 65, 2586-2587. 

Asymmetric alkylation of esters. HMPT tias a marked influence on the asymmetric alkylation of enolates of chiral esters, such as the propionates 1, where R is a derivative of (+ )-camphor. A typical example is shown in equation (I). The esters are deprotonated with lithium cyclohexylisopropylamide (LICA) cither in THE (A) or in THF/HMPT (B). In the first case, alkylation with benzyl bromide results mainly in (2S)-2 in the second case, formation of (2R)-2 is markedly favored The effect of HMPT is considered to result, at least in part, from preferential formation of the (E)-enolate of 1. 

Asymmetric alkylation of a-alkyl- -keto esters.1 The sense of asymmetric alkylation of the chiral enamines prepared from (S)-valine t-butyl ester with a-alkyl-(3-keto esters is markedly controlled by the solvent. Thus alkylation of the anion 1, prepared with LDA in toluene, with CH3I in the presence of HMPT (1 equiv.) results in (R)-2 in 99% ee, whereas alkylation in THF (2 equiv.) results in (S)-2 in 92% ee. The effect of HMPT is general for a variety of electrophiles depending on the electrophile, dioxolane... 

Scheme 3.14. Helmchen s asymmetric ester enolate alkylation [73,74].

Helmchen and co-workers achieved good asymmetric induction in the alkylation of ester enolates using the camphor based sulfonamide auxiliary in acetate 439.Alkylation of the enolate derived from 439 with iodotetradecane proceeded primarily from the less hindered face (away from the sulfonamide group, to give a 98 2 mixture of 440 and 441. The diastereomer ratio was 98 2 favoring 440 and the yield of 74%. 

Helmchen G, Selim A, Dorsch D, Taufer I. Influence of cation complexing solvent additives and functional groups in asymmetric alkylations of esters via lithium enolates. Tetrahedron Lett. 1983 24 3213-3216. 

Esters are alkylated in the presence of strong bases in aprotic solvents. A common combination is LDA in tetrabydrofuran at low temperatures. Equimolar amounts of base are sufficient and only the mono-carbanion Js formed. After addition of one mole of alkyl halide the products form rapidly, and no dialkylation, which is a problem in the presence of excess base, is possible. Addition of one more mole of LDA and of another alkyl halide leads to asymmetric dialkylation of one or-carbon atom in high yield (R.J. Cregge, 1973). 

A great advantage of catalyst 24b compared with other chiral Lewis acids is that it tolerates the presence of ester, amine, and thioether functionalities. Dienes substituted at the 1-position by alkyl, aryl, oxygen, nitrogen, or sulfur all participate effectively in the present asymmetric Diels-Alder reaction, giving adducts in over 90% ee. The reaction of l-acetoxy-3-methylbutadiene and acryloyloxazolidinone catalyzed by copper reagent 24b, affords the cycloadduct in 98% ee. The first total synthesis of ewt-J -tetrahydrocannabinol was achieved using the functionalized cycloadduct obtained [23, 33e] (Scheme 1.39). 

A similar but asymmetric variant of the reaction, involving the radical addition of alkyl iodides and trialkylboranes to chiral azirine esters derived from 8-phenyl-menthol and camphorsultam, in the presence of a Cu(i) catalyst, has subsequently been reported [64]. The diastereoselectivity of the addition is variable (0-92% de)... 

Cyclodextrins, toroidal molecules composed of 6, 7 and 8 D-glucose units, are now commercially available at reasonable cost. They form inclusion compounds with a variety of molecules and often differentially include sulfoxide enantiomers29,30. This property has been used to partially resolve some benzyl alkyl, phenyl alkyl and p-tolyl alkyl sulfoxides. The enantiomeric purities after one inclusion process ranged from 1.1 % for t-butyl p-tolyl sulfoxide to 14.5% for benzyl r-butyl sulfoxide. Repeating the process on methyl p-tolyl sulfoxide (10) increased its enantiomeric purity from 8.1% to 11.4% four recrystallizations raised the value to 71.5%. The use of cyclodextrins in asymmetric oxidations is discussed in Section II.C.l and in the resolution of sulfmate esters in Section II.B.l. 

Dynamic kinetic resolution of racemic ketones proceeds through asymmetric reduction when the substrate does racemize and the product does not under the applied experimental conditions. Dynamic kinetic resolution of a-alkyl P-keto ester has been performed through enzymatic reduction. One isomer, out of the four possible products for the unselective reduction (Figure 8.38), can be selectively synthesized using biocatalyst, and by changing the biocatalyst or conditions, all of the isomers can be selectively synthesized [29]. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

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