Lithium enolates 2-methyl-2- -3-pentanone

In the absence of chelation, comparison of the destabilizing syw-pentane interactions recently encouraged Evans and coworkers to use the Comforth model to justify the exalted 3,4-anti selectivity observed for a series of chiral a-oxygenated aldehydes reacting with the Z(O) boron and lithium enolates of 2-methyl-3-pentanone (Scheme 117)568. Comple-mentarily, the corresponding E(O) isomers showed, as expected, a striking difference in their 2,3-selectivities, while the 3,4 anti-selectivity was lowered in both cases a finding inconsistent with the PFA model. 

Stereoselective aldol condensation. Heathcock and Buse have previously employed 2-methyl-2-trimethylsiloxy-3-pentanone (1) in a highly stereoselective route to 3-hydroxy-2-methylcarboxylic acids (8, 295). Aldol condensation of the lithium enolate derived from 1 with a chiral aldehyde yields ery//iro-aldols, which are cleaved with periodic acid to -hydroxy carboxylic acids. However, when 1 is condensed with a chiral aldehyde such as 2, two eryt/iro-products (3 and 4) are produced. Heathcock and co-workers now report that the 1,2-diastereoselectivity of these aldol condensations can be enhanced by use of the ketone 5. Reaction of racemic 5 with racemic aldehyde 2 furnishes a single (racemic) adduct 6. 

In one of the first such examples, the lithium enolate of (S)-3-methyl-2-pentanone was allowed to react with several aldehydes in the case of propanal, the two products are formed in 15% diastereomeric excess, favoring (179 equation 115). The di- -butylboron enolate of this ketone has been studied and found to give (179) and (180) in a ratio of 63 37 in CH2CI2 and 64 36 in pentane. ... 

Fig. 7.2. Crystal structures of some lithium enolates to ketones of ketones. (A) Unsolvated hexameric enolate of methyl t-butyl ketone. (B) Tetrahydrofuran solvate of tetramer of enolate of methyl t-butyl ketone. (C) Tetrahydrofuran solvate of tetramer of enolate of cyclopentanone. (D) Dimeric enolate of 3,3-dimethyl-4-(t-butyldimethylsiloxy)-2-pentanone. Structural diagrams are reproduced from Refs.

In a pioneering investigation, the lithium enolate derived from 3-methyl-2-pentanone was added to aldehydes. Only moderate diastereoselectivity was obtained, however [119]. Exceptionally high induced stereoselectivity was observed when camphor-derived ketone 69 was converted into the lithium enolathe and subsequently added to aldehydes. a-Cleavage at the carbonyl group enabled the formation of y -hydroxy aldehydes and acids in high enantiomeric excess (Eq. (31)) [60]. The work on the aldol addition of methyl ketones led to a variety of stereoselective variants which rely mainly on boron enolates and will be discussed in Chapter 3 of Part I of this book. 

Lithium Enolate trans-30 [X = CHiMejj, M = Li] by Deprotonation of 2-Methyl-3-pentanone with LiHMDS/triethyiamine [41]... 

Lithium enolate trans-30 [X = CH(Me)2, M = Li] by deprotonation of 2 methyl-3- 24 pentanone with LiHMDS/triethylamine... 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

In contrast to LDA, LiHMDS favors the Z-enolate.14 Certain other bases show a preference for formation of the Z-enolate. For example, lithium 2,4,6-trichloroanilide, lithium diphenylamide, and lithium trimethylsilylanilide show nearly complete Z-selectivity with 2-methyl-3-pentanone.15... 

The E.Z ratio can be modified by the precise conditions for formation of the enolate. For example, the E.Z ratio for 3-pentanone and 2-methyl-3-pentanone can be increased by use of a 1 1 lithium tetramethylpiperidide(LiTMP)-LiBr mixture for... 

Little steric differentiation is observed with either the lithium or boron enolates of 2-methyl-2-pentanone.102... 

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