3- Pentanone lithium enolates

Several enolates of 4,4-dimethyl-3-(trimethylsiloxy)-2-pentanone have been investigated.106 The lithium enolate reacts through a chelated TS with high 2,2 -anti stereoselectivity, based on the steric differentiation by the f-butyl group. 

AUylic alkylation. In the presence of this Pd(0) complex and hls(tl iphcnylphosphine)ethane, allylic acetates can be alkylated by lithium enolates of cyclohexanone, 3-pentanone, acetophenone, and mesityl oxide in 40-80% yield. The i I m I ion was shown to occur with overall retention of configuration in the case of the lithium enolate of acetone (equation I). 

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. 

LDA reacts with 2-pentanone at - 78 C to give mainly lithium enolate A rather tibai enolate B. Compare the energies of lithium enolate A and lithium enolate B umii SpartanView, tell which is more stable, and explain the observed result. 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

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. ... 

This is in contrast to the results noted by Dubois for the corresponding lithium enolates derived from 3-pentanone, see J.-E. Dubois and P. Fellmann, Tetrahedron Lett., 1975, 1225. 

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.

First, recognize that the two carbonyl-containing compounds to be joined in the aldol reaction are 3-pentanone and acetaldehyde. Treat the symmetrical ketone with LDA to form its lithium enolate. Treatment of this enolate anion with acetaldehyde followed by aqueous workup gives the desired aldol product. 

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. 

Using preformed lithium enolates, complete kinetic stereoselection has been achieved. The kinetic enolate of 2,2-dimethyl-3-pentanone is exclusively the Z isomer it adds to benzaldehyde to give only the erythro aldol product.Similar... 

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

Scheme 3.2 Preparation and structure of a mixed aggregate 4 composed of c/s-configured lithium enolate of 3-pentanone and lithiated chiral amino alcohol 3.

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

Control of Regioselectivity and Stereoselectivity. The recognition by Ireland and co-workers that Hexamethylphosphoric Triamide has a profound effect on the stereochemistry of lithium enolates has led to the examination of the effects of other additives, as the ability to control enolate stereochemistry is of utmost importance for the stereochemical outcome of aldol reactions. Kinetic deprotonation of 3-pentanone with Lithium 2,2,6,6-Tetramethylpiperidide at 0 C in THF containing varying amounts of HMPA or TMEDA was found to give predominantly the (Z)-enolate at a base ketone additive ratio of ca. 1 1 1, whereas with a base.ketone.additive ratio 1 0.25 1, formation of the ( )-enolate was favored (Table I). This remarkable result contrasts with those cases where HMPA base ratios were varied towards larger amounts of HMPA, which favored formation of the (Z)-enolate. ... 

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... 

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