Aldol condensation with enolates

Aldol Condensation with Enol Silyl Ethers. The first example of an aldol condensation between an unactivated enolate and an electrophilically activated carbonyl substrate was accomplished using enol silyl ethers and acetals or orthoesters in conjunction with a catalytic amount of Trimethykilyl Trifluoromethanesul-fonate. The reaction proceeds very readily at —78 C and affords the eo /W-aldol product with high stereoselectivity. The use of 2,2-dimethoxypropane in this reaction affords p-methoxy ketones (eq 10). 

Diastereoselective Aldol Condensation with Boron Enolates... 

In contrast, fluorinated ketones have been used as both nucleophilic and electrophilic reaction constituents The (Z)-lithium enolate of 1 fluoro 3,3-di-methylbutanone can be selectively prepared and undergoes highly diastereoselec-tive aldol condensations with aldehydes [7] (equation 8) (Table 4)... 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

A magnesium enolate of 99 is susceptible to aldol condensation with 4-pentenal, and the crude product can be directly protected to give its ethyl carbonate 100. a-Hydroxylation of the carbonyl group yields the hydroxyl carbonate 101. Reduction of the carbonyl group generates a triol, and this compound can be simultaneously converted to carbonate 102. Swern oxidation of 102 gives ketone 103, which can be rearranged25 to produce lactone product 104 (Scheme 7-32). 

Directed Aldol Condensations with Preformed Lithium Enolates in the Presence of Zinc Chloride... 

Enolates, lithium salts, aldol condensation with, 54, 49 Enol esters, preparation, 52,... 

The studies just cited demonstrate several important design features pertaining to the objective of achieving highly stereoselective aldol condensations with Group I-II metal enolates. 

The kinetic enolization of esters with amide bases such as lithium diisopropylamide (LDA) and the resultant aldol condensations with representative aldehydes have been investigated by several groups (2,32,33). The enolate stereochemical assignments were determined by silylation in direct analogy to studies reported by Ireland (34). The preponderance of (E )-enolate observed with LDA (THF) in these... 

In studies not yet published (66), the A/-acyl-oxazolidine-2-one 62 has been found to exhibit exceptionally high levels of (Z)-enolization stereoselection with either amide bases (LDA, THF, -78°C) or boryl triflates [(n-C4H9)2BOTf, CH2CI2, -78°C] in the presence of diiso-propylethylamine (DPEA). Upon aldol condensation, the enolates 63a and 63b afford the aldolates 64 (Scheme 11), which react readily with nucleophiles at the carbonyl function (Table 22). As discussed earlier, the large preference for (Z)-enolate formation in this system can be attributed to allylic strain considerations (37)... 

A summary of representative stereochemically defined metal enolates and their respective kinetic aldol condensations with benzaldehyde is provided in Table 24. Both the metal center and the enolate substituent Ri for the substituted carbonyl derivatives... 

Earlier studies had demonstrated that such enolates would participate in aldol condensations with aldehydes however, the stereochemical aspects of the reaction were not investigated (68). For the cases summarized in Table 25, the zirconium enolates were prepared from the corresponding lithium enolates (eq. [54]). Control experiments indicated that no alteration in enolate geometry accompanies this ligand exchange process, and that the product ratio is kinetically controlled (35). From the cases illustrated, both ( )-enolates (entries A-E) and (Z)-enolates (entries F-H) exhibit predominant kinetic erythro diastereoselection. Although a detailed explanation of these observations is clearly speculative, certain aspects of a probable... 

Aldol Condensation of Enolate 165 with Representative Carbonyl Compounds, R RlC = 0 (eq. [109]) (122)... 

The central point of Evans s methodology is the induction of a 7t-enantiotopic facial differentiation through a conformationally rigid highly ordered transition state. Since the dialkylboron enolates of AT-acyl-2-oxazolidinones exhibit excellent syn-diastereoselectivity syn.anti >97 3) when reacted with a variety of aldehydes, Evans [14] studied the aldol condensation with the chiral equivalents 32 and 38. which are synthesised from fS)-valine (35) and the hydrochloride of (15, 2R)-norephedrine (36) (Scheme 9.11), respectively, and presently are commercially available. 

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. 

In contrast, aldol condensation with (Z)- and (E)-chlorobis(eyclopenladienyl)-/irconium enolates results in frj7/iro-diastcrcoselcction regardless of the geometry of the enolate. -3 These enolates are prepared from lithium enolates by metal exchange with Cp,ZrCU at —78°. The effect is particularly marked with amide enolates (equation II). 

Aldol reaction. The reagent (I) adds in a 1,4-fashion to an a,/J-unsaturated ketone lo give an aluminum enolate, which undergoes aldol condensation with an aldehyde. The adduct is converted into an a-substituted-a./l-unsaturated ketone on sulfoxide elimination.1... 

Stereoselective aldol-type condensation.1 Enol silyl ethers do not undergo aldol condensation with aldehydes or ketones in the presence of this triflate,. but the reaction occurs at —78° (4-12 hours) with the corresponding acetals or ketals (and certain orthoesters). Moreover the erythro-aldol is formed with high stereoselectivity. 

Conjugate addition-aldol reactions. A novel synthesis of a-substituted a,(3-enones involves conjugate addition of 1 to an a,p-enone the resulting 0-phenyl-selenoboron enolate undergoes aldol condensation with aldehydes. The adduct on oxidative elimination furnishes unsaturated p-hydroxy ketones.1 Example ... 

This work raises the possibility that some eryfAro-selective aldol condensations with metal enolates may actually involve the a-metallo ketone. 

Asymmetric alkylation andaldol condensations.2 The enolate (2) of 1 reacts with primary iodides to give essentially a single product (3), in which the alkyl group is syn to the cyclopentadieny ring. Aldol condensation with acetone leads to only one observable product (4). Only two isomeric products are obtained on aldol condensation with prochiral aldehydes and ketones as expected for a rranx-enolate, the i/ww-aldol predominates or is the exclusive product (5) as in the case of pivaldehyde. 

Enanantioselective aldol reactions. Divalent tin enolates of aldehydes and aryl ketones generated with tin(II) triflate undergo aldol condensation with aldehydes to form aldols.2 The reaction is highly enantioselective if conducted in the presence of chiral diamines derived from (S)-proline, such as l.3... 

In the aldol condensation, an enolate anion acts as a carbon nucleophile and adds to a carbonyl group to form a new carbon-carbon bond. Thus, the a-carbon of one aldehyde molecule becomes bonded to the carbonyl carbon of another aldehyde molecule to form an aldol (a 3-hydroxyaldehyde). In the mixed aldol condensation, the reactant with an a-hydrogen supplies the enolate anion, and the other reactant, usually without an a-hydrogen, supplies the carbonyl group to which the enolate ion adds. The aldol reaction is used commercially and also occurs in nature. 

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