Aluminum enolates aldol reactions

Similar to aluminum, the synthetic application of metallic gallium or its salts in the aldol reaction produced gallium enolate and its Lewis acidic salt (161). The first example of the gallium enolate aldol reaction was reported by Han and Huang in 1998 (162). The gallium enolates could be formed easily from a-bromoketones and unmodified ketones with gallium triiodide and triethylgal-lium, respectively (163). 

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

Transmetalation of lithium enolate 1 a (M = Li ) by treatment with tin(II) chloride at — 42 °C generates the tin enolate that reacts with prostereogenic aldehydes at — 78 °C to preferentially produce the opposite aldol diastereomer 3. Diastereoselectivities of this process may be as high as 97 3. This reaction appears to require less exacting conditions since similar results are obtained if one or two equivalents of tin(ll) chloride arc used. The somewhat less reactive tin enolate requires a temperature of —42 C for the reaction to proceed at an acceptable rate. The steric requirements of the tin chloride counterion are probably less than those of the diethyla-luminum ion (vide supra), which has led to the suggestion26 44 that the chair-like transition state I is preferentially adopted26 44. This is consistent with the observed diastereoselective production of aldol product 3, which is of opposite configuration at the / -carbon to the major product obtained from aluminum enolates. 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

In the general context of donor/acceptor formulation, the carbonyl derivatives (especially ketones) are utilized as electron acceptors in a wide variety of reactions such as additions with Grignard reagents, alkyl metals, enolates (aldol condensation), hydroxide (Cannizzaro reaction), alkoxides (Meerwein-Pondorff-Verley reduction), thiolates, phenolates, etc. reduction to alcohols with lithium aluminum hydride, sodium borohydride, trialkyltin hydrides, etc. and cyloadditions with electron-rich olefins (Paterno-Buchi reaction), acetylenes, and dienes.46... 

Homologation of ECHO to a-bromo-a, -enones.4 The initial steps of this homologation involve addition of dibromomethyllithium (1) to an aldehyde followed by oxidation of the adduct to a dibromomethyl ketone (2). The aluminum enolate of 2 undergoes an aldol reaction to provide an a-bromo-p-hydroxy ketone... 

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... 

Reductive dehalogenation of fi-halo ketones.1 a-Bromo or a-chloro ketones undergo reductive dehalogenation on reaction with freshly prepared A1I3 in refluxing CH3CN (80-95% yield). The reaction probably involves an aluminum enolate since addition of benzaldehyde results in an aldol condensation. 

Oshima and Nozaki generated the aluminum enolate regiospecifically by treatment of a-halo carbonyl compounds with Bu3SnAlEt2 subsequent reaction with aldehydes or ketones under mild conditions gave /3-hydroxy carbonyl compounds [117]. This subsequent aldol reaction is accelerated by the addition of catalytic Pd(PPh3)4 (Sch. 81). 

An early reference teaches us that even trimethylaluminum can cause deprotonation of a specialized ketone to generate the aluminum enolate under rather drastic conditions (toluene, reflux) [42]. As expected, the reaction proceeded under thermodynamic control, in which aldol and retro-aldol reactions occurred reversibly, to give a high level of anti diastereoselectivity, with concomitant removal of chelation complex 46 from the solvent (Scheme 6.22). 

Nozaki and coworkers reported that diethylaluminum 2,2,6,6-tetramethylpiperidine (DATMP) is capable of producing diethylaluminum enolates by deprotonation of ketones or esters at -23°C in THF (Scheme 6.23) [43]. Unlike the instabih-ty of the corresponding lithium enolate, the aldol reaction of the aluminum enolate of t-butyl acetate prevails over the alkoxy ehmination that produces the ketene species, even at -23 °C. 

Whereas a lower temperature is essential to mediate deprotonation with DATMP, diisobutyl aluminum phenoxide requires quite a high temperature (THF, reflux) to generate the aluminum enolates, with the aid of a shght excess of pyridine (Scheme 6.24) [44], Self aldol condensation of ketone 47 proceeded with acceptable yield under these conditions. An efficient synfhesis of tfl-muscone was achieved by way of an intramolecular aldol reaction by use of these reagents. 

Zinc(O) is capable of reducing alkyl halides. The interplay of the reductive action of zinc and the ability of aluminum Lewis acids to activate the carbonyl group enabled effective generation of aluminum enolates from a-bromo carbonyl compounds (Scheme 6.25) [45]. This method is convenient for aldol cyclization reaction, producing macrolactones in moderate to high yields. Note that the possibility of a zinc enolate, rather than the aluminum enolate, promoting the actual reactions could not be excluded. 

Another approach, originally discovered by Nozaki and coworkers, is available for the generation of aluminum enolates from a-halo ketones (Scheme 6.26) [46]. This method involves reduction of a bromo group with Bu3SnAlEt2 subsequent reaction with aldehydes or ketones under mild conditions gave aldol adducts in acceptable yields. The aldol step is accelerated by participation of catalytic amounts of PdlPPhj),.. 

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