Lithium aldol

Although lithium aldolates generally display a rather moderate preference for the u/f/z-isomer4, considerable degrees of diastereoselectivity have been observed in the reversible addition of doubly deprotonated carboxylic acids to aldehydes20. For example, the syn- and uw/z-alkox-ides, which form in a ratio of 1.9 1 in the kinctically controlled aldol addition, equilibrate in tetrahydrofuran at 25 C after several hours to a 1 49 mixture in favor of the anti-product20. 

Other studies have provided additional data on the relative stabilities of the lithium aldolates 14 and 15 derived from the condensation of dilithium enediolates 13 (Rj = alkyl, aryl) with representative aldehydes (eq. [ 10]) (16). Kinetic aldol ratios were also obtained for comparison in this and related studies (16,17). As summarized in Table 4, the diastereomeric aldol chelates 14a and ISa, derived from the enolate of phenylacetic acid 13 (R = Ph), reach equilibrium after 3 days at 25° C (entries A-D). The percentage of threo diastere-omer 15 increases with the increasing steric bulk of the aldehyde ligand R3 as expected. It is noteworthy that the diastereomeric aldol chelates 14a and 15a (Rj = CH3, C2HS, i-C3H7) do not equilibrate at room temperature over the 3 day period (16). In a related study directed at delineating the stereochemical control elements of the Reformatsky reaction, Kurtev examined the equilibration of both... 

The mechanism of the aldol-Tishchenko reaction has been probed by determination of kinetics and isotope effects for formation of diol-monoester on reaction between the lithium enolate of p-(phenylsulfonyl)isobutyrophenone (LiSIBP) and two molecules of benzaldehyde. ". The results are consistent with the formation of an initial lithium aldolate (25) followed by reaction with a second aldehyde to form an acetal (26), and finally a rate-limiting intramolecular hydride transfer (Tishchenko... 

Simple, clear-cut examples of aldol reactions exhibiting such solvent effects are scarce. Heathcock et al. [526] have reported that the erythro threo equilibration of lithium aldolates via retro-aldol reaction) is much faster in pentane than in tetrahy-drofuran or diethyl ether. 

Thus, the erythro lithium aldolates given in Eq. (5-37) (R = Me, Et, n-Pr, n-Bu) equilibrate to their threo eounterparts in less than two hours at 25 °C in pentane tij2 = 45 min for the aldolate with R = CH3), whereas in diethyl ether the rate of equilibration is mueh slower (ti/2 = 8 hours for the aldolate with R = CH3) [525, 526]. 

Aldol reactions of aldehydes with the -stannyl a-selanyl enolate generated from 2-phenylselanylcyclopent-2-enone directly produced 2-(l-hydroxyalkyl) cyclopenten-2-ones in high yields [55] (Scheme 43, reaction l).The n-Bu3SnSePh elimination was explained by lithium aldolate assistance. The nature of the nucleophile has a dramatic effect on the stereochemistry of the 1,4-addition products isolated after protonolysis. The use of lithium dibutylcuprate afforded cz5-compounds, whereas Me3SiLi or, better, a mixed silylcuprate, furnished the trans-isomers as the major products [56] (Scheme 43, reaction 2). 

After this chapter had been completed, there appeared a paper describing the first determination of the thermochemistry of an aldol reaction of a preformed enolate (E. M. Arnett, F. J. Fisher, M. A. Nichols and A. A. Ribeiro, J. Am. Chem. Soc., 1989, 111, 748). The enthalpy of reaction of the hexameric lithium enolate of pinacolone with pivalaldehyde in hexane at 25 C is -30.19 0.76 kcal mol. With one equivalent of various added ligands, enthalpies of reaction are -17.94 0.36 kcal mol in tetrahydrofu-ran (THF) -20.85 0.72 kcal mol in tetramethylethylenediamine (TMEDA) and -19.05 0.44 kcal mol in dimethoxyethane (DME). The product is believed to be a tetrameric lithium aldolate in each case. In view of the discussion given in this section, these reactions are surprisingly exothermic. Note, however, that one equivalent of THF makes the reaction about 10 kcal mol less exothermic. The enthalpy of reaction in pure THF has yet to be determined experimentally. 

Even when the retroaldol reaction is fairly facile, stereoisomer equilibration can be slow. This phenomenon is illustrated in Scheme 16. A solution of the lithium aldolate (243) and benzaldehyde equilibrates to (244) and p-anisaldehyde with a half-life of 15 min at 0 °C. However, the syn lithium aldolate (244) equilibrates with its anti diastereomer (246) with a half-life of approximately 8 h at room temperature. The reason for this apparent dichotomy is that enolate (245) is so stereoselective in its reactions with aldehydes. Since the kinetic syn.anti ratio is 98.7 1.3, the syn aldolate must dissociate approximately 75 times in order for one syn aldolate molecule to be converted into one anti aldolate molecule. Of course, for less stereoselective enolates, such as the cyclohexanone enolate referred to above, stereochemical isomerization will more nearly parallel the rate of actual aldol reversal. 

The successive replacement of the enolate by aldolate moieties en route from an enolate tetramer to an aldolate tetramer might involve severe reconstruction of the skeleton. Thus, a mixture of pinacolone, its lithium aldolate with pivalaldehyde, and the enolized aldolate dianion was recently reported to cocrystallize in a 1 1 3 ratio as a heptalithium cage compound missing any cube-shaped unit [15]. Rather complex crystal structures aldolate-enolate aggregates were also found for calcium enolates [8b]. 

Fluvastatin (28, Scheme 2.4) is a member of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor family and is prescribed to treat hypercholesterolemia. As part of their nonracemic synthesis of fluvastatin, researchers at Novartis used a monoacetyltri-phenylglycol chiral auxiliary 25 originally reported by Braun and Devant. A diastereoselective lithium aldol reaction between Braun and Devant s reagent 25 and the fluarophenylindolenal 24 afforded the allylic alcohol 26 as... 

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