Chelation controlled aldol condensation

An example of a chelation-controlled titanium tetrachloride-catalyzed aldol condensation has been featured in a recent synthesis of pestalotin (eq. [86]) (100). The condensation illustrated afforded... 

This dual behaviour must allow control of the configuration at the a carbon atom in an aldol reaction, provided that one can control whether or not the metal is chelated at the time the aldol condensation occurs. Thornton and Nerz-Stormes [35] reported an approach to this problem by using titanium enolates to obtain "non-Evans" 5jn-aldols. On the other hand, Heathcock and his associated found that aldehydes react with chelated boron enolates 100b to afford the anh-aldols 102 or the "non-Evans" i yn-aldols 103 depending upon the reaction conditions (Scheme 9.32). 

Conseqnently, the magnesinm chelate 71 can also react as a nucleophilic donor in aldol reactions. In the chemistry involving magnesium chelates, these two aspects model their mode of action as nucleophilic partners in aldol condensations. This is exemplified in aldol condensations of y-diketones . Thus, sodium hydroxyde catalyzed cyclization of diketone 73 to give a mixtnre of 3,5,5-trimethyl-cyclopent-2-enone 74 and 3,4,4-trimethyl-cyclopent-2-enone 75 in a 2.2/1 isomeric ratio (equation 100). When treated with magnesinm methanolate, the insertion of a a-methoxy carbonyl group as control element, as in 76, allows the formation of a chelated magnesium enolate 77, and the major prodnct is now mainly the aldol 78. This latter treated with aqueous NaOH provides the trimethylcyclopent-2-enones 74 and 75 in a 1/49 ratio. 

On the other hand, chelation-controlled aldol reactions usually provide the awh -Cram aldol. This has been early illustrated by Heathcock and coworkers76 who reported that the proportion of the exclusive syn condensation products B and C (>98%) of the bulky enolate A (Scheme 116) was completely reversed when a chelating group was present on the aldehyde backbone (although the chelating ability of the f-butyl dimethylsilyloxy group is questionable566). 

Aldol condensations of zinc enolates under conditions of thermodynamic control are reasonably discussed in terms of the relative stability of the two chelated aldolates (19), which leads to the syn aldol, and (20), which leads to the anti aldol. If R is larger than R, the anti chelate, with R and R trans in a six-atom ring, is expected to be the more stable form. Heathcock has noted that the most common mechanism for equilibration of aldolate stereochemistry is reverse aldolization (reversal of equation 29). Aldolates obtained by reaction of an enolate with ketone substrates are expected to undergo reverse aldolization at a faster rate than those obtained with aldehyde substrates, in part for steric reasons. Similarly, aldolates derived from ketone enolates are expected to undergo reverse aldolization at a faster rate than those derived from the more basic ester or amide enolates. 

Aldol condensation. The Eu complex can recognize the difference of a- and 5-alkoxy aldehydes and also the size of ketene silyl acetals. Thus, depending upon the particular substrates, it catalyzes the aldolization either in the chelation-controlled or n the non-chelation-controlled mode. 

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... 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

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