Doubly deprotonated carboxylic acid

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. 

A completely different dipolar cycloaddition model has been proposed39 in order to rationalize the stereochemical outcome of the addition of doubly deprotonated carboxylic acids to aldehydes, which is known as the Ivanov reaction. In the irreversible reaction of phenylacetic acid with 2,2-dimethylpropanal, metal chelation is completely unfavorable. Thus simple diastereoselectivity in favor of u f/-adducts is extremely low when chelating cations, e.g., Zn2 + or Mg- +, are used. Amazingly, the most naked dianions provide the highest anti/syn ratios as indicated by the results obtained with the potassium salt in the presence of a crown ether. 

Braun and coworkers finally tackled a group of enolates that may be considered the hardest one doubly deprotonated carboxylic acids 54 [33]. It turned out that here again, the standard allylation protocol with the ingredient lithium chloride could be used in an efficient manner and led to the p,y-unsaturated carboxylic... 

Scheme 5.18 Palladium-catalyzed allylic alkylations of doubly deprotonated carboxylic acids.

Figure 10-4. The double- and single-site titration models for His and Asp groups [42]. (A) In the double site model, only one X is used for describing the equilibrium between the protonated and deprotonated forms, while the tautomer interversion process is represented by the variable x. (B) In the single-site model, protonation at different sites is represented by different X variables. HSP refers to the doubly protonated form of histidine. HSD and HSE refer to the singly protonated histidine with a proton on the h and e nitrogens, respectively. ASP1 and ASP2 refer to the protonated carboxylic acid with a proton on either of the carboxlate oxygens...

Without an acid catalyst, the alcohol cannot react with the carboxylic acid in fact, the backward reaction is doubly impossible because the basic conditions straight away deprotonate the acid to make a carboxylate salt (which, incidentally, consumes the base, making at least one equivalent of base necessary in the reaction). 

Naturally, it is possible to synthesise a similar ligand system without central chirality and in fact without the unnecessary methylene linker unit. A suitable synthesis starts with planar chiral ferrocenyl aldehyde acetal (see Figure 5.30). Hydrolysis and oxidation of the acetal yields the corresponding carboxylic acid that is transformed into the azide and subsequently turned into the respective primary amine functionalised planar chiral ferrocene. A rather complex reaction sequence involving 5-triazine, bromoacetal-dehyde diethylacetal and boron trifluoride etherate eventually yields the desired doubly ferrocenyl substituted imidazolium salt that can be deprotonated with the usual potassium tert-butylate to the free carbene. The ligand was used to form a variety of palladium(II) carbene complexes with pyridine or a phosphane as coligand. 

Subsequent deprotonation to afford the carboxylic acid enolate requires the formation of a doubly deprotonated species, which is disfavored relative to the formation of an ester enolate. In fact, activated esters such as phenyl esters1291 or thioesters1301 are especially prone to racemization, since enolization is easier than for simple esters. 

The principle of enolate controlled stereochemistry can be demonstrated by use of the chiral acetate 83. When doubly deprotonated (R)- and (S)-HYTRA 83 reacts with enantiomerically pure 3-benzyloxybutanal 99 the (R)-configured acetate enolate attacks the aldehyde 99 (irrespective of its chirality) predominantly from the Re face so that, after hydrolysis, anti hydroxycarboxylic acid 100a results. On the other hand, the (S)-configured enolate of 83 attacks the enantiomerically pure aldehyde preferentially from the Si side to give syn carboxylic acids 100b with comparable selectivity, as shown in Scheme 1.22 [175]. 

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