Aerobic living features metabolize sugars and fatty acids to carbon dioxide. Accordingly, there are some kinds of decarboxylation reactions. TPP-mediated decarboxylation of pyruvic acid to acetaldehyde is one of the most important steps of the metabolism of sugar compounds (Fig. 1). When the intermediate reacts with lipoic acid instead of a proton, pyruvic acid is converted to acetylcoenzyme A, which is introduced to TCA cycle (Fig. 2).
This cycle is a series of reactions starting from the reaction of oxaloacetic acid with acetylcoenzyme A and finally regenerates oxaloacetic acid again, forming two moles of carbon dioxide during one cycle. The first step of the decarboxylation is conjugated with the oxidation of isocitric acid (Fig. 3).
This is the decarboxylation of a ^-keto acid which undergoes smoothly even in the absence of an enzyme. Thus, it can be said that the mother nature utilizes an organic reaction with a low activation energy. The second step of the decarboxylation is the conversion of a-ketoglutaric acid to succinic acid (Fig. 3). This is the same type of reaction as the decarboxylation of pyruvic acid.
On the other hand, a carboxyl group is effective to increase the acidity of the proton on the a-carbon. Thus, carboxylation of a methylene group is an important step for the following C—C bond-forming reactions as seen in the biosynthesis of fatty acids (Fig. 4).
Figure 2: Oxidative decarboxylation of pyruvic acid.
Figure 2: Oxidative decarboxylation of pyruvic acid.
COgH a-Ketoglutaric acid
COgH Succinic acid
Figure 3: Oxidative decarboxylation of isocitric acid.
After the C—C bond is formed, the carboxyl group used for the activation of the position should be removed. This will be the decarboxylation of malonic acid-type compounds, which is the same type of the famous synthetic reaction, i.e., malonic ester synthesis (Fig. 5).
Another interesting type of reaction is the transketolase-catalyzed reaction. As shown in Figs 1 and 2, a-carbon of pyruvic acid reacts as a nucleophile with a proton or a disulfide bond, in spite of the fact that it is a carbonyl carbon in
CO? Et HzO
Figure 5: Malonic ester synthesis.
the final product (aldehyde and ester, respectively). This characteristic reaction becomes possible by converting the sp2 carbonyl carbon to sp3 by the reaction with TPP and in addition, by stabilizing carbanion by the resonance effect of the thiazolium ring and anion-stabilizing effect of the sulfur atom. This is also the representative example of smartness of the nature. This nucleophile is capable of attacking the carbonyl carbon of aldehydes to give acyloin derivatives (Fig. 6). As the starting compound is pyruvic acid, this type of reaction is also an example of decarboxylation reactions.
Many, if not all, of the above decarboxylation reactions are demonstrated to be enantioselective even in the case that the reaction does not result in an
asymmetric carbon in normal metabolic pathway. For example, oxidative decarboxylation of isocitric acid has been proved to be perfectly enantioselective by carrying out the reaction in D2O.: It gives (R)-P-deuterio-a-ketoglutaric acid (Fig. 7-1).
Also, decarboxylations of malonate-type compounds have been confirmed to proceed with retention of configuration. Indeed, malonyl-CoA decarboxylase from uropygial gland is enantioselective to the substrate as well as the product.2 Only
(S)-enantiomer of racemic mixture of methylmalonyl-CoA was decarboxylated to give 2-(3H)-propionyl-CoA, while (R)-isomer of the substrate remained intact (Fig. 7-2), when the reaction was carried out in 3H2O. The product was revealed to be optically active, whose absolute configuration was (R). Thus, this decarboxylase distinguishes the chirality of the starting material and gave enantiomerically pure (R)-isomer via retention of configuration.
Another interesting example is SHMT. This enzyme catalyzes decarboxylation of a-amino-a-methylmalonate with the aid of pyridoxal-5'-phosphate (PLP). This is an unique enzyme in that it promotes various types of reactions of a-amino acids.3 It promotes aldol/retro-aldol type reactions and transamination reaction in addition to decarboxylation reaction. Although the types of apparent reactions are different, the common point of these reactions is the formation of a complex with PLP. In addition, the initial step of each reaction is the decomposition of the Schiff base formed between the substrate and pyridoxal coenzyme (Fig. 7-3).
The decarboxylation of a-amino-a-methylmalonic acid catalyzed by serine hydroxymethyl transferase (SHMT) is enantioselective. Thomas et al. synthesized chiral substrate containing 13C in either one of the two carboxyl groups.4Both enantiomers were incubated with SHMT in the presence of PLP. When (R)-isomer was used, no 13 C was found in the product. On the contrary, 13 C was retained in the resulting alanine when (S)-enantiomer was employed as the starting material. Apparently, pro-(R) carboxyl group of a-amino-a-methylmalonic acid was removed as carbon dioxide. The absolute configuration of resulting alanine is R, indicating that the stereochemical course of the reaction is retention of configuration, as illustrated in Fig. 7-3. This mechanism also works in the case of a-aminomalonic acid. In this case, however, the starting material is prone to racemize under reaction conditions and careful experiments to evaluate the stereochemistry of the reaction are required.5
Thus, if we can apply the type of asymmetric decarboxylation reactions mentioned above to synthetic substrates, unique asymmetric reactions and C—C bond-forming reactions will be realized which are otherwise difficult to be realized.
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