Methylmalonic acid decarboxylation

Serine hydroxymethyl transferase catalyzes the decarboxylation reaction of a-amino-a-methylmalonic acid to give (J )-a-aminopropionic acid with retention of configuration [1]. The reaction of methylmalonyl-CoA catalyzed by malonyl-coenzyme A decarboxylase also proceeds with perfect retention of configuration, but the notation of the absolute configuration is reversed in accordance with the CIP-priority rule [2]. Of course, water is a good proton source and, if it comes in contact with these reactants, the product of decarboxylation should be a one-to-one mixture of the two enantiomers. Thus, the stereoselectivity of the reaction indicates that the reaction environment is highly hydro-phobic, so that no free water molecule attacks the intermediate. Even if some water molecules are present in the active site of the enzyme, they are entirely under the control of the enzyme. If this type of reaction can be realized using synthetic substrates, a new method will be developed for the preparation of optically active carboxylic acids that have a chiral center at the a-position. 

To screen a microorganism which has an ability to decarboxylate a-aryl-a-methylmalonic acids, a medium was used in which phenylmalonic acid was the sole source of carbon, because we assumed that the first step of the metabolic path would be decarboxylation of the acid to give phenylacetic acid, which would be further metabolized via oxidation at the a-position. Thus, a... 

Furthermore, microbial decarboxylation of a-aryl-a-methylmalonic acids... 

Interestingly, the Marckwald definition is taken from a paper that was rebutting a criticism [33] of Marckwald s claim to have achieved an asymmetric synthesis by a group-selective decarboxylation of the bmcine salt of 2-ethyl-2-methylmalonic acid [34,35] ... 

Formulate a detailed mechanism for the decarboxylation of CH3CH(COOH)2 (methylmalonic acid). 

Q2. As for question 1, as far as stearic acid, then addition of one propionate (= methylmalonate) unit and two more acetate units gives 6-methyl-tetradecanoic acid. Decarboxylation gives 5-methyltricosane. 

Possible errors due to the methods used have been referred to in the sections of Part I and include the dehydration of hydroxy acids, for example 3-methyl-crotonic acid from 3-hydroxyisovaleric acid, crotonic acid from 3-hydroxy-butyric acid, either on acid steam distillation or alkaline treatment, decarboxylation of 2-oxo acids, for example phenylpyruvic acid to phenylacetic acid (Thompson et al., 1975b) and similar effects with branched-chain oxo acids, during sample preparation, particularly by solvent extraction. Derivatization artefacts produced during methylation have been detailed in Part I, and decarboxylation of free non-volatile acids during the analysis of volatile acids, for example, methylmalonic acid to propionic acid, are also detailed elsewhere. 

So far we have referred to the decarboxylative enzymes that work on the naturally occurring intermediates of biochemical pathways. Due to the high affinity for the native substrates by these enzymes, however, the applicability to nonnatural synthetic substrates was somewhat limited. Thus we intended to develop a new biocatalysis, such as an enzyme which can decarboxylate a-aryl-a-methylmalonic acids to yield enantiomerically enriched a-substituted a-arylacetic acids because those products are useful compounds as antiinflammatory agents [8-10] and the chiral derivatizing agents [11]. 

Table 1 Asymmetric Decarboxylation of a-Aryl-a-methylmalonic Acid...

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. 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). 

Both the synthesis of propionate and its metabolism may take place under anaerobic conditions. In Desulfobulbuspropionicum, degradation could plausibly take place by reversal of the steps used for its synthesis from acetate (Stams et al. 1984)—carboxylation of propionate to methylmalonate followed by coenzyme Bi2-mediated rearrangement to succinate, which then enters the tricarboxylic acid cycle. The converse decarboxylation of succinate to propionate has been observed in Propionigenium modestum (Schink and Pfennig 1982),... 

Biotin enzymes are believed to function primarily in reversible carboxvlahon-decarboxylation reactions. For example, a biotin enzyme mediates the carboxylation of propionic acid to methylmalonic add, which is subsequently converted to succinic acid, a dtric acid cycle intermediate. A vitamin Bl2 coenzyme and coenzyme A are also essential to this overall reaction, again pointing out the interdependence of the B vitamin coenzymes. Another biotin enzyme-mediated reaction is the formation of malonyl-CoA by carboxylation of acetyl-CoA ( active acetate ). Malonyl-CoA is believed lo be a key intermediate in fatly add synthesis. 

The first enantioselective total synthesis of (+)-macbecin I was accomplished by R. Baker and co-workers. A key vinyl iodide precursor was prepared stereoselectively using the malonic ester synthesis. Diethyl methylmalonate was treated with in situ generated diiodocarbene in ether at reflux to afford diiodomethylmethylmalonate in good yield. This dialkylated malonic ester then was converted to ( )-3-iodo-2-methyl-2-propenoic acid by reacting it with aqueous KOH. The saponification was accompanied by a concomitant decarboxylation. 

A general method leading to the stereospecific synthesis of 3-fluoroacrylate derivatives arose from the early work of Shen et al. (37) who demonstrated that chlorodifluoromethane adds to malonate carbanions to give a-difluoromethylmalonate derivatives (Scheme 21). Bey and co-workers (38-40) made extensive use of this reaction in a major program directed towards the synthesis of a-difluoromethylamines and amino acids. A key step in these syntheses is the acid catalyzed decarboxylation of the a-difluoro-methylmalonates (70) (Scheme 22). On occasion, 3-fluoroacrylates (72) were observeJTas side-products in addition to the expected compounds (71). 

The best-studied example of a CoA-dependent nonphosphorylating ALDH is the methylmalonate-semi-aldehyde dehydrogenase, which has been isolated from both mammalian and bacterial sources. This enzyme transforms malonate semialdehyde and methylmalonate semialdehyde into acetyl-CoA and propionyl-CoA, respectively, through an oxidation reaction as described above, followed by a decarboxylation reminiscent of other (3-keto acids. Mechanistic studies of the B. sukilis enzyme have shown that it is activated by NAD" " binding, that it exhibits half-of-sites reactivity (only two moles of NADH forms per tetrameric protein unit) and that the decarboxylation reaction occurs after formation of the acyl-enzyme intermediate. Acyl transfer from the enzyme to CoA completes the reaction. 

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