Decarboxylation anion intermediates

Decarboxylation of the pyrrolizinone-2-carboxylic acid gives very little of the parent pyrrolizinone instead 24 is produced when the anionic intermediate, formed on decarboxylation, adds in a Michael manner to the pyrrolizinone26 [Eq. (2)]. 

When a carboxylic acid loses CO the reaction is called decarboxylation. Although the reaction is usually exothermic, the energy of activation is usually high, making the reaction difficult to carry out. The energy of activation is lowered when the flea r bon is a carbonyl because either the anion intermediate is stabilized by resonance or tire acid forms a more stable cyclic intermediate. (A carboxylic acid with a carbonyl p-carbon is called a fi-keto acui.)... 

Further persuasive evidence in support of the expectation that the mechanism of the ECH-catalyzed reaction involves an Elcb mechanism with a stabilized thioester enolate anion intermediate is obtained from the membership of ECH in the mechanistically diverse enoyl-CoA hydratase superfamily [70]. Such superfamilies are derived from a common ancestor by divergent evolution the members of these share a partial reaction, usually formation of a common intermediate, e.g., an enolate anion. The reactions catalyzed by members of the enoyl-CoA hydratase superfamily (almost) always utilize acyl esters of CoA as substrates the reactions invariably can be rationalized with mechanisms that involve the formation of a thioester enolate anion intermediate, e.g., 1,3-proton transfer, 1,5-proton transfer, Dieckman and reverse Dieckman condensations, and yS-decarboxylation. Although mechanisms with thioester enolate anion intermediates are plausible for each of these reactions, as in the ECH-catalyzed reaction, evidence for their existence on the reaction coordinate is circumstantial because the intermediates do not accumulate, thereby avoiding spectroscopic detection. 

The geometry of the transition state for the carboxylation/decarboxylation step is an important aspect of mechanism. The anion intermediate [Eq. (2)] is usually a conjugated anion (often an enolate) in which the negative charge lies above and below a planar atomic framework. Attacking or departing CO2 will approach from above or below the plane of the conjugated system (Scheme I), rather than from within the plane. The distinction between the two faces of the planar system can usually be made based on the stereochemistry of the carboxylated substrate or product. 

As we have noted, most carboxylations and decarboxylations occur by way of anionic intermediates, and the stabilities of these anions are important in determining rates of carboxylations and decarboxylations. The simplest conceivable case is formation of acetic acid from methane and CO2. Methane has a pAa of approximately 48 14) consequently, removal of a proton from methane is precluded in nature and acetic acid is not formed in nature by the carboxylation of methane, nor is acetic acid decarboxylated. Instead, other substrates are used wherein the pA a is more favorable. 

Most carboxylations and decarboxylations involve anionic intermediates [cf. Eq. (2)]. The stability of the anion is an important factor in determining reaction rates. An unstable anion will be very reactive toward CO2, but it will be difficult to form. A stable anion will be less reactive toward CO2, but it will be easy to form. Many carboxylations involve removal of a proton from an acid of pKa 15-18. Enzymic stabilization of such anions is very important. 

Like 6-phosphogluconate dehydrogenase and UDPglucuronate decarboxylase, this enzyme decarboxylates a /3-keto acid with an a-oxygen function without the involvement of a metal ion or other cofactor (70). Apparently the electronic properties of this oxygen function are sufficient to stabilize the enolate anion intermediate, so that no metal ion is needed. 

By comparison, decarboxylation is largely a kinetic problem. Enzymes have developed a variety of strategies for stabilizing the anionic intermediate that is produced in the decarboxylation step. Metal ion stabilization of enolates is a common theme, particularly for decarboxylation of /8-keto acids. The most elegant solutions are perhaps the extensive electron delocalizations seen in pyri-doxal phosphate and thiamin pyrophosphate. 

Thiamine pyrophosphate (13) is the co-factor for a number of enzymes that can be described as stabilizing hypothetical acyl anion intermediates. For instance, it is the coenzyme for the enzyme carboxylase that catalyses the conversion of pyruvic acid to acetaldehyde. We had early shown that this mechanism involves a thiazolium anion (14) whose second resonance form (15) is a carbene. Ionization of the C-2 proton of the thiazolium ring generates this species that can add nucleophilically to carbonyl groups such as that in pyruvic acid, forming an intermediate whose decarboxylation generates a stabilized anion. 

The biological decarboxylation of a P-keto acid presents a slight difficulty. We recall that carboxyhc acids exist as carboxylate anions at pH 7. And, the decarboxylation of P-keto acids occurs from the carboxylic acid, not the anion. Why, then, is this decarboxylation a favorable process Decarboxylation of oxalosuccinate produces an enolate anion. An enolate anion has a piST of -20 and is very unstable at pH 7. A reaction that produces an unstable intermediate has a high activation energy and is slow. Thus, the enzyme-catalyzed decarboxylation of the anionic form of a P-keto acid has to stabilize the enolate anion intermediate. Isocitrate dehydrogenase requires Mg ions. An Mg ion forms a complex with the carbonyl group of the P-keto acid. This has two effects. 

Using the decarboxylative photocyclization, the synthesis of medium- and macrocyclic amines, lactones, polyethers, lactams, as well as cycloalkynes were accessible in ring sizes up to 26 (Scheme 14) and even in multigram quantities. The regioselectivity of the radical cyclization step was studied for unsymmetrically substituted pyridinecarboximides and trimeUitic acid imides, respectively, where the site of the C-C-bond formation is controlled by the maximum spin density of the radical anion intermediates. ... 

Animals caimot synthesize the naphthoquinone ring of vitamin K, but necessary quantities are obtained by ingestion and from manufacture by intestinal flora. In plants and bacteria, the desired naphthoquinone ring is synthesized from 2-oxoglutaric acid (12) and shikimic acid (13) (71,72). Chorismic acid (14) reacts with a putative succinic semialdehyde TPP anion to form o-succinyl benzoic acid (73,74). In a second step, ortho-succmY benzoic acid is converted to the key intermediate, l,4-dihydroxy-2-naphthoic acid. Prenylation with phytyl pyrophosphate is followed by decarboxylation and methylation to complete the biosynthesis (75). 

Condensation of an appropriately substituted phenylacetic acid with phthalic anhydride in the presence of sodium acetate leads to aldol-like reaction of the methylene group on the acid with the carbonyl on the anhydride. Dehydration followed by decarboxylation of the intermediate affords the methylenephthal-ides (12). Treatment of the phthalides with base affords directly the indandiones, probably via an intermediate formally derived from the keto-acid anion (13). The first agent of this class to be introduced was phenindandione (14) this was followed by anisindandione (1S) and chlorindandione (16). ... 

A number of lyases are known which, unlike the aldolases, require thiamine pyrophosphate as a cofactor in the transfer of acyl anion equivalents, but mechanistically act via enolate-type additions. The commercially available transketolase (EC 2.2.1.1) stems from the pentose phosphate pathway where it catalyzes the transfer of a hydroxyacetyl fragment from a ketose phosphate to an aldehyde phosphate. For synthetic purposes, the donor component can be replaced by hydroxypyruvate, which forms the reactive intermediate by an irreversible, spontaneous decarboxylation. 

Schneider and Simon82 prepared / -ketosulfoxides 47a and 47b by sulfinylation of the dianions of the methyl acetoacetates 48a and 48b with sulfinate ester 19 followed by decarboxylation of the intermediate products (Scheme 2). Apparently this avoids racemiz-ation experienced by others in the direct synthesis of these compounds9. /J-Ketosulfoxides are also available from the reaction of the anion derived from methyl p-tolyl sulfoxide with esters (see Section II.E). They can also be obtained, in some cases, through the hydrolysis of a-sulfinylhydrazones whose synthesis is described below. Mention has already been made of the synthesis of 2-p-tolylsulfinylcycloalkanones such as 32. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

Fig. 8 Irreversible photoconversion of AvGFP. (a) Modification of the absorption spectra of AvGFP under UV light (A = 254 nm, 100 s irradiation, 12.9 mW) at 293 K, pH 8.0, showing the increase in anionic B band (maximum at 483 nm). (b) Proposed Kolbe mechanism for Glu222 decarboxylation through transient formation of a CH2 radical intermediate. Reproduced with permission from [166]...

Recently, the solvolyses of l-chloro-l,3,3-triarylallenes 10 (andof 1-butyl-3,3-diphenyl-allenyl chloride) were carried out in the presence of thiocyanate and o-ethyl dithiocar-bonate anions as nucleophiles and found to give the corresponding allenyl derivatives 11 and 12 in good yield (equation 3)18. However, when potassium cyanate was used as a nucleophile, the cyanate ion attacked at the /-position to give the propargyl amines 14 after decarboxylation of the unstable intermediate 13 (equation 4). 

Radiolysis of isobutyric acid at 195 K results in the formation of only one radical intermediate, the hydrogen abstraction radical III. The decarboxylation radical and the anion radical are both unstable at this temperature and react forming the abstraction radical and other products. The hydrogen which is abstracted is generally that which is attached to the carbon atom a to the carboxyl group. 

A variety of radical products is observed following gamma radiolysis of the N-acetyl amino acids at 77 K (6), depending on the nature of the side chain of the parent amino acid. In the case of N-acetyl alanine, for example, the intermediates are (i) the anion radical IV (ii) the decarboxylation radical V (iii) the deamination radical VI and (iv) the alpha carbon radical VII. 

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