Malonic acid Claisen condensation

By analogy, the chemical Claisen condensation using the enolate anion from diethyl malonate in Figure 2.10 proceeds much more favourably than that using the enolate from ethyl acetate. The same acetoacetic acid product can be formed in the malonate condensation by hydrolysis of the acylated malonate intermediate and decarboxylation of the gem-diacid. 

The conversion of acetyl-CoA into malonyl-CoA increases the acidity of the a-hydrogens, and thus provides a better nucleophile for the Claisen condensation. In the biosynthetic sequence, no acy-lated malonic acid derivatives are produced, and no label from [14C]bicarbonate is incorporated, so the carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation (Figure 3.1). Accordingly, the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base. 

The Claisen condensation of diethyl oxalate with esters of fatty acids (cf. method 211) produces a-ethoxalyl esters which are thermally de-carbonylated to alkylmalonic esters. The over-all yields range from 78% to 91% for the conversion of fatry esters up to ethyl stearate. Phenyl-malonic ester is made in 85% yield. Powdered glass is sometimes used... 

With a Ph-BOX ligand (e.g., ent-lB) to complex Cu(OTf (2 for decarboxylative aldol reaction of substituted malonic acid monothioesters, yyn-selectivity is observed/ This reaction operates on a different mechanism than enz3mie-catalyzed decarboxylative Claisen condensation. 

The polyketide synthesis chemically and biochemically resembles that of fatty acids. The reaction of fatty acid synthesis is inhibited by the fungal product ceru-lenin [9]. It inhibits all known types of fatty acid synthases, both multifunctional enzyme complex and unassociated enzyme from different sources like that of some bacteria, yeast, plants, and mammalians [10]. Cerulenin also blocks synthesis of polyketides in a wide variety of organisms, including actinomycetes, fungi, and plants [11, 12]. The inhibition of fatty acid synthesis by cerulenin is based on binding to the cysteine residue in the condensation reaction domain [13]. Synthesis of both polyketide and fatty acids is initiated by a Claisen condensation reaction between a starter carboxylic acid and a dicarboxylic acid such as malonic or methylmalonic acid. An example of this type of synthesis is shown in Fig. 1. An acetate and malonate as enzyme-linked thioesters are used as starter and extender, respectively. The starter unit is linked through a thioester linkage to the cysteine residue in the active site of the enzymatic unit, p-ketoacyl ACP synthase (KS), which catalyzes the condensation reaction. On the other hand, the extender... 

Benzophenones are derived from several pathways. In higher plants, most benzophenones arise by cyclization of a polyke-tide chain of three malonates added to a hydroxybenzoic acid precursor (Manitto, 1981). Cyclization occurs via a Claisen condensation mechanism (Fig. 10.14). These compounds serve as precursors for xanthones in many plants. In some instances [e.g., in the heartwood of Symphonia globulifera (Clusiaceae)], the benzophenone and the corresponding xan-thone co-occur [in this case maclurin (33) and 1,3,5,6-tetra-hydroxyxanthone (34)] (Weiss and Edwards, 1980). 

Malonic acid derivatives are not the only compounds capable of decarboxylation. At least one COOH unit is required, as well as a suitable basic atom such as the oxygen of a carbonyl that is attached to the a-carbon of the acid. Reexamining the Claisen condensation shows that the P-keto ester products (61 from Section 22.7.1) fit the criterion for decarboxylation. The requisite COOH unit is obtained by hydrolysis of the ester unit in 61 to give P-keto acid 101. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

The intra-molecular Claisen condensation is called a Dieckmann condensation, and it generates a cyclic compound 58,99,101,118. Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or add derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation 59, 60, 61, 62, 69, 99,108,110,112, 113,119,124. 

Recall from Section 18.4C that hydrolysis of an ester in aqueous sodium hydroxide (saponification) followed by acidification of the reaction mixture with aqueous HCl converts an ester to a carboxylic acid. Also recall from Section 17.9 that j8-ketoacids and j8-dicarboxylic adds (substituted malonic acids) readily undergo decarboxylation (lose CO2) when heated. Both the Claisen and Dieckmann condensations yield esters of j8-ketoacids. The following equations illustrate the results of a Claisen condensation followed by hydrolysis of the ester, acidification, and decarboxylation. 

Both forward and reverse Claisen condensations feature prominently in the biochemical synthesis and degradation of fatty acids (p. 862). A critical step in the construction of these long-chain carboxylic acids involves enzyme-mediated Claisen condensations in which activated two-carbon fragments are sewn together. Of course, Nature has a thermodynamic problem here—how is the endothermicity of the Claisen condensation to be overcome The trick is to use an activated malonate in the condensation. Loss of carbon dioxide is used to drive the equilibrium toward the product (Fig. 19.110). 

In examining the overall conversion of pyruvate into a fatty acid (Schemes 1.1 and 1.2) it is interesting to note the exploitation of particular chemical properties of sulphur (i), as an easily reduced disulphide (1.6) (ii), as an easily oxidized dithiol and (iii) in reactive thioesters which aid the Claisen-type condensation reactions. Also of crucial importance for the condensation is the use of a malonic acid derivative (1.14) as a source of a stable anion. (Further discussion of fatty acid biosynthesis in relation to polyketide formation is taken up in Chapter 3.)... 

The basic principle of polyketide assembly is highly related to that of fatty acid biosynthesis [14, 16]. In both biosynthetic systems, an acyl-primed ketosynthase (KS) catalyzes chain extension by decarboxylative Claisen condensation with malonate activated by its attachment to coenzyme A or an acyl carrier protein (ACP) via a thioester bond (Scheme 2.2). hi fatty acid synthases (FASs), the resulting ketone is rednced to the corresponding alcohol by a ketore-ductase (KR), dehydrated by action of a dehydratase (DH) to give the alkene with snbseqnent donble-bond reduction by an enoyl rednctase (ER) yielding the saturated system (cf. Section 3.2). The latter can then be transferred onto the KS domain and enter the next cycle of chain extension and complete rednction. This homologation process facilitates the assembly of long-chain satnrated fatty acids, for example, palmitic acid, after seven cycles, which will ultimately be released from the catalytic system by saponification of the... 

Claisen Condensation Reparation of Ethyl Cinnamateand Cinnamic Acid 9-16. Malonic Ester Synthesis—Preparation of Ethyl-n-Butylmalonate... 

Acetogenins. Acetogenins are produced upon chain elongation with activated acetate units (or malonate followed by loss of carbon dioxide). A simplified sketch of this sequence is given in Fig. 1. During the first steps, a Claisen-type condensation of two acyl precursors yields a (3-ketoacyl intermediate A. Upon reduction to B and dehydration to C, followed by hydrogenation to D and hydrolysis, the chain elongated fatty acid E is produced. The next cycle will add another two carbons to the chain. Similarly, a reversed sequence leads to chain... 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

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