Claisen condensation in synthesis

The term condensation refers to the joining of two molecules with the splitting out of a smaller molecule. The Claisen condensation is used extensively in the synthesis of dicarbonyl compounds. In biochemistry it is used to build fatty acids in the body. The Dieckmann condensation, the crossed Claisen condensation, and others (with other carbanions) cire variations of the Claisen condensation. In this section we briefly look at these variations. 

C.H. Heathcock and co-workers devised a highly convergent asymmetric total synthesis of (-)-secodaphniphylline, where the key step was a mixed Claisen condensation. In the final stage of the total synthesis, the two major fragments were coupled using the mixed Claisen condensation] the lithium enolate of (-)-methyl homosecodaphniphyllate was reacted with the 2,8-dioxabicyclo[3.2.1]octane acid chloride. The resulting crude mixture of (3-keto esters was subjected to the Krapcho decarboxylation procedure to afford the natural product in 43% yield for two steps. 

Intramolecular Claisen condensation. The synthesis of /f-diketones by Claisen condensation6 is ordinarily only possible when the product can be stabilized as the enolate. Gerlach and Miiller7 report that the nonenolizable /1-diketone (2, bicyclo[2.2.2]octane-2,6-dione) can be obtained from 3-keto-l-cyclohexaneacetic acid (1) in 75 % yield when a solution of (1) dissolved in glacial acetic acid is treated with polyphosphoric acid. The... 

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). 

Synthesis a is a Dieckmann condensation featuring attack of the a-carbon of the ketone enolate on the ester carbonyl at the other end of the molecule. S5mthesis fc is a mixed Claisen condensation in which cyclohexanone enolate attacks one of the two ester groups of diethyl ethanedioate (diethyl oxalate). 

Depending on the respective reaction partner, acetic acid esters can react either as C-H acidic compounds or as acylating agents. Both are illustrated by the self-condensation of ethyl [ 1 acetate in the presence of 0.5 equivalent of sodium ethoxide or triphenymethyl sodium to give ethyl [1,3- C2]acetoacetate (Claisen condensation). In the first case, however, because of the relatively low radiochemical yields (40-45%) obtained by this procedure, it is of minor importance for the preparation of labeled ethyl acetoacetate. The deprotonation of alkyl acetates with LiHMDS followed by acylation with unlabeled or labeled acyl halides to labeled give /3-keto esters is discussed in Section 6.4. Claisen condensation of alkyl [ CJacetates with esters lacking a-hydrogens (i.e. ethyl formate, diethyl oxalate, aromatic/heteroaromatic carboxylic acid esters) proceed unidirectionally and are valuable pathways in the synthesis of ethyl [ C]formyl acetate (521. diethyl [ C]-oxaloacetate (53) and ethyl 3-oxo-3-pyrid-3-yl[2- C]acetate (54). The last example... 

Mixed Claisen-like reactions can also be carried out between an ester and a ketone, resulting in the synthesis of a jS-diketone. The reaction works best when the ester component has no a hydrogens and thus can t act as the nucleophilic donor. For example, ethyl formate gives high yields in mixed Claisen condensations with ketones. 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

In the course of the first total synthesis of (+)-halichlorine <1999TL6513, 1999AGE3542>, the spiroquinolizidine unit 460 was constructed by a two-carbon chain extension in compound 458 through a crossed Claisen condensation, leading to 459, and an intramolecular Mannich reaction of this compound with formaldehyde (Scheme 109). 

In the synthesis route from acetyl-CoA to poly(3HB), at least three steps and three enzymes are involved (Fig. 1). The first step is catalyzed by the 3-keto-thiolase (EC 2.3.1.9) which reversibly links two acetyl-CoA moieties to aceto-acetyl-CoA in a Claisen-condensation. The conversion of acetoacetyl-CoA into D-(-)-3-hydroxybutyryl-CoA can be mediated by a reductase (step 2) or via a sequence catalyzed by a reductase (step 4) and two hydratases (steps 5,6). The last step, i.e., the polymerization, is catalyzed by a polymerase (step 3). This... 

Industry, in fact, has a major interest in these diesters as building blocks for nylon 6,6 and nylon 7,7 in the production of polyesters and polyamides. However, their present synthesis raises an environmental concern. For instance, the oxidation of cyclohexanone by nitric acid (for the preparation of adipic acid), accounts for more than 10% of the total yearly release of N2O, which is among the main gases responsible for the greenhouse effect. The reaction of Scheme 4.14 represents an eco-friendly alternative synthesis of a,(i)-diesters which uses green reagents and, relevantly, has a 100% atom economy. The overall process is mechanistically described as a retro-Claisen condensation. 

In principle, the synthesis of a consonant molecule or a bifunctional relationship within a more complex polyfunctional molecule, does not offer too many difficulties. In fact, all the classical synthetic methods of carbon-carbon bond formation that utilise reactions which are essentially reversible, lead to consonant relationships. For instance, the book by H.O. House "Modem Synthetic Reactions" [22], after dealing, for almost 500 pages, with functional group manipulations, devotes the last 350 pages to carbon-carbon bond formation, all of which lead to consonant relationships. These methods can, actually, be reduced to the following four classical condensations (and their variants) Claisen condensation, aldol condensation, Mannich condensation and Michael addition (Table 2.5). 

The method described is that of Hampton, Harris, and Hauser6 and is an improvement over the benzyne method, which gives poor yields.6,7 This /J-diketone has been prepared by Claisen condensation of ethyl phenylacetate with acetone,8 but the yield is poorer and the product has been shown by gas chromatography to be impure.6 The j8-diketone has also been prepared by the hydrolysis of 4-methoxy-5-phenyl-3-penten-2-one and by hydrolysis and decarboxylation of ethyl a-acetyl-/3-oxo-y-phenylbutyrate10 but these compounds are more difficult to obtain than the starting materials used in the present synthesis. 

Lithium amide is used in synthesis of histamine and analgesic drugs. The compound also is used in many organic synthetic reactions including alkylation of ketones and nitriles, Claisen condensation, and in synthesis of antioxidants and acetylenic compounds. 

Benzene and thiophene rings can of course often be interchanged in biologically active agents. The very broad structural latitude consistent with NSAID activity is by now a familiar theme as well. Preparation of the fused thiophene counterpart of the NSAID piroxicam (Chapter 11) starts with the reaction of thiophene (25-1), itself the product of a multistep sequence, with ethyl A-methylglycinate to give the sulfonamide (25-2). Treatment of that intermediate with a base leads to intramolecular Claisen condensation and thus the formation of the 3-ketoester (25-3). An amide-ester interchange with 2-aminopyridme (25-4) completes the synthesis of tenoxicam (25-5) [25]. 

With regard to the synthesis of celecoxib (1), several routes were described in the 1995 patent by G. D. Searle As shown in Scheme 1, dione 7 was prepared by the Claisen condensation of 4-methylacetophenone with ethyl trifluoroacetate in the presence of NaOMe in methanol under reflux. Subsequent diarylpyrazole formation from the condensation of dione 7 and 4-sulfonamidophenylhydrazine hydrochloride then delivered... 

Amino groups in compounds of type (23, Z=NH) are frequently derived from nitro groups. In the Reissert indole synthesis, o-nitrotoluene undergoes Claisen condensation with oxalic ester to yield the pyruvic ester (24). When this is reduced with Zn-AcOH the corresponding amino derivative spontaneously cyclizes to the 2-ethoxycarbonylindole (25) (63OS(43)40). 

Other Claisen condensations are involved in synthesis of fatty acids and polyketides217 (Chapter 21) and in formation of 3-hydroxy-3-methylglutaryl-CoA, the precursor to the polyprenyl family of compounds (Chapter 22). In these cases the acetyl group of acetyl-CoA is transferred by a simple displacement mechanism onto an -SH group at the active site of the synthase to form an acetyl-enzyme.218 219 The acetyl-enzyme is the actual reactant in step b of Eq. 17-5 where this reaction, as well as that of HMG-CoA lyase, is illustrated. 

Both bacteria and plants have separate enzymes that catalyze the individual steps in the biosynthetic sequence (Fig. 17-12). The fatty acyl group grows while attached to the small acyl carrier protein (ACP).54 58 Control of the process is provided, in part, by the existence of isoenzyme forms. For example, in E. coli there are three different P-oxoacyl-ACP synthases. They carry out the transfer of any acyl primer from ACP to the enzyme, decarboxylate malonyl-ACP, and carry out the Claisen condensation (steps b, e, and/in Eq. 17-12)58a e One of the isoenzymes is specialized for the initial elongation of acetyl-ACP and also provides feedback regulation.58c The other two function specifically in synthesis of unsaturated fatty acids. 

The conversion of the substituted 1,3-dicarbonyl compound into homophthalic acid is remarkably facile loss of the acetyl group by a retro-Claisen condensation and hydrolysis of the ester group are complete in a few minutes in aqueous sodium hydroxide. The overall synthesis of homophthalic acids from o-bromobenzoic acids occurs in high yield and provides an attractive route. 

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