P-Keto carboxylic acids

P-Keto esters tend to decarboxylate after hydrolysation to p-keto carboxylic acid and heating to give one or two alkyl-substituted ketones, respectively. 

Step 1 Intramolecular condensation of two esters (Dieckmann condensation). Step 2 Saponification of the ethyl ester provides the P-keto carboxylic acid. 

One remarkable process is the photochemical synthesis of 3,4-dihydro-2H-l,3-oxazin-4-ones from a-sulfonyloxy-(3-keto amides (obtained by coupling of P-keto-carboxylic acids with amines, followed by treatment with an iodanyl mesylate). This allows the regioselective oxidation of less-activated C—H bonds and a C—O bond formation which is unusual for a Norrish-Yang reaction [69]. The formation of a 1,6-0—C biradical has been postulated as an intermediate (Scheme 9.42). 

This concept is based on the decarboxylation of p-keto carboxylic acids. Commer-... 

P-keto-carboxylic acid benzyl esters, (Bu-cyano-acetate, sulfur... 

Plausible biosynthetic relationships between the various pre-anthra-quinones discussed above and some of the anthraquinones of Section 3.5.1 are depicted in Scheme 60. Atrochrysone (321) may be considered as the biogenetic precursor of all of the anthraquinones of the emodin family (598). Thus, if water is lost from atrochrysone, emo-din anthrone (335) is produced which could then lead by oxidation to emodin (288). The hypothetical p-keto carboxylic acid precursor (334) to atrochrysone could provide the link between the acidic and the neutral fungal anthraquinones since dehydration followed by oxida-... 

A comparison of the mass spectral fragmentation patterns of the dimethyl ester of caperatic acid (41) and the corresponding di(trideutero-methyl) ester located the position of the ester function in this molecule and established the structure as methyl 3,4-dicarboxy-3-hydroxyoctadecanoate (41) (25). In a corroborative chemical degradation (41) was oxidized by treatment with sodium bismuthate, whereupon methyl 3-oxo-octadecano-ate (42), the decarboxylation product of the initially formed P-keto-carboxylic acid, was detected (25). 

The former passes into the second on further oxidation with hydrogen peroxide, indicating that it is an a-keto-carboxylic acid. Acid (b) loses carbon dioxide on fusion and gives a neutral substance, CjaHj OgN, m.p. 238°, which was shown to be 6 7-methylenedioxy-A-methylphenanthri-done (I), by comparison with a synthetic specimen. The position of the carboxyl group in (b) could not be determined by synthetic methods but is probably at since dihydrolycorineanhydromethine, Cl 7 7 2 ) m.p. 87-5° [picrate, m.p. 174° (dec.) methiodide, m.p. 236° (dec.)] on distillation with zinc dust yields a mixture of phenanthridine, 1-methyl-phenanthridine and 6 7-methylenedioxyphenanthridine, m.p. 142° [picrate, m.p. 257° (dec.)], the identity of the two latter being established by comparison with the synthetic products. These results indicate for lycorineanhydromethine formula (II). 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

Asymmetric catalysis undertook a quantum leap with the discovery of ruthenium and rhodium catalysts based on the atropisomeric bisphosphine, BINAP (3a). These catalysts have displayed remarkable versatility and enantioselectivity in the asymmetric reduction and isomerization of a,P- and y-keto esters functionalized ketones allylic alcohols and amines oc,P-unsaturated carboxylic acids and enamides. Asymmetric transformation with these catalysts has been extensively studied and reviewed.81315 3536 The key feature of BINAP is the rigidity of the ligand during coordination on a transition metal center, which is critical during enantiofacial selection of the substrate by the catalyst. Several industrial processes currently use these technologies, whereas a number of other opportunities show potential for scale up. 

This ligand, MeO-BIPHEP (96a), has shown similar reactivities and enantioselectivities to catalysts that contain BINAP.117 Ruthenium catalysts that contain MeO-BIPHEP have been used in several asymmetric hydrogenations from bench scale to multi-ton scale, which include the large-scale preparation of a P-keto ester, an aryl ketone, allylic alcohol, and several oc,P-unsaturated carboxylic acid substrates, which are shown in Figure 12.5. 

Ruthenium and rhodium complexes that contain TMBTP have shown utility in the asymmetric hydrogenation of allylic alcohols,155,156 P-keto esters,155,157 and a,P-unsaturated carboxylic acids.155... 

Walphos (138), developed by Sturm at the University of Vienna and optimized at Solvias, is derived from the Ugi amine 54.174175 Walphos can be electronically fine-tuned as various phosphine groups are introduced in separate steps of the synthesis. Walphos catalysts have been used to reduce enamide esters to a-amino esters, P-keto esters, a,P-unsaturated carboxylic acids, and itaconate esters with enantioselectivities >90%.176... 

The reactivity of achiral Ru compounds for the hydrogenation of functionalized ketones has not been extensively studied. RuCl2 P(C6H5)3 3 reduces y-keto carboxylic acid at 180 °C to the corresponding y-lactone (Eq. 2.15) [115]. Heterogeneous Ru/C catalyzes the atmospheric pressure hydrogenation of furfural in water at 25 °C [86]. Under such mild conditions, glucose is industrially converted to sorbitol (Eq. 2.16) [116]. At elevated temperature and pressure, tetramethyl-l,3-cyclobutanedione can be converted to a 98 2 diastereomer mixture of the diol (Eq. 2.17) [117]. 

The oxidation of methyl ketones to a-keto carboxylic acids is rare and is accomplished by treatment with a cold solution of potassium permanganate. However, the reaction is not general acetophenone, p-methyl-acetophenone, and 3,4-dimethylacetophenone are oxidized all the way to the corresponding benzoic acids. On the other hand, 2,4-dimethylaceto-phenone, when shaken with approximately 1% aqueous potassium permanganate at room temperature, gives 6 72% yields of 2,4-dimethyl-phenylglyoxylic acid [555, 559],... 

Scheme 15 illustrates the asymmetric hydrogenation of 3-keto phosphonates catalyzed by a BINAP-Ru complex, giving P-hydroxy phosphonates in up to 99% ee [61]. The sense of enantioface differentiation is the same as that of hydrogenation of P-keto carboxylic esters (see table of Scheme 3). The reactivity of the phosphonates is much higher than that of the carboxylic esters so that the hydrogenation proceeds even at 1 to 4 atm of hydrogen and at room temperature. A Ru complex of BDPP also shows high enantioselectivity [46b]. Chiral P-hydroxy phosphonates thus obtained are useful intermediates for the syntheses of phosphonic acid-based antibiotics as well as haptens of catalytic antibodies. Similarly, P-keto thiophosphates are hydrogenated enantioselectively with a MeO-BIPHEP-Ru catalyst [61b].

Analogous p-hydroxy and p-amino carboxylic acids can be decarboxylated under similar conditions, as in their keto and imino forms they can be regarded... 

The reaction of 10-undecenoic acid [2a], for example, with an acyl chloride such as acetyl chloride, heptanoyl chloride, hexadecanoyl chloride, and EtAlCl2 in a ratio of 1 1 2 in dichloromethane gave the corresponding P,y-unsaturated keto carboxylic acid [5a]-[5c] (Scheme 1) after a reaction time of 2 h at room temperature with high regioselectivity. The products were obtained as a mixture of ( /(Z)-stereoisomers ([( )] [(Z)] = 3 1) in isolated yields of 50-67%. Catalytic hydrogenation of the unsaturated ketocarboxylic acids [5a]-[5c] gave the saturated products in quantitative yields (2). 

Indeed three of the four possible reactions calculated with IGOR are known. The first is the well known ketone cleavage (decarboxylation of fi-keto carboxylic acids and P-dicarboxylic acids) at about 100°C. The second is the decarboxylation of the mixed anhydride of a carboxylic add with carbonic acid. The third, the decarboxylation of... 

A favourable feature of the Petasis reaction, in relation to NDE synthesis, is its triple convergence to form products with multiple sites for introduction of chemical diversity. Moreover, ready availability of alkenyl boronic acids in stereochemically (E or Z) pure forms and their easy handling, prompted development of this new method for broad application in organic synthesis. Particularly important is the extension of the Petasis reaction to a-keto-carboxylic acids (V) in a practical synthesis of p,y-unsaturated a-amino acids (Scheme 8.2, route b). 

Goossen and coworkers reported the decarboxylative coupling of a-keto carboxylic acids with aryl bromides (Scheme 4.67) [69]. Thus, treatment of potassium 2-oxo-2-phenylacetates with 4-bromotoluene in the presence of 1 mol% of palladium 1,1,1,5,5,5-hexafluoroacetylacetonate, 2mol% of P(o-tolyl)3, 15mol% of CuBr, 15mol% of 1,10-phenanthroline in NMP/quinoline at 170 C gives the corresponding benzophenones. 

Decarboxylation of Carboxylic Acids and Derivatives.—A palladium-catalysed decarboxylation-dehydrogenation of allyl P-keto-carboxylates and allyl enol carbonates occurs in good yield for ten examples however, mixtures of isomers are obtained in some cases (Scheme 32). ... 

Nemoto T, Ohshima T, Shibasaki M. Catalytic asymmetric synthesis of a,p-epoxy esters, aldehydes, amides, and -y,8-epoxy p-keto esters unique reactivity of a,p-unsaturated carboxylic acid imidazolides. J. Am. Chem. Soc. 2001 123 (38) 9474-9475. 

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