P-Keto carboxylic esters

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].

Noyori R, Ohkuma T, Kitamura M, Takaya H, Sayo N, Kumobayashi H, Akutagawa S. As)umnetric hydrogenation of p-keto carboxylic esters. A practical, purely chemical access to p-hydroxy esters in high enantiomeric purity. J. Am. Chem. Soc. 1987 109 5856-5858. 

Asymmetric hydrogenation has been achieved with dissolved Wilkinson type catalysts (A. J. Birch, 1976 D. Valentine, Jr., 1978 H.B. Kagan, 1978). The (R)- and (S)-[l,l -binaph-thalene]-2,2 -diylblsCdiphenylphosphine] (= binap ) complexes of ruthenium (A. Miyashita, 1980) and rhodium (A. Miyashita, 1984 R. Noyori, 1987) have been prepared as pure atrop-isomers and used for the stereoselective Noyori hydrogenation of a-(acylamino) acrylic acids and, more significantly, -keto carboxylic esters. In the latter reaction enantiomeric excesses of more than 99% are often achieved (see also M. Nakatsuka, 1990, p. 5586). 

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. 

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

There are two good routes for the S5mthesis of unsymmetricaUy substituted 1,4-diketones. The classical route involves the alkylation of a p-keto-ester (1,3-keto-ester) with a 2-haloketone followed by hydrolysis and thence decarboxylation of the resulting p-keto-carboxylate (for some typical modem examples see... 

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). 

Catalytic asymmetric transamination of i-keto carboxylic esters 94 catalyzed by a chiral base was firstly reported by Soloshonosk et al. [40a] providing an original biomimetic approach to p-fluoroalkyl- 3-amino acids. This transformation involves the formation of A-benzyl enamines 96 in tautomeric equilibrium with A-benzyl... 

Hydrogenation of a-at lamino or a-halogeno P-keto phosphonates with a BINAP Ru complex gives the corresponding syn alcohols selectively with >98% ee (Scheme 1.58) [243a,251]. The sense of enantio- and diastereoface discrimination is the same as that in the case of a-substituted -keto carboxylic esters (see Table of Scheme 1.57). 

These substances, as well as the parent compound, are p-keto esters and undergo hydrol3rtio cleavage in two directions. One type of cleavage, ketonlc hydrolysis, is effected by the action of dilute caustic alkali in the cold, followed by acidification and boiling the free acetoacetic acid produced has a carboxyl and carbonyl group on the same carbon atom and therefore readily undergoes decarboxylation to yield a ketone, for example ... 

The carbon-carbon bond forming potential inherent m the Claisen and Dieckmann reac tions has been extensively exploited m organic synthesis Subsequent transformations of the p keto ester products permit the synthesis of other functional groups One of these transformations converts p keto esters to ketones it is based on the fact that p keto acids (not esters ) undergo decarboxylation readily (Section 19 17) Indeed p keto acids and their corresponding carboxylate anions as well lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation... 

Titanium chelates are formed from tetraalkyl titanates or haUdes and bi- or polydentate ligands. One of the functional groups is usually alcohoHc or enoHc hydroxyl, which interchanges with an alkoxy group, RO, on titanium to Hberate ROH. If the second function is hydroxyl or carboxyl, it may react similarly. Diols and polyols, a-hydroxycarboxyflc acids and oxaUc acid are all examples of this type. P-Keto esters, P-diketones, and alkanolamines are also excellent chelating ligands for titanium. 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

Carboxylic esters can be treated with ketones to give p-diketones in a reaction that is essentially the same as 10-118. The reaction is so similar that it is sometimes also called the Claisen condensation, though this usage is unfortunate. A fairly strong base, such as sodium amide or sodium hydride, is required. Yields can be increased by the catalytic addition of crown ethers. Esters of formic acid (R H) give P-keto aldehydes. Ethyl carbonate gives P-keto esters. 

Other carbanionic groups, such as acetylide ions, and ions derived from a-methylpyridines have also been used as nucleophiles. A particularly useful nucleophile is the methylsulfinyl carbanion (CH3SOCHJ), the conjugate base of DMSO, since the P-keto sulfoxide produced can easily be reduced to a methyl ketone (p. 549). The methylsulfonyl carbanion (CH3SO2CH2 ), the conjugate base of dimethyl sulfone, behaves similarly, and the product can be similarly reduced. Certain carboxylic esters, acyl halides, and DMF acylate 1,3-dithianes (see 10-10. )2008 Qxj(jatjye hydrolysis with NBS or NCS, a-keto aldehydes or a-... 

When P-keto esters are treated with concentrated base, cleavage occurs, but is on the keto side of the CR2 group (arrow) in contrast to the acid cleavage mentioned on page 810. The products are a carboxylic ester and the salt of an acid. However, the... 

RCH(OH)=CHCOR or p-keto esters RCH(OH)=CHCOOR ) dissolve in dilute sodium hydroxide solution, i.e., contain an acidic group of sufficient strength to react with the alkah. Carboxylic acids and sulphonic acids are soluble in dilute solutions of sodium bicarbonate some negatively-substituted phenols, for example, picric acid, 2 4 6-tribromo-phenol and 2 4-dinitrophenol, are strongly acidic and also dissolve in dilute sodium bicarbonate solution. 

The above transformation takes place via the catalytic effect of copper (I), which generated the corresponding carbenoid from a-diazo-p-keto esters. These Cu-carbenoides react with the thiocarbonyl group of thioamides, after cyclocondensation to afford 2-aryl-l,3-thiazole-5-carboxylates (Scheme 18).40... 

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