Keto-acids, reaction with

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

Sorm" " found that when cholesterol acetate (67) is oxidized by chromic acid in acetic acid-water at 55°, crystalline keto seco-acid (69) is obtained in 25-30 % yield from the mother liquors after removal of successive crops of 7-ketocholesterol acetate (68). Reaction of keto acid (69) with benzoyl chloride in pyridine gives a dehydration product, shown" to be the )5-lactone... 

Table 3 shows melting points of a few representative keto acids (72). The reaction of keto acids (66) with phenols (67) is usually carried out in 70-90% sulfuric acid at 50-150°C, or in an aromatic solvent such as benzene, toluene, or chlorobenzene at reflux in the presence... 

Table 5 shows results of a few representative of diaminofluorans (74) prepared by the reaction of the keto acid (66b) with aminophenols or aminoanisoles. 2 -Amino-6 -diethylaminofluoran (74a) is an important precursor for 2 -dibenzylamino-6 -diethylaminofluoran developing green color. 

The reaction of the keto acids (66) with 4-alkoxydiphenylamines (75 R = CH3, C2H5) is widely used to prepare fluoran compounds developing green or black colors. The reaction in concentrated sulfuric acid gives intermediate phthalide compounds (76), which are then treated with base to convert into 2 -anilino-6 -aminofluorans (77) (Eq. 5). 

The synthesis of 6-oxo-2,3,4,6-tetrahydro[l,2,4]triazino[5,6-c]isoquino-line-3-thione 178 was achieved by the reaction of the keto acid 174 with thiosemicarbazide to give azauracil 175. Its esterification gave 176, which was converted to the amide 177 and cyclized (84PHA186 92CCC123) in presence of acetic acid to give 178. 

Aldol reaction of keto-acid 21 with aldehyde 10 and esterification of the resulting acids with alcohol 22 led rapidly to cyclization precursor 23 and its 6S,7R-diastereomer (not shown). RCM using ruthenium initiator 3 (0.1 equiv) in dichloromethane (0.0015 M) at 25 °C afforded macrolactones 24a and 24b in a 1.2 1 ratio. Deprotection and epoxidation of the desired macrolactone, 24a, afforded epothilone A (4) via 25a (epothilone C) (Scheme 5). Varying a number of reaction parameters, such as solvent, temperature and concentration, failed to improve significantly the Z-selectivity of the RCM. However, in the context of the epothilone project, the formation of the E-isomer 24b could actually be viewed as beneficial since it allowed preparation of the epothilone A analog 26 for biological evaluation. 

The reactions of fi-keto acid derivatives with tnfluoromethylsulfenyl chlonde give the a-tnfluoromethanesulfenyl substitution products [4 The products can be treated with a dimethyl sulfoxide-water solution to form tnfluoromethylthioke-tones or with potassium hydroxide solution to give tnfluoromethylthioacetic acid (equation 3) (Table 2)... 

The amino acid is then hydrolyzed to form an a-keto acid and pyridoxamine phosphate, the a-amino group having been temporarily transferred from the amino acid substrate on to pyridoxal phosphate (Fig. 5). These steps constitute one half of the overall transamination reaction. The second half occurs by a reversal of the above reactions with a second a-keto acid reacting with the pyridoxamine phosphate to yield a second amino acid and regenerate the enzyme-pyridoxal phosphate complex (Fig. 5). 

Dinitrophenylhydrazones (DNPHs) were applied to the GC analysis of keto acids. As with carbonyl compounds, they are prepared by reaction with 2,4-dinitrophenylhydrazine and are also used mainly for the preliminary isolation of keto acids. They can be isolated from a dilute aqueous sample by adsorption on activated carbon and selective desorption [178] hydrazones of aldehydes with a methyl formate-dichloromethane mixture and hydrazones of keto acids with a pyridine-water azeotropic mixture. Hydrazones of acids are released from their pyridine salts with methanol containing hydrogen chloride. After... 

In this reaction, sodium metal is reacted with absolute alcohol to make sodium ethoxide (NaOCH2CH3). Ethyl acetoacetate and bromobenzene are then added to this to produce a beta keto ester. Reaction with acid then produces phenylacetone. 

Regiospecific aldol reaction. 2,2,2-TrichIoroethyl esters of /3-keto acids react with aldehydes in the presence of zinc to form a- ubstituted (3-hydroxy ketones (equation 1). The first step probably involves reduction of the ester to form a zinc salt with elimination of dichloroetbylene.°... 

Reaction 1 is a transamination reaction to form mercaptopyruvate. A transaminase in higher plants which will utilize cysteine or cystine as the amino donor has never been reported. In fact Forest and Wightman (1972) showed that cystine was not an amino donor to any keto acid tested with extracts of bush bean cotyledons or seedlings. It was unique in this respect in that the only other protein amino acids which acted in this manner were the two imino acids proline and hydroxyproline. 

The most usual and major keto acid involved with fransamination reactions is a-ketoglutaric acid (R = (CH2)2COOH), an intermediate in the citric acid cycle. 

Apart from reductive amination and the reaction of -keto acid derivatives with ammonia or amines, there are other carbonyl derivatives that can serve as precursors to amino acids. One sequence begins with the conversion of a,co-dicarboxylic acids... 

An interesting rearrangement of -keto acids esterified with polyols produces diesters (112) (Scheme 34), via a retro-Claisen reaction yields are heavily dependent on the nature of the polyol used. 

A semi-synthetic approach by the Merck group (775) makes use of the 4-chloro-azetidinone (153) which can be obtained from 6-aminopenicillanic acid. Reaction with the silylated diazo-intermediate (154) in the presence of silver tetrafluoroborate followed by desilylation provides a one-step process to (148) from (153). A similar displacement with a 4-acetoxy substituted azetidinone derived from aspartic acid provides another route (776) to (148). The amidine derivative (155) of thienamycin is chemically more stable than the amine and a direct introduction of this side-chain by way of the keto-ester has also been achieved (777). It is this amidine (MK 0787) that is undergoing clinical investigation rather than thienamycin itself... 

The reduction of the lactone grouping of compound (119) required the preliminary protection of the two keto groups. Reaction with ethylene glycol formed the diketal, the controlled reduction of which with lithium aluminum hydride enabled the cyclohemiacetal (118) to be obtained. In itself, the reduction takes place with a high yield and the main difficulty is the deketalization of the extremely unstable compound (118). Consequently, the products of lithium aluminum hydride reduction were immediately acetylated with acetic anhydride to a mixture of the 21-mono-and 18,21-diacetates. Hydrolysis of this mixture with 90% acetic acid at 100 C led to the 21-acetate of dl -aldosterone (123). Deacetylation of the latter with potassium carbonate gave not only dl -aldosterone (124) with a yield of 50%, but also its 17o -epimer. Natural -aldosterone was obtained by the same route from the tZ-enantiomer of (119). By Wettstein s first method (Scheme 66), cZZ-aldosterone (124) was formed from Sarett s ketone (67) in 22 stages with an over-all yield of 1.7%. 

Recently, Groger et al. [51] developed a process for preparing (S)-tertiary leucine 22 by reacting the corresponding keto acid 23 with an ammonium ion donor in the presence of a whole cell of E. coli expressing amino acid dehydrogenase and cofactor-regenerating enzyme FDH. The substrate addition was metered such that the stationary concentration of 2-ketocarboxylic acid remains <500 mM and the external addition of cofactor, based on the total input of substrate, corresponds to <0.0001 equivalents. In this process, a reaction yield of 84% and ee of 99% were obtained for (S)-tertiary leucine at 130 g/1 substrate input. 

PdCb, and the allylated lactone 232 is formed. Regeneration ofPdCl2 as shown by 231 makes the reaction catalytic. In this reaction, use of the Li salt 227 of 4-pentynoic acid (223) is recommended. Reaction of lithium 3-octynoate (233) with allyl chloride affords the unsaturated lactone 234, which is converted into the 7-keto acid 235 by hydrolysis[126]. 

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