Diketo acids

The submitters obtained pure 7,16-diketodocosanedioic acid by the following procedure. A solution of 300 ml. of 12A hydrochloric acid in 31. of water is stirred into a warm solution of 250 g. of the crude disodium 7,16-diketodocosanedioate in 3 1. of water. The resultant suspension of the diketo acid is boiled for a few minutes to make the acid easier to filter, then cooled to room temperature and collected on a Buchner funnel. The filter cake is suspended in 3 1. of water with mechanical stirring and collected on a Bilchner funnel, and this procedure is repeated. The moist well-pressed filter cake is recrystallized from 600 ml. of 2-meth-oxyethanol. The reciystallized acid is suspended in 500 ml. of 95% ethanol, separated on a Buchner funnel, and dried in air. About 120 g. (61%) of pure 7,16-diketodocosanedioic acid is ob-... 

Consequently, S-1360, a triazole analogue of DKA, was the first integrase strand transfer inhibitor (INSTI) to enter clinical trials, but the development was stopped during phase Eli (Billich 2003). Subsequently, a novel series of potent INSTIs, which replaced the 1,3-diketo acid moiety by an isosteric 8-hydroxy-1,6-naphthyridine core, showed improved metabohc stabihty (Zhuang et al. 2003). The compound L-870,810 moved into clinical trials, where it provided proof of concept in antiretroviral therapy-experienced and antiretroviral therapy-naive... 

Kehlenbeck S, Betz U, Birkmann A, Fast B, Goller AH, Henninger K, Lowinger T, Marrero D, Paessens A, Paulsen D, Pevzner V, Schohe-Loop R, Tsujishita H, Welker R, Kreuter J, Riibsamen-Waigmann H, Dittmer F (2006) Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore. J Virol... 

Dayam R, Sanchez T, Clement O, Shoemaker R, Sei S, Neamati N. P-Diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 integrase inhibitors. J Med Chem 2005 48 111-20. 

This arrangement of subgroups is due to the hypothetical biosynthetic sequence. It assumes that precursors for these alkaloids are the Af-methylphth-alideisoquinolinium salts, whose presence in plants is well documented. Enol lactones may be the initial degradation products formed in a Hofmann-type jft-elimination process. They could be hydrated to the keto acids and in the next step oxidated in air to the diketo acids. Diketo adds may undergo further oxidative cleavage to yield simple alkaloids of the fumariflorine (87) type 85,86), which seem to be the final products of the metabolism of phthalideiso-quinoline alkaloids. 

Parent phthalideisoquinoline alkaloid Configuration Enol lactone Configuration Keto acid Diketo acid Ene lactam Configuration... 

Potassium permanganate oxidizes both adlumidiceine (103) and ad-lumiceine (105) to the corresponding diketo acids bicucullinine (108) and bicucullinidine(llO), respectively (/13). Air oxidation of N-methylhydrasteine (104) leads to the expected N-methyloxohydrasteine (109) as well (J). Another way of transforming the keto acids (e.g., 104) to diketo acids (e.g., 109) utilizes the isonitroso derivatives (e.g., 133), which on hydrolysis gives the diketone (102). 

In the mass spectra (4,5,106,116-119) of diketo acids peaks derived from molecular ions and M — 18 ions are present. The characteristic of N,N-dimethylaminoethyl side chain base peak at m/z is present as well. The rupture of the C—C bond between the two central carbonyls is represented by peaks due to ions formed from upper and lower fragments of the molecules. The respective structures 141 and 142 can be ascribed to them. 

The diketo acids were transformed to their methyl esters under the action of diazomethane (5), SOCl2/CH3OH (102), or methanolic hydrogen chloride (117). Like other benzils, JV-methyloxohydrasteine (109) when... 

A four-component Ugi reaction between the thienopyrrole-diketo-acid 280, an isonitrile and an amine gives the fused tricycle 281 with two nitrogens in the six-membered ring <2006SC903> (Equation 44). 

It took nearly a decade from the time the first purified IN protein was reported to the elucidation of the basic pharmacophore through the discovery of diketo acids (DKAs) and acid isostere analogs which were nearly simultaneously reported by independent groups [7]. Examples of these early generation IN inhibitors (INIs) are shown in Figure 1. 

Figure 1 Diketo acid (DKA) and acid isostere analogs.

Aryl-2,4-dioxobutanoic acids (67) upon treatment with IBD afford the corresponding furans 70. The first step of the reaction is the formation of coupling products 68, which then expel CO2 to give diketo acids 69. The loss of water from the tautomer of 69 gives cyclized products, enolic lactones 70 (72MI1) (Scheme 22). 

Dioxocarboxylic acid 238 upon treatment with HTIB, cyclizes to dioxo-5-lactone 239 by intramolecular participation of the carboxylic group. When cyclic diketo acid 240 is the substrate, spirolactone 241 is obtained (90TL201). 

An early example is cleavage of an alkene linkage with RnO (Fig. 3.18) in the conversion of a diketo diphenyl ethylene to a nor-diketo acid by RnOyaq. Na(IO )/ acetone concomitant destruction of the phenyl rings also occnrs [206]. 

Included in this section are oxidations of benzene and phenyl rings, and in general the oxidation of aromatic and polycyclic aromatic compounds. The main catalyst for this type of reaction is RuO. The earliest example was the use of stoich. RuOy CCI4 for phenanthrene oxidation [239], while the first catalytic reagent was RuO / aq. Na(I04)/acetone for oxidation of pyrene [240]. Another early example was the conversion of diketo compounds to the nor-diketo acids, with concomitant destruction of the two phenyl rings by RuO /aq. NallO l/acetone (Fig. 3.18, 3.2.2.1) [206]. 

Dissolution in sulfuric acid is sufficient to convert 5-(4-chlorophenyl)penta-2,4-diynoic acid into the 6-aryl-4-hydroxypyran-2-one (73BSF1293) other p-substituents are compatible with the synthesis. The intermediacy of a 2,4-diketo acid is assumed. Preparation of the alkynic acids is achieved through the coupling of 2-aryl-1-bromoacetylenes with propynoic acid. 

Whereas several anti-cholestemic drugs are produced wholly by fermentation, the side chain of several others is accessible through enzymatic synthesis. (3R,5S)-Dihydroxyhexanoate, a key intermediate of fluvastatin, is accessible by reduction of the diketo acid, either by bioreduction with whole cells (85% yield, 97% e.e.), or cell extracts (72% yield, 98.5% e.e.), or, for syn-(3h,5.S)-dihydroxy-6-Cl-hexanoate, regioselective and (ft)-specific reduction with ADH to yield (5S)-6-chloro-3-ketohexanoate. 

The side chain of such statins, the (3i ,5S)-dihydroxyhexanoates, is a key intermediate and are accessible by reduction of the diketo acids. One way is bioreduction with whole cells (Patel, 1993) with glycerol-grown suspensions of Adnetobacter calcoaceticus SC 13876, yields of 85% and 97% e.e. were achieved for the benzyloxy-(3P,5S)-derivative. If cell extracts were used and NAD+, glucose, and glucose dehydrogenase supplied, both intermediate monohydroxy (in the 3- and 5-position) compounds were produced before the desired dihydroxyhexanoate, and the overall reaction resulted in 72% yield and 98.5% e.e. (Patel, 2001). 

Another way to statin side chains, via the intermediate syn-(i K,5,S )-6-chloro-hexanoate, employs regioselective and (K)-specific reduction with alcohol dehydrogenase (ADH) from Lactobacillus brevis to yield the intermediate (5S)-6-chloro-3-ketohexanoate from the 3,5-diketo acid (Wolberg, 2001) (Figure 13.16). Further reduction of (5S)-6-chloro-3-ketohexanoate to syn-(3R,5S)-6-chlorohexanoate is afforded chemically with NaBH4/B(OMe)Et2. 

The hydrogenation of 2,4-diketo acid derivatives 6-9 to the corresponding 2-hydroxy compounds with cinchona-modified Pt catalysts as depicted in Scheme 18.1 can be carried out with chemoselectivities... 

The 4-ary 1-2,4-diketobutanoic acid class of IN inhibitors (also known as 1,3-diketo acids, or DKAs) was discovered independently by researchers from Merck and Shionogi, with patents from both groups published in the same year.13 From a random screen of > 250,000 compounds, the Merck group identified DKAs as the most active IN inhibitors. Compound 7 was the most potent compound found in this screen (Table 1), completely inhibiting HIV-1 infection in a cell-based assay at a concentration of 10 pM.10... 

Heating of the derived diketo acid (303) with naphthalene-l-sulfonic add in benzene-dioxane solution promoted cyclization and formation of304 (60 %). 

The cleavage of S-diketo acid is commonly seen in polyphenol metabolism and degradation such as orcinol (5-methylbenzene-l,3-diol) catabolism in Pseudomonas putida. Acetylpyruvate hydrolase (ca 38 kDa) is the terminal enzyme of orcinol catabolism, catalyzing the conversion of acetylpyruvate into acetate and pyruvate (equation 12). ... 

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