Triketone synthesis

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Crocq et al. (1997) have synthesized trimegestone through Bakers yeast mediated reduction of a ketone (this material is a new progestomimetic molecule for the treatment of postmenopausal diseases). The key step of the multistep synthesis is the chemo-, regio- and almost stereospecific bioreduction of a triketone to the desired alcohol. 

An analogous reaction is known with aromatic nitroso-compounds, but for it an exceptionally mobile hydrogen atom must be present in the ketone and hence no condensation occurs with simple ketones such Us acetone. The products of the reaction are, of course, azomethines. This condensation has made possible the synthesis of 1 2 3-triketones (F. Sachs), e.g. 

The diacylation of isopropenyl acetate with anhydrides of dicarboxylic acids is applicable for the synthesis of several other cyclic jS-triketones in moderate yield. - It has been used for the synthesis of 2-acetylcyclohexane-l,3-dione (40% yield), 2-acetyl-4-methylcyclopentane-l,3-dione (10% yield), 2-acetyl-4,4-dimethylcyclopentane-l,3-dione (10% yield), 2-acetyl-5,5-dimethylcyclohexane-l,3-dione (10% yield), 2-acetylcyclo-heptane-l,3-dione (12% yield) and 2-acetylindane-l,3-dione (26% yield). Maleic anhydrides under more drastic conditions give acetylcyclopent-4-ene-l,3-diones in yields from 5% to 12%. The corresponding acylation of the enol acetate of 2-butanone with succinic anhydride has been used to prepare 2-methylcyclopentane-l,3-dione, an important intermediate in steroid synthesis. - ... 

Triketone (57), a key intermediate in the synthesis of 4,4,7,7,11,11-hexanitropentacyclo [6.3.0.0 .0 °.0 ]undecane (61) (Zlj-hexanitrotrishomocubane), has been synthesized independently by both Marchand and co-workers, and Fessner and Prinzach. Marchand and co-workers prepared the trioxime (58) from the corresponding triketone (57). Oxidation of (58) with peroxytrifluoroacetic acid in acetonitrile provides a direct route to the trinitro derivative (59) in 35 % yield, this yield reflecting an efficiency of 70 % for the oxidation of each oxime group. Subsequent oxidative nitration of (59) with sodium nitrite and potassium ferricyanide in aqueous sodium hydroxide yields the target T>3-hexanitrotrishomocubane (61). 

The molecular target site of triketone herbicides is the enzyme -hydroxyphenylpyruvate dioxygenase (HPPD). Inhibition of this enzyme disrupts the biosynthesis of carotenoids and causes a bleaching (loss of chlorophyll) effect on the foliage similar to that observed with inhibitors ofphytoene desaturase (e.g. norflurazon). However, the mechanism of action of HPPD inhibitors is different. Inhibtion of HPPD stops the synthesis of homogen tisate (HGA), which is a key precursor of the 8 different tocochromanols (tocopherols and tocotrienols) and prenyl quinones. In the absence of prenylquinone plastoquinone, phytoene desaturase activity is interrupted. The bleaching of the green tissues ensues as if these compounds inhibited phytoene desaturase. 

The overall carbon-nitrogen framework was confirmed by synthesis. Reductive amination of the triketone (336) (429) with sodium cyanoborohydride and ammonium acetate formed a mixture of four isomeric pyrrolizidines. Pure sam-... 

Takano et al. 69) exploited the asymmetric aldolization for the synthesis of more functionalized chiral products which possess units suitable for the construction of certain tetracyclic triterpenes, such as gibberellins and kaurenes. They described the enantioselective synthesis of the tricyclic enone (33) from the symmetric triketone (32) and its conversion into the gibbane framework. Again, (S)-proline was used as the catalyst. 

Acylation of the dianion of ethyl acetoacetate by an ester is a useful addition to this area of pyranone synthesis. In this reaction and in the formation of the trianions of 2,4,6-triketones the use of lithium diisopropylamide as the base is valuable (76JA7733). The triketo acid from the trianion cyclizes in mineral acids to the pyran-4-one, but in acetic anhydride the pyran-2-one is formed (Scheme 101) (71JA2506). 

A triketone is also an intermediate in a synthesis of 6-methyI-4-oxopyran-2-carboxylic acid from pentane-2,3-dione in which one carbonyl group is initially protected as the ketal (67JOC4105). Acylation by ethyl oxalate is accomplished under basic conditions, and ring closure and hydrolysis of the ketal are effected with acid. 

The synthesis of 3-methylsulfinylchroman-4-one (600) from ethyl salicylate follows a related pathway (72JHC171), whilst the triketone (601), derived from pentane-2,4-dione and the benzoate ester, exists as the substituted chromanone, a cyclic hemiacetal (81JOC2260). 

Formation of the imine and subsequent reduction can often be achieved in one pot . Thus, a microwave-assisted reductive amination-cyclisation domino reaction was used as the key step in the synthesis of perhydrocyclo-penta[ij]quinolizines from 1,5,9-triketones. This type of heterocycle is an important structural element in a series of alkaloids. The reaction of the triketone with ammonium formate in PEG-200 was performed within 1 min using microwave irradiation of370 W in a domestic microwave oven. Amixture oftwo ofthree possible stereoisomers was obtained in 87% overall yield (Scheme 4.29)52. 

On the pages which follow, general methods are illustrated for the synthesis of a wide variety of classes of organic compounds including acyl isocyanates (from amides and oxalyl chloride p. 16), epoxides (from reductive coupling of aromatic aldehydes by hexamethylphosphorous triamide p. 31), a-fluoro acids (from 1-alkenes p. 37), 0-lactams (from olefins and chlorosulfonyl isocyanate p. 51), 1 y3,5-triketones (from dianions of 1,3-diketones and esters p. 57), sulfinate esters (from disulfides, alcohols, and lead tetraacetate p. 62), carboxylic acids (from carbonylation of alcohols or olefins via carbonium-ion intermediates p. 72), sulfoxides (from sulfides and sodium periodate p. 78), carbazoles... 

Another example is the cyclization of the racemic allylic alcohol 232 at -80°C which furnished the racemic tetracyclic bis-olefin 233 in 70% yield (89, 90). Ozonolysis of 233 gave the bicyclic triketone aldehyde 234 which underwent under acidic conditions a double intramolecular aldol cyclodehydration to produce racemic 16,17-dehydroprogesterone 235. This represents the first synthesis of a steroid via the now so-called "biomimetic" polyene cyclization method. 

A further interesting case is provided by the synthesis of ninhydrin (Expt 5.99, cognate preparation) from indane-l,3-dione (Expt 7.9) in which the methylene group is activated by two adjacent carbonyl groups. Ninhydrin is the stable monohydrate of the triketone, indane-l,2,3-trione, and is a well-known colorimetric reagent for amino acids (Section 2.31). 

The intramolecular aldol reaction of triketones with asymmetric desymmetrization has been known for a long time. When Eder, Sauer, and Wiechert [97, 98], and in parallel Hajos and Parrish [99-101] reported this reaction in the early 1970s it was the first example of an asymmetric catalytic aldol reaction, and one of the first examples of an organocatalytic asymmetric synthesis [104]. 

The organocatalytic asymmetric intramolecular aldol reaction has also been used in the synthesis of a gibbane framework [117]. The proline-catalyzed aldol cycliza-tion of the triketone 104 into the tricyclic system 106 proceeds via the unstable ketol 105 (Scheme 6.47). For this reaction, which occurred at room temperature, a catalytic amount (10 mol%) of L-proline was used. The enone 106 was furnished in 92% yield and a single recrystallization resulted in an enantiomerically pure sample of 106. This aldol product 106 served as a useful intermediate in the synthesis of the desired gibbane framework. 

The synthesis can be done in stages under very mild conditions. The conjugate addition happens simply in water, as with 23. Amines catalyse the cyclisation and the dehydration of 77 is catalysed by acid.10 Triketone 74 can be made in one pot if KOH and MeOH are used with an excess of butanone 65 R = Me. Pyrrolidine then catalyses the cyclisation and dehydration.11... 

Reaction of phosphorus pentasulfide with j3,8-triketones leads to l fiayS -trithiapentalenes.1,2-8> 52 This was the first synthesis of trithiapentalenes known, but its development was delayed until practical methods for preparing 3,8-triketones were available. One of these procedures is the acylation of ketones in the presence of sodium hydride.53 Another method begins with the diacylation of the enamine derived from a cyclanone.38... 

Inhibitors of carotenoid synthesis also lead to chlorophyll destruction by destabilizing the photosynthetic apparatus. Total carotenoid content decreased with increased (-)-usnic concentration (Fig. 1.4). Carotenoid biosynthesis can be interrupted by inhibiting the enzyme phytoene desaturase that converts phytoene to carotenes or by inhibiting the enzyme HPPD responsible for plastoquinone (required for phytoene desaturase activity) synthesis.14 Usnic acid possesses some of the structural features of the triketone HPPD inhibitors, such as sulcotrione (Fig. 1.1C).8 (-)-Usnic acid had a strong inhibitory activity on HPPD, with an apparent IC50 of 70 nM, surpassing the activity obtained with the commercial herbicide sulcotrione (Fig. 1.5). 

Phenyliodonium /S-diketonates underwent ozonolytic fragmentation, providing a useful synthesis of unsolvated v/c-triketones in high yields. 

The synthesis of the triketone has been included (Part A of the Procedure), since identification of the crystalline compound originally claimed1 to be the triketone has been shown to be in error. After completion... 

The venomous constituent of the cryptic thief ant, Solenopsis xenovenenum, has been identified as the 3-heptyl-5-methylpyrrolizidine (50) from its mass spectrum and the fact that a related pyrrolidine (51) has been isolated from another species of ant.47 This is the first reported occurrence of a 3,5-dialkyl-pyrrolizidine, and its structure was confirmed by synthesis. Reductive amination of the known triketone (52) with sodium cyanoborohydride and ammonium acetate gave a mixture of four isomers of 3-heptyl-5-methylpyrrolizidine, which were separated by preparative g.l.c. The stereochemistry of the ring-junction of each isomer was established from its i.r. and n.m.r. spectra. 

Base catalysis is not required for conjugate addition. If the nucleophile is sufficiently enolized under the reaction conditions then the enol form is perfectly able to attack the unsaturated carbonyl compound. Enols are neutral and thus soft nucleophiles favouring conjugate attack, and p-dicarbonyl compounds are enolized to a significant extent (Chapter 21). Under acidic conditions there can be absolutely no base present but conjugate addition proceeds very efficiently. In this way methyl vinyl ketone (butenone) reacts with the cyclic P-diketone promoted by acetic acid to form a quaternary centre. The yield is excellent and the triketone product is an important intermediate in steroid synthesis as you will see later in this chapter. 

The synthesis of triketone 324, functionalized in all three rings, began by ketali-zation and ozonolysis of 321 (Scheme 50). Chain extension of dialdehyde 322 to... 

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