Keto-alcohols

The term acjdoin is commonly used as a class name for the symmetrical keto-alcohols RCOCH(OH)R, and the name of the individual compound Is derived by adding the suffix oin to the stem name of the acid to which the acyloin corresponds, e.g., acetoin, propionoin, butyroin, etc. 

Diacetone Alcohol. Diacetone alcohol (DAA) (4-hydroxy-4-methyl-2-pentanone) is a colorless, mild smelling Hquid which is completely miscible with water and most organic solvents. It is the simplest aldol condensation product of acetone, and because of its keto-alcohol functionahes it has special utility in the coatings industry where it is used to dissolve cellulose acetate to give solutions with high tolerance for water (115). 

Methyl Isoamyl Ketone. Methyl isoamyl ketone [110-12-3] (5-methyl-2-hexanone) is a colorless Hquid with a mild odor. It is produced by the condensation of acetone and isobutyraldehyde (164) in three steps which proceed via the keto-alcohol dehydration to 5-methyl-3-hexen-2-one, and hydrogenation to 5-methyl-2-hexanone. 

Diehlorotriphenylantimony has been suggested as a flame retardant (177,178) and as a catalyst for the polymerization of ethylene carbonate (179). Dihromotriphenylantimony has been used as a catalyst for the reaction between carbon dioxide and epoxides to form cycHc carbonates (180) and for the oxidation of a-keto alcohols to diketones (181). 

Oxidation by Chromic Acid. Under mild conditions, e.g., in acetic acid at atmospheric temperature this converts the dihydric alcohol or keto-alcohol bases to diketo-bases, e.g., the lelobanidines, Ci3H2902N, to lelobanines, C13H25O2N. Under more vigorous action the keto-alcohol and the diketo-bases are oxidised to benzoic acid (side-chain, Ph. CO. ), acetic and i iropionic acids (side-chain, C2H5. CO. ) and either scopolinic acid l-methylpiperidine-2 6-dicarboxylic acid (IV)) or methylgranatic acid (l-methylpiperidine-2-carboxylic-6-acetic acid) or both, these being from the methylpiperidine nucleus with residues of the two side-chains. 

Water adds to the triple bond of perfluorobutylalkynols in refluxing 98% formic acid to give the perfluorobutyl keto alcohol Methanolic potassium hydroxide or prolonged reflux m formic acid converts the keto alcohol to 2,2-dimethyl-5-perfluoropropyl-2,2-dimethylturan-3(2//)-one [2] (equation 3). 

The first asymmetric Mn(salen)-catalyzed epoxidation of silyl enol ethers was carried out by Reddy and Thornton in 1992. Results from the epoxidation of various silyl enol ethers gave the corresponding keto-alcohols in up to 62% ee Subsequently, Adam and Katsuki " independently optimized the protocol for these substrates yielding products in excellent enantioselectivity. 

Pyrethrins are esters and therefore may be discussed in terms of the chrysanthemumic or pyrethric moiety and the keto alcohol moiety. 

Pyrethrolone and cinerolone make up the keto alcohol moiety of the pyrethrins. Both of these keto alcohols have one asymmetric carbon at the 4-position and a double bond in the side chain which is capable of cis-trans isomerism in the 2-position. It is possible, therefore, to have four stereoisomers for each keto alcohol. Katsuda et al. (22) show that only the ( + ) form occurs in the natural esters. Elliott (8) has shown recently, by a new procedure developed to obtain pure ( + ) pyrethrolone, that the hitherto unidentified prye-throlone C is in reality pyrethrolone contaminated with thermally isomerized material. (+) Pyrethrolone forms a crystalline monohydrate from which the pure alcohol is obtained. The natural configurations of the keto alcohols in the esters are insecticidally more active, as is the case with the acid moiety. 

The detection of microgram quantities of pyrethrins, cinerins, keto alcohols, and chrysanthemum acids by paper chromatography and by application of these techniques to a study of possible metabolites enabled certain tentative conclusions that imply hydrolysis in insects of a large portion of the radioactive pyrethrins and synergists to corresponding keto alcohols and chrysanthemum acids. 

Both of these compds yield expls on nitration. It is claimed that these expis have a high detonation velocity, can be pouted at temps below 100°, and are stable when stored at 50° The same investigators proposed the use of nitrates of other cyclic keto-alcohols, such as tetramethylolcyclohexanone, tetramethylolcyclo-pentanone, etc, as expls. All of these alcohols can be prepd by condensing cyclic ketones with formaldehyde in the presence of alkalies or al-... 

Pd metals immobilized on SBA-15 and NaY were applied as catalysts in the synthesis of amino alcohol. These catalysts afford a high level of enantioselectivity in the asymmetric hydrogenation of a-keto alcohol to corresponding amino alcohol. The large peilladium metal exhibited higher catalytic activity and enantioselectivity than well dispersed one over porous supports in the hydrogenation. 

The enantioselective mechanism proposed in the literature stated that the structure I might be the most predominant structure and structure II might be a minor structure. Structure I resulted in (S)-amino alcohol when (S)-amine additive was used. On the other hand, structure II resulted in (R)-amino alcohol when (S)-amine additive was used. When the alkyl group of keto alcohol is methyl, conformation of reactant might he composed mainly of structure I, therefore resulting in highly optically active alaninol as indicated in Scheme 2. However, according to the experimental results, structure I can be a major conformation in this reaction. 

The effect of 6 g of aqueous sulphuric acid in 0.6% mole of aqueous propargyl in alcohol at 30% in the presence of mercury (II) sulphate was used when preparing the corresponding keto-alcohol in the following way ... 

L.K. Dalton, and J. A. Lamberton, Studies of the Optically Active Compounds of Anacardiaceae Exudates I. The Long chain Alicyclic Keto Alcohol of Tigaso Oil, Aust. J. Chem., 11, 46 63 (1958). 

Photo-addition of allene to the enone (90) yield adduct (91) in 75 % yield, which was subjected to ketalization in 77% yield. Epoxidation of (92) with perbenzoic acid followed by chromatography on alumina afforded two expoxides (93) and (94). Both (93) and (94) could be converted separately through (95) and (96) respectively which was the common intermediate leading to isoishwarane (98) and ishwarane following a deketalization-retroaldol-aldol process to furnish the keto-alcohol (97) (99) 30>. 

However, when there is a substituent on the bridgehead carbon, the product of the oxidation would be the keto-alcohols (461) and the ketone (462) (Table 20) 157). 

Table 9.1 Enzyme-catalysed stereoselective reduction of diketones/keto esters to keto alcohols/hydroxy esters...

Table 9.1 shows some examples of the different substrates that can be reduced to various single diastereomers of the same compound, as the keto alcohols and hydroxy esters, by choosing the use of different enzymes. The chemoenzymatic syntheses of the aggregation pheromones (+)-Sitophilure and Sitophilate by the use of the above isolated, NADPH-dependent KREDs were successfully accomplished by our group" with high chemical and optical purities (98 % de, >99 % ee). 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

An alternative method for benzoxepine ring assembly uses the formation of cyclic ethers. Thus, benzoxepino[4,3-f>]indole 130 can be synthesized by the treatment of the keto-alcohol 129 with hot alcoholic base to produce the product in 90% yield as a result of intramolecular nucleophilic substitution (Equation (19) (1993AX(C)2126)). 

Another method by mercuration starts with keto alcohol 207 (390). The amino alcohol (208) obtained from 207 by reductive amination was protected by a standard procedure to afford the phthalimide (209). Successive treatment of 209... 

The last synthesis to evolve which is due to Ito and his coworkers is interesting in that it relies on a stereospecific skeletal rearrangement of a bicyclo[2.2.2]octane system which in turn was prepared by Diels-Alder methodology (Scheme XLVIII) Heating of a toluene solution of cyclopentene 1,2-dicarboxylic anhydride and 4-methylcyclohexa-l,4-dienyl methyl ether in the presence of a catalytic quantity of p-toluenesulfonic acid afforded 589. Demethylation was followed by reduction and cyclization to sulfide 590. Desulfurization set the stage for peracid oxidation and arrival at 591. Chromatography of this intermediate on alumina induced isomerization to keto alcohol 592. Jones oxidation afforded diketone 593 which had earlier been transformed into gymnomitrol. 

By suitable modification of reaction conditions, it was found possible to reduce 859 to keto alcohol 873 K The subsequent conversion of this intermediate to 874 proceeded without event. However, 874 could not be oxidized to aldehyde 875. Overoxidation to produce 876 or 877 (Jones conditions) invariably was observed due to the extreme sensitivity of874. This potentially expedient route to dodecahedrane therefore had to be abandoned and recourse made to blocking group methodology. 

The standard pharmacokinetic parameters of the compound such as a half-life or bioavailability cannot be reliably calculated, because the concentrations in plasma are below lOpg/mL. As analogously expected from the results on the shift in keto-alcohol equilibrium of 16,16-difluoro-PGE2, it is rapidly metabolized by C-15 reduction mediated by the ubiquitously expressed carbonyl reductase. The metabolism followed by jS-oxidation and co-oxidation forms a mixture of a and fi epimers at the 15-hydroxy moiety as a sole measurable metabolite [46], In 2006, the US Food and Drug Administration approved the drug application for an oral treatment of chronic idiopathic constipation in adults, estimating that 4-5 million Americans are affected. Lubiprostone has also completed a phase II trial in constipation-predominant irritable bowel syndrome, and has been further evaluated for other bowel dysfunctions. 

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