Ketols mechanism

The mechanism of the oxidation of tertiary cyclobutanols with Jones reagent is believed to involve the intermediate lactols (Eq. (18)) and the cleavage of the lactol to ketol and its subsequent oxidation to diketone when R1 = H157). 

According to Sato and Herring (39), ascorbic acid can function as an antioxidant by interfering with the free radical mechanism due to the presence of the ene-diol portion of the molecule. However, St. Angelo et al (5) reported that reductone-type compounds, such as maltol, kojic acid, 3-hydroxyflavone, etc., were effective antioxidants and suggested that the alpha ketol structure may also play an important role concerning free radical mechanisms. 

Fig. 2.2.S.3 Structure of rhamnose isomerase, and proposed hydride-shift mechanism for the ketol isomerization.

The dehydration of the aldol (ketol) proceeds more rapidly with acidic than with basic catalysts, and this is the reason why, with the former, the a,]3-unsaturated carbonyl compounds are the products most frequently encountered. The dehydration follows one of the elimination mechanisms discussed in Sect. 2.1, depending on the particular nature of the used catalyst and on the temperature. 

Saturated Ketones and Ketol Acetates. Reductive Alkylation / 27 Mechanism of reduction / 27 Stereochemistry of reduction / 34 Side reactions in reductions / 37... 

A. Mechanism of Reduction 1. Conjugated Enones and Ketol Acetates... 

An example of an a-ketol formation that does not involve decarboxylation is provided by the reaction catalyzed by transketolase, an enzyme that plays an essential role in the pentose phosphate pathway and in photosynthesis (equation 21) (B-77MI11001). The mechanism of the reaction of equation (21) is similar to that of acetolactate synthesis (equation 20). The addition of (39) to the carbonyl group of (44) is followed by aldol cleavage to give a TPP-stabilized carbanion (analogous to (41)). The condensation of this carbanionic intermediate with the second substrate, followed by the elimination of (39), accounts for the observed products (B-7IMIHOO1). 

The decarboxymethylation of substituted o -hydroxy-o -carbomethoxy hexacyclic substituted ketones (43), one of these used as an advanced intermediate in the synthesis of the alkaloid aspidophytine, can be effected by heating with Mgl2 in CH3CN in good yields (75-84%) (Scheme 12).34 The reaction was shown to proceed through a novel a-hydroxy /3-dicarbonyl to a-ketol ester rearrangement mechanism, which is supported by the isolation of the carbonate (45) intermediate. 

Lewis acids readily isomerize both 1,3-dioxolanes and 1,3-oxathiolanes in ether solution. The reaction proceeds by coordination with the oxygen atom in the latter case since 1,3-dithiolanes do not isomerize under the same conditions. With trityl carbonium ion, an oxidative cleavage reaction takes place as shown in Scheme 6. Hydride extraction from the 4-position of 2,2-disubstituted 1,3-dioxolanes leads to an a-ketol in a preparatively useful reaction. 1,3-Oxathiolanes are reported to undergo similar cleavage but no mention of products other than regeneration of the ketone has been made (71CC861). Cationic polymerization of 1,3-dioxolane has been initiated by a wide variety of proton acids, Lewis acids and complex catalytic systems. The exact mechanism of the polymerization is still the subject of controversy, as is the structure of the polymer itself. It is unclear if polymerization... 

Other 1,2-isomerases combine intramolecular transfer and solvent exchange to various extents,1" 141 but, with D-xylose ketol isomerase, solvent exchange was not found,140 although there is no evidence that the mechanism operates by other than an enediol intermediate. Lack of solvent exchange alone, therefore, cannot be used to exclude the possibility of an enediol intermediate in an enzyme reaction. 

G3P) and D-sedoheptulose 7-P as illustrated in Scheme 5.53. In addition D-erythrose 4-phosphate can function as the ketol acceptor thus producing D-fructose-6-P and G3P (Scheme 5.53). The enzyme relies on two cofactors for activity — thiamin pyrophosphate (TPP) and Mg2+—and utilizes the nucleophilic catalysis mechanism outlined in (Scheme 5.54).83 When TPP is used as a cofactor for nucleophilic catalysis, an activated aldehyde intermediate is formed. This intermediate functions as a nucleophile, and thus TK employs a strategy that is similar to the umpolung strategy exploited in synthetic organic chemistry. 

An alternative mechanism has also been proposed in which oxidation at the double bond leads to a ketol derivative, elimination of water from which then gives the unsaturated ketone (Scheme 18a)." Limited kinetic data are available and suggest diat Scheme 17 is obtained for chromic acid oxidations. 

In an examination of the mechanism of the solvolysis of the tricyclic alcohol (627) which led to the successful synthesis of seychellene (628), Frater has shown that the minor product is the tricyclic olefin (629) which is formed by the process depicted in Scheme 79. An alternative synthesis of seychellene (628) and patchouli alcohol (635) depends upon the construction of the key tricyclic ketol (631) by an intramolecular Michael reaction followed by an aldol cyclization of (630) (Scheme 80). The minor ketol (632) can be converted into epi-sey-... 

The mechanism of the proline-catalyzed enantioselective aldol reaction has been studied. An extension of the asymmetric aldolization deals with the cyclization of diketones. Also investigated was the dehydration of racemic p-ketols in the presence of (S)-proline and a kinetic resolution was observed. ... 

Ironically, until 1953, Nazarov incorrectly described the mechanism of the general transformation which now bears his name. In 1952, Braude and Coles were the first to suggest the intermediacy of car-bocations and demonstrated that the formation of 2-cyclopentenones actually proceeds via the a,a -divi-nyl ketones (equation 1). This fact together with further mechanistic clarification, has led to the specific definition of the Nazarov cyclization as the acid-catalyzed closure of divinyl ketones to 2-cyclopentenones. This process was already documented in 1903 by Vorliinder who isolated a ketol of unknown structure by treatment of dibenzylideneacetone with concentrated sulfuric acid and acetic acid followed by mild alkaline hydrolysis (equation 2). The correct structure of Vorliinder s ketol, finally proposed in 1955, ° arises from Nazarov cyclization followed by oxidation and isomerization. Other examples of acid-catalyzed cyclizations of divinyl ketones exist in the early literature. ... 

Strong experimental support for the biochemical pathway is provided by the isolation and characterization of the allene oxide (105) by Brash. ° Further, solvolysis of (105) produced (107) along with a-ketols. ° ° The biochemical mechanism for formation of an allene oxide from 8-HPETE remains to be clarified. 

Cordes, E.H. Mechanism in catalysis for the hydrolysis of acetols, ketols and ortho esters. Prog. Phys. Org. Chem. 1967, 4, 1 4. 

Most known thiamin diphosphate-dependent reactions (Table 14-2) can be derived from the five halfreactions, a through e, shown in Fig. 14-3. Each half-reaction is an a cleavage which leads to a thiamin- bound enamine (center. Fig. 14-3) The decarboxylation of an a-oxo acid to an aldehyde is represented by step h followed by fl in reverse. The most studied enzyme catalyzing a reaction of this type is yeast pyruvate decarboxylase, an enzyme essential to alcoholic fermentation (Fig. 10-3). There are two 250-kDa isoenzyme forms, one an tetramer and one with an (aP)2 quaternary structure. The isolation of a-hydroxyethylthiamin diphosphate from reaction mixtures of this enzyme with pyruvate provided important verification of the mechanisms of Eqs. 14-14,14-15. Other decarboxylases produce aldehydes in specialized metabolic pathways indolepyruvate decarboxylase in the biosynthesis of the plant hormone indole-3-acetate and ben-zoylformate decarboxylase in the mandelate pathway of bacterial metabolism (Chapter 25). Formation of a-ketols from a-oxo acids also starts with step h of Fig. 14-3 but is followed by condensation with another carbonyl compound in step c, in reverse. An example is decarboxylation of pyruvate and condensation of the resulting active acetaldehyde with a second pyruvate molecule to give l -a-acetolactate, a reaction catalyzed by acetohydroxy acid synthase (acetolactate synthase). Acetolactate is the precursor to valine and leucine. A similar ketol condensation, which is catalyzed by the same S5mthase, is... 

Not all dienone-phenol rearrangements are acid catalyzed. The 4-hydroxy-4-methyl-2,5-cyclohexadi-enones (38 R = H) and (38 R = Me) react in refluxing aqueous alkali to afford the methylhydroquinones (39 R = H) and (39 R = Me 95%), respectively. This is understandable as migration in an electron-rich, vinylogous a-ketol system (40). A different mechanism operates in the rearrangement of the decala-dienone (41), induced by sodium hydroxide-aqueous methanol, to the tetralindiol (42 76%) which appears to proceed by a retro-aldol-aldol sequence, by way of the aldehyde (43). ... 

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