Ketols cleavage

Metal-ammonia solutions reduce conjugated enones to saturated ketones and reductively cleave a-acetoxy ketones i.e. ketol acetates) to the unsubstituted ketones. In both cases the actual reduction product is the enolate salt of a saturated ketone this salt resists further reduction. If an alcohol is present in the reaction mixture, the enolate salt protonates and the resulting ketone is reduced further to a saturated alcohol. Linearly or cross-conjugated dienones are reduced to enones in the absence of a proton donor other than ammonia. The Birch reduction of unsaturated ketones to saturated alcohols was first reported by Wilds and Nelson using lithium as the reducing agent. This metal has been used almost exclusively by subsequent workers for the reduction of both unsaturated and saturated ketones. Calcium has been preferred for the reductive cleavage of ketol acetates. 

The reductive cleavage of ketol acetates involves addition of two electrons to the system with fragmentation into an acetate ion and a ketone carbanion... 

Occasionally a free ketol rather than its acetate may be cleaved successfully in other cases cleavage does not occur. Starr and Smith " have summarized the available data including that covering the reduction of vinylogs of ketols. The experimental findings may be rationalized in several ways, but no firm conclusions seem possible. Smith has discussed some of the pertinent factors that must control the reduction of ketols. 

Nickel peroxide is a solid, insoluble oxidant prepared by reaction of nickel (II) salts with hypochlorite or ozone in aqueous alkaline solution. This reagent when used in nonpolar medium is similar to, but more reactive than, activated manganese dioxide in selectively oxidizing allylic or acetylenic alcohols. It also reacts rapidly with amines, phenols, hydrazones and sulfides so that selective oxidation of allylic alcohols in the presence of these functionalities may not be possible. In basic media the oxidizing power of nickel peroxide is increased and saturated primary alcohols can be oxidized directly to carboxylic acids. In the presence of ammonia at —20°, primary allylic alcohols give amides while at elevated temperatures nitriles are formed. At elevated temperatures efficient cleavage of a-glycols, a-ketols... 

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). 

The reduction of diketones is very complex. They can be partially reduced to ketols (hydroxy ketones) or ketones, or completely reduced to hydrocarbons. Depending on the mutual distance of the two carbonyl groups and reagents used, carbon-carbon bond cleavage may occur and may be followed by recyclizations or rearrangements. Some reactions may result in the formation of alkenes. Quinones react in their own specific way. 

Use has been made of the bond cleavage processes initiated by an adjacent carbonyl function for the modification of steroidial ketols such as 18 [97], Reduction in ethanol eliminates the hydroxyl function and in the same reaction, the carbonyl function is reduced to a secondary alcohol. In compound 19 where there are several groups to act as electrophores, carbon-oxygen bond cleavage is initiated from the most easily reduced dienone function [98], Cleavage of the carbon-oxygen bond in an a-acetoxycarbonyl function is achievable in good yields from multifunctional compounds such as the sesquiterpene taxol [99]. 

The strong oxidants Cr(VI) and Mn04 can also be used for oxidative cleavage of double bonds, provided there are no other sensitive groups in the molecule. The permanganate oxidation proceeds first to the diols and ketols, as described earlier (p. 757), and these are then oxidized to carboxylic acids or ketones. Good yields can be obtained provided care is taken to prevent subsequent oxidative degradation of the products. Entries 5 and 6 in Scheme 12.17 are illustrative. 

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). 

Ring fused products can be elaborated from isoxazolines (80S757). Several nitrocyclo-alkenes (516) were prepared and reacted with phenyl isocyanate to generate the intermediate nitrile oxides which underwent internal cycloaddition to afford the tricyclic isoxazolines (517). Cleavage of the N—O bond by hydrogenation in the presence of a catalytic amount of Raney nickel and subsequent hydrolysis afforded the /3-ketol (518 Scheme 113). 

The remarkable stability of the thiazole ring allowed synthetic manipulations of the thiazolyl ketol acetates, which extended considerably the scope of the above C-formylation method of furanoses and pyranoses. Instead of the reductive removal of the acetoxy group, the /V-glycosidation of either a- or p-anomer 73 with TMSN3 afforded stereoselectively the azido galactopyranoside 75 in 88% isolated yield (Scheme 22) [77]. The cleavage of the... 

Below the structures of the adducts in Eq. 14-20 are those of a 2-oxo acid and a (3-ketol with arrows indicating the electron flow in decarboxylation and in the aldol cleavage. The similarities to the thiamin-dependent cleavage reaction are especially striking if one remembers that in some aldolases and decarboxylases the substrate carbonyl group is first converted to an N-proto-nated Schiff base before the bond cleavage. 

Ketols can also be formed enzymatically by cleavage of an aldehyde (step a, Fig. 14-3) followed by condensation with a second aldehyde (step c, in reverse). An enzyme utilizing these steps is transketolase (Eq. 17-15),132b which is essential in the pentose phosphate pathways of metabolism and in photosynthesis. a-Diketones can be cleaved (step d) to a carboxylic acid plus active aldehyde, which can react either via a or c in reverse. These and other combinations of steps are often observed as side reactions of such enzymes as pyruvate decarboxylase. A related thiamin-dependent reaction is that of pyruvate and acetyl-CoA to give the a-diketone, diacetyl, CH3COCOCH3.133 The reaction can be viewed as a displacement of the CoA anion from acetyl-CoA by attack of thiamin-bound active acetaldehyde derived from pyruvate (reverse of step d, Fig. 14-3 with release of CoA). 

Cleavage of vic-diols to carboxylic acids.2 In the presence of catalytic amounts of Na2W04 2H20 and H3P04 and at a pH of 2, H202 (40%) oxidizes a variety of water-soluble 1,2-diols to carboxylic acids at 90° via an a-ketol. Addition of a phase-transfer catalyst permits oxidation of water-insoluble diols. 

Oxidative cleavage of alkenes to carboxylic acids.1 Alkenes are oxidized to carboxylic acids by H202 (35%) catalyzed by H2W04 in a weakly acidic medium (pH 4-5) maintained by addition of KOH. The oxidation probably involves initial oxidation to a 1,2-diol followed by dehydrogenation to an a-ketol, which is then cleaved to a mono- or dicarboxylic acid. 

Most of the compounds that had been reported (before March, 1942) to show cleavage oxidation by periodic acid are recorded in the table the substances are listed alphabetically in the following groups of related compounds (1) carbocyclic compounds (2) carbohydrates (3) a-diketones and a-ketols (4) hydroxyamino compounds (5) polyhydroxy and hydroxyketo acids (6) polyhydroxy alcohols (7) steroids (8) miscellaneous compounds. French journals after May, 1940, and the majority of other foreign publications after June, 1941, were unavailable for the survey. 

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... 

---