A-Hydroperoxy acids

In the oxidative lipid metabolism, an intermediary a-hydroperoxy acid is formed by a-oxidation of the corresponding fatty acid [82, 83]. Presumably, peroxidase-catalyzed reduction of the hydroperoxide leads to enantiomerically pure (R)-2-hydroxy acids [84]. 

The only method for the synthesis of dioxetanones reported within the last decade relies on the cyclization of a-hydroperoxy acids. This method furnished the desired dioxetanones in reasonable yields and relies on removal of water by the use of a dehydrating reagent such as dicyclohexylcarbodiimide (DCC). For example, spiro-adamantyl dioxetanone was prepared in 55% yield utilizing this method (Equation 7) <1997JOC1623>. The reader is directed to CHEC-II(1996) <1996CHEC-II(1B)1041> for examples prior to 1996. 

Ten years ago Adam (Adam and Liu, 1972 Adam and Steinmetzer, 1972) reported the first synthesis and characterization of authentic dioxetanones, prepared by dehydrative cyclization of the corresponding a-hydroperoxy acids (26). They were shown to thermolyze as anticipated to carbon dioxide and the corresponding ketone with the concomitant emission of light. 

Bis-silyl ketene acetals devoid of -protons undergo a clean silatropic ene reaction with singlet oxygen (see Sections 2.3.2.1,3.ii and 2.3.2.4.3.H) to generate the a-silylperoxy silyl ester quantitatively. Treatment with methanol affords the a-hydroperoxy acid, also quantitatively (Scheme 23). Hytkogenation over platinum reveals the a-hydroxy acid, once again, quantitatively. Despite diis encouragement the substrate limitation is severe. 

The chemical history of the a-peroxylactones is almost as long. Derivatives (3a, b) were postulated as labile reaction intermediates in the autoxidation of ketenes (Eq. 6) to explain the formation of ketones and carbon dioxide. Indeed, very recent work confirmed these claims, except that singlet oxygenation of ketenes is preparatively more effective. However, the first stable a-peroxylactone that was isolated and characterized was the tert-butyl derivative (4), obtained from the corresponding a-hydroperoxy acid via dicyclohexylcarbodiimide (DCC) dehydration (Eq. 7). In the meantime, a number of stable a-peroxylactones have been reported (Table 2). 

A problem of considerable difficulty in this synthetic sequence (Eq, 21) has been the preparation of the exceedingly sensitive a-hydroperoxy acids (13) that serve as precursors to the a-peroxylactones. Unfortunately these substances undergo readily base- and acid-catalyzed Grob-type fragmentations (Eq. 22) and must, therefore, be prepared under mild, preferably neutral, conditions. The successful routes are summarized in Eq. 23. 

The second method (Route B Eq. 23) took advantage of the fact that a-lactones add protic nucleophiles at the a-carbon. Thus, hydrogen peroxide adds to a-lactones to give the desired a-hydroperoxy acids (13) in essentially quantitative yields. However, the big limitation in this route is the availability of the elusive a-lactones. Sterically hindered a-lactones that are sufficiently stable at low temperatures for preparative purposes can be made by ozonization of the respective ketenes, e.g. di-t( f-butylketene. The unstable ones, which necessarily must be prepared insitu, are now quite readily available through photodecarboxylation of malonyl peroxides. Again, the synthesis of a-hydroperoxy acids via a-lactones takes place under perfectly neutral conditions ... 

The third method (Route C Eq. 23) engages the autoxidation of a-enolate car-boxylates. Since the latter are prepared from the corresponding carboxylic acids by deprotonation with lithium diisopropylamide (LDA) or n-butyllithium (BuLi), obviously very strong basic conditions, the autoxidation step and the subsequent protonation must be executed under strictly controlled low temperature (< — 78°C) conditions. Otherwise, the base- and acid-sensitive a-hydroperoxy acids are destroyed during their preparation. Undoubtedly, this method is the most convenient and most general of the three listed in Eq. 23. 

These exceedingly unstable substances, which are invoked as the active intermediates in bioluminescence,20 were first prepared and isolated by Adam and Liu.2 The /-butyl system (2a) was the originally synthesized derivative by dehydrative cyclization of the a-hydroperoxy acid (6) by dicyclohexylcarbodiimide (DCC) [Eq. (5)]. It was not possible to isolate the pure material in view of its great thermal instability but its characteristic carbonyl band at 1875 cm-1 in the infrared (IR) served as unequivocal structure identification of these novel cyclic peroxides. 

A considerable difficulty in the preparation of a-peroxylactones (2) has been the availability of the precursors, i.e., the a-hydroperoxy acids (6). In view of their acid and base sensitivity, we devised the novel process shown in Eq. (6).2 On treatment of the ketene acetal (7) with... 

Oxidative decarboxylation. Dianions of carboxylic acids (prepared with LDA) react with O2 in ether at -78° to form a-hydroperoxy acids. These need not be isolated when DMF dimethyl acetal or an acid is added at room temperature, carbon dioxide is lost with formation of a carbonyl compound. 

Ary a-hydroperoxy acids. These substances can be prepared easily as formulated in equation (I). It is essential to use /i-butyllithium rather than LDA for the a-lithiation step since traces of amines are deleterious to the oxygenation step. Unfortunately only fair results obtain with nonaromatic acids. Of course O2 can be replaced by other electrophiles [(CH lsSiCl, (CeH6)2C=0] in related syntheses. ... 

A variety of oxygenated derivatives is formed during the reaction of lipoxygenases with fatty acid substrates. The biosynthesis of the monohydroxy and dihydroxy acids proceeds via the corresponding hydroperoxy acids, as is the case in the plant systems. The immediate product of the lipoxygenase thus is a hydroperoxy acid. This product is reduced to the corresponding hydroxy acid, presumably both enzymatically by peroxidases and through non-enzymatic decomposition. However, the hydroperoxy acid can also be converted to a ketone or to an epoxy-hydroxy acid that can hydrolyze into a trihydroxy acid (see below). 

The initial product resulting from the action of a lipoxygenase is a hydroperoxy acid. This is quickly followed by reduction to a hydroxyacid by peroxidase. Some common anti-inflammatory drugs have been shown to cause accumulation of 12-HPETE in platelets by inhibition of the enzymatic reduction into 12-HETE [186,188]. Among the drugs showing this effect are aspirin, indomethacin, sodium salicylate and phenylbutazone. 

A seemingly simple approach to a-hydroperoxy-acids is the direct addition of oxygen at low temperatures to carboxylic acid enolates (see also ref. 62). 

The formation of the a-hydroperoxy acid is virtually absolute for the (R)-enantiomer. 

Peracids.—Acyl chlorides have been converted into peracids, in ca. 60% yields, by treatment with hydrogen peroxide and pyridine the precise amount of the latter used is crucial to the success of the method. Two reports have appealed on the preparation and uses of polymer supported peracids detailing their application in the epoxidation of olefins, and the oxidation of sulphides, notably penicillins to the corresponding sulphoxides. a-Hydroperoxy acids are available in high yield by addition of oxygen to lithium enolates at -100 °C. 

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