Oxidation enolate

Reaction sequence E removed an extraneous oxygen by Sml2 reduction and installed an oxygen at C(15) by enolate oxidation. The C(l) and C(15) hydroxy groups were protected as a carbonate in Step E-5. After oxidation of the terminal vinyl group, the C-ring was constructed by a Dieckmann cyclization in Step F-4. After temporary protection of the C(7) hydroxy as the MOP derivative, the (1-ketoestcr was subjected to nucleophilic decarboxylation by phenylthiolate and reprotected as the BOM ether (Steps F-5, F- 6, and F-7). 

Scheme 12.19 gives some examples of enolate oxidation using jV-sulfonyloxaziridincs. 

The C-l oxygen was introduced at step F-l by enolate oxidation. The C ring was constructed by building up a substituent at C-l6 (steps G and H) and then performing an intramolecular aldol addition (step I). 

Oxidation of 2,2-dimethylthiochroman-4-ones to the 3,4-diones is readily achieved with isoamyl nitrite <1994T7865> and 8-hydroxy-2,2-dimethylthiochroman-4-one with Fremy s salt, potassium nitrodisulfonate, yields the benzothiopyranoquinone 387. Following cycloaddition with a cyclohexa-1,3-diene, enolization, oxidation, and aromatization led to a naphtho[2,3-A]-thiopyranoquinone (Scheme 103) <1997TL153, 2000H(53)585>. 

A number of enol oxidations of -keto esters utilizing, for example, peracid, singlet oxygen or the peroxy ester reaction have been recorded (see Section 2.3.2.l.l.iv). 

In some cases, where enolate oxygenation with molecular oxygen failed, it has been reported that quenching with 90% hydrogen peroxide allows efficient conversion to the hydroxy ketone, e.g. (49) to (50). Similarly enolate oxidation with organic peracids is possible vide infra). a-Hydroxylation via preformed enolates comprises one of most synthetically expedient approaches for achieving this transformation. 

A rational approach to either a-carbonyl radical or cation chemistry from enol oxidation thus necessitates explicit knowledge of the oxidation potentials of... 

A useful preparative application of enolate oxidation was presented by Torii in the context of a facile synthesis of 4-hydroxyindole 59 [145]. Similar to Schafer s work [114], the anion of 1,3-cyclohexadione was added anodically to ethyl vinyl ether providing products 56 and 57 in 65%. The mixture of both can be transformed by reaction with (NH4)2C03 in methanol into 58 that is finally converted to 59. 

Recent work has now provided a comprehensive view on enolate oxidation since the controlled generation of either a-carbonyl radicals or a-carbonyl cations was possible depending on the conditions [147]. In line with the prediction made in Scheme 5 enolates 60-63 could be oxidized by 2 eq. of FePHEN ( i/2 = 109 V) to the corresponding benzofurans 19-21,24. 

Certainly, it is not unexpected to see the oxidation potentials of the enolates to be much lower than the ones of the parent enols. This behavior has been observed for niunerous RH/R pairs [8,9]. However, it is important to stress that the enolate oxidation potentials are lower than the ones of the correspond-... 

As shown in equation 2, the lithium enolate oxidation with O2, followed by sodium sulphite reduction, has been applied with success to oxidation of the enolate derived from 1 the nature of the reducing agent has been decisive for the direct preparation of the hepatoprotective agent Clausenamide (2). As a matter of fact, 2 forms when the treatment with O2 is done in the presence of triethyl phosphite as reducing agent, whereas sodium sulphite reduction affords compound 3. It has been postulated that the transformation 1 —3 occurs through the intermediacy of the peroxide 4. 

Another example of zirconium enolate oxidation is the facile reaction of the enolate 63 with molecnlar oxygen to give a mixtnre of a-hydroxy ketone 64 and hydroperoxide 65 (equation 46)" . 

Asymmetric a-Hydroxylation of Enolates. a-Hydroxy lation of enolates represents one of the simplest and most direct methods for the synthesis of a-hydroxy carbonyl compounds, a key structural unit found in many natural products. Enolate oxidations using (+)- and (—)-(l) and their derivatives generally effect this transformation in good to excellent yields with a minimum of side reactions (e.g. over-oxidation). Furthermore, these reagents are the only aprotic oxidants developed to date for the direct asymmetric hydroxylation of prochiral enolates to optically active a-hydroxy carbonyl compounds. 

The required a-hydroxy ketones are accessible via a variety of synthetic methods, including the acyloin condensation (see Chapter 9), oxidation of ketone enolates, oxidation of enol ethers,and oxidation of a, 3-unsaturated ketones,as depicted below. 

The most widely used application of (V-sulfonyloxaziridines is for the synthesis of a-hydroxy carbonyl compounds (125), a key structural unit found in many biologically important molecules (Scheme 24). Compounds containing this array are also useful as chiral auxiliaries and as synthetic building blocks for asymmetric synthesis. Although a number of indirect methods have been devised to prepare a-hydroxy carbonyl compounds, the enolate oxidation protocol, using (V-sulfonyloxaziridines, is undoubtedly the most versatile because of the great diversity of metal enolate... 

S) -( — )-2-Methyl-2-hydroxy-y-butyrolactone (176a) is a useful synthon for the asymmetric construction of acyclic tertiary a-hydroxy acids found in natural products such as the pheromone frontalin and mevalonolactone, the biosynthetic precursor of terpenoids and steroids. This compound is readily prepared from lactone (175) using the asymmetric enolate oxidation protocol and dimethoxy oxaziridine ( + )-(158) <95JOC6l48>. The a-hydroxy lactone (176b), isolated as the benzoate, was obtained in 84% ee and 70% yield. A single crystallization from ethyl acetate improved the ee to >94% (Equation (41)). 

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