A-hydroxylation of enolates

E. Vedejs (1978) developed a general method for the sterically controlled electrophilic a-hydroxylation of enolates. This uses a bulky molybdenum(VI) peroxide complex, MoO(Oj)2(HMPTA)(Py), which is rather stable and can be stored below 0 °C. If this peroxide is added to the enolate in THF solution (base e.g. LDA) at low temperatures, one O—O bond is broken, and a molybdyl ester is formed. Excess peroxide is quenched with sodium sulfite after the reaction has occurred, and the molybdyl ester is cleaved to give the a-hydroxy car-... 

Chiral Davis oxaziridines allow the oxidation of phosphonates to a-hydroxy-phosphonates in good ee with apparently wide generality and with a sense of induction that is well controlled by the chirality of the reagent used.109 mCPBA oxidation of a bi-cyclic e do-camphorylsulfonylimine surprisingly resulted in an exo-camphorylsulfonyl-oxaziridine, whereas all other camphorylsulfonylimines resulted only in endo-oxaziiidines.110 Asymmetric oxidation of sulfides to sulfoxides and the a-hydroxylation of enolates were predicted by models in which steric interactions are minimized. 

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. 

One strategy for tetracycline synthesis is to build a B/C precursor with suitable functionality for extension to ring A and with the tertiary a-hydroxy-carbonyl unit already in place. Two potential starting materials for different tetracyclines are 293 and 295 and both might be made by a-hydroxylation of enolates. 

The Li—F chelation is also useful for stereoselective reactions. In particular, chelation between lithium of enolates and a fluorine of a trifluoromethyl group results in conformational fixation of substrates, leading to markedly enhanced stereoselection. This concept has often been employed to achieve stereocontrol in fluorinated enolate chemistry. Morisawa reported Li—F chelation-controlled stereoselective a-hydroxylation of enolate of 40 [22]. The oxidant approaches from the less hindered side of the Li—F chelated enolate intermediate (41), affording anti-alcohol (42) exclusively (Scheme 3.11). The syn-alcohol (45) was prepared by NaBlrh reduction of ketoester (43) via a reaction course predicted by Felkin-Anh s model (44). 

Oxaziridine 206 has been utilized in combination with several chiral auxiliary-based approaches to effect diastereoselective a-hydroxylations of enolates [23, 24, 118]. A striking example using chiral oxazolidinones was reported by Evans and is depicted in Equation 20 [119]. In the course of devel-... 

A magnesium enolate of 99 is susceptible to aldol condensation with 4-pentenal, and the crude product can be directly protected to give its ethyl carbonate 100. a-Hydroxylation of the carbonyl group yields the hydroxyl carbonate 101. Reduction of the carbonyl group generates a triol, and this compound can be simultaneously converted to carbonate 102. Swern oxidation of 102 gives ketone 103, which can be rearranged25 to produce lactone product 104 (Scheme 7-32). 

Lactone product 104 is now susceptible to reductive C-3 hydroxyl removal, providing an enol product 105 that can be converted to the ketone 106 upon silica gel treatment. C-l a-hydroxylation of compound 106 provides compound 107. Compound 108 is then produced via Red-Al reduction of 107 and subsequent formation of the cyclic carbonate upon phosgene treatment (Scheme 7-33). 

The hydroxyl group in alcohol 122 is then oxidized. Deprotonation of this ketone with KHMDS (1 eq.), followed by the addition of Davis oxaziridine (see Chapter 4 for a-hydroxylation of ketones)28 (2 eq.) allows the stereo-controlled introduction of the C-10 oxygen from the less hindered enolate face, providing only the (i )-hydroxyketone 123. Subsequent reduction of 123 with excess LAH provides the tetra-ol 124. Treatment of this compound with imidazole and TBSC1 followed by PPTS and 2-methoxypropene provides in one operation the acetonide 125 with 91% yield (Scheme 7-37). 

Diastereoselective hydroxylation of enolates of chiral amides. Davis and coworkers1 have examined the asymmetric hydroxylation of the tetrasubstituted enolates of a chiral amide (2) with these chiral camphoryloxaziridines. Oxidation of the lithium enolate of 2 with (+ )-l proceeds with only moderate diastereoselectivity (48.4% de), which is somewhat less than that observed on hydroxylation with the achiral 2-(phenylsulfonyl)-3-phenyloxaziridine (4). Oxidation of the enolate of 2... 

The procedure reported here provides a convenient method for the a-hydroxylation of ketones which form enolates under the reaction conditions. The reaction has been applied successfully to a series of para-substituted acetophenones, 1-phenyl-1-propanone, 3-pentanone, cyclopentanone, cyclohexanone, cycloheptanone, cyclododecanone, 2-methyl cyclohexanone, 2-norbornanone and benzalacetone. In the case of a steroidal example it was shown that a carbon-carbon double bond and a secondary hydroxyl group are not oxidized. A primary amino function, as in the case of p-aminoacetophenone, is not affected.5 Similarly, a tertiary amino ketone such as tropinone undergoes the a-hydroxy at ion reaction.5... 

Ketones can be a hydroxylated in good yields, without conversion to the enolates, by treatment with the hypervalent iodine reagents162 o-iodosobenzoic acid163 or phenyliodoso acetate PhI(OAc)2 in methanolic NaOH.164 The latter reagent has also been used on carboxylic esters.165 02 and a chiral phase transfer catalyst gave enantioselective a hydroxylation of ketones, if the a position was tertiary.166... 

Hydroxy-etJI-cnones. (8, 100-101 10, 92). Complete details for the a -hydroxylation of a./ -enones via the kinetic enol silyl ether are available. DME is recommended as the solvent for preparation of the intermediate, which is best isolated by using a nonaqueous workup.2... 

Eschenmoser s pyrone 38 on treatment with cyclopropenone ketal 39 in refluxing benzene afforded lactone 40 (73%). Lactone 40 on hydrolysis with acetic acid at 100°C afforded, after deprotection and decarboxylation, tropone 37 (70%). Introduction of the tropolonic hydroxyl group was achieved with hydrazine hydrate in ethanol, to give a mixture of deacetyl-colchiceinamides 41 (53%) and 42 (37%), followed by reaction with ethano-lic potassium hydroxide, which afforded tropolones 43 and 44, respectively. Tropolone 43 was converted to 44 which, therefore, became the major reaction product. Methylation of 44 gave a mixture of enol ether 18 and 45 which were separated by chromatography. 

Enantioselective a-hydroxylation of carbonyl compounds,2 Useful enantiose-lectivity (60-95% ee) obtains in the oxidation of enolates of a number of carbonyl compounds (ketones, esters, amides) with the simplest member of this series, ( + )-or (— )-l. This reagent, however, is not useful for enantioselective oxidations resulting in tertiary a-hydroxyl ketones. For this purpose, the 8,8-dichloro derivative (2) of ( + )-l is markedly superior, as shown in equation (I). This derivative can also be... 

A catalytic route using a manganese (III) complex has been developed for a-hydroxylation of ketones avoiding the use of water or a protic solvent mixtures of a-hydroxyketones and their silyl derivatives were formed in excellent yield. By using a chiral pyrrolidine-based manganese (III) complex as catalyst, asymmetric oxidation was effected, with enantiomeric excess varying from 14 to 62% [30], Another kind of a-functionalized ketones resulted from silyl enol ethers which after the addition of IOB.BF3 were treated with triethyl phosphite a-ketophosphonates were obtained in this way [31] ... 

N-Sulfonyloxaziridines are an important class of selective, neutral, and aprotic oxidizing reagents.11 Enantiopure N-sulfonyloxaziridines have been used in the asymmetric hydroxylation of enolates to enantiomerically enriched a-hydroxy carbonyl compounds,9 11-13 the asymmetric oxidation of sulfides to sulfoxides,14 1S selenides to selenoxides,16 sulfenimines to sulfinimines,17 and the epoxidation of alkenes.18... 

Enolate hydroxy lotion. a-Hydroxylation of the ketone 1 is best effected by reaction of the enolate with dibenzoyl peroxide. In this case Vedejs oxidation fails, and m-chlo-... 

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