Enantioselective Oxidation of Enolates

These reagents exhibit good stereoselectivity toward chiral reactants, such as acylox-azolidinones.253 Chiral oxaziridine reagents have been developed that can achieve enantioselective oxidation of enolates to a-hydroxyketones.254... 

In 1992, Thornton et al. reported that Mn(salen) (43) catalyzed the asymmetric oxidation of silyl enol ethers to give a mixture of a-siloxy and a-hydroxy ketones, albeit with moderate enantioselectivity (Scheme 28).135 Jacobsen et al. examined the oxidation of enol esters with Mn(salen) (27) and achieved good enantioselectivity.136 Adam et al. also reported that the oxidation of enol ethers with (27) proceeded with moderate to high enantioselectivity.137 Good substrates for these reactions are limited, however, to conjugated enol ethers and esters. Based on the analysis of the stereochemistry,137 enol ethers have been proposed to approach the oxo-Mn center along the N—Mn bond axis (trajectory c, vide supra). 

Another useful method for the asymmetric oxidation of enol derivatives is osmium-mediated dihydroxylation using cinchona alkaloid as the chiral auxiliary. The oxidation of enol ethers and enol silyl ethers proceeds with enantioselectivity as high as that of the corresponding dihydroxylation of olefins (vide infra) (Scheme 30).139 It is noteworthy that the oxidation of E- and Z-enol ethers gives the same product, and the E/Z ratio of the substrates does not strongly affect the... 

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... 

Several oxaziridines related to (14) (eq 8) have been used, most notably in the enantioselective oxidation of sulfides to sulfoxides, of selenides to selenoxides, and of alkenes to oxiranes, It is also the reagent of choice for the hydroxylation of lithium and Grignard reagents and for the asymmetric oxidation of enolates to give a-hydroxy carbonyl compounds, - A similar chiral fluorinating reagent has also been developed, ... 

Oxidation of the dienolate of (17) with (+)-( ) affords a-hydroxy ester (18), a key intermediate in the enantioselective synthesis of the antibiotic echinosporin (eq 19) whereas oxidation of enolates derived from 1,3-dioxin vinylogous ester (19) gives rise to both a - and y-hydroxylation depending on the reaction conditions (eq 20). With (+)-( ) the lithium enolate of (19) gives primarily the a -hydroxylation product (20), while the sodium enolate gives )/-hydroxylation product (21). Only low levels of asymmetric induction (ca. 16% ee) are found in these oxidations. Birch reduction products are also asymmetrically hydroxylated in situ by (+)-( ) (eq 21). ... 

Adam, W., Fell, R. T., Saha-Moller, C. R., Zhao, C.-G. Synthesis of optically active a-hydroxy ketones by enantioselective oxidation of silyl enol ethers with a fructose-derived dioxirane. Tetrahedron Asymmetry 1998, 9, 397-401. 

Oxaziridines, prepared by the oxidation of imines, are selective oxygen-transfer reagents. In particular, the camphor-derived reagent is widely nsed for enantioselective oxygenation of enolates and other nucleophiles. 

Expanding upon these results, Schultz et al. analyzed the oxidation of enolates produced via the Birch reduction of carboxylic acid derivatives.15 It was found that when 21 was reduced and treated with (+)-5, 22 was obtained with only marginal yield and modest enantioselectivity. The enantioselectivity increased when 23 was deprotonated and then treated with (+)-5. 

Camphor-derived, V- s u 1 fo n y 1 ox azi ri d in es 51-58 are chiral oxidants which are able to oxidize a variety of substrates enantioselectively. They have been used for the epoxidation of alkenes (Section D.4.5.2.I.), the preparation of chiral sulfoxides and selenoxides (Section D.4.11.2.1.), and enantioselective hydroxylation of enolates (Section D.4.I.). 

Scheme 5.126 Enantioselective oxidation of silicon enolates 512 mediated by salen complex 511b.

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

Katsuki et al. have reported that high enantioselectivity can be obtained in the oxidation of nonconjugated cyclic enol ethers by using Mn(salen) (34) as the catalyst.138 The reactions were performed in an alcoholic solvent to obtain a-hydroxy acetals as the products, because a-hydroxy acetals are tolerant to a weak Lewis acid like Mn(salen) and do not racemize during the reaction and the isolation procedure (Scheme 29). 

The value of 2-acyl-1,3-dithiane 1-oxides in stereocontrolled syntheses has been extended to the enantioselective formation of (3-hydroxy-y-ketoesters through ester enolate aldol reactions <00JOC6027>. 

Oxidation of silyl enol ethers. Oxidation of silyl enol ethers to a-hydroxy aldehydes or ketones is usually effected with w-chloroperbenzoic acid (6, 112). This oxidation can also be effected by epoxidation with 2-(phenylsulfonyl)-3-( p-nitrophenyl) oxaziridine in CHC1, at 25-60° followed by rearrangement to a-silyloxy carbonyl compounds, which are hydrolyzed to the a-hydroxy carbonyl compound (BujNF or H,0 + ). Yields are moderate to high. Oxidation with a chiral 2-arene-sulfonyloxaziridine shows only modest enantioselectivity. 

Camell and co-workers have recently applied lipase-catalysed resolution to formally desymmetrize prochiral ketones that would not normally be considered as candidates for enzyme resolution, through enantioselective hydrolysis of the chemically prepared racemic enol acetate. " For example, an NK-2 antagonist was formally desymmetrized by this approach using Pseudomonas fluorescens hpase (PFL) (Scheme 1.40). By recychng the prochiral ketone product, up to 82 % yields of the desired (5)-enol acetate (99 % ee) could be realized. This method offers a mild alternative to methodologies such as base-catalysed asymmetric deprotonation, which requires low temperature, and biocatalytic Baeyer-Villiger oxidation, which is difficult to scale up. 

Another enantioselective synthesis of longifolene, shown in Scheme 13.27, uses an intramolecular Diels-Alder reaction as a key step. The alcohol intermediate is resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the pyrone ring is introduced by y addition of the ester enolate of methyl 3-methylbutenoate. 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

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