Ketones sulfoximines

Asymmetric induction by sulfoxide is a very attractive feature. Enantiomerically pure cyclic a-sulfonimidoyl carbanions have been prepared (98S919) through base-catalyzed cyclization of the corresponding tosyloxyalkylsulfoximine 87 to 88 followed by deprotonation with BuLi. The alkylation with Mel or BuBr affords the diastereomerically pure sulfoximine 89, showing that the attack of the electrophile at the anionic C-atom occurs, preferentially, from the side of the sulfoximine O-atom independently from the substituent at Ca-carbon. The reaction of cuprates 90 with cyclic a,p-unsaturated ketones 91 was studied but very low asymmetric induction was observed in 92. 

Racemic 5-methyl-5 -(sodiomethyl)-A-(4-methylphenylsulfonyl)sulfoximine reacts with ketones to give an initial methylene transfer which produces an intermediate epoxide that is ring expanded to the oxctanc56. Application to 4-rerf-butylcyclohexanonc affords a single oxetane in 69% yield. While only achiral alkylidcne transfer reagents were utilized, in principle this reaction is amenable to the asymmetric synthesis of oxetanes. 

Scheme 10.55 Borane reductions of ketones with p-hydroxy sulfoximine ligand.

In order to avoid the use of a rather expensive and potentially dangerous borane complex, Bolm et al. have developed an improved procedure for the borane reduction of ketones, which involved two inexpensive reagents namely NaBH4 and TMSCI. The reduction of a series of ketones was examined applying these novel reaction conditions and the same p-hydroxy sulfoximine ligand to that described above (Scheme 10.56). For most ketones, both the level of asymmetric induction and the yield compared favorably to the precedent results. 

The reaction of ortho- uh tituxed chlorophenyl ketones in the [3+3] coupling reaction generally requires long reactions times and results in poor yields of the 1,2-thiazine products. A microwave-assisted reaction of chloroaryl ketones 272 with sulfoximine 268 has been developed which provides the cyclized products 273 in improved yields after two cycles of treatment with the Pd-catalyst (Scheme 39) <2004TL5233>. 

Ketones. The lithio derivative of ( +)-(.S )-. Y,.S -dimethyl-S-phenylsulfoxiinine (16), or its enantiomer, may be used both to resolve racemic ketones164 and to determine absolute configurations of ketones. For example, rac-19 on addition of 16 formed the diastereomeric /j-hydroxy-sulfoximines 17 and 18 which were separated. The configuration of 17 was established by an X-ray analysis. The ketones can be regenerated from the /1-hydroxysulfoximines by thermolysis. Thus, heating of 17 and 18 to 80 °C (for 12 h) furnished 19 [a precursor of (+ )-modhephen] and ent-l9165. 

Extension of this elimination to the similar -hydroxy sulfoximines 5 having a chiral bicyclic ring system which can be obtained in a similar way from the corresponding chiral ketone and (R) or (.S )-.S -lithiomethyl-/V-methyl-5 -phenylsulfoxime, leads to the formation of the diastereomeric alkenylsulfoximines 6 in the same diastereomeric ratio of S 98 2. The steric course of the elimination of these /i-hydroxy sulfoximines is determined by the configuration of the sulfoximine group. 

A very promising new method for converting oxiranes, as well as ketones, into oxetanes has recently been reported. This method uses the carbanion of dimethyl(N-tosyl)sulfoximine and gave good yields in the several cases reported. When this reagent is employed with ketones, oxirane formation is presumably an intermediate stage, but the oxirane is not isolated. The method thus provides an excellent synthesis of spiro-oxetanes from ketones, as the example with camphor in equation (85) shows (79JA6135). 

Another example of the superiority of the alkoxy group as a directing group was reported by Johnson in his synthesis of enantiomericaUy pure cyclopropyl ketones after auxiliary cleavage (equation 56). In that case, the product resulting from a sulfoximine directed cyclopropanation was never observed. 

Kwart and Kahn have found that benzenesulfonyl azide forms a complex with freshly reduced copper powder.189 190 This copper azide complex decomposes at a lower temperature than the pure sulfonyl azide. In refluxing methanol, benzene-sulfonamide (27) is isolated as the major product. In the presence of dimethyl sulfoxide, N-benzenesulfonyldimethyl-sulfoximine (28) is obtained in almost quantitative yield. In cyclohexene solution benzenesulfonamide (29), N-benzenesul-fonyl-7-azabicyclo[4.1.0]heptane (30), and 1-cyclohexenylben-zenesulfonamide (31) are isolated as the main reaction products. According to the authors, Schemes VII and VIII represent an acceptable interpretation of the experimental data.189 190 In pure alcohol, the decomposition should occur by two competitive reactions (Scheme VII) producing benzenesulfonamide together with a ketone and oxidized copper. These last two products have indeed been observed in the reaction mixture. In the presence of DMSO, it seems that a copper-nitrene intermediate is formed which is trapped by DMSO. In cyclohexene solution, the authors have observed that the aziridine (30) disappears from the product composition when DMSO is added. The yield of enamine 31, however, is... 

The use of sulfoximines in the syntheses of optically active compounds has been reported [429]. A remarkable ketone methylcnation with optical resolution was realized. A highly selective diastereofacial addition of an enantiopure sulfoximine to a racemic ketone, chromatographic separation of the two diastereoisomers and reductive cleavage yielded both enantiomers of p-panasinsene [430], isolated from the root of ginseng, a herb used in Chinese folk medicine. 

Fu reported the enantioselective addition of diphenylzinc to ketones catalyzed by chiral amino alcohol 6, and observed a slight asymmetric amplification [13]. Bolm also reported asymmetric amplification in enantioselective alkylations using diethylzinc promoted by a chiral 2-pyridyl alkanol 7 and (1-hydroxy sulfoximine 8 (Scheme 9.6) [14,15]. 

Reactions with Aldehydes and Ketones Synthesis offi-Hydroxy Sulfoximines... 

Addition to ketones. In 1982, Johnson and Stark31 reported the condensation reactions of (+)-(S)-Af,5-dimethyl-S-phenylsulfoximine (2a) with various aldehydes and prochiral ketones. The reaction of lithiated 2a with phenyl aryl ketones (PhCOR, R=Me, Et, n-Pr, n-Bu, and c-C6Hn) gave a mixture of two diastereomeric P-hydroxy sulfoximine adducts 54 with modest diastereoselectivity. Unfortunately, the diastereoselectivities of all of these reactions were not documented. 

The reaction of ketones with excess of the sulfoximine salt Na-2b gives oxetanes formed by ring opening of the initially formed oxirane and subsequent ring closure. These reactions are highly diastereoselective and generally the thermodynamically more stable oxetane, in which the C-O bond is axial, is formed from cyclic ketones since the intermediate oxirane is formed under thermodynamically controlled conditions.61... 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

Reductive elimination of (3-hydroxy sulfoximines with aluminum amalgam in acetic acid gives alkenes in good yields.70In one study, the resolved carbinol adducts of the ketone 93 and (+)-(S)-2b were individually treated with aluminum amalgam in acetic acid to give natural (-)-(3-panasinsene and its antipode in high enantiomeric purity.71... 

Axially chiral vinyl sulfoximines have been prepared with high diastereoselec-tivity (> 99 1) by asymmetric elimination of LiOSiMe3 from 3-siloxy sulfoximines.72 For example, addition of lithiated (+)-(S)-2a to ketone 94 gave the (3-hydroxy sulfoximines 95 with a 99 1 diastereoselectivity. When the dianion of 95 was quenched at -78 °C with chlorotrimethylsilane, the vinyl sulfoximine 97 was... 

Osmylation of diastereomerically pure P-hydroxy sulfoximines, derived from 2a and cyclic enones, with a catalytic amount of osmium tetroxide (5 mol%) and trimethylamine V-oxide (1.5 equiv) gives diastereomerically pure triols which on thermolysis yield 2,3-dihydroxy cyclic ketones in high enantiomeric purity ( 100% ee). Osmylation occurs syn to the sulfoximine group.74... 

Heating racemic y-sulfonimidoyl ketone 194 in the solid state under similar conditions afforded the analogous dihydrofuran 196 in 45% yield plus the sulfonamides 198 (12%) and 199 (49%) after purification by column chromatography. The dihydrofuran 196, however, was an 87 13 mixture of trans and cis isomers, respectively, that could not be separated. A tentative mechanistic scheme, involving cyclization of the enol form of the ketone and nucleophilic displacement of the sulfoximine group, was proposed to account for this chemistry.100... 

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