Sulfoxide diastereoselective addition

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

The addition of enolate anions to (E)- and (Z)-3,3,3-trifluoro-l-[(4-methylphenyl)sulfinyl]-1 -propene has been investigated (E)- and (Z)-a,/(-unsaturated sulfoxides undergo addition in the opposite stereochemical sense3,4. In general, yields and product diastereoselection are high. When the -position of the double bond of the enolate is substituted then all four diastereomer-ic products result. 

In contrast, few examples of conjugate additions of nonallylic a-sulfinyl (or a-sulfonyl) carbanions have been reported (for allylic oc-sulfinyl carbanion additions, see Section 1.2.2.5.1). Notable is the dia-stereoselective addition of alkyl f-butyl sulfoxides (245) to a,(3-unsaturated esters (equation 20)187 which is complementary to the diastereoselective addition of enolates to 3-substituted-a,f3-unsaturated sulfoxides (equation 20). 

Trichloromethyltitanium (10, 270 12, 355 13, 216). Diastereoselective addition to the chiral p-keto sulfoxide (1) is difficult because of ready enolization in the presence of a base. However, this titanium reagent reacts with marked dias-tereoface selectivity, which is the opposite of that observed with (CH,),A1. Similar... 

Piperidine and benzylamine have been utilized in diastereoselective addition reactions to other a,/ -unsaturated vinyl sulfoxides bearing the R absolute configuration92,93 at sulfur. A conjugate addition of piperidine to (f )-l-methyl-4-[(Z)-l-propenylsulfinyl]benzene (20) in a polar solvent such as methanol gives an 83 17 (21A/21B) diastereomeric mixture of adducts94,95. 

The required ketosulfoxide 69 (Scheme 15) was obtained in two steps in a one-pot procedure from 1,4-dimethoxybenzene (66). Ortho Hthiation of 66, lithium-copper exchange, and addition to methyl acrylate gave ester 67. Reaction of the anion obtained from (R)-methyl(p-tolyl)sulfoxide (68) [89] by treatment with LDA, with ester 67 afforded ketone 69. Diastereoselective addition of diethylaluminum cyanide to the carbonyl group of 69 [90] furnished sulfinylcyanohydrin 70 as the sole product. The (S) configuration of the new stereogenic center was inferred from the previous studies of acycUc P-ketosulfoxides [91,92]. 

Of related interest is the diastereoselective addition of Grignard reagents to 2-acyl-l,3-dithiane 5-oxides [75], which gave results in accordance with chelated Cram-type transition states [76] involving equatorial sulfoxides (Scheme 3.46). 

The intermediate 139 formed following the addition of z-butylmagnesium chloride to the nitrile 138 was then treated with sulfoxide 137 to afford the sulfinyl ketimine 140. " Diastereoselective addition of hydride to the chiral imine 140 in the presence of Ti(0 Pr)4 afforded the chiral amine 142. This reaction may proceed via a closed-transition state (e.g., 141) in which the sulfoxide coordinates to the metal center and directs the stereoselective addition of hydride, as has been proposed for related reactions.Treatment of the sulfoxide 142 with acid and base effected removal of the auxiliary. 

High diastereoselectivity at the sulfinyl group bearing carbon and low diastereoselectivity at the prostereogenic carbonyl group resulted on addition of a chiral sulfoxide carbanion to an... 

The anions derived from racemic alkyl and benzyl tert-butyl sulfoxides undergo 1,4-addition to a,/J-unsaturated esters to give adducts with high product diastereoselection (>5 1)10,11. Alkyl 4-methylphenyl sulfoxides were found to be less diastereoselective. In the case of 2-methyl-2-(methylsulfinyl)propanc the highly hindered 2,6-di-rer7-butyl-4-methylphenyl ester was required to prevent a competing acylation reaction. 

Addition of racemic allylic sulfoxide anions to 2(5//)-furanone gives y-1,4-addition adducts1. The simple and induced diastereoselectivities are completely analogous to that of 2-cyclopen-tenone described earlier. 

The stereochemical outcome and the diastereoselectivity of the addition of the anion of diethyl propanedioate to a,/ -unsaturated sulfoxides is dependent on the reaction solvent, the metal counterion and the geometry of the a,/ -unsaturated sulfoxide1 - 3. 

Enantiomerically pure 3-tolyl-2-sulfinyl-2-cyclopentenone 37 undergoes smooth, mild and diastereoselective conjugate hydride addition with lithium tri(sec-butyl)borohydride to afford ultimately 3-tolylcyclopentanone 38 in 93% enantiomeric purity (equation 35)78. The absolute stereochemistry of product 38 is consistent with a chelated intermediate directing hydride addition from that diastereoface containing the sulfoxide lone pair. 

The present method is practical and efficient as it employs readily available enantioenriched propargylic alcohols as precursors to the allenylindium reagents. With achiral aldehydes the diastereoselectivity is high for branched aldehydes, moderate for unbranched aldehydes, and low for benzaldehyde (Table I). With cHral a-methyl aldehydes the additions proceed under effective reagent control to afford anti adducts of high ee and with excellent diastereoselectivity (eq. 1 and 2). Comparable results were obtained with 3 1 dimethyl sulfoxide-tetrahydrofuran (DMSO-THF) as the solvent. 

Garretero has demonstrated the feasibility of the reaction of electron-deficient vinylsulfoxides. Details will be discussed in Section 11.10.5.1.3. The chiral sulfoxide group next to an olefinic moiety controls the reaction pathway efficiently and provides high diastereoselectivity. In addition, a mixture of (E)- and (Z)-vinylsulfoxides gives only one... 

A remarkably high diastereoselective excess was obtained in the addition of the anion of (S)-(-)-methyl 1-naphthyl sulfoxide to n-alkyl phenyl ketones. The sulfoxide was prepared in optically pure form by oxidation of the complex of methyl 1-naphthyl sulfide and 13-cyclodextrin with peracetic acid followed by crystallization. Desulfurization of the adducts provided enantiomerically pure tertiary alcohols (393]. 

Diastereoselective Diels-Alder reactions The (S)- and (R)-3-(2-pyridylsul-finyl)acrylates (1) are obtained by addition of 2-mercaptopyridine to ( + )-menthyl propiolate followed by oxidation and fractional crystallization of the diastereoiso-meric sulfoxides. In the presence of (QH AIG, both undergo highly diastereoselective Diels-Alder reactions with furan to give mainly endo-adducts without epimerization of the sulfoxide group. The products are converted as shown into ( + )- and ( - )-ewdo-2-hydroxymethyl-7-oxabicyclo[2.2.1]heptane (2). 

Vinyl sulfoxides (221), which are aldehyde a-cation equivalents, and vinylthiolium ions (230), which are a.jj-unsaturated carbonyl 3-cation equivalents, are also suitable acceptors for silyl ketene acetals and enol silyl ethers (Scheme 36). Kita reports that the bulky r-butyldimethylsilyl ketene acetals and tri-methylsilyl ketene acetals form 1 1 adducts (224) and 1 2 adducts (225) with (221), respectively 91 mechanistically, these additions proceed via an initial Pummerer rearrangement The vinylthiolium ion additions are notable for their synthetic flexibility for example, additions to the ketene dithioacetal (229) proceed with higher diastereoselectivity than the corresponding enolate additions to a,3-unsaturated esters.9 lc,91d... 

Proline was among the first compounds to be tested in asymmetric conjugated reactions, both as a chiral ligand [8] and also as an organic catalyst [3]. The earliest asymmetric intermolecular Michael-type addition, in which proline catalyzed the reaction (arguably via enamine formation) was reported by Barbas and colleagues [9, 10] and by List and co-workers [11]. The reaction, which proceeded in high chemical yield (85-97%) and diastereoselectivity, albeit afforded near-racemic products in dimethyl sulfoxide (DMSO) [11] (Scheme 2.37). The enantio-selectivity of the addition was later ameliorated by Enders, who demonstrated that a small amount of methanol rather than DMSO was beneficial to the enantiose-lectivity of the addition reaction [12]. 

Chiral homoallylic alcohols and amines were prepared by using a four-component condensation reaction based on a zinc homologation followed by a trapping with an aldehyde or an imine.301 A regio- and stereospecific carbocupration reaction on alkynyl sulfoxide provides the corresponding metallated /3,/3-dialkylated a,/ -ethylenic sufoxide 98. Addition of aldehydes or imines, followed by addition of the bis(iodomethyl)zinc carbenoid, provides adducts 99 in good overall yield and with very high diastereoselectivity (Scheme 36). 

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