P-Ketosulfoxides

A similar complementarity has been observed in LAH vs. DIBAL reduction of P-ketosulfoxides in which the keto group is also part of a conjugated enone system (equation 32) . After reductive cleavage (Li, EtNHj) of the alkyl-sulfur bond, 3-alken-2-ols of high enantiomeric purity are produced . 

It is also a strong base and an excellent reagent for the generation of ylides (Wittig and related reagents, for example). It reacts with esters to yield anions of p-ketosulfoxides. As the methylsulfinyl group of these compounds is easily removed by an aluminum amalgam, a useful synthesis of ketones is at hand. 

Total syntheses of coniochaetones A and ( )-B feature the reaction of P-ketosulfoxide 756 with succindialdehyde to form the cyclopentane-fused chromone 757 in modest yield (Scheme 196) <1998SL259>. 

The generality of the method was demonstrated by the preparation of various oxisuran bioisosters where the pyridyl moiety was replaced by phenyl, furyl, and thienyl moieties. The optical purities of these products were determined by proton NMR spectroscopy using the chiral shift reagents Eu(hfc)3140 and (-)-A-(3,5-dini-trobenzoyl)-a-phenylethylamine,141 following conditions established by the study of racemic mixtures of the P-ketosulfoxides. 

Sulfinyl carbanions easily add to aldehydes and ketones to yield p-ketosulfoxides, thus providing another route to substituted ketones. With a,p-unsaturated ketones (49), sulfinyl carbanions undergo 1,4-addition to give y-ketosulfoxides (50) (Scheme 24). 

Dimsylsodium (24) functions as a highly basic sulfur ylide. It can be used to convert phosphonium salts to phosphorus ylides for use in the Wittig reaction. Dimsylsodium also reacts with aldehydes and ketones by nucleophilic addition to form epoxides and with esters by nucleophilic substitution to yield p-ketosulfoxides (25) (Scheme 11). The p-ketosulfoxides (25) contain acidic a-hydrogens which can be readily removed to allow alkylation, and the products (26) suffer reductive desulfuration on treatment with aluminium amalgam to yield ketones (27) (Scheme 11) This procedure can, for instance, be applied to the conversion of ethyl benzoate to propiophenone (28) (Scheme 12). 

The presence of a chiral sulfoxide group in the P-position allows the highly selective reduction of imines by Li 5-BU3BH or LiBEt3H [482, 1120] (Figure 6.20). Reduction of P-sulfonylimines with DIBAH/ZnCl2 at -78°C is also very efficient, and produces nonracemic amines after Raney nickel desulfurization [1121, 1122] (Figure 6.20). A chelated complex that is similar to the one involved in the reduction of p-ketosulfoxides ( 6.1.2.2) is proposed as a reaction intermediate. 

The experimental procedures given below for the synthesis of both enantiomers of 4-substituted butenolides [390] emphasize some aspects of the reactivity of chiral p-ketosulfoxides their reduction with hydrides can... 

To a solution of p-ketosulfoxide (2 mmol) in THF (20mmol) at -78°C was added dropwise a 1 m solution of DIBAH in hexane (2.2 ml, 2.2 mmol). After 1 h at -78°C the reaction mixture was quenched by adding methanol (20 ml). The solvent was evaporated and the residue was diluted with water and extracted with dichloromethane. The organic layer was washed with a 5% sodium hydroxide solution, dried and evaporated. Chromatography on silica gel (ether/hexane 60 40) afforded (R,S)-(3a) in an 80% yield, m.p. 124-126°C, diastereoisomeric ratio (R,S)I(R,R)>95 5 (NMR). 

An important group of reactions occur in (usually P-) ketosulfoxides, in which it is clear that the ketone is the chromophore and the sulfoxide merely an important actor in subsequent chemistry. A few of these have been seen already, such as the extrusion of SO from 146 [140]. The most common reaction of the P-ketosulfoxides is S-C cleavage, typically P to the ketone and a to the sulfoxide, as is common for other ketones with good P-leaving groups. 

Also reported in the early 1970s was the photochemistry of some alkyl a-substituted p-ketosulfoxides 290 [148]. Stereomutation at suliiir was observed in all cases where it could be detected due to diastereomeric interconversions. In addition to the products that are parallel to the previous example, ketone 293 and thioester 294 were observed. A mechanism in which Type I cleavage competed with p-cleavage was proposed. It included a cyclic sulfuranyl radical 297 in order to accomplish the oxygen migration. An alternative h3rpothesis has formation of a sulfenic ester 301, secondary photolysis, and typical chemistry of alkoxy radicals to get to the same intermediates. Sulfenic esters were not detected, but analysis was by GC or after column chromatography, neither of which would have been survived by such compounds. 

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]. 

Solladie and Hunt [96] proposed an interesting synthesis of this segment whereby the five chiral centers were constructed by successive stereocontrolled transformations from chiral sulfoxide 133 (Scheme 17), prepared by a previously described method [98]. Dibal reduction [98] of R-P-ketosulfoxide 133 afforded the R,R-hydroxy sulfoxide 134 (94% de). This sulfoxide was then reduced to... 

Over the past decade, the stereocontrolled reduction of enantiomerically pure P-ketosulfoxides by hydride reagents, particularly within the Solladid research group, has sparked considerable interest, as an approach to many synthetically important intermediates and biologically active molecules of defined chirality. The applications described below outline the effectiveness of the chiral sulfoxide moiety as a stereocontrol element, and highlight the ready removal of the sulfoxide group after its contribution to the synthetic scheme. In all cases, the sense of stereochemical induction can be rationalized and predicted on the basis of steric, stereoelectronic and/or chelation control factors. 

In 1982, Solladi reported a highly efficient, asymmetric synthesis of both enantiomers of methyl carbinols based on the stereoselective reduction of an enantiomerically pure P-ketosulfoxide [1], Prior to this work, only low to moderate levels of enantiomeric purity had been observed by Cinquini [2] and Johnson [3] in similar studies. The P-ketosulfoxides used in Solladie s study were prepared by condensation of the a-sulfinyl carbanion of (J )-methyl p-tolyl sulfoxide with esters (Scheme 4.1). 

Guanti established [4] that the LAH reduction of a-tolylthio-p-ketosulfoxides, prepared by direct acylation of the lithio-anion of optically pure (S)-(+)-p-tolyl p-tolylthiomethyl sufoxide was highly diastereoselective, yielding diastereoisomeric product alcohols in ratios up to >99 1 (4a 4b) (Scheme 4.3) [5]. The p-hydroxysulfoxide products (4a) and (4b) can be considered as protected a-hydroxyaldehydes indeed, the synthesis of enantiomerically pure (R)-(-)-a-methoxyphenylacetaldehyde (5) (and its (S )-(+) antipode) was demonstrated through application of a previously established procedure [6]. 

More recently, Simpkins has described a route to functionalized epoxides by diastereoselective reduction of racemic cychc P-ketosulfoxides (Scheme 4.7) [10]. Exclusive formation of (12a), (R = Bu, Pr DIBAL), or (12b) (R = Me, Et, Bu, Pr, Ph ZnCl2/DIBAL), could be realised by appropriate selection of reaction conditions. Preference for (12a) was rationalized by intramolecular hydride delivery from... 

The asymmetric synthesis of both enantiomers of various butenolides was reported by Solladie in 1986. based upon his diastereoselective p-ketosulfoxide reduction chemistry (Scheme 4.10) [13], Butenolides are widely found as subunits in many naturally occurring compounds [14-17]. 

Both enantiomers of 4-hydroxy-cyclohex-2-enone (16a) and (16b) are useful synthetic intermediates in the synthesis of compactin [18] a stereoselective synthesis of this class of compound has been reported by Solladi6 using P-ketosulfoxide chemistry, and is highlighted in Scheme 4.11 [19],... 

The P-ketosulfoxide reduction methodology is also successful with a,P-unsaturated substrates. The asymmetric synthesis of both enantiomers of a range of allylic alcohols was achieved by Solladie from the corresponding a,P-unsaturated p-ketosulfoxide substrates [20, 21]. The reactions were found to be... 

While much effort has been concentrated on the stereoselective reduction of p-ketosulfoxides (Section 4.1), relatively little attention has been paid to the analogous reactions of P-iminosulfoxides or the corresponding enamine tautomers as an approach to chiral P-aminosulfoxides. 

Ogura prepared P-enaminosulfoxides of types (23) and (25) by condensation of primary and secondary amines, respectively, with p-ketosulfoxide substrates (Scheme 4.15) [26]. 

The reduction of (23) is believed to proceed via imine tautomer (24) since enamines (25) are not reduced under identical reaction conditions. The high levels of diastereoselectivity were rationalized by postulation of a chelated transition state (27), which is similar in structure to those used to rationalize the diastereoselective reduction of p-ketosulfoxides described in Section 4.1. 

In direct analogy to Solladi6 s work with P-ketosulfoxides, Ruano has investigated the DIBAL reduction of A-benzyl-P-iminosulfoxides (30) [27]. DIBAL alone was found to be inactive toward (30) however in the presence of ZnBr2 as Lewis acid, the reduction was observed to be highly diastereoselective (Scheme 4.18, Table 4.6). This behaviour can be explained by assuming that the Lewis acid stabilizes the (E) regioisomer of the P-iminosulfoxide tautomer by formation of a chelate which shifts the enamine-imine equilibrium toward the latter. This chelated tautomer is now readily reduced by DIBAL. To verify this proposal, the influence of the Lewis acid on the enamine-imine equilibrium was studied by NMR spectroscopy (R = Ph). It was observed that the initially formed enaminic tautomer was converted completely into the iminic form by addition of the ZnBrj. 

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