Asymmetric sulfoxidation racemic sulfoxides

It should be noted that the related imine-oxaziridine couple E-F finds application in asymmetric sulfoxidation, which is discussed in Section 10.3. Similarly, chiral oxoammonium ions G enable catalytic stereoselective oxidation of alcohols and thus, e.g., kinetic resolution of racemates. Processes of this type are discussed in Section 10.4. Whereas perhydrates, e.g. of fluorinated ketones, have several applications in oxidation catalysis [5], e.g. for the preparation of epoxides from olefins, it seems that no application of chiral perhydrates in asymmetric synthesis has yet been found. Metal-free oxidation catalysis - achiral or chiral - has, nevertheless, become a very potent method in organic synthesis, and the field is developing rapidly [6]. 

Another class of peroxidases which can perform asymmetric sulfoxidations, and which have the advantage of inherently higher stabilities because of their non-heme nature, are the vanadium peroxidases. It was shown that vanadium bromoperoxidase from Ascophyllum nodosum mediates the production of (R)-methyl phenyl sulfoxide with a high 91% enantiomeric excess from the corresponding sulfide with H202 [38]. The turnover frequency of the reaction was found to be around 1 min-1. In addition this enzyme was found to catalyse the sulfoxidation of racemic, non-aromatic cyclic thioethers with high kinetic resolution [309]. 

Enantiomerically pure sulfoxides are important intermediates in organic synthesis (21) and quite a number of pharmaceuticals and other biologically active compounds harbor a chiral sulfoxide unit (22). With respect to oxidation catalysis, enantiomerically enriched sulfoxides can either be accessed by asymmetric sulfoxidation of prochiral thioethers (Scheme 7, path a), or by kinetic resolution of racemic sulfoxides (Scheme 7, path b). For the latter purpose, enantio-specific oxidation of one sulfoxide enantiomer to the sul-fone, followed by separation, is the method of choice. 

The radical initiation has been reported to give optically active products also in the case of vinyl monomers containing a rather labile chirality center such as an asymmetric sulfoxide moiety [22]. Similarly to racemization occurs in the polymerization of chiral 1-alkynes by Fe(AcAc)3 /AIR3 catalyst which gives linear polymers with alternate double bonds along the main chain [23]. 

Several approaches have been described for the preparation of optically active sulfoxides [5-7]. The three main routes to obtain these compounds are as follows (i) the asymmetric sulfoxidation of prochiral sulfides, (ii) nucleophilic substitution using a chiral sulfur precursor, and (iii) the kinetic resolution of racemic sulfoxides. The first of tiiese methods involves the use of various oxidants and catalysts and has been the most extensively employed. There are many examples in the scientific literature and reviews are available on this approach. In recent years, much attention has been focused on the synthesis of organic sulfoxides by emplo5dng conditions compatible with the green chemistry procedures [8-10]. For this reason, mild oxidants such as molecular oxygen or hydrogen peroxide are considered in combination with novel catalysts in order to develop a mild and environmentally friendly process. 

The addition of the anion of the racemic 2-methyl-2-propenyl sulfoxides, rac-2-methyl-3-(phenyl-sulfinylpl-propene and /w-3-(rerr-butylsulfinyl)-2-methyl-l-propene to 2-cyclopentenone gives mixtures of (E)- and (Z )-y-l, 4-addition products which are a mixture of diastereomers at sulfur2. The (T )-products usually predominate, with the relative proportions of the (Z)-product increasing as the reaction temperature is increased. No asymmetric induction originating from the stereocenter at sulfur was observed when the sulfoxide substituent was phenyl however, there was a marginal improvement in the case of the (Zi)-product when the sulfoxide substituent was ferf-butyl. 

In principle, it should be possible to selectively reduce one of the enantiomers in a racemic sulfoxide mixture that is, an asymmetric kinetic resolution via reduction should... 

An optically active sulfoxide may often be transformed into another optically active sulfoxide without racemization. This is often accomplished by formation of a new bond to the a-carbon atom, e.g. to the methyl carbon of methyl p-tolyl sulfoxide. To accomplish this, an a-metallated carbanion is first formed at low temperature after which this species may be treated with a large variety of electrophiles to give a structurally modified sulfoxide. Alternatively, nucleophilic reagents may be added to a homochiral vinylic sulfoxide. Structurally more complex compounds formed in these ways may be further modified in subsequent steps. Such transformations are the basis of many asymmetric syntheses and are discussed in the chapter by Posner and in earlier reviews7-11. 

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

Racemic pyrone sulfoxide 52 undergoes a diastereoselective inverse-electron-demand 2 + 4-cycloaddition with 1,1-dimethoxyethylene to afford adduct 53 in > 95% yield (equation 49)100 this is the first example of an asymmetric Diels-Alder cycloaddition using a sulfinyldiene as an electron-deficient enophile101. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

This chapter, however, does not deal with above-mentioned reactions of sulfoxides. Rather it is limited to asymmetric synthesis using a-sulfinyl carbanions and -unsaturated sulfoxides, specifically in which the stereogenic sulfoxide sulfur atom is enantiomerically pure. Therefore reactions of racemic sulfoxides are for the most part excluded from this review. For more general discussions, the reader is referred to other chapters in this volume and to other reviews on the chemistry of sulfoxides. Especially useful are the reviews by Johnson and Sharp and by Mislow in the late 1960s and by Oae and by Nudelman as well as a book by Block . A review by Cinquini, Cozzi and Montanari" through mid-1983 summarizes the chemistry and stereochemistry of optically active sulfoxides. This chapter emphasizes results reported from 1984 through mid-1986. 

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