Preparation of Chiral Sulfoxides

Preparation of Chiral Sulfoxides. The sulfur atom in a sulfoxide has four different groups (R, R1, O, and the lone pair electrons). There is virtually no inversion at sulfur (in contrast to nitrogen) so the sulfur can be a stereogenic center under these circumstances, which raises two points when using unsymmetrical sulfoxides. The first is the presence of diastereomers that can complicate separation and identification. The second is the ability to resolve the enantiomeric sulfoxides or produce one enantio-selectively, and use this material as a chiral auxiliary or as a chiral template (sec. 10.9). 

Cram reported an example that illustrates both the oxidation of sulfides to sulfoxides and the formation of diastereomers.575 Oxidation of erythro- or threo-l-alkylthio-l,2-diphenyl-propane with peroxybenzoic acid gave syn- and anti- sulfides. The erythro-sulfide (anti-sulfide 416) gave two erythro- (anti) sulfoxides, 417 and 418.575 Similarly, the threo- sulfide (syn-sulfide 419) gave two threo-(syn-sulfides, 420 and 421. The two 

A greater percentage of asymmetric induction has been achieved by procedures that generate a reactive coihplex where the sulfide and the oxidant are tightly bound. Kagan and Dunach,578 as well as DiFuria et al., used titanium tetraisopropoxide [Ti(OiPr)4] and optically active diethyl tartrate (DET) to catalyze the 

Davis et al. used a chiral oxaziridine for the asymmetric oxidation of sulfides to sulfoxides.Oxidation of isopropyl- -tolyl sulfide (427) with oxaziridine 428, for example, gave 60.3% ee (S) of 429 (at -78°C in chloroform).5 0 The absolute configuration of the sulfide is determined by approach of the sulfide to the oxaziridine oxygen, as illustrated by 430. Steric factors appear to be the primarily reason for the chiral recognition. 5 1 In this model, attack by sulfur minimizes the Rl and Rs interactions with the oxaziridine 

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The asymmetric oxidation of thioethers as well as kinetic resolution of sulfoxides with 30% H2O2 catalyzed by a stable, recyclable and commercially avialable solid WO3 catalyst provides a simple and effective procedure for the preparation of chiral sulfoxides in good enantimeric purity. The procedure is very easy to perform. 

Asymmetric oxidation of prochiral sulfides is one of the most effective routes for the preparation of chiral sulfoxides. These latter molecules attract great interest, as they are useful synthons for some drugs. They can also be used as chiral auxiliaries due to their configurational stability. The oxidation can be performed by using complexes... 

Biooxidation of chiral sulfides was initially investigated in the 1960s, especially through the pioneering work of Henbest et al. [101]. Since then, many developments have been reported and are summarized in reviews [102,103], It would be helpful to reveal some structural or mechanistic details of enzymes involved in theoxidation processes. Biotransformations are also of great current interest for the preparation of chiral sulfoxides, which are useful as synthetic intermediates and chiral auxiliaries. Because extensive review of these transformations is beyond the scope of this chapter, only highlights are discussed in comparison with the abiotic enantioselective oxidations described earlier. Biooxidations by microorganisms and by isolated enzymes are discussed in Sections 6C.12.1. and 6C.12.2. 

Remarkably, there is a noticeable lack of general methods for the asymmetric preparation of chiral sulfoxides from sulfides. The most satisfactory method would be a generally applicable enantioselective sulfoxidation reaction which would allow the preparation of sulfoxides from any prochiral sulfide with high ee s and in which the sulfoxide would be amenable to enantioselective preparation in both senses. 

Many organosulfur compounds can be resolved into optically active forms (enantiomers) owing to the presence of a chiral (asymmetric) sulfur atom 5 important examples include sulfoxides and sulfonium salts. Chiral sulfoxides containing amino or carboxylic acid groups have been resolved by formation of the diastereoisomeric salts with d-camphor-10-sulfonic acid or d-brucine. The salts can then be separated by fractional crystallisation and the free optically isomeric sulfoxides liberated by acid hydrolysis. However, a more convenient synthetic procedure for the preparation of chiral sulfoxides of high optical purity is Andersen s method (see p. 30). 

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.). 

Preparation of chiral sulfoxides can be achieved by the biocatalytic reduction of sulfoxides. One example is the reduction of alkyl aryl sulfoxides by intact cells of Rhodobacter sphaeroides f sp. denitrificans (Fig. 10.15). ° In the reduction of methyl para-substituted phenyl sulfoxides, S-enantiomers were exclusively deoxygenated while enantiomerically pure R-isomers were recovered in good yield. For poor substrates such as ethyl phenyl sulfoxide, the repetition... 

Since the mid-2000s, biocatalysis has been demonstrated to be a very powerful tool for the preparation of optically active sulfoxides using mild conditions. Among all the biocatalysts employed for the preparation of chiral sulfoxides, in particular flavo-enzymes have proven their efficiency. Flavoprotein oxidases have been employed as... 

With this encouraging result from the model system, a gram quantity of the racemic sulfoxide 40 was prepared by oxidation of benzoxathiin 16 with mCPBA and a small amount of chiral sulfoxide (A)-40 with 94% ee was isolated by subsequent chiral HPLC separation (Scheme 5.12). When chiral sulfoxide (S)-40 was treated with borane-dimethylsulfide, a clean reduction of the olefin and the sulfoxide was observed. More surprisingly, only the desired cis-diaryl dihydrobenzoxathiin 12 was observed in high yield and unchanged 94% ee. No trans-isomer or 16 was observed. With this proof of concept in hand, an efficient... 

Here an alkynyl sulfoxide 55 is first carbocuprated with an organocopper reagent 56 to provide a vinylcopper intermediate 57, which is then zinc homologated with the primary zinc sp3-carbenoid 58 to yield the allylzinc intermediate 59. This, in a spontaneous syw-/)-climination, gives the corresponding allene 60. This protocol could also be adopted to the preparation of chiral allenes. 

The Andersen synthesis of chiral sulfoxides has also been extended to diastereomerically or enantiomerically pure arenesulfinamides, which on treatment with methyllithium give optically active methyl aryl sulfoxides (83,85). The use of menthyl sulfinates in the synthesis of sulfoxides has been exploited in the preparation of optically active sulfoxides 47 and 48, which are chiral by virtue of isotopic substitution, H- D (86), and (87), respectively. More recent... 

Wudl and Lee (96,97) reported the first preparation and resolution of the cyclic diastereomeric amidosulfites 58, which have been successfully used in the synthesis of chiral sulfoxides. A mixture of diastereomeric menthyl dimethylamidosulfites (100) was obtained in the reaction of racemic dimethylaminosulfinyl chloride (101) with menthol in the presence of pyridine (149). The degree of asymmetric... 

The second synthesis of the enantiomer of this sulfone entails two transformations. First, (-)-a-naphthyl p-tolyl [ 0] sulfoxide 141 was converted into the corresponding [ 0] sulfoxide 141 by the method of Johnson (with inversion of configuration). Its oxidation with m-chloroperbenzoic acid afforded the chiral sulfone (+)-142 (Scheme 8). The latter procedure was also used for the preparation of chiral (-)-[ H2lbenzyl p-tolyl [ 0 0]sulfone (143) from (-)-[ H2] benzyl p-tolyl sulfoxide 37. 

OpticaUy active iV-tosylsulfoximides produced in the copper-catalyzed reaction of chiral sulfoxides with tosyl azide may be hydrolyzed with strong acid (H2SO4) to optically active free sulfoximides. However, this procedure often fails and/or results in decomposition. It is interesting to note in this connection that a simple one-step method for the preparation of optically active unsubstituted sulfoximides has been reported recently by Johnson and co-workers (180). It involves the reaction between optically active sulfoxides and 0-mesi-tylsulfonylhydroxylamine and results in sulfoximides 60 of high optical purity. As expected, this imidation process occurs with retention of configuration at sulfur. 

Fluorinated analogues of (/ )-(—)-sulcatol and of frontalin, which are aggregative pheromones of wood destructive insects have been prepared by means of chiral sulfoxides (Figures 4.40 and 4.41). ... 

Many other uses of a-sulfinyl carbanions are found in the literature, and in the recent past the trend has been to take advantage of the chirality of the sulfoxide group in asymmetric synthesis. Various ways of preparation of enantiopure sulfoxides have been devised (see Section 2.6.2) the carbanions derived from these compounds were added to carbonyl compounds, nitriles, imines or Michael acceptors to yield, ultimately, with high e.e. values, optically active alcohols, amines, ethers, epoxides, lactones, after elimination at an appropriate stage of the sulfoxide group. Such an elimination could be achieved by pyrolysis, Raney nickel or nickel boride desulfurization, reduction, or displacement of the C-S bond, as in the lactone synthesis reported by Casey [388]. 

As a further stereoselective organic synthesis [40-47] using reactive sp2 carbon-centered radicals, eq. 10.23 shows the preparation of chiral 4-te/7-butylcyclohexene (49) from the optically pure o-bromophenyl sulfoxide (48) through 1,5-H shift by sp2 carbon-centered radical, followed by (3-elimination. This reaction looks like a thermal concerted intramolecular elimination reaction (Ei). 

Chiral sulfoxides are useful intermediates in asymmetric synthesis. A number of methods for their preparation were developed in the last decade. An interesting displacement of dimethylphosphonylmethyl moiety, a carbon leaving group, from sulfur by Grignard reagents was used to obtain enantiomerically purep-tolyl sulfoxides.3 4 Optically pure methyl 4-bromophenyl sulfinate was subjected to a one-pot sequence yielding unsymmetrical dialkyl sulfoxides in 60-97% yield and >98% ee. A simple one-pot synthesis of chiral sulfoxides from norephedrine-derived... 

The purpose of this article is to present recent developments in the preparation of optically pure sulfoxides using both methods, mainly from 1990 to the present. Emphasis has been given to the bibliographic impact of each method. An application section is included after each route, especially in the case of variation in the Andersen methodology, where important advances have been achieved. It is not the aim of this article to review the chemistry of chiral sulfoxides—several excellent review articles have appeared on this subject, from the seminal review by Solladie19 in 1981 to other recent reviews.20 The literature has been surveyed up to January 1999. The preparation and utilization of chiral sulfoxides in asymmetric synthesis have been the subject of valuable comprehensive as well as specialized accounts which should be consulted for details and considered as complementary to this article. 

Preparation of Chiral Reagents. 3-Bromocamphor-8-sulfonic acid has been used as a starting material for the synthesis of chiral reagents. Although the oxidation of sulfides to sulfoxides can be accompUshed with the oxaziridine (5) or (6),... 

Preparation of Chiral Sulfinates. Optically active sulfinates can be prepared by reaction of a symmetrical sulfite with t-Butylmagnesium Chloride in the presence of an optically active amino alcohol. The best enantioselectivity has been observed using quinine as the optically active amine (eq 2)3 An alternative approach to this new enantioselective asymmetric synthesis of alkyl t-butylsulfinates would be reaction of a racemic sulfinate with r-butylmagnesium chloride complexed by optically active alkaloids (eq 3). In this case, kinetic resolution of the racemic sulfinate leads to an optically active sulfinate and an optically active sulfoxide. 

The asymmetric oxidation reaction of prochiral poly(ester 0-sulfide)s to optically active poly(ester 0-sulfoxide)s can be accomplished with almost theoretical chemoselactivity and moderate to high enantioselectivity degrees. While the asymmetric oxidation of prochiral sulfides should not be a preparative method for chiral sulfoxides, we expect that the structure of the parent polymers might be specifically designed for the preparation of chiral thermotropic poly(ester 0-sulfoxi-de)s. 

The availability of f j-di-r-butyl disulfide monoxide from selective oxidation catalyzed by vanadyl-88 enables the preparation of chiral r-butyl sulfinamides, sulfoxides, and sulfinimines. Very similar reaction conditions bring about the transformation of various 1,3-dithianes to chiral monoxides. (/ ,Rl-2,2,5,5-Tetramethyl-3,4-hexanediol is a chiral ligand for the Ti(IV)-catalyzed oxidation of sulfides with cumene hydroperoxide. ... 

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