Sulfonium salt chirality

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). 

There are a number of important kinds of stereogenic centers besides asymmetric carbon atoms. One example is furnished by sulfoxides with nonidentical substituents on sulfur. Sulfoxides are pyramidal and maintain dieir configuration at room temperature. Unsymmetrical sulfoxides are therefore chiral and exist as enantiomers. Sulfonium salts with three nonidentical ligands are also chiral as a result of their pyramidal shape. Some examples of chiral derivatives of sulfur are given in Scheme 2.1. 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

Solladie-Cavallo s group used Eliel s oxathiane 1 (derived from pulegone) in asymmetric epoxidation (Scheme 1.3) [1]. This sulfide was initially benzylated to form a single diastereomer of the sulfonium salt 2. Epoxidation was then carried out at low temperature with the aid of sodium hydride to furnish diaryl epoxides 3 with high enantioselectivities, and with recovery of the chiral sulfide 1. 

Solladie-Cavallo has recently reported a two-step asymmetric synthesis of dis-ubstituted N-tosylaziridines from (R,R,R,Ss)-(-)-sulfonium salt 2 (derived from Eliel s oxathiane see Section 1.2.1.1) and N-tosyl imines with use of phosphazine base (EtP2) to generate the ylide (Scheme 1.42) [67], Although the diastereoselectiv-ity was highly substrate-dependent, the enantioselectivities obtained were very high (98.7-99.9%). The chiral auxiliary, although used in stoichiometric quantities, could be isolated and reused, but the practicality and scope of this procedure is limited by the use of the strong - as well as expensive and sensitive - phospha-zene base. 

An alternative process for the synthesis of vinylepoxides was clearly needed, so reactions with stoichiometric amounts of chiral sulfide were investigated (Scheme 9.16a) [74]. Indeed, when benzyl sulfonium salt 20 was treated with unsaturated aldehydes, the ees and des were high in all cases, whereas the yields [75] were highly substrate-dependent. The same products could be formed by treatment of an unsaturated sulfonium salt with benzaldehyde, but the yields and se-lectivities were generally slightly lower. 

Chiral sulfonium salts derived from oxathianes have been developed for stoichiometric epoxidation reactions. The sulfonium salts were deprotonated and allowed to react with a, 3-unsaturated aldehydes to give trons-vinylepoxides with excellent ees and transxis ratios (Scheme 9.16b) [76]. The yields were generally high [75], and the best results were obtained with Ar = 4-OMePh. 

Metzner and co-workers reported a one-pot epoxidation reaction in which a chiral sulfide, an allyl halide, and an aromatic aldehyde were allowed to react to give a trons-vinylepoxide (Scheme 9.16c) [77]. This is an efficient approach, as the sulfonium salt is formed in situ and deprotonated to afford the corresponding ylide, and then reacts with the aldehyde. The sulfide was still required in stoichiometric amounts, however, as the catalytic process was too slow for synthetic purposes. The yields were good and the transxis ratios were high when Ri H, but the enantioselectivities were lower than with the sulfur ylides discussed above. 

Sulfur ylides are a classic reagent for the conversion of carbonyl compounds to epoxides. Chiral camphor-derived sulfur ylides have been used in the enantioselective synthesis of epoxy-amides <06JA2105>. Reaction of sulfonium salt 12 with an aldehyde and base provides the epoxide 13 in generally excellent yields. While the yield of the reaction was quite good across a variety of R groups, the enantioselectivity was variable. For example benzaldehyde provides 13 (R = Ph) in 97% ee while isobutyraldehyde provides 13 (R = i-Pr) with only 10% ee. These epoxy amides could be converted to a number of epoxide-opened... 

Certain chalcogen structures display the phenomenon of chirality (Chapter 10.2). As with carbon,2 chirality at sulfur can influence physiological events there are many stereoselectivities in the interactions of chiral sulfur compounds with enzymes and receptor molecules. Sulfur chirality in secondary metabolites is most commonly observed with sulfonium salts, sulfoxides and sulfoximines.3... 

Finally, chiral epoxides can be prepared from a,p-unsaturated carbonyl compounds through an entirely different approach, in which the epoxide oxygen is derived from the carbonyl moiety. For example, trans-aryl-vinyl epoxides 52 can be synthesized from conjugated aldehydes 50 and chiral sulfonium salts 51, with excellent ee s. The protocol is especially effective for substrates which bear a p-mcthoxy group on the aryl substituent <00TL7309>. 

Although the first optical resolutions of chiral organosulfur compounds, sulfonium salts 1 and 2, were reported in 1900 by Pope and Peachey (1) and by Smiles (2), the stereochemistry of organosulfur compounds is a relatively new field, which has developed mostly... 

From the synthetic viewpoint the optical resolution of sulfonium salt 110 is of great interest because its enantiomers served as starting material for the synthesis of chiral a-dehydrobiotin 111(156). 

Two methods are described for the preparation of chiral amino-sulfonium salts. The first is based on the alkylation of nitrogen in chiral sulfimides. In this way the optically active aminosulfonium salt 123 was obtained from sulfimide 124, as shown in eq. [63] (164). 

More recently, the chiral o-substituted diarylsulfonium ylides 128 were obtained from menthoxysulfonium salts 129 and sodium dimethylmalonate (59). The desired sulfonium salts 129 were prepared from the corresponding sulfides and menthol in the presence of t-butyl hypochlorite and used further without isolation. 

Another example of asymmetric induction in the transfer of chirality from tricoordinate sulfur to the nitrogen atom was reported by Kobayashi (157), who found that methylation of benzylethylani-line with (+)-methoxymethyl-p-tolylsulfonium salt 113 yields (-)-benzylethylmethylphenylammoniumtetrafluoroborate 268. A similar asymmetric methylation reaction was observed with benzyl ethyl sulfide. Chiral ammonium 268 and sulfonium salts 112 were formed... 

It is interesting to note that asymmetric induction was also observed (308) during generation of ylide 288 from achiral sulfonium salt 287a by means of chiral lithium 2,2,2-trifluoromethyl-a-phenylethoxide. The [2,3]sigmatropic rearrangement of the chiral ylide 288 obtained in situ in this way leads to optically active sulfide 289 of 5% optical purity. 

Compounds containing a pyramidally arranged (hence, chiral) sulfur to which are linked three alkyl or aryl groups, resulting in a net positive charge on the sulfur. A biologically important example is S-adenosyl-L-methi-onine chloride. Sulfonium salts can also be utilized as analogs or mimics of carbocation intermediates in enzyme-catalyzed reactions. For example, methyl-(4-meth-ylpent-3-en-l-yl)vinylsulfonium perchlorate proved to be an excellent inhibitor (Ki = 2.5 tM) of the enzyme that catalyzes the formation of the bicyclic (+)- -pinene ... 

Chiral bis-lithium amide bases have been used for enantiotopic deprotonation of the sulfonium salt of 1,4-oxathiane 86. The anion undergoes an enantioselective thia-Sommelet rearrangement to afford the 3-substituted-1,4-oxathiane 87. Only bis-lithium amide bases were effective, giving products with high diastereoselectivity and with low to moderate enantioselectivity (Equation 13) <2003TL8203>. 

Alkylation of Etiolates with Chiral Selenonium Salts, Sulfonium Salts and Mixed Sulfates... 

The selenonium and sulfonium salts act as chiral alkylating agents for carbon nucleophiles under weakly basic conditions which avoid any ylide formation from the salt. When 2-methoxycarbonyl-l-oxoindane is treated with an (.S )-etliyl(methyl)phenylselenoniurn perchlorate, the (S)-2-methyl and (i )-2-ethyl derivatives are obtained with a low enantiomeric excess (Table 1). Reac-... 

Table 1. Enantioselective 2-Alkylation of 1,3-Dicarbonyl Compounds with Chiral Selenonium or Sulfonium Salts...

An analogous study has been carried out on ylide formation in cyclic sulfonium salts. Using the conformationally rigid systems in Table 12, relative kinetic acidities for Ho and Heq were determined. The results show that it is possible to remove one proton selectively, and thereby transfer chirality at sulfur to the neighbouring carbon atom (78JA200). As rigidity increases the differential kinetic acidity also increases but this is due not to an increase in overall acidity, rather to a decrease in lability of the axial proton in these... 

Generally, chiral tricoordinate centers are configurationally stable when they are derived from second-row elements. This is exemplified by sulfonium salts, sulfoxides and phosphines. In higher rows, stability is documented for arsines and stibines. In contrast, tricoordinate derivatives of carbon, oxygen, and nitrogen (first-row atoms) experience fast inversion and are configurationally unstable they must therefore be viewed as conformationally chiral (see Fig. 3, Section 3.b). Oxonium salts show very fast inversion, as do carbanions. Exceptions such as the cyclopropyl anion are known. Carbon radicals and carbenium ions are usually close to planarity and tend to be achiral independently of their substituents [21-23]. 

Coordinated thioether S is often asymmetric. In (302) the asymmetry is frozen by the configuration of the attached chelate rings but in (301) it is not and inversion is fast. Conventional resolution via diastereoisomeric salts has never been substantiated for a purely enantiomeric Co—SR Ril+ system devoid of other chirality. I3C and H studies on diastereoisomeric systems1079 however show that inversion rates are normally of the order 0.1-10 s1, which makes coordinated thioethers decidedly more configurationally labile than organic sulfonium salts. The effects of asymmetry in (302) are readily seen in diastereoisomeric systems where the lone pair on S is often stereospecifically orientated. It usually directs stereochemical change and ligand replacement processes. 

Chiral induction can also be quite effective when the locus of asymmetry is attached to the sulfur ylide itself The sulfonium salt 637, derived from Eliel s oxathiane, can be used to deliver a benzylic center to tosylimines (e.g., 638) and efficiently produces phenylaziridines with a very high degree of asymmetric induction. The method is amenable to gram-quantity synthesis, and the chiral auxiliary can be easily recovered. In general, cisitrans-mxxtmcs are obtained, depending upon the steric bulk of the imine substituent (Scheme 156) <2004JOC1409>. 

The achiral reaction with diphenyl vinyl sulfonium triflate 73 (Table 8) has been extended to an asymmetric process in the synthesis of five- and six-membered tings, using the chiral vinyl sulfonium salt 74, with very good levels of asymmetric induction being achieved (Table 8) <2006AGE7066>. 

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