Sulfur stereochemistry

Reactivity toward nucleophiles and comparison with other electrophilic centers 152 Paths for nucleophilic substitution of sulfonyl derivatives 156 Direct substitution at sulfonyl sulfur stereochemistry 157 Direct substitution at sulfonyl sulfur stepwise or concerted 158 The elimination-addition path for substitution of alkanesulfonyl derivatives 166 Homolytic decomposition of a-disulfones 172 10 Concluding remarks 173 Acknowledgement 174 References 174... 

However, the major factor stimulating the rapid development of static and dynamic sulfur stereochemistry was the interest in the mechanism and steric course of nucleophilic substitution reactions at chiral sulfur. Very recently, chiral organic sulfur compounds have attracted much attention as useful and efficient reagents in asymmetric synthesis. 

Although many previous reviews (5-12) and literature compilations (13-16) have dealt with sulfur stereochemistry, we decided to write a new report on chiral sulfur compounds to provide a survey of the topic with emphasis on the most recent findings. This chapter consists of four major parts treating syntheses of chiral sulfur compounds, methods for determination of their absolute configuration and optical purity, the dynamic stereochemistry of organosulfur compounds, and the use of chiral sulfur compounds in asymmetric synthesis. 

Chiral sulfoxides play a key role in sulfur stereochemistry. Therefor much effort has been devoted to elaboration of convenient methods for their synthesis. Until now, chiral sulfoxides have been obtained in the following ways ... 

The most frequently encountered reactions in organic sulfur chemistry are nucleophilic displacement reactions. The mechanism and steric course of reactions have been the main points of interest of research groups all over the world, in particular, Andersen, Cram, Johnson, and Mislow in the United States Kobayashi and Oae in Japan Kjaer in Denmark and Fava and Montanari in Italy. The results of these investigators have been discussed exhaustively in many reviews on sulfur stereochemistry. In a recent report on nucleophilic substitution at tricoordinate sulfur, the literature was covered by Tillett (10) to the end of 1975. Therefore only some representative examples of nucleophilic substitution reactions at chiral sulfur are discussed here. However, recent results obtained in the authors laboratory are included. 

We hope that this review of chiral sulfur compounds will be useful to chemists interested in various aspects of chemistry and stereochemistry. The facts and problems discussed provide numerous possibilities for the study of additional stereochemical phenomena at sulfur. As a consequence of the extent of recent research on the application of oiganosulfur compounds in synthesis, further developments in the field of sulfur stereochemistry and especially in the area of asymmetric synthesis may be expected. Looking to the future, it may be said that the static and dynamic stereochemistry of tetra- and pentacoordinate trigonal-bipyramidal sulfur compounds will be and should be the subject of further studies. Similarly, more investigations will be needed to clarify the complex nature of nucleophilic substitution at tri- and tetracoordinate sulfur. Finally, we note that this chapter was intended to be illustrative, not exhaustive therefore, we apologize to the authors whose important work could not be included. 

As noted above, the stereochemical outcome at sulfur in these cycloadditions is not yet understood. Relatively few systems, particularly among the older examples, have been well characterized with respect to sulfur stereochemistry and thus existing data are sparse. Moreover, although N-sulfinyl compounds prefer to exist as the (Z)-isomers, it is not clear if they always undergo cycloaddition in this geometrical form. It is also known that the Diels-Alder reactions of N-sulfinyl compounds are sometimes reversible, which complicates the issue. ... 

Bis-imines (117) have been used far less than the monoimines as dienophiles. However, there are enough examples of these cycloadditions to indicate clearly that they are regioselective and, provided at least one electron-withdrawing group is present on nitrogen, that they proceed under mild reaction conditions. As with the monoimines, little is known with regard to the establishment of sulfur stereochemistry in the dihydrothiazine imines (118). Equations (55)," (56) and (57) demonstrate both the regio-selectivity of the process and some of the structural types of bis-imino compounds which have been... 

Sulfur occurs in three formally positive oxidation states, usually designated by the roman numerals II, IV and VI. The formation of multiple bonds (especially with oxygen) is characteristic of sulfur and gives rise to a variety of stereochemical types. Sulfur can have 11 different valency states in nonionized structures under normal conditions. Unfortunately, there are relatively few gas-phase studies of molecules containing the SN bond, and this complicates the analysis of sulfur stereochemistry. 

In the absence of any substituent at the C-6 position, the sulfur stereochemistry controls the stereochemical outcome of the [2,3]-sigmatropic reaction, and hence the imine (60) can be stereo specifically converted to the cw-thiadiazolidine (61) <88JOCl 116>. The epimeric dihydrothiazine... 

The key step here involved cycloaddition of the Af-sulfinyl carbamate 30 to give exclusively adduct 31, whose structure was proved by X-ray crystallography. It was suggested that the cyclization occurred via the con-former shown in 30 to minimize nonbonded interactions. It seems reasonable that the reaction proceeded through an intermediate ( )-Af-sulfinyl carbamate to provide the sulfur stereochemistry shown in structure 31. This cycloadduct was subsequently converted to the amino sugar by a short series of transformations. 

Mock and Nugent investigated the mechanism of the [4 + 2] cycloaddition of iV-sulfinyl-p-toluenesulfonamide (9) and the isomeric 2,4-hex-adienes 10,11, and 12 in detail (Scheme l-II).11 These workers determined the relative stereochemistry of the resulting adducts and proposed a stepwise dipolar mechanism based primarily on the difference in sulfur stereochemistry between adducts produced from dienes 11 and 12. 

Chiral separations are concerned with separating molecules that can exist as nonsupetimposable mirror images. Examples of these types of molecules, called enantiomers or optical isomers are illustrated in Figure 1. Although chirahty is often associated with compounds containing a tetrahedral carbon with four different substituents, other atoms, such as phosphoms or sulfur, may also be chiral. In addition, molecules containing a center of asymmetry, such as hexahehcene, tetrasubstituted adamantanes, and substituted aHenes or molecules with hindered rotation, such as some 2,2 disubstituted binaphthyls, may also be chiral. Compounds exhibiting a center of asymmetry are called atropisomers. An extensive review of stereochemistry may be found under Pharmaceuticals, Chiral. 

Reaction of acetic acid and a catalytic amount of sulfuric acid at reflux temperatures for 6—8 hours with dihydromyrcene can cause rearrangement of the dihydromyrcenyl acetate to give a mixture of the cycHc acetates analogous to the cycHc formate esters (108). The stereochemistry has also been explained for this rearrangement, depending on whether (+)- or (—)-dihydromyrcene is used (109). The cycHc acetates are also commercially avaUable products known as Rosamusk and CyclocitroneUene Acetate. 

In the olivanic acid series of carbapenems the ( )-acetamidoethenyl grouping can be isomerised to the (Z)-isomer (19) (22) and reaction with hypobromous acid provides a bromohydrin that fragments to give a thiol of type (20) when R = H, SO H, or COCH. The thiol is not isolated but can react to provide new alkyl or alkenyl C-2 substituents (28). In the case of the nonsulfated olivanic acids, inversion of the stereochemistry at the 8(3)-hydroxyl group by way of a Mitsunobu reaction affords an entry to the 8(R)-thienamycin series (29). An alternative method for introducing new sulfur substituents makes use of a displacement reaction of a carbapenem (3)-oxide with a thiol (30). Microbial deacylation of the acylamino group in PS-5 (5) has... 

Electrophilic attack on the sulfur atom of thiiranes by alkyl halides does not give thiiranium salts but rather products derived from attack of the halide ion on the intermediate cyclic salt (B-81MI50602). Treatment of a s-2,3-dimethylthiirane with methyl iodide yields cis-2-butene by two possible mechanisms (Scheme 31). A stereoselective isomerization of alkenes is accomplished by conversion to a thiirane of opposite stereochemistry followed by desulfurization by methyl iodide (75TL2709). Treatment of thiiranes with alkyl chlorides and bromides gives 2-chloro- or 2-bromo-ethyl sulfides (Scheme 32). Intramolecular alkylation of the sulfur atom of a thiirane may occur if the geometry is favorable the intermediate sulfonium ions are unstable to nucleophilic attack and rearrangement may occur (Scheme 33). 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

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. 

Chapter 9, Stereochemistry —A discussion of chirality at phosphorus and sulfur has been added to Section 9.12, and a discussion of chiral environments has been added to Section 9.14. 

The silicon- and sulfur-substituted 9-allyl-9-borabicyclo[3.3.1]nonane 2 is similarly prepared via the hydroboration of l-phenylthio-l-trimethylsilyl-l,2-propadiene with 9-borabicy-clo[3.3.1]nonane36. The stereochemistry indicated for the allylborane is most likely the result of thermodynamic control, since this reagent should be unstable with respect to reversible 1,3-borotropic shifts. Products of the reactions of 2 and aldehydes are easily converted inlo 2-phenylthio-l,3-butadienes via acid- or base-catalyzed Peterson eliminations. 

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