Chiral sulfur

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... 

Enantiomers of a chiral compound show many different physiological responses, including those of odor and taste2 and it has long been known that enantiomers of some sulfur-containing compounds may have different odors. The examples discussed here are for sulfur-containing compounds where the chirality is based on carbon. While certain compounds can show sulfur-based chirality, there are apparently no known cases where enantiomers dependent on sulfur chirality exhibit different odors. 

Scheme 18.13 Carbon sulfur chirality transfer via [2.31 rearrangement. ...

Some chiral sulfoxides have biological activity associated with a given configuration at sulfur. Chiral sulfoxides may also be useful in material science (eg ferroelectric liquid crystals). However the main interest of these compounds is related to their usefulness as chiral auxiliaries in asymmetric synthesis The sulfmyl moiety increases the acidity of the a-hydrogens, allowing for facile formation of carbanions which can undergo asymmetric addition on aldehydes or imines. Several classes of vinyl... 

The large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into a carbon compound. Thermal equilibrations of chiral sulfoxides are slow, and parbanions with lithium or sodium as counterions on a chiral carbon atom adjacent to a sulfoxide group maintain their chirality. The benzylic proton of chiral sulfoxides is removed stereoselectively by strong bases. The largest groups prefer the anti conformation, e.g. phenyl and oxygen in the first example, phenyl and rert-butyl in the second. Deprotonation occurs at the methylene group on the least hindered site adjacent to the unshared electron pair of the sulfur atom (R.R. Fraser, 1972 F. Montanari, 1975). 

In cyclic sulfoxides Che diastereomeric product ratio is even higher, and the chirality of the sulfur atom has been efficiently transferred to the carbon atom in synthesis. 

Tricoordmate sulfur compounds are chiral when sulfur bears three different sub stituents The rate of pyramidal inversion at sulfur is rather slow The most common compounds m which sulfur is a chirality center are sulfoxides such as... 

Section 7 16 Atoms other than carbon can be chirality centers Examples include those based on tetracoordmate silicon and Incoordinate sulfur as the chirality center In principle Incoordinate nitrogen can be a chirality center m compounds of the type N(x y z) where x y and z are different but inversion of the nitrogen pyramid is so fast that racemization occurs vrr tually instantly at room temperature... 

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. 

The polyamides are soluble in high strength sulfuric acid or in mixtures of hexamethylphosphoramide, /V, /V- dim ethyl acetam i de and LiCl. In the latter, compHcated relationships exist between solvent composition and the temperature at which the Hquid crystal phase forms. The polyamide solutions show an abmpt decrease in viscosity which is characteristic of mesophase formation when a critical volume fraction of polymer ( ) is exceeded. The viscosity may decrease, however, in the Hquid crystal phase if the molecular ordering allows the rod-shaped entities to gHde past one another more easily despite the higher concentration. The Hquid crystal phase is optically anisotropic and the texture is nematic. The nematic texture can be transformed to a chiral nematic texture by adding chiral species as a dopant or incorporating a chiral unit in the main chain as a copolymer (30). 

Chirahty at the phosphoms is an unavoidable problem in all phosphorothioate syntheses. The phosphoramidite method produces a mixture of both the and the diastereomers having a small excess of the isomer (53). Although some progress has been made in the chiral synthesis of dinucleoside phosphorothioates, low yields have limited the utility of these approaches. The chiral center may be eliminated by replacing the other, nonbridging oxygen with sulfur. Avoidance of the chirahty problem is one reason for the interest in phosphorodithioates. 

Some of the newer compounds may contain both saturated and unsaturated rings, heteroatoms such as oxygen, nitrogen, or sulfur, and halogen substituents. Others, such as synthetic pyrethroids, may have one or more chiral centers, often needing stereospecific methods of synthesis or resolution of isomers (42). Table 4 Hsts examples of some more complex compounds. Stmctures are shown ia Eigure 1 (25). 

J. D. Morrison and J. W. ScoXt, Asymmetric Synthesis, Vol. 4, The Chiral Carbon Pool and Chiral Sulfur, Nitrogen, Phosphorus, and Silicon Centers, Academic Press, Inc., Odando, Fla., 1984. 

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. 

Scheme 2.1. Chiral Compounds with Stereogenlc Centers at Sulfur and Phosphorus...

The reaction of diethyl tartrate with sulfur tetrafluonde at 25 °C results in replacement of one hydroxyl group, whereas at 100 °C, both hydroxyl groups are replaced by fluonne to form a,a -difluorosuccinate [762] The stereochemical outcome of the fluonnation of tartrate esters is retention of configuration at one of the chiral carbon atoms and inversion of configuration at the second chiral center [163,164, 165] Thus, treatment ofdimethyl(+)-L-tartrate with sulfur tetrafluonde gives dimethyl meso-a,a difluorosuccinate as the final product [163, 164], whereas dimethyl meso tartrate is converted into a racemic mixture of D- and L-a,a -difluorosuccmates [765] (equation 80)... 

Verify, by making molecular models, that the bonds to sulfur are arranged in a trigonal pyramidal geometry in sulfoxides and in a tetrahedral geometry in sulfones. Is phenyl vinyl sulfoxide chiral What about phenyl vinyl sulfone ... 

Since cbiral sulfur ylides racemize rapidly, they are generally prepared in situ from chiral sulfides and halides. The first example of asymmetric epoxidation was reported in 1989, using camphor-derived chiral sulfonium ylides with moderate yields and ee (< 41%) Since then, much effort has been made in tbe asymmetric epoxidation using sucb a strategy without a significant breakthrough. In one example, the reaction between benzaldehyde and benzyl bromide in the presence of one equivalent of camphor-derived sulfide 47 furnished epoxide 48 in high diastereoselectivity (trans cis = 96 4) with moderate enantioselectivity in the case of the trans isomer (56% ee). ... 

Reagent-controlled asymmetric cyclopropanation is relatively more difficult using sulfur ylides, although it has been done. It is more often accomplished using chiral aminosulfoxonium ylides. Finally, more complex sulfur ylides (e.g. 64) may result in more elaborate cyclopropane synthesis, as exemplified by the transformation 65 66 ... 

New reactions utilizing features of sulfur atom in chiral sulfoxides, derivatives of heterocycles 99YZ126. 

A great advantage of catalyst 24b compared with other chiral Lewis acids is that it tolerates the presence of ester, amine, and thioether functionalities. Dienes substituted at the 1-position by alkyl, aryl, oxygen, nitrogen, or sulfur all participate effectively in the present asymmetric Diels-Alder reaction, giving adducts in over 90% ee. The reaction of l-acetoxy-3-methylbutadiene and acryloyloxazolidinone catalyzed by copper reagent 24b, affords the cycloadduct in 98% ee. The first total synthesis of ewt-J -tetrahydrocannabinol was achieved using the functionalized cycloadduct obtained [23, 33e] (Scheme 1.39). 

Determination of the enantiomeric distribution of some chiral sulfur-containing trace components of yellow passion fruit"... 

Figure 13.2 MDGC-ECD chromatograms of PCB fractions from sediment samples, demonstrating the separation of the enantiomers of (a) PCB 95, (b) PCB 132, and (c) PCB 149 non-labelled peaks were not identified. Reprinted from Journal of Chromatography, A 723, A. Glausch et al, Enantioselective analysis of chiral polyclilorinated biphenyls in sediment samples by multidimensional gas cliromatography-electi on-capture detection after steam distillation-solvent exti action and sulfur removal , pp. 399-404, copyright 1996, with permission from Elsevier Science.

The most common cause of chirality is the presence of four different substituents bonded to a tetrahedral atom, but that atom doesn t necessarily have to be carbon. Nitrogen, phosphorus, and sulfur are all commonly encountered in organic molecules, and all can be chirality centers. We know, for instance, that trivalent nitrogen is tetrahedral, with its lone pair of electrons acting as the fourth "substituent" (Section 1.10). Is trivalent nitrogen chiral Does a compound such as ethylmethylamine exist as a pair of enantiomers ... 

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. 

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