Stereogenic sulfur

The stereogenic sulfur atom in sulfoxides is usually configurationally stable at room temperature thus, sulfoxides may be chiral based on this property alone1. In fact, there are many examples of optically active sulfoxides of both synthetic and natural origin. This chapter reviews the important methods for obtaining optically active sulfoxides, and discusses some reactions at sulfur which either leave the coordination number at three or increase it to four, generally with preservation of optical activity. It also describes briefly some recent studies on the conformational analysis and chiroptical properties of sulfoxides. 

Associated to copper(II) pre-catalysts, bis(oxazolines) also allowed the asymmetric Diels-Alder and hetero Diels-Alder transformations to be achieved in nearly quantitative yield and high diastereo- and enantioselectivities. Optically active sulfoximines, with their nitrogen-coordinating site located at close proximity to the stereogenic sulfur atom, have also proven their efficiency as copper ligands for these asymmetric cycloadditions. Other precursors for this Lewis acid-catalyzed transformation have been described (e.g., zinc salts, ruthenium derivatives, or rare earth complexes) which, when associated to bis(oxazolines), pyridine-oxazolines or pyridine-bis(oxazolines), led to efficient catalysts. 

Bolm et al. [108] prepared a C2-symmetric bis (sulfoximine) as ligand for the copper-catalyzed hetero-Diels-Alder reaction. The stereogenic sulfur atom being located near the AT-coordinating atom, these structures were assumed to be promising for asymmetric catalysis. Their Hgand (79 in Scheme 43) was synthesized by palladium-catalyzed N-aryl imination from 1,2-dibromobenzene and (S)-S-methyl-S-phenylsulfoximine with Pd2dba3 in 70% yield. 

From all these results, optically active sulfoximines, with their nitrogencoordinating site located at the close proximity to the stereogenic sulfur atom, have thus proven their efficiency as copper-ligands for asymmetric Diels-Alder and hetero Diels-Alder reactions. 

The sulfinyl imine catalyst 63, which has a stereogenic sulfur atom, hydrogenated substrate 36 in 94% ee however, high catalyst loadings were used [45]. The full results for substrates 36 40 are detailed in Tables 30.7 to 30.11. 

A wide variety of sulfonyl or carboxyl amides can be applied as nitrogen sources and nontoxic iodobenzene diacetate serves as a mild oxidant. Furthermore, the reaction conditions (e.g., room temperature) are mild, and the imina-tion proceeds with retention of configuration at the stereogenic sulfur (as shown in Scheme 2.1.1.3 for the conversion of (R)-14 into (i )-15). Most importantly, sulfoximine derivatives with easy-to-cleave protective groups at the sulfoximine nitrogen are obtainable, which allow access to the synthetically important free NH-sulfoximines (vide infra). 

The chiral discrimination in cyclic dimers and trimers of mono-substituted sulfoxides and thioperoxides (Scheme 3.21) has been studied by means of DFT (B3LYP/6-31+G ) and ab initio (MP2/6-311+G ) calculations [5]. In addition, the inter- and intramolecular proton transfer processes that interconvert these two classes of compounds have been considered for the isolated molecules and the clusters. These two classes of compounds present different kinds of chirality, while the sulfoxides show a stereogenic sulfur atom, the thioperoxides present axial chirality. 

A similar effect is observed in the osmylation of allylamides bearing a bis-homoallylically located sulfoxide group94. In this case the asymmetric 1,5-induction of the stereogenic sulfur atom totally overwhelms the weak bias of the allylic chirality. The concomitant sulfoxide-to-sulfone transformation suggests sulfoxide involvement in the oxidation mechanism. In this example, as well as in the previous one, replacement of the sulfur-based directing group by a sulfone moiety leads to a drop in diastereoface differentiation. 

The reaction of A -[A -(benzoylimino)-A -phenylsulfonyl]amide 429 with iodosylbenzene 426 leads efficiently to nitrene intermediates that convert olefins 411 into aziridines 430 in good yields, through a copper(ll)-mediated (Cu(OTf)2) reaction. Owing to the stereogenic sulfur atom present in the molecules, the reactions proceed with some degree of diastereoselectivity (Scheme 111) <2004OL3573>. 

For the acetylenic sulfoxide, because of its configurationally stable pyramidal stereogenic sulfur atom (a lone electron pair, an oxygen and two different carbon substituents), it can exist in chiral forms. Therefore, in chiral acetylenic sulfoxide, the sulfoxide moiety not only serves as a chemical activator of the acetylene unit, it can also induce stereochemical control at the adjacent carbon centers to achieve enantioselective synthesis. In this article, we shall discuss the preparation of these a, /J-unsaturated synthons and their applications in Diels-Alder reactions, heterocycle and alkaloid syntheses. 

There are several efficient methods available for the synthesis of homochiral sulfoxides [3], such as asymmetric oxidation, optical resolution (chemical or bio-catalytic) and nucleophilic substitution on chiral sulfinates (the Andersen synthesis). The asymmetric oxidation process, in particular, has received much attention recently. The first practical example of asymmetric oxidation based on a modified Sharpless epoxidation reagent was first reported by Kagan [4] and Modena [5] independently. With further improvement on the oxidant and the chiral ligand, chiral sulfoxides of >95% ee can be routinely prepared by these asymmetric oxidation methods. Nonetheless, of these methods, the Andersen synthesis [6] is still one of the most widely used and reliable synthetic route to homochiral sulfoxides. Clean inversion takes place at the stereogenic sulfur center of the sulfinate in the Andersen synthesis. Therefore, the key advantage of the Andersen approach is that the absolute configuration of the resulting sulfoxide is well defined provided the absolute stereochemistry of the sulfinate is known. 

Similar to the sulfoxides, sulfoximides are able to stabilize carbanions and transfer chirality from sulfur to carbon. They have, therefore, found many applications as chiral reagents. To obtain chiral sulfoximides, one may start either with a chiral sulfoxide, which is treated with azide [e.g., tosyl azide under copper catalysis, e.g., formation of (/ )-1820], or with a racemic sulfoximide, which often can be resolved with a chiral acid, in particular (lS,4/ )-10-camphorsulfonic acid, e.g., formation of (S )- )20. The reagents used almost exclusively contain a methyl and a phenyl group at the stereogenic sulfur which allows easy modification employing the acidity of the methyl group. 

An efficient, stereocontrolled synthesis of a- or yS-l-C-alkyl-imino-L-arabinols (6) depends on the nucleophilic addition of pentose-derived imines generated from enan-tiopure f-butanesulfinamide. The stereoselectivity of this key step can be controlled 0 either by the sugar moiety or by the stereogenic sulfur centre. 

Although stereogenic sulfur centers had been used as the source of chiral auxiliaries and hgands [190-195], organocatalysts incorporating chirality solely through the sulfur atom had been almost overlooked in the hterature before the development of... 

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