Enantiomeric separation sulfoxide

Finally, we would like to describe the enantiomeric separation of racemic methyl phenyl sulfoxide by the dipeptide (1). Optically active sulfoxides are utilized as a... 

A suspension of the dipeptide (1) (1 mmol) in water (2 ml) was stirred together with racemic methyl phenyl sulfoxide (2 mmol) at room temperature for one day. The formed inclusion compound was collected by filtration and washed with water (20 ml) and dichloromethane (20 ml). From the inclusion compound, we recoverd the included methyl phenyl sulfoxide by extraction with dichloromethane to give (/ )-methyl phenyl sulfoxide. The dipeptide (1) remained as a solid. When the recovered dipeptide (1) was again subjected to the formation of inclusion compound with racemic methyl phenyl sulfoxide, (A1 (-methyl phenyl sulfoxide was obtained as summarized in Table 5. Thus, it was shown that the dipeptide (1) can be used repeatedly for enantiomeric separation of methyl phenyl sulfoxide. 

Enantiomerically pure sulfoxides are important intermediates in organic synthesis (21) and quite a number of pharmaceuticals and other biologically active compounds harbor a chiral sulfoxide unit (22). With respect to oxidation catalysis, enantiomerically enriched sulfoxides can either be accessed by asymmetric sulfoxidation of prochiral thioethers (Scheme 7, path a), or by kinetic resolution of racemic sulfoxides (Scheme 7, path b). For the latter purpose, enantio-specific oxidation of one sulfoxide enantiomer to the sul-fone, followed by separation, is the method of choice. 

The binaphthol host 10b was found to be very effective for enantiomeric separation of some sulfoxides. When a solution of 10b and two molar equivalents of rac-me-thyl m-methylphenyl sulfoxide (85c) in benzene-hexane was kept at room temperature for 12 h, a 1 1 complex of 10b and (-i-)-85c was obtained, after one recrystallization from benzene, as colorless prisms in 77% yield. Chromatography of the complex on sihca gel gave (-i-)-85c of 100% ee in 77% yield [32]. By the same procedure, rac-85d was separated by 10b to give (-i-)-85d of 100% ee in good yield. However, rac-85a was poorly separated with 10b, giving approximately 5% ee enantiomer, while 85b and 85e did not form complexes with 10b. In order to establish why the chirality of the m-substituted derivatives 85c and 85d is so precisely recognized by 10b, the crystal structure of the complex of 10b and (-i-)-85c was studied by X-ray analysis [33]. 

The chiral host 10b was effective for enantiomeric separations of alkyl aryl sul-foximines (89a-g). By complexation of rac-89b, rac-89d and rac-89e with 10b, (-)-89b (100% ee, 37%), (-)-89d (100% ee, 70%) and (-F)-89e (100% ee, 50%), respectively, were obtained in the optical and chemical yields indicated [35]. However, separation of rac-89a with 10b was not effective and (-)-89a of 35% ee was obtained in 45% yield after five recrystallizations of the complex of (-)-89a and 10b from benzene. 89c, 89f and 89g did not form complexes with 10b. These results show that the efficiency of the enantiomeric separation is highest when the alkyl group is methyl or ethyl and the aryl group is m-tolyl. Since this tendency is similar to that in the case of sulfoxide, the efficiency of the enantiomeric separation of 89 probably depends on the packing of 10b and 89 molecules in the crystalline lattice of their inclusion complex, as has been reported for the complex of 10b and (-f)-85c [32]. Although 10b did not form complexes with dialkyl sulfoximines (90), 8 formed complexes with some of them, and some were separated into enantiomers efficiently by the complexation. For example, by complexation of 8 with rac-90a and rac-90b in ether, (-)-90a (100% ee, 80%) and (-)-90b (100% ee, 88%), respectively, were finally obtained in the optical and chemical yields indicated [35]. 

The low vapor pressure and high thermal stability of CILs render them suitable for enantioseparations in gas chromatography (GC). Recently, CILs have been used as chiral stationary phases (CSPs) in GC [40]. Armstrong and coworkers carried out enantiomeric separation of chiral alcohols and diols, chiral sulfoxides, some chiral epoxides and acetamides using a CIL based on ephedrinium salt. Using an ephedrinium CIL (4) as the CSP, enantiomeric separation of alcohols and diols was achieved (Fig. 1). The presence of both enantiomeric forms of ephedrine makes it possible to produce CSPs of opposite stereochemistry, which could reverse the enantiomeric elution order of the analytes. This offers an additional advantage that may not be easily achieved with common and widely used chiral selectors in GC such as the cyclodextrins. However, there was a decrease in enantiomeric recognition ability of the CSP after a week which the authors attributed to dehydration-induced... 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

Racemic mixtures of sulfoxides have often been separated completely or partially into the enantiomers. Various resolution techniques have been used, but the most important method has been via diastereomeric salt formation. Recently, resolution via complex formation between sulfoxides and homochiral compounds has been demonstrated and will likely prove of increasing importance as a method of separating enantiomers. Preparative liquid chromatography on chiral columns may also prove increasingly important it already is very useful on an analytical scale for the determination of enantiomeric purity. 

Owing to its conceptual simplicity and manifest utility, the direct liquid chromatographic separation of enantiomeric sulfoxides on chiral columns has also been attempted. Thus, Montanari et al. (32) found that racemic unsaturated vinyl disulfoxides 23 may be par-... 

It is of interest to note that the magnetic nonequivalence of the enantiomers of the a-phosphoryl sulfoxide 49 in the presence of TFMC was observed (88) not only in Hbut also in and NMR spectra. With regard to the accuracy of the NMR method, the P H NMR spectra proved very useful in this case, since only two well-separated singlets that were due to enantiomeric sulfoxides 49 were observed. 

A special mention in the field of enantioselective HPLC separations must be made of chiro-optical detection systems, such as circular dichroism (CD) and optical rotation (OR), which can be also used to circumvent the low UV detectability of chromophore-lacking samples [40, 61]. While sensitivity of chiro-optical detection is not always sufficient to perform enantiomeric trace analysis, the stereochemical information contained in the bisignate spectropolarimetric response is useful in establishing elution order for those compounds not available as single enantiomers of known configuration. An example of application of different online detection systems (UV and CD at 254 nm) in the enantioselective separation of a racemic sulfoxide on a commercially available TAG CSP is reported in Figure 2.12, under NP conditions. 

The N-sulfonyloxaziridines are an important class of selective, aprotic oxidizing reagents.12 Enantiomerically pure N-sulfonyloxaziridines have been used in the asymmetric oxidation of sulfides to sulfoxides (30-91% ee),13 selenides to selenoxides (8-9% ee),14 disulfides to thiosulfinates (2-13% ee),5 and in the asymmetric epoxidation of alkenes (19-65% ee).15-16 Oxidation of optically active sulfonimines (R S02N=CHAr) affords mixtures of N-sulfonyloxaziridine diastereoisomers requiring separation by crystallization and/or chromatography.13... 

Another approach to enantiomerically pure planar chiral azaferrocenes involves 2-lithiation of (367) followed by addition of (-)-menthyl-(5 ) — jo-toluenesulfinate. The diastereomeric sulfoxides thus obtained are chromatograph-ically separable, and treatment of each diastereomer with t-BuLi produces an enantiomerically pure planar chiral anion that may be trapped with an electrophile (Scheme 98). Finally, in order to obviate the need for performing a resolution or a chromatographic separation, chiral ligand-mediated enantioselective deprotonations have been investigated. Lithiation of (367) in the presence of (-)-sparteine followed by addition of an electrophile gives the 2-substituted azaferrocene in good enantioselectivities (Scheme 99). However, lateral lithiation of (370) mediated by 5-valine-derived bis(oxazoline) (371) provides planar chiral products with excellent enantios-electivity. 

Palumbo et a/. 202-204 developed a new asymmetric synthesis of 3 -oxa-4 -thionucleosides in high enantiomeric excess. Treatment of benzoyloxyethanal with mercaptoethanol in the presence of a Lewis acid gave 245, which by a modified Sharpless oxidatiotf led to the separable chiral sulfoxides ( ) 246 (60% ee) and (Z) 247, in an 82 to 18 ratio. The ( ) isomer, treated with thymine or cytosine, under Pummerer-type glycosylatioir " gave 248 after separation of die a anomer and debenzoylation. 

Magnus et al. obtained both enantiomers of 9 with considerable effort by acylation of 6 with (+)-(/ )-p-toluenesulfinylacetic acid and cyclization of the resulting sulfoxide 7b, separation of the four diastereomers formed this way, combination of the pairs with the same absolute configurations at C6 and C7, and subsequent conversion into the two enantiomers 9 and ent-9. [9a] The cyclization of sulfoxide 7b yields the two products enantiomeric at C6 and C7 in a 55 45 ratio. This is why this route is not only laborious but then only insignificantly more efficient than resolution. 

A.ii. 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). 

Some dialkyl sulfoxides (86) were also separated into enantiomers by complexation with 10b. n-Butyl methyl sulfoxide (86a) and methyl -propyl sulfoxide (86d) were easily separated with 10a to give enantiomerically pure (-i-)-86a and (-)-86d, respectively, in good yields. However, 86b and 86f were poorly separated with 10b, and 86c and 86e did not form complexes with 10b [32]. 

Scheme 7. Examples for Enantiomer Separations by Crystallization with TADDOLs. Besides the original TADDOL (from tartrate acetonide and PhMgX), Toda et al. [44] have often used the cyclopentanone- and cyclohexanone-derived analogs. The dynamic resolution (resolution with in-situ recychng) of 2-(2-methoxyethyl)cyclohexanone was reported by Tsunoda et al. The resolved compounds shown here are only a small selection from a large number of successful resolutions, which include alcohols, ethers, oxiranes, ketones, esters, lactones, anhydrides, imides, amines, aziridines, cyanohydrins, and sulfoxides. The yields given refer to the amount of guest compound isolated in the procedure given. Since we are not dealing with reactions (for which we use % es to indicate enantioselectivity with which the major enantiomer is formed), we use % ep (enantiomeric purity of the enantiomer isolated from the inclusion...

HPLC is one of the most universal methods for determining the enantiomeric composition of substances and mixtures in a short time frame. Its application is not restricted to molecules in which chirality is based on a quaternary carbon atom with four different substituents it can also be employed for compounds containing a chiral silicon, nitrogen, sulfur, or phosphorus atom. Likewise, asymmetric sulfoxides or aziridines, the chirality of which is based on a lone electron pair, can be separated. Chirality can also be traced back to helical structures, as in the case of polymers and proteins to the existence of atropiso-merism, the hindered rotation about a single bond, as observed, for example, in the case of binaphthol, or to spiro compounds. 

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