Chirality chiral sulfonates, alkylation

Oxidation of sulfur-containing azoles quite often leads to the formation of sulfones and sulfoxides. Thus, 3-alkyl-1,2-benzisothiazoles 142 with MCPBA give the oxaziridines 143, and the use of a chiral 3-alkyl substituent leads to pure diastereomers. Reaction of 1,2,3-benzothiadiazole with 30% hydrogen peroxide in a mixture of acetic acid and methanol for 45 days affords 144 in 60% yield. 

N.S. Mani and co-workers utilized the organoaluminum promoted modified Beckmann rearrangement during their efficient synthetic route to chiral 4-alkyl-1,2,3,4-tetrahydroquinoline. (4R)-4-Ethyl-1,2,3,4-tetrahydroquinoline was obtained by rearrangement of the ketoxime sulfonate of (3R)-3-ethylindan-1-one. The resulting six-membered lactam product was reduced to the corresponding cyclic secondary amine with diisobutylaluminum hydride. 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

The main evidence in support of this mechanism derives from studies of stereochemical inversions as in the reaction of a chiral sulfonate with a Grignard Reagent isotopic experiments on the hydrolysis of arylsulfonates and the rates of hydrolysis of alkyl and arylsulfonyl halides. ... 

Alkyl halides or alkyl sulfates, treated with the salts of sulfinic acids, give sulfones. A palladium catalyzed reaction with a chiral complexing agent led to sulfones with modest asymmetric induction. Alkyl sulfinates (R SO—OR) may be side products. Sulfonic acids themselves can be used, if DBU (p. 1337) is... 

Pritchett et al.119 found that Ti(OPr )4 did not react with the bis(sulfon-amide) ligand itself, so they postulated that a chiral ligand initially reacted with the diethylzinc and was subsequently transferred to the titanium in the next step. Based on this assumption, they presented an improved procedure for the asymmetric alkylation of aldehyde to overcome the poor solubility of the li-... 

A more recent synthesis of 197 [365] is shown in Fig. 9. Enders introduced the stereogenic centre of (S)-lactic acid into the crucial position 10 in 197. The vinylsulfone B, readily available from lactic acid, was transformed into the planar chiral phenylsulfonyl-substituted (q3-allyl)tetracarbonyliron(+l) tetra-fluoroborate C showing (IR,2S,3 )-configuration. Addition of allyltrimethyl silane yielded the vinyl sulfone D which was hydrogenated to E. Alkylation with the dioxolane-derivative of l-bromoheptan-6-one (readily available from 6-bro-mohexanoic acid) afforded F. Finally, reductive removal of the sulfonyl group and deprotection of the carbonyl group furnished 197. A similar approach was used for the synthesis of 198 [366]. 

Use of the water-soluble analogues of complexes 90 and 91 were later reported by Williams and coworkers [83]. In this study, water solubility was achieved by replacing the chiral diamines TsDPEN and TsCYDN with the p-sulfonated derivatives TsDPEN-S03Na and TsCYDN-S03Na (Scheme 4.41). The ATH of aryl alkyl... 

Alkylation of hydroxylamines with secondary alkyl halides and alkyl sulfonates like 10 (equation 7) is one of the most frequently used synthetic approaches, especially to enantiomerically pure hydroxylamines such as 11 (equation 7). The reaction proceeds with inversion of configuration and does not produce appreciable amounts of diaUcyla-tion products. Both hydroxylamine as well as N- and O-alkylhydroxylamines have been successfully used. Alkyl trillates are probably the most useful substrates for these transformations since they can be prepared from a large pool of commercially available enantiomerically pure chiral secondary alcohols. 

Sulfides are generally oxidized much faster than alkenes, and in the presence of excess oxidant further oxidation to the sulfone occurs. In the cases where the reaction is conducted in an asymmetric way, the chiral catalytic system may react faster with one enantiomeric sulfoxide to form the sulfone than with the other, so that kinetic resolution of the primarily formed sulfoxide may occur. In general, the reaction is carried out with alkyl hydroperoxides like TBHP in the presence of a metal catalyst like Mo, W, Ti or V complexes. In some cases the sulfoxidation with hydroperoxides can take place without the need of a metal catalyst. Both examples will be discussed in the following. 

Chiral derivatives of hemiacetal from fluoral have been prepared by adding an alcohol to fluoral in the presence of (l )-BlNOL— Ti(0—iPr)2 or by HPLC resolution of the racemate. The displacement of the sulfonate moiety from the tosyl derivative, by an alkyl lithium aluminate, affords the trifluoromethyl ether with inversion of configuration and an excellent chirality transfer (Figure 2.49). ° ... 

Based on this gathered experience the diastereoselective alkylation of enantio-pure a-lithiated sulfonates was extended to the Michael addition with aliphatic nitroolefins [95]. Thus the Michael adducts 118 could be achieved in excellent yields (84-99%) with high diastereoselectivities de of 80-88% (84 to >98% after recrystallization or chromatography). Cleavage of the chiral auxiliary and treatment with diazomethane furnished the anti-configured a,j3-disubstituted y-nitro-methyl sulfonates 119 in overall yields of 41-70% and with excellent de- and ee-values (Scheme 1.1.32). 

The authors reported the chiral separation of proline and thereonine amino acid up to 20 and 6g, respectively, in a single run. Micropreparative resolution of lecucine was presented. The resolution was discussed with respect to the degree of sorbent saturation with copper(II), elution rate, eluent concentration, temperature, and column loading condition [16]. Weinstein [74] reported the micropreparative separation of alkylated amino acids on a Chiral ProCu column. In another article, a preparative chiral resolution of 3-methylene-7-benzylidene-bicyclo[3.3.1]nonane was achieved on 7.5% silver(I)-d-camphor- 10-sulfonate CSP [75]. Later, Shieh et al. [71] used L-proline-loaded silica gel for the chiral resolution of (ft,5 )-phcnylcthanolaminc as the Schiff base of 2-hydroxy-4-methoxyacetophenone. Gris et al. [76] presented the preparative separations of amino acids on Chirosolve L-proline and Chirosolve L-pipecolic acid CSPs. 

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