Sulfinimines, chiral

Within the biooxidation of disulfides, chiral thiosulfinates become available. Tert-Butyl tert-butanethiosulfinate represents a particularly valuable chiral auxiliary for the preparation of several chiral sulfoxides and sulfinimines, which can be subsequently transformed into branched amine compounds, P-aminoacids, and chiral aziridines. This product is accessible readily by mediated biooxidation of tert-butyl... 

The preparation of chiral isoquinoline derivatives continued to be investigated. Sulfanamide 59 was prepared by addition of a lateral lithiated o-toluonitrile with the corresponding sulfinimine. Treatment of 59 with MeLi followed by acidification afforded cyclic imine 60. Reduction of imine 60 with liAlHi/MejAl afforded the trans-1,3 derivative, and... 

Chiral sulfinimines 236 are very useful intermediates for the preparation of enantiomer-ically pure primary amines 237 (equation 158) . This reaction has been applied to the synthesis of a-amino acids . For sulfinimines obtained from simple ketones, lithium reagents are preferable for the addition , while for cyclic ketones organomagnesium compounds gave the best results. Addition of alkyl and aryl Grignard compounds to sulfinimines, derived from 3- and 4-substituted cyclohexanones, proceeds with excellent diastereoselectivity, depending on the stereochemistry of the ring substituents rather than the sulfinyl group . 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

Addition of phosphates to chiral sulfinimines derived from aromatic aldehydes has been used to prepare a-amino phosphonate esters asymmetrically.35 The sulfinimines employed, p- Me Ph S (= O) N=C H A r. have sufficiently bulky substituents to prevent inversion, as shown by 1H-NMR over a wide range of temperatures. 

The addition of Grignard reagents to chiral trifluoromethyl r-butyl sulfinimine-ethanol adducts has afforded protected trifluoromethylamines in high yields with good ... 

Asymmetric aza Morita-Baylis-Hillman reactions of N-sulfonylimines or N-sulfinimines with Michael accepters in the presence a Lewis base catalyst to give the corresponding chiral a-methylene-/ -amino compounds have been described [27]. 

Diastereoselective Mannich-type reactions between ketene silyl acetals and chiral sulfinimines using simple metal-free Lewis bases such as tetraalkylammonium car-boxylates have been reported. The sulfinimine can even be generated in situ (from aldehyde and a chiral sulfonamide), using cesium carbonate, followed by addition of ketene silyl acetal at -78 °C, and as little as 1 mol% of catalyst.32... 

Strecker-type reaction of TMS cyanide with chiral sulfinimines gives diastereoselective cyanations at the imine carbon, at —78 °C in DMF, using simple metal-free Lewis base catalysts such as tetraalkylammonium carboxylates.73... 

Unusual -branched Baylis-Hillman adducts have been prepared by Li and coworkers by a novel Et2AlCl promoted domino Michael-aldol reaction of propynoates 50 with organo-cuprates and chiral p-toluenesulfinimines 52 (Scheme 10) [42], These condensations proceeded with very good diastereoselectivity to give allylic amines 53. The selectivity can be explained through the chairlike transition state 54. The anion intermediate approaches the sulfinimine from the sterically less hindered side of the lone pair of electrons. The nucleo-... 

A recently reported novel asymmetric aziridination route involves the action of methylene transfer reagents on chiral sulfinimines 97, whereby the selectivity is conferred by the asymmetric sulfinyl center. The stereochemical outcome of this reaction is dependent upon the methylene transfer reagent. Thus, dimethyloxosulfonium methylide provided predominantly isomer 98, whereas the use of dimethylsulfonium methylide led to the formation of 99 as the major product [95TL295]. 

Diastereoselectivity in functionalized piperidine synthesis has also been reported using chiral sulfinimines (Scheme 18) <2003OL3855>. It was postulated that the observed selectivity arose from an intermediate alkoxy aluminium species shielding one face of the imine during reduction. 

Finally, enantiomerically pure sulfinimines have also been used as precursors of chiral imidazolidines by 1,3-dipolar cycloaddition with azomethine ylids [181]. Reactions of different arylsulfinimines 245 with dipoles 246 are highly stereoselective, mainly affording diastereoisomer 247 (absolute configuration unequivocally established by X-ray studies), which was readily transformed into vicinal diamine 248 (Scheme 111). 

The presence of a coordinating group in the sulfinimine may strongly influence the selectivity of the reaction with Grignard derivatives. In the case of 2-pyridyl ftrt-butylsulfinimines, the diastereoselectivity of the addition is reversed due to the coordination with the pyridine nitrogen. " Attempts have been made to prepare sulfinyl chiral... 

Thiosulfinate 129 has been used for the synthesis of various chiral sulfinyl derivatives such as sulfoxides, sulfmamides, and sulfinimines in good yield, tert-Butanesulfinyl ketimines have been successfully used for the asymmetric synthesis of a,a-dibranched aminesI09h as well as for the synthesis of o.p. amino acids.109 ... 

Optically active sulfinimines were prepared by Yang and co-workers by oxidation of nonracemic sulfenimines.20 Thus, treatment of 11 with m-CPBA or MMPP afforded sulfinimines 12 in 83-99% yield. The diastereoselectivity, however, was highly dependent on the R group in the chiral auxiliary. When R = H, diastereopure sulfinimine (/ s)-12 was obtained. 

Enantiopure bis-P-amino acids can be prepared from chiral bis-sulfinimines.37 Bis-sulfinimine (Ss,Ss)-160 and the sodium enolate of methyl acetate react to give 161 as a diastereomeric mixture. The major isomer (5s,/ ,Ss,/ )-161 can be isolated by preparative reverse-phase HPLC in 46% yield. Hydrolysis of (Ss,/ ,Ss,/ )-161 gave bis-P-amino ester (/ ,/ )-162 in >97% ee and 86% yield.37... 

Dienolates. Garcia Ruano and co-workers reported that N-2-methoxynaphthyl sulfinimine (Ss)-163 reacts with the lithium dienolate of 3-butenoic methyl ester (164) to afford a-ethylidene-P-sulfinylamino ester 165 as a single isomer in 82% yield.90 In the presence of ZnBr2, a-vinyl-P-sulfinylamino esters 166 were obtained in 90% as a diastereomeric mixture in a ratio of 30 70. Both (Ss,2S,3R)-166/(Ss,2/ ,3/ )-166 can be converted to the same a-ethylidene-P-amino ester 168 via deprotection of the N-sulfinyl group and subsequent base promoted epimeriza-tion of the a-chiral center.90... 

Addition of the lithium anion of chloromethylphosphonate to sulfinimine 126 gave a-chloro-P-aminophosphonates 195 in a ratio of 59 41 and 98% total yield.104 The diastereomeric products can be separated and each converted to the corresponding aziridine-2-phosphonates 196, new building chiral blocks for the enantioselective synthesis of a-aminophosphonates 197 and azirinyl phosphonates 198.104... 

---