Addition reactions sulfoximines

Chiral (-E)-vinyl-substituted sulfoximines, in which the iV-substituent was derived from (+)-norephedrine or ( —)-(S)-l-phenylethylamine2, underwent addition reactions with organolithi-um and organocopper reagents1,2. The diastereoselection ranged from moderate to good. 

The addition of chiral amines to a,/(-unsaturated sulfoximines has been employed for the resolution of racemic sulfoximines 3 utilizing 0.5 equivalents of a chiral amine in chloroform 117. After completion of the reaction, the unreacted starting material is isolated by column chromatography and its optical purity determined by comparison with the reported optical rotation, or by HNMR using a chiral shift reagent. While (—)-(l/f,2.S,)-2-mcthylamino-1-phenyl-l-propanol [(l/ ,2S)-ephedrine] affords material of moderate optical purity, racemic products are isolated from addition reactions with (—)-l-phenyl-2-propanamine [(—)-am-phetamine] or ( + )-( )-l-phenylethylamine. 

Addition of nitrogen to the lone pair of sulfoxides or of oxygen to the lone pair of sulfilimines is quite common and leads to sulfoximines (see also Section II.G). Such reactions have been reviewed12,13. 

In order to prepare a new range of ligands incorporating both sulfoximine and phosphine moieties, Tye et al. reported, in 2001, the synthesis of a novel chiral phosphine-sulfoximine, which was tested as a ligand in the copper-catalysed 1,4-addition of ZnEt2 to enones. Whilst the reaction of acyclic enones gave the corresponding racemic 1,4-products, the best result was obtained upon... 

The Harmata group also found that certain ort/w-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (7 )-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the p-carbon of the a,P-unsaturated ester, thus favoring cyclization. 

We have developed asymmetric syntheses of isocarbacyclin [3] (Scheme 1.3.2) and cicaprost [4] (Scheme 1.3.3) featuring a Cu-mediated allylic alkylation of an allyl sulfoximine [5-7] and a Ni-catalyzed cross-coupling reaction of a vinyl sulf-oximine [8-10], respectively, transformations that were both developed in our laboratories. The facile synthesis of an allyl sulfoximine by the addition-elimination-isomerization route aroused interest in the synthesis of sulfonimidoyl-sub-stituted aiiyititanium complexes of types 1 and 2 (Fig. 1.3.2) and their application as chiral heteroatom-substituted allyl transfer reagents [11]. 

Synthesis of the polymer-bound allyl sulfoximine 60 was accomplished by the addition-elimination-isomerization route starting from the enantiomerically pure polymer-bound N-methyl-S-phenylsulfoximine 59, which was prepared as previously described from Merrifield resin and sulfoximine 12 with a loading of 84% (Scheme 1.3.23) [42]. The successive treatment of resin 59 with n-BuLi in THF and with isovaleraldehyde furnished the corresponding polymer-bound lithium alcoholate, which upon reaction with ClC02Me and DBU afforded the corresponding polymer-bound vinylic sulfoximine (not shown in Scheme 1.3.23), the isomerization of which with DBU in MeCN afforded sulfoximine 60. 

The synthetic utility of a-phosphorus- and a-thio-stabilized carbanions is the subject of numerous reviews.21 Notable are additions of phosphonium ylides (237),183 sulfonium ylides (238),l84 ° oxosulfo-nium ylides (239)184 " and sulfoximine ylides (240)184,1 to electron-deficient alkenes which afford nucleophilic cyclopropanation products. In contrast, with a-(phenylthio)-stabilized carbanions, which are not acyl anion equivalents, either nucleophilic cyclopropanation or retention of the hetero substituent occurs, depending on the acceptor and reaction conditions used. For example, carbanion (241) adds to 1,1-... 

In addition to primary or secondary amines, attachment of hydro-xylamine, hydrazines, sulfoximines, or phenols proceeds equally well (Scheme 10). Secondary amines can be cleaved directly from the resin, while primary amines give rise to a different reaction pathway (see below). 

More recently Braganca, Faulkner, and Quastel (B15) showed that this inhibition of acetylcholine synthesis in brain slices by ammonia is consistent only in the diminution of bound acetylcholine. They further showed that the addition of inhibitors of glutamine synthesis, such as methionine sulfoxide, ethionine sulfoxide, and methionine sulfoximine (the toxic product, causing convulsions, formed in flour chemically aged with nitrogen trichloride) would partially reverse the ammonium inhibition. These observations were confirmed and extended to a wide variety of ATP-requiring reactions by Weil-Malherbe. In support of this suggestion was the observation that ammonia is taken up by the brain in hepatic coma (B8). The observations are valid and have been confirmed, but the interpretation of the data and the hypothesis are questionable. A quantitative basis for the evaluation of this mechanism can... 

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

Finally, a structural and electronic features required for highly potent GS inhibitor were determined. Comparison of electrostatic potential on a molecular surface of enzymatic reaction transition state and phosphorylated forms of phosphinothricin and methionine sulfoximine revealed high similarity, while less potent inhibitors showed some differences. On the basis of these results, it was concluded that these inhibitors are typical transition state analogues. Moreover, charge distribution near tetrahedral atom of inhibitor (phosphorus or sulfur) should consist of two negatively charged centers and additional positively charged or neutral one. 

Addition to ketones. In 1982, Johnson and Stark31 reported the condensation reactions of (+)-(S)-Af,5-dimethyl-S-phenylsulfoximine (2a) with various aldehydes and prochiral ketones. The reaction of lithiated 2a with phenyl aryl ketones (PhCOR, R=Me, Et, n-Pr, n-Bu, and c-C6Hn) gave a mixture of two diastereomeric P-hydroxy sulfoximine adducts 54 with modest diastereoselectivity. Unfortunately, the diastereoselectivities of all of these reactions were not documented. 

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