Synthesis from sulfoximines

The enantiopure acyclic and cyclic allyl sulfoximines 13 and 14, respectively, required for the synthesis of the corresponding titanium complexes 1 and 2, are available from sulfoximine 12 [13] and the corresponding aldehydes and cycloal-kanones by the addition-elimination-isomerization route, which can be carried... 

In general, sulfoximines are accessible by various routes, and most of them involve sulfur oxidation/imination sequences. For example, enantiopure 9 is commonly prepared starting from sulfide 10, which is oxidized with hydrogen peroxide (under acidic conditions) giving sulfoxide 11 (Scheme 2.1.1.1). Subsequent imina-tion of 11 with a mixture of sodium azide and sulfuric acid affords sulfoximine 9 as a racemate. Enantiomer resolution can then be achieved with camphorsul-fonic acid, leading to both enantiomers of 9 with high efficiency [15]. Alternatively, many sulfoximine syntheses start from enantiopure sulfoxides [16, 17], which can be stereospecifically iminated with 0-mesitylenesulfonylhydroxyl-amine (MSH) [18], as shown for the synthesis of sulfoximine (1 )-13 in Scheme 2.I.I.2. 

The reaction proceeds stereospecifically, giving sulfoximines from the corresponding enantiomerically enriched sulfoxides without racemization. The NH-sulfoxi-mines can then be obtained after Boc cleavage with trifluoroacetic acid. Bolm et al. applied this reaction in the synthesis of sulfoximines having a benchrotene skeleton (Scheme 3.55) [171]. 

The first synthesis of a 1 HA, 2,4-benzothiadiazine 1-oxide and simultaneously of the first cyclic sulfoximine were reported in 1964. 22 1 //-1,2,4-Benzothiadiazines were later prepared123 by reaction of S-(2-aminophenyl)sulfoximine 1 with cyanogen bromide to give 1//-1,2,4-thiadi-azin-3-amine 1-oxide 2a. Compounds 1 also react with phosgene to yield 1//-1,2,4-benzo-thiadiazin-3-amine 1-oxides 2b and c.123 An alternative route to 1 H-, 2,4-benzothiadiazine 1-oxides from sulfoximines and C-synthons has also been reported. 24 128... 

When a high-yield synthesis of the enantio- and diastereomerically pure mono-cyclic 2,3-dihydrofurans 44 from the vinyl sulfoximines 39 had been developed, the synthesis ofbicyclic 2,3-dihydrofurans of type 50 (Scheme 1.3.19) was investigated. Since a number of tetrahydrofuranoid natural products contain a fused bicyclic ring skeleton, the attainment ofbicyclic 2,3-dihydrofurans of the 50 type would also be desirable. 

Chiral alkenyl and cycloalkenyl oxiranes are valuable intermediates in organic synthesis [38]. Their asymmetric synthesis has been accomplished by several methods, including the epoxidation of allyl alcohols in combination with an oxidation and olefination [39a], the epoxidation of dienes [39b,c], the chloroallylation of aldehydes in combination with a 1,2-elimination [39f-h], and the reaction of S-ylides with aldehydes [39i]. Although these methods are efficient for the synthesis of alkenyl oxiranes, they are not well suited for cycloalkenyl oxiranes of the 56 type (Scheme 1.3.21). Therefore we had developed an interest in the asymmetric synthesis of the cycloalkenyl oxiranes 56 from the sulfonimidoyl-substituted homoallyl alcohols 7. It was speculated that the allylic sulfoximine group of 7 could be stereoselectively replaced by a Cl atom with formation of corresponding chlorohydrins 55 which upon base treatment should give the cycloalkenyl oxiranes 56. The feasibility of a Cl substitution of the sulfoximine group had been shown previously in the case of S-alkyl sulfoximines [40]. 

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 loading of resin 60 and the success of each step of its synthesis was determined by an off-bead analysis involving the removal of the reaction products from the resin through an oxidative hydrolysis of the sulfoximine group at the S—N bond with formation of the corresponding sulfones by a method we have described recently [42]. 

The acyclic sulfonimidoyl-substituted amino acids 24 were selected as starting material for the synthesis of the unsaturated prolines of type 63. Because of the facile synthesis of the unsaturated bicyclic tetrahydrofurans 53 from the vinyl aminosulfoxonium salts 46 (cf. Scheme 1.3.20), it was speculated that upon treatment with a base the vinyl aminosulfoxonium salts 67 would experience a similar isomerization with formation of the allyl aminosulfoxonium salts 69, which in turn could suffer an intramolecular substitution of the allylic aminosulfoxonium group (Scheme 1.3.24). The methylation of sulfoximines 24 with Me30Bp4 gave... 

Later, this reaction sequence was further optimized [42], and also shown to be useful for the synthesis of other N-alkylated sulfoximines, including those (such as 57) prepared from amino acids (Scheme 2.1.1.16). 

A very promising new method for converting oxiranes, as well as ketones, into oxetanes has recently been reported. This method uses the carbanion of dimethyl(N-tosyl)sulfoximine and gave good yields in the several cases reported. When this reagent is employed with ketones, oxirane formation is presumably an intermediate stage, but the oxirane is not isolated. The method thus provides an excellent synthesis of spiro-oxetanes from ketones, as the example with camphor in equation (85) shows (79JA6135). 

Another example of the superiority of the alkoxy group as a directing group was reported by Johnson in his synthesis of enantiomericaUy pure cyclopropyl ketones after auxiliary cleavage (equation 56). In that case, the product resulting from a sulfoximine directed cyclopropanation was never observed. 

The treatment of N-aminourazole (38) with two equivalents of BAIB in DMSO results in imidation of the sulfoxide and oxidation of the urazole ring to give the sulfoximine 39 (Scheme 20) [46]. The preparation of 39 from 38 can also be accomplished stepwise, by isolation of the dihydro sulfoximine intermediate and BAIB-oxidation of this compound in acetonitrile. The sulfoximine 39 was not isolated, but was generated in solution and employed for the synthesis of bicyclic diazenes. 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

Johnson disclosed the synthesis of the first reported allylic sulfoximine 104a in 1979 5 Treatment 0f racemic phenyl N-methylbenzenesulfonimidate 103 (X=OPh) with allyl lithium at 0-3 °C gave racemic S-allyl-/V-methyl-S-phenylsulfoximine 104a in 71% yield. Harmata75 has used a method related to that developed by Johnson6 to prepare the allylic sulfoximine 104b from the reaction of allyllithium with the sulfonimidoyl fluoride 103 (X=F). The yield, however, was low (20%). 

The osmylation of l-[Af-methylphenylsulfoximinomethyl]-l-hydroxy-2-cyclopentenols and -2-cyclohexenols, obtained in turn from the corresponding 2-cycloalkenones by the addition of lithiated, V,.S -dimethyl-5-phenylsulfoximine, occurs from the same side as the sulfoximino functionality with complete Ik topicity. Subsequent thermal elimination of the sulfoximine group allows the synthesis of optically pure 2,3-dihydroxycycloalkanones. This method can, therefore, be regarded as proceeding via an auxiliary-controlled osmylation92-93. 

Ylides derived from the salts obtained by A. A -dialkylation of sulfoximines and anions derived from A -tosylsulfoximines are useful reagents for the synthesis of epoxides or cyclopropanes from aldehydes and ketones or enones. ... 

The most commonly used reagents to effect the addition of a methylene group to an aldehyde or ketone are sulfur ylides such as dimethylsulfonium methylide (1) or dimethyloxosulfonium methylide (2) (Corey-Chaykovsky reaction). This reaction is well reviewed in standard treatises of organic synthesis - and several useful monographs. - This update will concentrate on progress attained from 1975. The reader is also encouraged to consult reviews on the chemistry of the related sulfoximine-derived ylides such as (3). -"... 

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