Allyl sulfoximine

In contrast to allylic phosphine oxides, phosphonates, sulfones and sulfoxides, the chemistry of lithiated allylic sulfoximines has been less extensively developed25 27. The reaction of lithiated racemic A-phenyl-A -(4-rnethylphenyl)-S -(2-propenyl)sulfoximine with either 2-cy-clopentenone or 2-cyclohexenone gave a complicated mixture with 1,4-oc-ad ducts being slightly favored over the 1,4-7-adducts. The yields of these adducts were poor25. In contrast, lithiated racemic Ar-tert-butyldiphenylsilyl-5-phenyl-5,-(2-propenyl)sulfoximine gives mainly 1,4-y-ad-ducts on reaction with the same enones26. 

Endocyclic allylic sulfoximines 5 were synthesized from cydoalkanones and lithi-ated enantiomerically pure (S)-S-methyl-S-phenylsulfoximine, by addition and subsequent elimination and isomerization of the intermediate vinylic sulfoximines. 

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]. 

Scheme 1.3.2 Asymmetric synthesis of isocarbacyclin by the vinyl-allyl sulfoximine route.

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... 

Scheme 1.3.4 Synthesis of acyclic and cyclic allyl sulfoximines by the addition-elimination-isomerization route.

The lithiation of the T-configured acyclic allyl sulfoximines T-13 with n-BuLi gave the corresponding lithiated allyl sulfoximines -15 [15] which upon treatment with 1.1 equiv ofClTi(OiPr)3 at-78 to 0 °C in THF furnished the bis (allyl) titanium complexes -16, admixed with equimolar amounts of Ti(OiPr)4, in practically quantitative yields (Scheme 1.3.5) [14, 16]. Surprisingly the bis (allyl) titanium complexes -16 together with Ti(OiPr)4 and not the corresponding mono (allyl) titanium complexes were formed. 

The treatment of the cyclic allyl sulfoximines 14 with n-BuLi gave the corresponding lithiated allyl sulfoximines 17, which upon reaction with ClTi(OiPr)3 afforded the cyclic bis (allyl) titanium complexes 18 and equimolar amounts of Ti(OiPr)4 in practically quantitative yields [14]. The hydroxyalkylation of the cyclic complexes 18 with saturated and unsaturated aldehydes also proceeded with >98% regioselectivity and >98% diastereoselectivity at the y-position and gave the corresponding Z-onti-configured homoallyl alcohols 5 in good yields [14]. 

The treatment of the lithiated allyl sulfoximines E-15 with 1.1-1.2 equiv of ClTi(NEt2)3 at -78 to 0°C in THF or ether afforded the corresponding mono (allyl) titanium complexes E-19 in practically quantitative yields (Scheme 1.3.7) [14, 16]. Similarly the Z-configured complexes Z-19 were obtained from the Z-configured allyl sulfoximines Z-15. Reaction of the titanium complexes E-19 with aldehydes at -78 °C took place at the a-position and gave the corresponding homoallyl alcohols 6 with >98% diastereoselectivity in medium to good yields (Scheme 1.3.8) [14, 16]. 

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]. 

Scheme 1.3.21 Asymmetric synthesis of cycloalkenyl oxiranes via substitution of allyl sulfoximines.

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. 

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%). 

Treatment of enantiomerically pure cyclic sulfonimidates 6 and 7 with allyllithium or allylmagnesium bromide gives optically active allylic sulfoximines 8 and 9 (R = allyl) as described in Section II.A.13 The reactions of /V-phenyl-S-(methyl-phenyl)sulfoximidoyl chloride 109 with allyltrimethylsilane or allyltributylstan-... 

The imination of racemic allyl phenyl sulfoxide 112 with O-mesitylsulfonylhy-droxylamine (MSH)17 using a modification of the procedure described by Johnson,16 gave the allylic sulfoximines 113 in poor yield (29%).81 This compound was readily converted to the iV-tosyl or N-silyl derivatives 114.79,81... 

The crystal structures of three lithiated allylic sulfoximines have been reported.44,82 The X-ray crystal structure of lithiated 116/12-crown-4 complex showed solvent-separated contact ion-pairs of [Li(12-crown-4)2]+ and the allylic sulfonimidoyl anion.82 The anion adopts a conformation in which the p orbital at... 

The alkylation of the lithiated allylic sulfoximine 118 (R=Ph or CH2Ph) is completely regioselective and gives only a-alkylation products 119.75 The products were formed as mixtures of diastereoisomers, but the diastereomeric ratios were not reported. 

Lithiation and then methylation of the optically active allylic sulfoximine 120 gave the a-alkylation products 122 as a single diastereoisomer.79 The stereochemistry of this compound was deduced by its transformation to a compound of known stereochemistry. The stereochemical outcome of this reaction was rationalized as arising from methylation of the lithiated species 121 in which the p orbital at Ca is gauche to both the oxygen and nitrogen substituents of the sulfur atom. Methylation of 121 would be expected to occur syn to lithium and anti to the S-Ph group. 

The reaction of lithiated 123 with benzaldehyde gave a 5.3 1 mixture of the a-adduct 124 and the y-adduct 125, while a similar reaction with pivaldehyde produced only the a-adduct 124.75 These products were formed as mixtures of diastereoisomers, but the diastereomeric ratios were not reported. In related examples, a-adducts were exclusively obtained from the reaction of lithiated N-tert-butyldiphenylsilyl81 and N-methyl83 allylic sulfoximines with aldehydes. Again, these products were mixtures of diastereoisomers. 

Lithiation of racemic N-tosyl allylic sulfoximine 126 followed by quenching the reaction at -78 °C with benzaldehyde or isobutyraldehyde gave the a-adducts 130a and 130b, respectively, as mixtures of diastereoisomers.84 Interestingly, when these reactions were performed with an excess of the aldehyde (2 molar equiv) and... 

The reactions of titanated 133 and 134 with (R) and (5) TBDMS-protected lactaldehyde [MeCH(OTBDMS)CHO] are also highly diastereoselective. Very high levels of diastereoselectivity (> 98%) were observed when the facial selectivity of the allylic sulfoximine anion matched that of the chiral aldehyde (the matched case).86,87 In the mismatched cases the diastereoselectivities were less but still... 

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