Allylic sulfoximines synthesis

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.

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%). 

Sulfoximines are versatile reagents for diastereoselective and asymmetric synthesis. They continue to find many synthetic applications as both nucleophilic and electrophilic reagents. While the nucleophilic character of sulfoximine reagents has been well exploited,1 the use of the sulfoximine group as a nucleofuge is more recent and adds to the synthetic use of these compounds. The palladium(0)-catalyzed chemistry of allylic sulfoximines and the use of chiral sulfoximines as ligands in catalytic asymmetric synthesis are areas of recent development that have potentially useful applications. Further work is required to understand the factors that determine the diastereoselection and the stereochemical outcomes of these reactions. These studies will result in enhanced product diastereo- and enantioselectivities and make these reagents even more attractive to the wider synthetic chemistry community. 

The chemistry of imidosulfinates is vastly unexplored [10] and nothing is known to date about the behavior of 0-allyl imidosulfinates in particular. By comparison with the known process C (Chart 1), the sulfinate-sulfone rearrangement (Sect. 2.2), it seems rather promising to try a new sulfoximine synthesis based on that rearrangement. 

Interestingly, when (1) reacted with allyltributyltin, no benzoth-iazine was formed at all. Instead, the allyl sulfoximine (2) was produced in 77% yield (eq 8). Although studies of the alkylation of the anion of 2 did not demonstrate high degrees of diastereoselection, subsequent work with allyUc sulfoximines demonstrated that such reagents could be quite useful in asymmetric synthesis. ... 

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... 

S. G. Pyne, Addition of Metalated Allylic Phosphine Oxides, Phosphonates, Sulfones, Sulfoxides and Sulfoximines to a,/3-Unsaturated Carbonyl Compounds , in Stereoselective Synthesis (Houben-Weyl) 4th ed. 1996, (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), 1996, Vol. E21 (Workbench Edition), 4, 2068-2086, Georg Thieme Verlag, Stuttgart. 

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