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those developed for selenium and silicon. Sulfenyl electrophiles are Lewis acidic as a result of their ability to accept electrons into the S-X σ* orbital.23 Thus, the interaction of a suitable Lewis base with sulfenyl electrophiles is expected to increase their reactivity, ideally to the point where they can be engaged by simple alkenes. If the Lewis base is chiral, the resulting sulfenium source would also be chiral, and potentially able to impart stereochemical information to the nascent thiiranium ion. The ability of the Lewis base to increase the reactivity of the sulfenium moiety is paramount in avoiding a stereoselectively deleterious background reaction. In light of these requirements, a plausible framework for catalytic, enantioselective sulfenylation of alkenes can be formulated. The process commences with the activation of the sulfenylating reagent 49 by a chiral Lewis base (LB) 48 to generate intermediate activated sulfenium source 50 (Figure 9).62 Consistent with the principles of Lewis base activation, the redistribution of the electron density from the S-atom toward the peripheral ligand (X) enhances the Lewis acidity of the S-center. The increased Lewis acidity facilitates the nucleophilic attack of the alkene onto 50 (step 2). The interception of the resulting thiiranium ion 51, enantioenriched as a consequence of the chirality of 48, by a nucleophile (step 3) leads to the formation of the product (53) and regenerates the Lewis base catalyst (step 4). In the desired reaction framework, both the enantioselectivity of thiiranium formation as well as the stereochemical integrity of the resulting thiiranium ion need to be well controlled. Furthermore, for high selectivity and chemical yield, nucleophilic attack on 51 needs to proceed site selectively among the carbon and sulfur atoms of the thiiranium ion.

Figure 9. Mechanistic Framework for a Lewis Base Catalyzed Sulfenofunctionalization Process

Efforts toward achieving catalytic, enantioselective sulfenylation of alkenes have hinged upon the discovery of conditions that allow for the controlled formation and capture of enantioenriched thiiranium ions. Although the stereoselective, stoichiometric synthesis of thiiranium ions has been accomplished (see Section 2.1.3), these methods did not provide any insights into the configurational stability of thiiranium ions under catalytic conditions.

Mechanistically, three major pathways can result in thiiranium ion racemization (Scheme 19).63 The first involves the unimolecular racemization of thiiranium ions through equilibrium with an open carbocation (path a). The second mechanism entails nucleophilic attack at the sulfur center followed by addition of the resulting sulfenium moiety to the alkene (path b). Finally, the racemization could occur via a bimolecular alkene-to-alkene transfer mechanism (path c). In a series of studies from these laboratories, each of these issues were separately addressed to provide the foundation for highly-enantioselective, catalytic, sulfenofunctionalization reactions.

Scheme 19

The configurational stability of thiiranium ions in the presence of hard nucleophiles was established by demonstrating high enantiospecificity in the formation and capture of enantiomerically enriched thiiranium ions.63 Specifically, thiiranium ion 54, prepared from enantioenriched β-chloro sulfide 55 at -40 o

C, undergoes highly stereospecific capture with a variety of nucleophiles at -20 oC to afford the corresponding enantioenriched thioether products (Scheme 20). The use of neutral and anionic oxygen nucleophiles as well as azides results in the formation of β-thioethers, esters, and azides with high enantiospecificity. Thus, thiiranium ions are configurationally stable in the presence of hard nucleophiles at -20 oC. Additionally, the high enantiospecificity observed with all nucleophiles investigated suggests that a unimolecular racemization process does not occur on the timescale of nucleophilic capture (Scheme 19, paths a and b).

Under catalytic conditions, thiiranium ions (e.g., 55, Scheme 21) are generated in low concentration in the presence of Lewis bases. Therefore, the configurational stability of thiiranium ions with respect to various Lewis bases is critical. The enantiospecificity for the methanolysis of thiiranium ion 55 is highly dependent on the nature of the Lewis base in the reaction mixture.63 Whereas complete loss of configurational homogeneity occurs in the presence of diphenyl disulfide, high enantiospecificity is observed for the reaction with tetrahydrothiophene as the Lewis base. These results suggest that the enantiomeric composition of the thiiranium ion in a reaction can be maintained using non-chalcophilic Lewis bases (e.g., tetrahydrothiophene) as catalysts.

Scheme 21

The direct transfer of thiiranium ions between two alkenes has been studied both experimentally and computationally.40,64 Rapid sulfenium ion transfer between trans-thiiranium ions occurs at 0 oC (Table 3, entries 1 and 2). In addition, the sulfenium ion can be transferred between cis- and trans- thiiranium ions (entries 3 and 4).

Table 3. Alkene-to-alkene Transfer of Thiiranium Ions.

entry R1 R2 Keq 1 (E)-n-Pr Bn 0 2 Bn (E)-n-Pr 100 3 (E)-n-Pr (Z)-n-Pr 2 4 (Z)-n-Pr (E)-n-Pr 1a a

Consequently complete racemization of enantioenriched thiiranium ion 55 occurs in the presence of an excess of (E)-4-octene at 0 oC as evidenced by the formation of racemic methoxylated product (Scheme 22). However, the olefin-to-olefin transfer process proved to be temperature-dependent, as the racemization of 55 is completely suppressed at -20 oC. These data implicated that the racemization of thiiranium ions via path c can be prevented by judicious choice of reaction conditions.

Scheme 22

2.3. Goals of the Project.

The detailed mechanistic experiments demonstrated that stereocontrol over thiiranium ion formation is possible. Furthermore, all known major racemization pathways of thiiranium ions can be suppressed for methanol capture. Thus, the challenge lay in identifying a suitable electrophile-Lewis base combination and reaction conditions that would allow for the catalytic formation of thiiranium ions with high stereoselectivity and prevent their racemization.