Practical and highly selective sulfur ylide-mediated asymmetric epoxidations and aziridinations using a cheap and readily available chiral sulfide: extensive studies to map out scope, limitations, and rationalization of diastereo- and enantioselectivities.

The chiral sulfide, isothiocineole, has been synthesized in one step from elemental sulfur, γ-terpinene, and limonene in 61% yield. A mechanism involving radical intermediates for this reaction is proposed based on experimental evidence. The application of isothiocineole to the asymmetric epoxidation of aldehydes and the aziridination of imines is described. Excellent enantioselectivities and diastereoselectivities have been obtained over a wide range of aromatic, aliphatic, and α,ß-unsaturated aldehydes using simple protocols. In aziridinations, excellent enantioselectivities and good diastereoselectivities were obtained for a wide range of imines. Mechanistic models have been put forward to rationalize the high selectivities observed, which should enable the sulfide to be used with confidence in synthesis. In epoxidations, the degree of reversibility in betaine formation dominates both the diastereoselectivity and the enantioselectivity. Appropriate tuning of reaction conditions based on understanding the reaction mechanism enables high selectivities to be obtained in most cases. In aziridinations, betaine formation is nonreversible with semistabilized ylides and diastereoselectivities are determined in the betaine forming step and are more variable as a result.

On the mechanism of ylide-mediated cyclopropanations: evidence for a proton-transfer step and its effect on stereoselectivity.

In this paper, we describe studies on the cyclopropanation of Michael acceptors with chiral sulfur ylides. It had previously been found that semi-stabilized sulfonium ylides (e.g., Ph-stabilized) reacted with cyclic and acyclic enones and substituted acrylates with high ee and that stabilized sulfonium ylides (e.g., ester-stabilized) reacted with cyclic enones again with high ee. The current study has focused on the reactions of stabilized sulfonium ylides with acyclic enones which unexpectedly gave low ee. Furthermore, a clear correlation of ee with ylide stability was observed in reactions with methyl vinyl ketone (MVK): ketone-stabilized ylide gave 25% ee, ester-stabilized ylide gave 46% ee, and amide-stabilized ylide gave 89% ee. It is believed that following betaine formation an unusual proton transfer step intervenes which compromises the enantioselectivity of the process. Thus, following addition of a stabilized ylide to the Michael acceptor, rapid and reversible intramolecular proton transfer within the betaine intermediate, prior to ring closure, results in an erosion of ee. Proton transfer occurred to the greatest extent with the most stabilized ylide (ketone). When the same reactions were carried out with deuterium-labeled sulfonium ylides, higher ee's were observed in all cases since proton/deuteron transfer was slowed down. The competing proton transfer or direct ring-closure pathways that are open to the betaine intermediate apply not only to all sulfur ylides but potentially to all ylides. By applying this model to S-, N-, and P-ylides we have been able to rationalize the outcome of different ylide reactions bearing a variety of substituents in terms of chemo- and enantioselectivity.