On the Mechanism of Ylide-Mediated Cyclopropanations: Evidence for a Proton-Transfer Step and Its Effect on Stereoselectivity

Abstract

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.

A novel system for the Suzuki cross-coupling reaction catalysed with light fluorous palladium–NHC complex

“…KOH was found to be the most effective base for the reaction (Table 2, entry 5). Because KOH has properly alkaline in this system, and the size of cation K + also has benefit to promote the synthesis of ylide(Pd) efficiently to give high yields [30][31][32]. Then, different catalyst loadings were tested for the reaction.…”

Asymmetric Synthesis of 2,3‐Dihydrobenzofurans by a [4+1] Annulation Between Ammonium Ylides and In Situ Generated o‐Quinone Methides

“…Another potential explanation involves the epimerisation of the betaine intermediate A by ad eprotonation/protonation mechanism, such as previously observed by Aggarwal and coworkers in sulfur ylide mediated cyclopropanation reactions. [22] Indeed, the computed relative free energy of B (0.7 kcal mol À1 ; Figure 2) indicatesafacile protont ransfer, and hence epimerisation, in cis-A (see the Supporting Information for full details). The observed high trans selectivity can thus be accounted for by selective cis-A formation followed by rapid epimerisation into trans-A,w hich then undergoes ring closure to give the Figure 2).…”

Racemic total synthesis of dactyloidin and demethyldactyloidin through the dl-proline-catalyzed Knoevenagel condensation/[4 + 2] cycloaddition cascade

“…1 H NMR (400 MHz, CDCl 3 ): δ = 9.76 (t, J = 1. (4-bromobutoxy)(tert-butyl)dimethylsilane (12). HBr (90.6 g, 0.54 mol, 48% in water) was added dropwise to refluxing THF (135 mL).…”