Understanding Regioselectivities of Corey–Chaykovsky Reactions of Dimethylsulfoxonium Methylide (DMSOM) and Dimethylsulfonium Methylide (DMSM) toward Enones: A DFT Study

Abstract

The Corey–Chaykovsky reaction, using either in situ generated dimethylsulfoxonium methylide (DMSOM) or dimethylsulfonium methylide (DMSM) to react with ketones or aldehydes, is widely used in the synthesis of epoxides. However, when DMSOM and DMSM react with enones (such as chalcone), the former reactions give cyclopropanation products whereas the latter reactions still generate epoxides. DFT calculations have been carried out to understand these different regioselectivities. We found that the cyclopropanation pathways for both DMSOM and DMSM toward chalcone (a model for enones) start with rate‐determining and irreversible 1,4‐addition reactions, followed by easier intramolecular substitution reactions to give cyclopropanes. The overall activation free energies for cyclopropanation are 17.5 and 15.5 kcal/mol for DMSOM and DMSM, respectively. The epoxidation pathways for both DMSOM and DMSM have reversible 1,2‐addition reactions, followed by rate‐determining intramolecular substitution reactions to give epoxides. The computed barriers for the epoxidation are 23.0 and 13.3 kcal/mol for DMSOM and DMSM, respectively. Therefore, the cyclopropanation pathway is favored for DMSOM while epoxidation is preferred for DMSM. We attribute these different reaction scenarios to thermodynamic reasons that DMSOM is more stable than DMSM. The reaction pathways for reactions of other derivatives of DMSM toward enones have also been discussed.

Gram-Scale, Seven-Step Total Synthesis of (−)-Colchicine

“…Additionally, the adoption of environmentally friendly reagent PIDA rather than highly toxic Pb­(OAc) 4 and Tl­(NO 3 ) 3 used stoichiometrically in Banwell’s route merits attention. Nucleophilic cyclopropanation of compound 18 with dimethylsulfoxonium methylide proceeded both regio- and stereoselectively to rapidly result in an 82% yield of a single tetracyclic product 19 within 10 min. The resulting cyclopropane’s configuration was tentatively assigned because it could not be established unequivocally with NMR techniques, and a single crystal of compound 19 could not be acquired.…”

Ring-Opening Cyclization of Spirocyclopropanes Using Sulfoxonium Ylides

“…Initially, the reaction was carried out using highly reactive dimethylsulfonium methylide (1a), which was prepared in situ from trimethylsulfonium iodide (6) (Chart 3). After treatment of sulfonium salt 6 using sodium hydride in dimethylsulfoxide (DMSO) at room temperature for 0.5 h, 3) the produced sulfonium ylide 1a was reacted with 2′-phenylspirocyclopropane 3a. 20) Unfortunately, reaction at room temperature for 24 h gave only decomposition products, indicating that the reactivity of 1a is too high to induce a ring-opening cyclization reaction.…”

“…Next, the reaction of the lower reactive sulfoxonium ylide 2a with 3a was examined (Table 1). When the dimethylsulfoxonium methylide (2a), which was prepared in situ from 2.1 eq of trimethylsulfoxonium iodide (7a) using 2.0 eq of sodium hydride in DMSO at room temperature for 0.5 h, 3) reacted with 3a, the desired ring-opening cyclization proceeded regioselectively at room temperature within 8 h to afford 3-phenyl-2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-one (5a) in 68% yield (entry 1). Trimethylsulfoxonium chloride (7b) proved to be a more suitable sulfoxonium ylide precursor than 7a, leading to a higher yield of 5a (76%, entry 2), presumably because side reactions caused by the presence of the highly nucleophilic iodide ion are prevented when switching to the lower nucleophilic chloride ion.…”

“…However, when reacted with enones, they behave differently. For example, dimethylsulfonium methylide (1a) reacts with calcone to afford epoxide in 87% yield, whereas dimethylsulfoxonium methylide (2a) produces cyclopropane in 95% yield 3) (Chart 1). Using density functional theory calculations, Yu and colleagues recently reported that these different reaction outcomes can be attributed to thermodynamics, as sulfonium ylide 1a is less stable, and therefore more highly reactive, than sulfoxonium ylide 2a.…”

Highly Enantio- and Diastereoselective Synthesis of 1,2,3-Trisubstituted Cyclopropanes from α,β-Unsaturated Amides and Stabilized Sulfur Ylides Catalyzed by a Chiral Copper(I) Complex

“…The 7-azaindoline amide 2p readily interacts with the Cu­(I)/ L* complex to form a Z -configured complex I , , which increases the electrophilicity of 2p for the nucleophilic attack of the ylide 1a in a chiral environment . After the initial stereodetermining asymmetric C–C bond formation at the β-position in an irreversible pathway, the resulting major Cu-enolate intermediate II undergoes the intramolecular S N 2 displacement to afford 4ap as the major diastereomer (confirmed by X-ray). The minor Cu-enolate intermediate III on the other hand gives 4ap′ , also confirmed by X-ray; see the Supporting Information).…”