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Chiral sulfoxides have discovered widespread purposes within the pharmaceutical trade. Examples of those compounds embrace Esomeprazole, a proton pump inhibitor, and Modafinil, which is used to deal with narcolepsy. Moreover, chiral sulfoxides play a vital position as ligands in uneven synthesis reactions catalyzed by transition metals. The addition response to unsaturated bonds is an efficient technique for synthesizing chiral sulfoxides. Though the racemic response of in-situ generated sulfenic acid and alkynes was reported as early as 1967 (J. Am. Chem. Soc. 1967, 89, 718.), the corresponding uneven catalytic response has but to be achieved. That is primarily as a result of excessive instability of sulfenic acids and their innate reactivity, that are key limiting components within the improvement of the response. Our analysis group has been extensively investigating nickel-catalyzed uneven synthesis and mechanistic research. Now we have proposed a brand new mechanism mannequin for the uneven hydrophosphinylation of conjugated enynes catalyzed by nickel (Chem. Sci. 2022, 13, 4095). Now we have uncovered a proton switch mechanism as an alternative of the basic oxidation addition/insertion/response elimination course of. Based mostly on these findings, we imagine that, underneath applicable situations, the uneven hydrosulfenation of alkynes to yield chiral vinyl sulfoxide compounds might be achieved by using nickel(0) because the catalyst.
Fig. 1. Consultant drugs molecules and ligands.
The nickel-catalyzed uneven hydrosulfenation of alkynes poses substantial challenges. In depth screening of chiral ligands revealed that solely strongly electron-donating ones, similar to (R,R)-Ph-BPE, can efficiently produce the specified product with wonderful enantioselectivity. Alkaline components play a vital position in controlling the response’s exercise. Weak bases end in considerably slower response charges, whereas using sturdy bases results in decomposition of the beginning supplies. Remarkably, the response reveals wonderful substrate compatibility. Alkynes with various digital properties, in addition to aryl-substituted and alkyl-substituted sulfenic acids, can take part within the response. The response additionally proves helpful for the post-modification of sure drug molecules and biologically energetic compounds, affording corresponding merchandise with reasonable to excessive yields and distinctive enantioselectivity. Moreover, the ensuing chiral vinyl sulfoxides will be additional reworked into varied structurally advanced compounds, thus demonstrating the practicality of the technique.
Fig. 2. Chosen examples.
Management experiments and density purposeful idea (DFT) calculations, carried out in collaboration with Prof. Gang Lu of Shandong College, have make clear the mechanism of the response. It has been decided that the response proceeds by a nickel-mediated innersphere proton switch course of. Comparability of the Pure Inhabitants Evaluation (NPA) prices reveals that the coordination of the alkyne with nickel enhances the digital density of the alkyne by π-backdonation (Bull. Soc. Chim. Fr. 1951, 18, C79; J. Chem. Soc. 1953, 2939.; J. Chem. Soc. 1955, 4456.). This results in a extra negatively charged terminal carbon, indicating a stronger fundamental website. Moreover, the coordination of the sulfenic acid with nickel by sulfur additional augments the basicity of the alkyne carbon. Concurrently, electron switch from sulfur to the alkyne renders the proton on the sulfenic acid extra acidic in comparison with the free type. These components collectively facilitate the next protonation course of. The nickel catalyst demonstrates the flexibility to activate each the alkyne and the coordinating component reagent, thus offering assist for the design of different uneven hydrofunctionalization reactions involving heteroatoms.
Fig. 3. Computational research.
Extra particulars of this work will be discovered right here: “Nickel-catalysed enantioselective hydrosulfenation of alkynes” in Nature Catalysis. (https://www.nature.com/articles/s41929-023-00966-9)
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