Time for a round-up of this weeks #Reactionoftheday. On offer this time we have enatioselective organocatalytic cyclopropanation of olefins, chiral α-arylation of ketones, a traceless non-metal mediated sulfoxide reduction, a nickel-catalysed cycloisomerization of 1,6-dienes giving complex pyrrolidines, and finally we flip the silicon switch with a robust approach to silyl-amino acids.
Nickel(II)-Catalysed Cycloisomerization of 1,6-Dienes
You et al, Synthesis 2025, 57, 1306–1312
https://doi.org/10.1055/a-2508-3790
The generation of complex pyrrolidines from simple acyclic precursors offers a rapid and efficient method for building molecular complexity. This report by You et al. describes the carbocyclisation of tethered 1,6-dienes using an in situ generated nickel–triphenylphosphine complex, with zinc as a reductant and ZnI₂ as an additive. Mechanistically, a nickel hydride species is proposed to mediate the transformation. The resulting olefin products undergo further synthetic elaboration, including oxidation, reduction and fluorination.
- Pyrrolidine in drug discovery: a versatile scaffold for novel biologically active compounds: G. Petri et al. Curr. Chem. 2021, 379,34
- Dienes as versatile substrates for transition metal-catalyzed reactions: S. Paradine et al, Chem. Int. Ed. 2024, 63, e202401550
- Nickel-catalszed desymmetrizing cyclization of 1,6-dienes to construct quaternary stereocenters: Q. L. Zhou et al, Org. Lett. 2021, 23, 3814-3817
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A Unified Approach to Chiral α‑Aryl Ketones and Aldehydes via Ni- Catalysed Asymmetric Reductive Cross-Coupling
Gong et al, J. Am. Chem. Soc. 2025, 147, 17251-17259
https://doi.org/10.1021/jacs.5c03418
The α-arylation of ketones is a well-established transformation. However, the enantioselective synthesis of tertiary α-aryl ketones and aldehydes remains a significant challenge, despite their importance as privileged pharmacophores and key scaffolds in natural products and drugs. A major obstacle is post-reaction epimerization, which commonly occurs in unprotected tertiary α-aryl carbonyl products.
In a noteworthy study, the Gong group reports a reductive α-arylation of α-halo ketals and acetals using aryl halides. The protecting groups not only impart steric hindrance around the carbon–iodide bond, promoting high enantioselectivity, but also stabilize the products against racemisation, making them amenable to further transformations.
The reaction employs a nickel catalyst in combination with a cy-BiOX ligand, and DFT calculations support a mechanism in which alkyl radical addition to an Ar–Ni(II)–X complex is both the enantioselectivity-determining and turnover-limiting step.
- Catalytic enantioselective α-arylation of carbonyl enolates and related compounds: J. S. Yu et al, ACS Catal. 2020, 10, 955–993
- Reactivity of (bi-oxazoline) organonickel complexes and revision of a catalytic mechanism: T. Diao et al, Am. Chem. Soc .2021, 143, 14458-14463
- Cross-electrophile coupling: principles, methods, and applications in synthesis: D. Weix et al, Chem. Rev. 2024, 124, 13397-13569
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Organocatalytic regio- and stereoselective cyclopropanation of olefins
List et al, Nature Cat. 2025
https://doi.org/10.1038/s41929-025-01340-7
The asymmetric synthesis of cyclopropanes from alkenes using chiral metal complexes and engineered P450 enzymes is now an established method for constructing these important cyclic alkanes. Typically, metallo-carbenes derived from diazo precursors deliver high yields and excellent selectivity in cyclopropanation reactions.
In a complementary and innovative development, the List group has reported a metal-free approach employing asymmetric counteranion-directed organocatalytic photoredox catalysis. This method utilizes an ion pair consisting of a thioxanthylium photocatalyst and a chiral imidodiphosphorimidate, in combination with a diazo precursor. The reaction affords very high enantioselectivity in the cyclopropanation of both styrenes and aliphatic dienes.
Mechanistically, the reaction is believed to proceed via olefin-derived radical cation intermediates. Remarkably, the enantioselectivity is wavelength-dependent, highlighting a unique aspect of this organophotoredox approach. This strategy effectively addresses a long-standing limitation of metal-based and enzymatic systems—namely, poor regioselectivity in substrates bearing multiple carbon–carbon double bonds.
An interesting example of the methodology’s utility is the enantioselective synthesis of chrysanthemic acid. Additionally, a noteworthy derivatisation step involves ruthenium-catalyzed oxidation of a para-methoxyphenyl group to the corresponding carboxylic acid.
- Visible light-mediated cyclopropanation: recent progress: J. Xuan et al, Eur. J. Org. Chem. 2022, 44, e202201066
- Catalytic asymmetric cyclopropanations with nonstabilized carbenes: C. Uyeda et al, J. Am. Chem. Soc. 2023, 145, 9441-9447
- Put a ring on it: application of small aliphatic rings in medicinal chemistry: RSC Med. Chem., 2021, 12, 448-471
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Metal-free and scalable sulfoxide reduction through the couple (COCl)2/Et3SiH: synthesis of albendazole hydrochloride
Gamba-Sánchez et al, Synthesis 2025,
https://doi.org/10.1055/a-2589-4908
In a recent paper, Gamba-Sánchez and co-workers report a metal-free reduction of sulfoxides to thioethers using a combination of oxalyl chloride and triethylsilane. This methodology builds on their earlier work (Processes 2022, 10, 1115), where they employed oxalyl chloride in the presence of ethyl vinyl ether as a chlorine scavenger to achieve similar transformations.
The new protocol is believed to proceed via electrophilic activation of the sulfoxide, resulting in the formation of a chlorosulfonium intermediate, accompanied by the traceless release of gaseous by-products. This reactive intermediate is then intercepted by a hydride source—in this case, triethylsilane—leading to clean reduction to the corresponding thioether.
In the paper this method is its use in the multi-gram scale synthesis of the anti-parasitic drug albendazole, demonstrating both the practicality and scalability of the approach. Importantly, both papers emphasise that the reactions proceed under mild, chemoselective conditions and avoid the need for chromatographic purification, factors important for larger scale application.
- Reduction of sulfoxides in multigram scale, an alternative to the use of chlorinated solvents: Gamba-Sánchez et al, Processes 2022, 10, 1115
- A decade updates (2011–2020): Reduction of sulfoxides to sulfides: M. Kazemi et al, Synthetic Communications, 2021, 51, 1609–1635
- Visible light induced deoxygenation of sulfoxides with isopropanol: J. Zhao et al, Chem. Front., 2023, 10, 5254-5259
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Modular access to silicon-containing amino acids and peptides by cobalt catalysis
Lie et al, Angew. Chem. Int. Ed. 2025, 64, e202421190
https://doi.org/10.1002/anie.202421190
The bioisosteric replacement of carbon with silicon, often referred to as the “silicon switch,” is an active area of research in biological and pharmaceutical chemistry. Unnatural silicon-containing amino acids serve as valuable building blocks for modified peptides with enhanced resistance to proteolytic degradation and the ability to modulate the physicochemical and biochemical properties of bioactive peptides.
However, the synthesis of silicon-containing amino acids remains a challenge. Recent work by Jie Li at Soochow University presents a rapid and modular approach to access these building blocks via a cobalt-catalyzed silylamidation of unconjugated internal alkenes using dioxazolones and silylzinc pivalates. The study includes several examples of modified natural products and pharmaceuticals.
A key reagent in this methodology, the salt-stabilised solid silylzinc pivalate (PhMe₂Si–ZnOPiv), is prepared via transmetalation of silyllithium reagents with zinc pivalate [Zn(OPiv)₂].
- Silicon-containing amino acids: synthetic aspects, conformational studies, and applications to bioactive peptides: F. Cavelier et al, Rev. 2016, 116,11654–11684
- Salt-stabilized silylzinc pivalates for nickel-catalyzed carbosilylation of alkenes: J. Li et al, Chem. Int. Ed. 2022, 61, e202202379
- Directed evolution of cytochrome c for carbon–silicon bond formation: bringing silicon to life: F. Arnold et al, Science 2016, 354, 1048-1051
