LG

Privileged chiral catalysts have transformed asymmetric synthesis, conferring generality to processes that are routinely leveraged in the construction of societally important functional small molecules. This mini-review is intended to survey the conception and evolution of privileged chiral photocatalyst scaffolds that enable simultaneous orchestration of reactivity and enantioselectivity in non-ground state regimes.

Abstract

Privileged chiral catalysts have transformed asymmetric synthesis, conferring generality to processes that are routinely leveraged in the construction of societally important functional small molecules. Operating in the ground state, these catalysts are conspicuous in their ability to simultaneously regulate reactivity and translate chiral information, often with broad substrate tolerance: this technology continues to expedite chemical space exploration. In stark contrast to the specificity of many enzymatic transformations, this promiscuity affords remarkable latitude for creative endeavour in synthesis. Given the transformative impact that stereoselective photocatalysis has had over the last decade, identifying privileged chiral catalysts that permit reactivity and enantioselectivity to be regulated in excited-state scenarios has emerged as an attractive but challenging frontier. Providing solutions to address this paradox will require the reactivity/selectivity divide to be reconciled through the validation of chiral scaffolds that effectively operate in non-ground state environments. Inspired by the venerable treatment by Yoon and Jacobsen entitled “Privileged chiral catalysts” (Science 2003, 299, 1691–1693), this mini-review is intended to survey the conception and evolution of privileged chiral photocatalyst scaffolds, and offer a perspective on emerging contenders.

Nature Chemistry, Published online: 01 August 2025; doi:10.1038/s41557-025-01893-x

Humans have a habit of overusing natural resources even though there are numerous examples through history of the issues that this causes. Chemists can sometimes help to avoid such tumultuous events, but in doing so can gravely impact sectors of society. Amid the backdrop of the Highland Clearances in Scotland, Bruce Gibb discusses the farming of kelp and how chemistry became its ‘enemy’ with the industrial generation of sodium carbonate.

An electrochemical approach has been developed for late-stage direct trideuteromethyl incorporation into thioethers by using stoichiometric methanol-d ₄ as the trideuteromethyl isotopic source. Mechanistic studies showed that the sulfonium salt generated in situ is the key intermediate. Control experiments revealed that in situ generation of the sulfonium and its subsequent reduction at the cathode is the key to alkyl displacement and precise late-stage trideuteration.

Abstract

Deuterated compounds exhibit significant pharmacokinetic advantages and have been widely applied in drug discovery. Trideuteromethyl-containing compounds represent a substantial portion of both approved deuterated drugs and those in development. Traditional approaches to incorporate trideuterated methyl group with trideuterated methyl sources (such as iodomethane-d ₃, dimethyl sulfate-d ₆) require preactivated synthetic precursor, limiting the application for the late-stage trideuteromethyl group incorporation of pharmaceutical molecules. Herein, we develop an electrochemical approach for late-stage trideuteromethyl incorporation of thioether by using stoichiometric methanol-d ₄ as the trideuteromethyl isotopic source via a sulfide alkyl displacement. This protocol features operational simplicity, selectivity, and scalability, enabling direct alkyl modification of various aryl alkyl sulfides as well as gram-scale production of trideuteromethyl drugs without the need for synthetic precursors. Mechanistic studies show that the in-situ generated sulfonium salt was the key intermediate. A series of control experiments reveals that alkanes as the departing moiety are the key to alkyl displacement and precise late-stage trideuteration.

Cooperative N-heterocyclic carbene and photoredox catalysis for C─H benzoylation and esterification of allenes is presented. This reaction proceeds through the cross-coupling of in situ generated ketyl and allyl radicals.

Abstract

This study demonstrates the use of cooperative photoredox and N-heterocyclic carbene (NHC) catalysis for sp² C─H acylation of allenes. The cascade comprises oxidative generation of an allene radical cation from an allene, its nucleophilic trapping to the corresponding allyl radical and highly regioselective cross coupling by a concomitantly reductively generated NHC-derived ketyl type radical. Ionic fragmentation of both the NHC and nucleophile ultimately yields the desired substituted allene. The organic photocatalyst, 4CzIPN, is highly effective in promoting both oxidative and reductive electron transfer steps. Tri- and tetra-substituted allenes can be obtained in good yields through such a cascade. Mechanistic studies—including radical trapping, acylazolium reactions, and Stern–Volmer quenching—support the proposed mechanism. Moreover, follow-up chemistry is conducted to demonstrate the synthetic value of the cascade products.

Vibrational Strong Coupling (VSC) was recently shown to modify chemical reactivity, but it is unclear why. We introduce the Diels–Alder (DA) reaction as a mechanistic probe for some of the most popular hypotheses and provide the first experimental investigation of the DA reaction under VSC by measuring the kinetics of six different DA reactions under various coupling conditions. No significant change in kinetics was observed.

Abstract

Vibrational Strong Coupling (VSC) has recently been reported to alter reaction kinetics. Hypotheses on how it does this have been proposed, but open questions remain regarding the importance of the polarity of the reaction mechanism and of intramolecular vibrational redistribution (IVR), among other factors. We propose the Diels–Alder (DA) reaction as a probe to study chemistry under VSC, owing to the high diversity of its reaction partners. Herein, fixed-width cavities and UV–vis spectroscopy were used to determine the rate constants for the reactions of the diene 1,3-diphenylisobenzofuran (DPIBF) with various dienophiles under different coupling conditions. We investigated the effect of coupling six different solvents and of cooperative coupling of the dienophile through the solvent. Secondly, as the DA reaction can be catalyzed by hydrogen bonding, we investigated how the reaction was influenced by coupling alcohol solvents. Finally, we explored the direct coupling of vibrational modes of the dienophiles, including the stretching mode of the reactive C═C bond. In all cases, no substantial changes to the reaction rate constants were observed among the diverse coupling scenarios explored. This work initiates the use of the DA reaction as a mechanistic platform to understand how VSC changes chemistry and invites further experimental and theoretical studies.

The air- and water-stable Ni(0) complex [Ni(PFPh₂)₄] is obtained via a unique in-situ reduction and fluorination mechanism from [Ni(MeCN)₄](BF₄)₂ and Ph₂P(═O)─PPh₂, incorporating typically unstable fluorophosphine ligands. In their Research Article (e202506271), Schirin Hanf et al. demonstrated its utility as a robust Ni(0) source, and showed its superior catalytic activity in coupling reactions compared to the conventional [Ni(COD)₂].

A nickel-catalyzed cross-electrophile coupling between homopropargyl halides and aryl/vinyl electrophiles provided direct access to polysubstituted cyclobutenes. Experimental data and computational studies support a reductive 4-endo-dig cyclization involving an alkenyl nickel(I) intermediate, which undergoes facile S_H2 attack to produce the strained cyclobutene ring with overall stereoinversion at the homopropargylic position.

Abstract

The synthesis of cyclobutenes remains inefficient owing to inherent ring strain and poor regioselectivity. We describe herein a nickel-catalyzed cross-electrophile coupling (XEC) between readily accessible homopropargyl halides and commercially available aryl/vinyl electrophiles for direct access to polysubstituted cyclobutenes. This approach provides the first reductive 4-endo-dig cyclization with high chemo- and regioselectivity, which paves the way for the synthesis of diverse cyclobutene containing compounds (including synthetically challenging macrocycles). The synthesis of an antitumor-active combretastatin A-4 analog has been significantly optimized; the original six-step procedure yielding 14% has been streamlined into a three-step process with a markedly improved yield of 51%. Experimental data and computational studies support a mechanism involving an alkenyl nickel(I) intermediate, which undergoes facile back-side S_H2 attack to produce the strained cyclobutene ring with overall stereoinversion at the homopropargylic position.