Finn Moeller

Nature, Published online: 09 April 2025; doi:10.1038/d41586-025-01083-2

Communities of researchers worldwide are taking on the toxic research cultures that drive poor psychological health among academics.

The synthesis of cyanocyclopropanes is achieved via asymmetric nitrogen insertion into prochiral cyclobutanones. Key mechanistic steps involve an organocatalyzed asymmetric condensation followed by chirality transfer via an intercepted Neber rearrangement. The reaction can be conducted in a one-pot, stereodivergent manner, allowing access to all possible cyclopropane isomers with precise control of stereochemistry.

Abstract

The condensation of prochiral cyclobutanones and diphenylphosphinyl hydroxylamine is achieved under Brønsted acid catalysis. Interestingly, the competing aza-Baeyer–Villiger reaction is completely suppressed and the axially chiral oxime esters can be isolated in excellent yield and selectivity (up to 96% yield, up to 97:3 er). Computational analysis highlights the crucial role of the Brønsted acid in facilitating a successful condensation. Building on the inherent reactivity of the corresponding oxime esters, a one-pot protocol toward cyanocyclopropanes was discovered, which establishes two consecutive stereocenters. This unusual ring contraction is triggered by strong base and permits an axial-to-point chirality transfer with good enantiospecificity (up to 98% es). Fine-tuning the reaction parameters enables stereodivergent access to both diastereomers of the cyanocyclopropanes, and the utility of this method is demonstrated through the formal synthesis of the drug tasimelteon.

The widely used [2+2] cycloaddition-retroelectrocyclization reaction between tetracyanoquinodimethane (TCNQ) and an activated alkyne has been shown to occur with “inverted” regiochemistry to give exclusive formation of an unexpected regioisomer. A combined experimental and theoretical study helped unravel the peculiar reaction mechanism underlying the regioselectivity switching.

Abstract

In recent years, the [2+2] cycloaddition-retroelectrocyclization (CA-RE) reaction between electron-rich alkynes and electron-deficient alkenes has emerged as one of the most effective synthetic routes to prepare a large variety of molecular and polymeric electron donor–acceptor systems. Besides its simplicity, fast rate, and high yield, this reaction may also display complete and predictable regioselectivity, as in the case when tetracyanoquinodimethane (TCNQ) is used in combination with unsymmetric, activated alkynes. Here, we report the first example of a [2+2] CA-RE reaction between TCNQ and an aniline-activated alkyne following an “inverted” regiochemistry, thus leading to the exclusive formation of an unexpected regioisomer in contrast to the expected one. A combined experimental and theoretical study helped us to unravel the peculiar reaction mechanism underlying the regioselectivity switching.

Strained spirocyclic 1,5-dioxaspiro[2.3]hexanes were synthesized via a lithium-amide induced single-electron transfer to a series of non-enolizable ketones generating a frustrated radical pair-like N-centered radical and ketyl radical anion. This pair works synergistically to selectively abstract the β-hydrogen from 3-iodooxetane, initiating a radical-radical coupling reaction. In-depth computational and experimental investigations support the proposed mechanistic pathway.

Abstract

Strained spiro-heterocycles (SSHs) have gained significant attention within the medicinal chemistry community as promising sp ³ -rich bioisosteres for their aromatic and non-spirocyclic counterparts. We herein report access to an unprecedented spiro-heterocycle—1,5-dioxaspiro[2.3]hexane. Our synthetic approach leverages a lithium-amide induced single-electron transfer to benzophenones generating an N-centered radical and a ketyl radical anion—reminiscent of a frustrated radical pair. This pair works synergistically to selectively abstract the β-hydrogen from 3-iodooxetane, initiating an exergonic radical-radical coupling reaction. This process enables the formation of the desired bond between the oxetane core and benzophenone derivatives, ultimately yielding the novel 1,5-dioxaspiro[2.3]hexane core. The stability and synthetic utility of the novel 1,5-dioxaspiro[2.3]hexane motif are showcased. An in-depth mechanistic investigation is presented, including cyclic voltammetry studies, as well as computational calculations and experiments to support the mechanism of this new single electron synthetic tactic.

The first all-electrochemical synthesis of performic acid starting from CO₂, O₂, and H₂O has been achieved in a two-step process using gas diffusion electrodes. Therefore, the electrochemical CO₂ reduction reaction (eCO ₂ RR) to formate was coupled to the electrochemical O₂ reduction reaction (eCO ₂ RR) to H₂O₂ without downstream processing.

Driven by anthropogenic climate change, innovative approaches to defossilize the chemical industry are required. Herein, the first all-electrochemical feasibility study for the complete electrosynthesis of the strong oxidizer and effective disinfectant performic acid is presented. Its synthesis is achieved solely from CO₂, O₂, and H₂O in a two-step process. Initially, CO₂ is electrochemically reduced to formate employing Bi₂O₃-based gas diffusion electrodes in a phosphate-buffered electrolyte. Thereby, high formate concentration (500.7 ± 0.6 mmol L⁻¹) and high Faradaic efficiency (86.3 ± 0.3%) are achieved at technically relevant current density (150 mA cm⁻²). Subsequently, the formate acts as (storable) feed electrolyte for the second electrolysis step. Employing carbon-based gas diffusion electrodes, O₂ is reduced to H₂O₂ and performic acid is directly formed in situ. As before, high H₂O₂ concentration (1.27 ± 0.06 mol L⁻¹) and high Faradaic efficiency (85.3 ± 5.4%) are achieved. Furthermore, performic acid concentration suitable for disinfection is obtained (82 ± 11 mmol L⁻¹). In summary, this innovative feasibility study highlights the potential of combining electrochemical CO₂ reduction with H₂O₂ electrosynthesis, which could provide sustainable access to performic acid in the future.

The synthesis of six-membered hypervalent bromine(III) and chlorine(III) compounds through their diazonium salts is demonstrated. High yielding chemo- and regioselective O- and S-arylations are possible at ambient temperature, which can also be utilized for intermolecular or intramolecular biaryl synthesis by modifying the reaction conditions.

Abstract

Despite the remarkable advancements in hypervalent iodine chemistry, exploration of bromine and chlorine analogues remains in its infancy due to their difficult synthesis. Herein, we introduce six-membered cyclic λ³-bromanes and λ³-chloranes. Through single-crystal X-ray structural analyses and conformational studies, we delineate the crucial bonding patterns pivotal for the thermodynamic stability of these compounds. Notably, these investigations reveal pronounced π–π stacking phenomena within the crystal lattice of hypercoordinated bromine(III) and chlorine(III) species. Their reactivity profile is explored as they are radical precursors or electrophilic reagents in metal-free intermolecular biaryl couplings, O- and S-arylations, and Cu(I)-promoted intramolecular biaryl couplings which is complementary to the known reactivity of five-membered bromanes and chloranes. Mechanistic insights are provided, elucidating the pathways governing their reactivity and underscoring the potential in organic synthesis.

Nature, Published online: 02 April 2025; doi:10.1038/d41586-025-01019-w

The Dreamer system reached the milestone by ‘imagining’ the future impact of possible decisions.

Nature Communications, Published online: 03 April 2025; doi:10.1038/s41467-025-58555-2

The ring opening of cyclopropenes provides a compelling platform for the rapid synthesis of various polysubstituted acyclic alkenes, but radical-mediated reactions of this type remain underexplored. Here, the authors report an aminative ring-opening of cyclopropenes with iron-aminyl radical to afford tetrasubstituted alkenyl nitriles.

Nature, Published online: 02 April 2025; doi:10.1038/d41586-025-00973-9

A single dose of the drug nitisinone could render a person’s blood lethal to mosquitoes for five days, modelling suggests.

Concise total syntheses of five leuconoxine alkaloids have been achieved using a pyrrole-centered strategy, which features a newly developed palladium/norbornene-catalyzed pyrrole double C─H functionalization method, a divergent late-stage oxidative dearomatization tactic, and no use of protecting groups.

Abstract

Concise total syntheses of five leuconoxine-type alkaloids, i.e., chloromelodinine, leuconodine A, leuconodine F, melodinine E, and leuconoxine, are achieved through a pyrrole-centered strategy. The approach features a newly developed palladium/norbornene-catalyzed pyrrole double C─H functionalization reaction to generate the core skeleton and a divergent oxidative dearomatization to complete the end game. In addition, no protecting group was employed, and the strategic use of a chloro substituent offers a number of advantages in these syntheses, which could have implications beyond this work. The discovery of an unusual chloro 1,2-migration reaction enabled the first total synthesis of chloromelodinine E. This work represents the shortest syntheses of these natural products to date with 10–11 total steps.

Science, Volume 387, Issue 6741, Page 1430-1430, March 2025.

A strategy for the α-arylation of carbonyl compounds is presented. The Cu- and Pd-catalyzed reaction involves 1,2-arylboration of electron deficient alkenes and proceeds with high levels of selectivity. The mechanism is addressed and suggests that a boron ligated enolate is responsible for high selectivity.

Abstract

Palladium-catalyzed cross coupling of enolates—α-arylation—is an established method for chemical synthesis. A major challenge in the field is control of stereochemistry for the α-carbon. This is typically due to facile epimerization under the basic reaction conditions for α-arylation. In this study, an alternative approach is presented that involves the Pd/Cu-catalyzed arylboration of electron deficient alkenes. The products are generated with high levels of diastereoselectivity for a broad range of substitution patterns. Enantioselective variants are also presented in addition to product derivatizations.

This study presents catalytically generated phosphine oxide radical anions, derived from commercial phosphines and water as potent single-electron reductants capable of reducing electron-rich aryl chlorides at potentials as low as −3.3 V (vs. SCE). Cyclic voltammetry studies and DFT calculations offer insights into these P-based ground-state electron donors, broadening the scope of phosphoranyl radical chemistry. This work highlights the potential of in situ generated reductants, achieving redox potentials comparable to elemental potassium.

Abstract

Electron donors that can be excited to higher energy states through light absorption can achieve oxidation potentials as low as −3.0 V (vs. SCE). However, ground-state organic electron transfer reagents operating at such potentials remain underdeveloped, often necessitating multi-step syntheses and elevated reaction temperatures for activation. The longer lifetime of ground-state reagents is an advantage compared to most photoexcited single-electron reductants, which typically have relatively short lifetimes. In this study, catalytically generated phosphine oxide radical anions derived from phosphines and water applying redox catalysis are introduced as highly efficient single-electron reductants. The in situ generated radical anions are capable of reducing electron-rich aryl chlorides at potentials as low as −3.3 V (vs. SCE). Cyclic voltammetry studies and DFT calculations provide valuable insights into the behavior of these phosphorus-based ground-state electron donors. These findings do not only expand the chemistry of phosphoranyl radicals but also unlock the potential of in situ generated organic ground state electron donors that reach potentials comparable to elemental potassium.