Finn Moeller

Nature, Published online: 25 March 2025; doi:10.1038/d41586-025-00925-3

How to get more women into mining

Nature, Published online: 24 March 2025; doi:10.1038/s41586-025-08887-2

Generalizing arene C−H alkylations by radical−radical cross-coupling

A stereoselective total synthesis of nimbolide has been achieved in a convergent, 11-step sequence from α-methyl-(R)-carvone. The strategy relied on a stereoselective palladium-catalyzed borylative Heck cyclization where the A-ring of the nimbolide core was constructed while simultaneously installing oxidation at C28. Selective manipulations delivered a fully decorated decalin moiety on large scale. Then, a stereoretentive etherification reaction brought together two fragments and forged the critical C–O bond with high selectivity. Finally, a regioselective radical cyclization and late-stage lactonization completed the total synthesis of nimbolide.

Topologically unique, 3D cage-like noradamantanes are synthesized in one pot from simple starting materials. Catalyzed by diphenylprolinol silyl ether, the reaction followed a domino sequence of Michael/epimerization/Michael/1,2-addition, achieving excellent enantioselectivity. This method formed three C─C bonds and six chiral centers, including a quaternary all-carbon center, with five fully stereocontrolled.

Abstract

Topologically unique chiral noradamantanes are synthesized using a diphenylprolinol silyl ether-mediated domino Michael/epimerization/Michael/1,2-addition or Michael/epimerization/aldol/1,2-addition reaction with excellent enantioselectivity in a single reaction vessel. Three carbon–carbon bonds are formed, and six chiral centers, including one all-carbon quaternary center, are generated, five of which are fully controlled. These functionalized noradamantanes are 3D, cage-like molecules that can serve as valuable chiral building blocks for drug design.

Nature Communications, Published online: 21 March 2025; doi:10.1038/s41467-025-57909-0

Retraction Note: Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells

Angewandte Chemie International Edition, Volume 64, Issue 16, April 11, 2025.

A novel Pd(0)/NBE-catalyzed trifunctionalization reaction has been successfully developed for the selective assembly of contiguously substituted aromatic compounds from ortho-unsubstituted iodoarenes and alkyl/aryl mixed anhydrides combined with a carboxylate anion activator. This domino reaction was realized through sequence-controlled ortho C─H alkyl-acylation, ortho' C─H aryl-acylation, and ipso-termination with an alkenyl or aryl nucleophile.

Abstract

Herein we report a novel palladium/norbornene-catalyzed trifunctionalization reaction of ortho-unsubstituted iodoarenes by incorporating two distinct acyl groups at their ortho C─H positions and replacing the ipso-iodide with an alkenyl or aryl group. Notably, this transformation was enabled by the alkyl/aryl mixed anhydrides, which were utilized as dual acylation reagents by abstracting their central oxygen atom with electrophilic 2-chloro-4,6-dimethoxy-1,3,5-triazine. Mechanistic studies revealed that the alkyl-acyl unit of such an anhydride was employed for the first C─H alkyl-acylation, and in situ released aryl carboxylate anion was then rapidly activated with triazine chloride to provide an aryl–acyl electrophile for the second C─H acylation, thus enabling the trifunctionalization of iodoarenes by termination with an intermolecular Heck or intramolecular arylation reaction. In addition, the synthetic utility of this method is exemplified by the selective manipulation of carbonyl groups of the products.

We present a programmable electrocatalytic method for mono-/di-alkylation N-alkylation of amines over a Pd ^{δ −}–H electrocatalyst, enabling the precise synthesis of alkylamines with two controllable alkyl groups and one methyl group while achieving satisfactory FE values (86%–96%).

Abstract

Programmable amine N-alkylation provides a new method to combine the required alkyl groups with amine molecules according to actual demand and to precisely regulate the biological and pharmaceutical properties of life science amine molecules. However, only the electrochemical mono-methylation of amines has been achieved via C─N coupling with CO₂ accompanied by an unsatisfactory Faraday efficiency (FE) lower than 10%. Herein, we developed programmable electrocatalytic N-alkylation of amines with two controllable alkyl groups and one methyl group. Both experimental characterization and density functional theory (DFT) calculations have demonstrated the critical role of electron-enriched Pd metals in transforming amines into alkylamines with two chosen alkyl groups and a methyl group. Moreover, the electrocatalytic transformation of amines to alkylamines with satisfactory FE values (86%–96%) has been achieved, further expanding the scope of electrochemical C─N coupling and possibly opening a new world of electrochemical amine N-alkylation.

ABSTRACT: We report the first total synthesis of (+)-daphnepapytone A, an unprecedented member of the guaiane-derived sesquiterpenoids, and several related guaiane-derived natural products including diarthroncha C, daphnenicillata W, and oleodaphnone. Our first-generation strategy was thwarted by an unsuccessful late-stage biomimetic [2+2] cycloaddition, however our second-generation de novo approach provided expedient access to the tetracyclic core of daphnepapytone A through an intramolecular allenyl thermal [2+2] cycloaddition and a cage-like Pauson–Khand reaction with a labile cyclobu-tane.

Free radicals were first discovered over 120 years ago by Gomberg and the first radical cross-couplings demonstrated by Kochi in the 1970's. Fueled by the need for general methods to couple C(sp3)-fragments, this area has seen an explosion of renewed interest. In contrast to widely employed polar cross-coupling chemistry to forge C(sp2)–C(sp2) bonds (Suzuki, Negishi, Kumada, etc.), radical cross-coupling is advantageous when applied to the coupling of saturated systems due to the mild conditions employed and enhanced chemoselectivity associated with single electron chemistry. Indeed, the ability to employ ubiquitous carbon-based fragments (carboxylic acids, alcohols, amines, olefins, etc.) in cross-coupling has dramatically simplified access to a variety of complex molecules. Despite these advantages, enantiospecific coupling reactions involving free radicals are unknown and generally believed to be impossible due to their near-instantaneous racemization (picosecond timescale). As a result, controlling the stereochemical outcome of radical cross-coupling can only be achieved on a case-by-case basis using bespoke chiral ligands or in a diastereoselective fashion guided by nearby stereocenters. Here we show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni-catalyst can be enlisted to solve this vexing challenge for the first time thereby enabling enantiospecific, stereoretentive radical cross-coupling between enantioenriched alkyl fragments and (hetero)aryl halides without exogenous redox chemistry or chiral ligands. Calculations support the intermediacy of a unique Ni-bound diazene-containing transition state with C–C bond formation driven by loss of N2.

Nature, Published online: 14 March 2025; doi:10.1038/d41586-025-00707-x

The drop in body temperature that occurs during a torpid state is linked to molecular markers of longer life in mice.

A photochemical synthetic strategy inspired by the angucyclinone biosynthesis culminated in the total synthesis of lugdunomycin. The keys in the total synthesis were 1) the design of the photoinduced spiroketalization to constitute elmonin from actinaphthoran B, and 2) photoinduced isobenzofuran Diels–Alder reaction between elmonin and iso-maleimycin to construct the polycyclic framework.

Abstract

The presence of sterically rigid contiguous quaternary stereocenters in natural products imposes conformational constraints with significant effects on their biological activities. However, achieving the direct synthesis of multiple contiguous quaternary stereocenters in a single step remains a formidable challenge. Here, we present the total synthesis of the antibacterial metabolite lugdunomycin (1) in thirteen steps via a sequence of photochemical transformations. A photoenolization, keto–enol tautomerization, and spiroketalization sequence was developed to generate the spiroketal 4 from actinaphthoran B (3). Subsequently, a photoinduced isobenzofuran Diels–Alder reaction between elmonin (4) and iso-maleimycin (5) was developed to construct the polycyclic benzaza[4,3,3]propellane framework bearing three contiguous quaternary stereocenters in the compact C-ring along with a distal hydroxyl group at C19. The mechanism of these photochemical reactions was investigated using synthetic and computational approaches.

Asymmetric total synthesis of fortimicin B was realized in 12 steps (LLS) from readily available starting materials. The fortamine fragment was synthesized in a concise manner based on a newly developed enantioselective inverse-electron-demand Diels–Alder reaction. The 6-epi-purpurosamine B fragment was constructed via a Cr(II)/Co(I)-mediated C─C bond coupling. These two fragments were connected through Au(I)-catalyzed α-glycosylation. This study provides a synthetic platform for future investigations into the structure–activity relationships of fortimicins.

Abstract

Fortimicins, featuring a pseudodisaccharide scaffold, are an unusual class of aminoglycosides (AGs) with potent efficacy against several aminoglycoside-resistant bacterial strains. Notably, these molecules also exhibit lower inherent ototoxicity and nephrotoxicity than common aminoglycosides. Consequently, fortimicins are a promising type of protoypical molecules for the development of the next generation of aminoglycoside antibiotics. Here, we report the asymmetric total synthesis of fortimicin B in 12 steps (longest linear sequence, LLS) from readily available starting materials. An enantioselective Cu(II)-catalyzed inverse-electron-demand Diels–Alder (IEDDA) reaction of 2-pyrones and N-substituted 2-oxazolones was developed for the efficient synthesis of the fortamine fragment, which previously required a lengthy multistep synthesis owing to its complex stereochemistry. The 6-epi-purpurosamine B fragment was efficiently synthesized through a Cr(II)/Co(I)-mediated C─C bond coupling between aldehydes and alkyl halides. Within these two fragments, the stereoselective construction of the α-glycosidic bond of fortimicin B was realized via the gold(I)-catalyzed glycosylation. Overall, this study provides an efficient synthetic platform for future investigations into the structure–activity relationships of fortimicins.

Science, Volume 387, Issue 6739, Page 1167-1174, March 2025.

Nature, Published online: 13 March 2025; doi:10.1038/d41586-025-00782-0

The device, to be tested in more people, could be used as a temporary measure for those waiting for a donor organ.

Nature Communications, Published online: 13 March 2025; doi:10.1038/s41467-025-57527-w

Ring contraction of easily available cyclic compounds to smaller cycles that are valuable but difficult to synthetically access is an important skeletal editing strategy. Here, the authors report a photo-promoted ring contraction of pyridines with silylborane to afford pyrrolidine derivatives bearing a 2- azabicyclo[3.1.0]hex-3-ene skeleton.

We report that an air-stable “naked nickel”, Ni(^4-CF3stb)₃, can efficiently catalyze heteroaryl–heteroaryl Suzuki–Miyaura cross-coupling (SMC) reactions in the absence of exogenous ligands. This protocol permits the construction of >15 different heterobiaryls containing multiple Lewis basic heteroatoms from a broad set of 6-membered heteroaryl bromides with 5- and 6-membered heterocyclic B-nucleophiles.

Abstract

In this article, we report that the air-stable “naked nickel”, [Ni(^4-CF3stb)₃], is a competent catalyst in the catalytic Suzuki–Miyaura cross-coupling reaction (SMC) between heteroaryl bromides and heteroaromatic boron-based nucleophiles. The catalytic system is characterized by its ability to avoid decomposition or deactivation in the presence of multiple Lewis basic sites. The protocol permits the formation of C‒C bonds between two heteroaryl moieties in the absence of complex exogenous ligands, thus minimizing screening procedures and simplifying reaction setups. This method accommodates combinations of distinct 6-membered heteroaryl bromides and 5- and 6-membered heterocyclic B-based nucleophiles.

A metal-free electrochemical method for the chlorination of terminal C(sp³)─H bonds of alkanes is described. The specific cavity size of organic molecular catalysts ensures high regioselectivity, while the use of inexpensive and readily reusable graphite felt electrodes, a simple electrochemical device, and mild conditions enables the reaction to maintain good efficiency even when applied in flow electrochemistry and used for kilogram-scale production.

Abstract

Although research on the activation of C─H bonds in alkanes has been ongoing for decades, there are still few strategies that are both highly selective and suitable for industrial production. Herein, we report a highly selective method for the chlorination of terminal C─H bonds in alkanes by combining electrochemistry and organocatalysis. The specific cavity size of organic molecular catalysts ensures high regioselectivity, while the use of inexpensive and readily reusable graphite felt electrodes, a simple electrochemical device, and mild conditions enables the reaction to maintain good efficiency even when applied to kilogram-scale production.