Finn Moeller

Nature, Published online: 20 May 2025; doi:10.1038/s41586-025-09159-9

Nature Communications, Published online: 20 May 2025; doi:10.1038/s41467-025-59816-w

We show a reductive cross-coupling reaction of bicyclo[1.1.1]pentyl (BCP)-thianthrenium reagents and alkyl bromides, which is catalyzed by a copper/photoredox catalyst system. The reaction provides a variety of BCP-alkylated products through the formation of a C(sp³)−C(sp³) bond.

Abstract

Herein, we report a reductive cross-coupling reaction of bicyclo[1.1.1]pentyl (BCP)-thianthrenium reagents and alkyl bromides. The reaction is catalyzed by a copper/photoredox catalyst system. The approach is the first example of a cross-coupling between BCP-based reagents with alkyl electrophiles.

Interrupted Dowd–Beckwith (IDB) reaction enables the highly regioselective deconstructive functionalization of cyclic ketones using electricity as the sole oxidant. This strategy transforms complex cyclic ketones into acyclic molecules and has been applied to the asymmetric synthesis of planococcol, citrilol acetate, maconelliol, and its derivatives. Mechanistic studies support an oxidative radical-polar crossover.

Abstract

Deconstructive functionalization of cyclic molecules has recently emerged as a prominent strategy to access unique architectures that are challenging to prepare through traditional methods. While significant progress has been made in the deconstructive functionalization of cyclic alcohols and amines, the strategies for deconstructing cyclic ketones remain largely unexplored. The Dowd–Beckwith reaction, a ring-expansion of cyclic ketones, is a powerful method for synthesizing medium- and large-ring compounds. Herein, we developed the first interrupted Dowd–Beckwith (IDB) reaction for highly regioselective deconstructive functionalization of cyclic ketones using electricity as the sole oxidant. This protocol is widely applicable for the deconstruction of small, medium-sized, and macrocyclic ketones bearing a diverse range of functional groups. Remarkably, various naturally occurring complex cyclic ketones were successfully deconstructed into acyclic molecules, which are difficult to access by known strategies. The method was applied to the asymmetric synthesis of planococcol, citrilol acetate, maconelliol, and its derivatives. Furthermore, the functional groups incorporated during the transformation provided versatile handles for subsequent synthetic modifications. Mechanistic experiments and computational studies support an oxidative radical-polar crossover followed by deconstructive functionalization.

We disclosed a palladium-catalyzed tandem radical Heck/allylic amination of α-bromoamides with 1,3-butadienes and enynes at room temperature to yield γ-lactams. Unlike previous alkyl Heck reactions, this transformation generates hybrid alkyl Pd(I)-radical and a transposed π-allyl Pd(I)-radical under ambient conditions.

Abstract

In contrast to traditional ground-state palladium-catalyzed alkyl Heck reactions, which are thermodynamically unfavorable and endothermic, excited-state palladium catalysis facilitates single-electron mechanisms, with light primarily driving the formation of alkyl radicals from triplet-state Pd(0). Here, we report a novel and mechanistically distinct Pd-catalyzed reaction, where the key hybrid alkyl Pd(I)-radical intermediate is generated by the halogen atom transfer (XAT) from alkyl bromide to the Pd(0) at room temperature, without the need for photoinitiation. This hybrid species engages in the addition to dienes and conjugated enynes, producing a transposed open-shell allyl Pd(I)-radical, which undergoes radical-polar crossover (RPC) to yield the desired products. Density functional theory (DFT) studies offer insights into the reaction mechanism, confirming the involvement of hybrid alkyl/allyl Pd(I) radical species as key intermediates.

Aziridination of alkenes is an important route to chiral nitrogen-containing building blocks. Here we report that carbamate-functionalized allylic alcohols undergo highly enantioselective aziridination using achiral dimeric Rh(II,II) complexes that are ion-paired with cinchona alkaloid-derived chiral cations. The aziridine-containing products are amenable to a variety of further reactions to generate useful groupings of functionality. Furthermore, we show that the carbamate group is effective for directing highly enantioselective benzylic C-H amination when it is appended to phenethyl alcohols. Intermolecular C-H amination of phenethyl alcohol derivatives has proven highly challenging to achieve asymmetrically yet gives rise to valuable β-amino alcohols. Both processes result in rapid access to versatile, highly enantioenriched small molecule building blocks for synthesis and highlight the effectiveness and generality of this chiral cation-based strategy for asymmetric catalysis. We report studies that probe important structural features of the chiral cation and demonstrate that the ion-paired complexes can be formed from their individual components without a separate isolation step.

A two-step protocol is developed for the efficient oxidative degradation of Kraft lignin. This method utilizes a highly concentrated peroxodicarbonate solution at moderate temperatures, followed by thermal treatment, significantly enhancing monoaromatic yield up to 15.6 wt%. Cogenerated carbonates in this transformation represent the make-up chemical of pulping plants.

The oxidative degradation of technically relevant types of Kraft lignin is efficiently accomplished by a significantly improved two-step protocol. The key is the use of highly concentrated peroxodicarbonate solution which selectively oxidizes the lignin particles at moderate temperature which are thermally treated in a subsequent step. The liberation of low-molecular-weight phenols occurs when the oxidizer is already consumed enhancing the yield of target compounds strongly up to 15.6 wt%. Co-generated carbonates in this transformation represent the make-up chemical of pulping plants. This makes this approach suitable and attractive to be implemented as a bolt-on or integrated into the Kraft pulping process. The green metrics clearly indicate the sustainable and superior features of the method established.

Malabaricane triterpenoid sodagnitin E is a chromogen found in various toadstools. This work represents the first total synthesis of (−)-sodagnitin E as well as the first total synthesis of any malabaricane natural product. A Mukaiyama aldol reaction was utilized to perform a convergent synthesis from two enantioselectively synthesized fragments. Additionally, a structural revision of the relative configuration of sodagnitin E is proposed.

Abstract

We report the total synthesis of malabaricane triterpene sodagnitin E, marking the first synthesis of any malabaricane natural product to date. The enantioselective synthesis of two key fragments, followed by their coupling via a Mukaiyama aldol reaction delivered the triterpene framework in a convergent synthesis. A thorough analysis of the synthetic material led to the elucidation of a previously unassigned stereocenter (C17) as well as the reassignment of the configuration at C27. This enabled the structural revision of the relative configuration at the central lactol moiety.

We present a metal-free method for aromatic deuterium labeling via photoexcitation in deuterated HFIP. This approach leverages the enhanced basicity of excited-state aromatics to achieve selective hydrogen isotope exchange at challenging positions. Demonstrated on complex drug molecules, this efficient strategy provides a valuable tool for isotope labeling, with mechanistic insights confirmed by transient absorption spectroscopy.

Abstract

Isotope labeling, particularly with deuterium (²H), plays a critical role in drug discovery due to its ease of incorporation and its potential to switch unwanted metabolic transformations. Deuterium incorporation can enhance drug stability, affect pharmacokinetics, and alter metabolism pathways. Current deuterium labeling methods focus on hydrogen isotope exchange (HIE), and typically rely on the use of transition metal catalysis. Herein, we present a metal-free approach for aromatic HIE, utilizing photoexcitation in deuterated hexafluoroisopropanol (HFIP-d ₁). By exploiting the enhanced basicity of excited-state aromatics, this method achieves selective deuteration at positions often inaccessible by traditional methods. The approach is efficient and was demonstrated across a broad number of complex drug molecules. Transient absorption spectroscopy confirms the formation of deuterated arenium ions.

A direct method for benzylic C─H sulfation via electrooxidation was developed. This transformation shows orthogonal reactivity to classical O-sulfonation, allowing for the direct sulfation of feedstock chemicals with hydroxyl groups without the need for complicated protecting-group strategies. The chemo- and site selectivity of this reaction makes it a valuable tool for the late-stage sulfation of natural products and drug molecules.

Abstract

Direct C─H sulfation represents a valuable transformation for the synthesis of organosulfates. However, it has been challenging to achieve owing to the presence of multiple C─H bonds with comparable strengths and steric environments. Current methods for producing organosulfates primarily rely on O-sulfonation, which limits their applicability to hydroxyl-containing compounds. Herein, we report a practical and cost-efficient method for the electrochemical sulfation of benzylic C─H bonds. This reaction avoids the need for strong oxidants, demonstrating broad substrate scope, excellent chemoselectivity, and site selectivity. The orthogonal reactivity of this protocol is particularly evident in the transformation of alcohol substrates.

Difunctionalization of less reactive aryl chlorides by cooperation of a norbornene (NBE) mediator with a palladium catalyst bearing an electron-rich phosphine ligand delivered ortho-C─H alkylation/ipso-olefination products. The protocol also enabled sequential Catellani reactions to increase molecular complexity. DFT calculations revealed that C─H⋯O interactions between the XPhos ligand and the NBE mediator promote the pivotal NBE insertion step.

Abstract

Herein we report a general and practical palladium/norbornene catalysis system that effectively promotes difunctionalization of less reactive aryl chlorides. The key to success lies in the use of a particular norbornene (NBE) derivative as a powerful mediator that synergistically cooperates with the palladium catalyst and an electron-rich phosphine ligand. A broad spectrum of electronically diverse aryl chlorides (57 examples) delivered the corresponding ortho-C─H alkylation/ipso-olefination products in moderate to good yields. Notably, this protocol features excellent functional-group tolerance, high concentration, scalability, and late-stage functionalization of complex aryl chlorides. Furthermore, by integrating this chemistry with its counterparts involving aryl iodides and bromides, an intriguing triple-Catellani reaction sequence was developed, rapidly increasing molecular complexity and diversity. Finally, DFT calculations were performed, revealing that noncovalent C─H⋯O interactions between the XPhos ligand and the NBE mediator promote the pivotal NBE insertion step.

Use of enolate chemistry to functionalise amino acids with β-heteroatom side-chains (serine, cysteine, threonine, etc.) is hampered by β-elimination. We show that α-arylation can be achieved by incorporating the side chain into a saturated heterocycle, making the unwanted elimination a disfavoured 5-endo-trig reaction. An alternative, now favoured, unactivated intramolecular S_NAr reaction provides a range of functionalised amino acid derivatives.

Abstract

The α-arylation of amino acids may be achieved by intramolecular nucleophilic aromatic substitution (S_NAr) reactions of amino-acid derived enolates, but for amino acids bearing β-leaving groups, such reactions are complicated by competing E1cB elimination of the β-substituent. In this paper we report an approach to the arylation of the polar amino acids serine, cysteine, diaminopropionic acid, and allothreonine by inducing intramolecular S_NAr reactions of heterocycles, which the heteroatom substituent is stereoelectronically protected from elimination by incorporating it into the ring system of N-carbamoyl oxazolidines, thiazolidines, or imidazolidines. The sequence comprises the diastereoselective formation of a heterocyclic urea followed by an intramolecular N-to-C aryl migration, yielding bicyclic hydantoins that can be further hydrolysed to afford quaternary α-aryl amino acids. The method is practical and scalable, avoids the use of transition metals or chiral auxiliaries, and provides the opportunity to access a variety of α-arylated products bearing electronically diverse benzenoid or heterocyclic substituents (35 examples).

The total synthesis of isodaphlongamine H was accomplished by a lactam strategy. This strategy started with alkylation and N-oxidation of a readily available chiral lactam. For the key functionalization of the amide carbonyl, an iridium-catalyzed reductive [3 + 2] cycloaddition of the N-hydroxylactam afforded the tricyclic isoxazolidine, which was successfully transformed to isodaphlongamine H. Bn = benzyl, TBAF = tetrabutylammonium fluoride.

Abstract

The total synthesis of isodaphlongamine H based on a lactam strategy, which enables quick access to complex cyclic amines, is described. The strategy begins with alkylation of a chiral lactam and subsequent N-oxidation via an imino ether to afford the N-hydroxylactam. For the key transformation to functionalize the amide carbonyl, an iridium-catalyzed reductive [3 + 2] cycloaddition of the N-hydroxylactam provides a tricyclic isoxazolidine in a one-pot process. After the coupling reaction with an allylic silane fragment, the total synthesis is accomplished through intramolecular Hosomi–Sakurai allylation to construct a pentacyclic core. The deoxygenated pentacyclic intermediate shows higher cytotoxicity against HeLa and U937 cell lines than isodaphlongamine H, and might become a lead compound for further biological study.

Nature, Published online: 06 May 2025; doi:10.1038/d41586-025-01207-8