Enrico

Nature Synthesis, Published online: 18 December 2025; doi:10.1038/s44160-025-00945-x

A divergent electrochemical nitrogen atom insertion into saturated carbocycles is reported, enabling selective access to either functionalized quinolines or N-alkylated saturated N heterocycles. This approach is applicable to late-stage functionalization and the synthesis of bioactive molecules.

Marine polyhydroxylated macrolides’ drug discovery potential is limited by structural complexity and scarce material supply, hindering structure assignment, synthesis, and biological studies. Here, we present an integrated workflow that combines chemogenomic profiling, ultra-high-resolution NMR-guided structural revision and stereochemical assignment, and modular total synthesis to enable comprehensive interrogation of the caylobolide B family.

Abstract

The unique potential of marine polyhydroxylated macrolides in chemical biology and drug discovery has long been constrained by their structural complexity and limited material availability, frustrating efforts in stereochemical assignment, synthesis, and mechanism-of-action elucidation. Here, we establish an integrated workflow, combining chemogenomic profiling, ultra-high-resolution NMR, and modular total synthesis, for the comprehensive functional and structural interrogation of this challenging natural product class. Applying this approach to caylobolides, natural products isolated from scarce samples of Okeania sp., we performed structure-activity relationship studies revealing that acetylation at C29 markedly reduces both cytotoxicity and antifungal activity, pinpointing a key pharmacophore. Mechanistic profiling suggests that these macrolides disrupt membrane integrity, similar to amantelide A. Using natural compound samples, we simultaneously revised the structure of caylobolide B through ¹H, 1D-selective TOCSY and HSQC NMR, and developed a modular fragment-based synthesis of these compounds. By providing a unified methodology for genetic sensitivity profiling, precise structure and stereochemistry determination, and modular total synthesis, this work unlocks new opportunities for the discovery and rational design of potent marine-derived therapeutics.

An intramolecular Mannich reaction (A/B/E/F rings) and intermolecular Diels–Alder reactions (C/D rings) afforded a cage-like hexacyclic core skeleton of denudatine alkaloids. Derivatization of the hexacyclic intermediate enabled the first asymmetric total syntheses of four denudatine alkaloids: (–)-cochlearenine, (–)-macrocentrine, (–)-dictizine, and (–)-15-veratroyl-17-acetyl-19-oxodictizine (see scheme).

Abstract

The first asymmetric total syntheses of four denudatine alkaloids, cochlearenine, macrocentrine, dictizine, and 15-veratroyl-17-acetyl-19-oxodictizine, along with the asymmetric synthesis of the proposed structure of acochlearine, were accomplished in a divergent manner. Highly fused tetracyclic skeletons (A/B/E/F rings) with different N-alkyl groups (Me and Et) were constructed by Brønsted acid promoted intramolecular Mannich reactions. The bicyclo[2.2.2]octane C/D rings were constructed via two-fold intermolecular Diels–Alder reactions. By utilizing these key processes, the common intermediates, possessing the complex cage-like hexacyclic skeleton, were constructed. From these common intermediates, the four denudatine alkaloids were synthesized through late-stage, chemo- and stereoselective modifications around the A/C rings. The spectroscopic data of the proposed structure of acochlearine were inconsistent with those of natural acochlearine.

A photocatalytic formal hydrocarbamoylation reaction that employs a cyanate anion as the C1 source and provides N-acyl iminophosphorane products from activated alkenes is described. Mechanistic investigations suggest generation of a phosphoranyl radical by addition of the cyanate anion to a phosphine radical cation, which enables the delivery of the carbamoyl group across alkenes.

Abstract

Catalytic methods that enable functionalization of alkenes with radical intermediates generated from common feedstock chemicals are valuable in synthetic chemistry. In this study, we disclose a photocatalytic formal hydrocarbamoylation strategy for preparation of N-acyl iminophosphorane products from activated alkenes through isocyanate-derived phosphoranyl radicals. Mechanistic investigations suggest generation of the phosphoranyl radical by addition of a cyanate anion to a phosphine radical cation and provide support for its reactivity through the isocyanate moiety. This redox-neutral method enables hydrofunctionalization of diverse alkenylarene and electron-deficient alkene substrates containing sensitive groups such as epoxide, unactivated alkene, amine, or electron-rich and electron-deficient heterocycles. The synthetic versatility of the N-acyl iminophosphorane functionality is demonstrated through one-step conversion to other valuable nitrogen-containing functional groups.

In this work, a general and practical Ni-electrocatalytic system for the remote hydro- and di-carboxylation of unactivated olefins or halides with carbon dioxide (CO₂) was developed. Various ectopic carboxylation products were conveniently accessible from a wide range of readily available substrates under mild reaction conditions.

Abstract

Coupling carbon dioxide (CO₂) with organic molecules through the electrocarboxylation reaction constitutes a promising approach for generating value-added carboxylic acids. Up to now, activated substrates (such as styrene and butadiene derivatives) have been predominantly focused on due to their high activity. In contrast, the unactivated substrates, with low reductive potentials and unstable radical intermediates but more abundant in nature and industry, have rarely been employed. Herein, we proposed a nickel-electrocatalytic system for the regioconvergent carboxylation of unactivated olefins or halides. Various carboxylic acids were obtained by the remote hydro- or di-carboxylation under mild reaction conditions with inexpensive catalysts and electrodes. It was noteworthy that readily available alkanes could also be utilized as starting substrates for the site-selective electrocarboxylation process by the unified catalytic strategy. This method expands the scope of organic molecules coupled with CO₂, and demonstrates the possibility of ectopic and remote C─H carboxylation. Mechanistic investigations indicated that the Ni─H species generated in the Ni-electrocatalytic system play a key role for promoting chain walking to efficiently produce activated olefin intermediates, which subsequently undergo radical addition with CO₂ radical anion and further transform into the desired products.

A convergent radical annulation strategy for the synthesis of complex terpenoids is disclosed. A 1,3-diradical synthon enabled rapid C-ring annulations through sequential radical couplings to synthesize serratene and cyclodammarane scaffolds from sclareolide. These concise routes feature unique hydrogen atom transfer-initiated (HAT) radical cascades including a 7-endo-trig cycloisomerization and a radical/polar crossover (RPC) bicyclization.

Abstract

The development of a convergent radical annulation strategy for the synthesis of complex terpenoids from sclareolide is disclosed. This approach employs a 1,3-diradical synthon to enable rapid C-ring annulation through inter- and intramolecular radical couplings, exemplified in the concise syntheses of serratene and cyclodammarane scaffolds from a common intermediate. Key features include a rapid alternating polarity (rAP) Kolbe electrolysis for onoceradiene assembly, a Co-electrocatalytic metal-catalyzed hydrogen atom transfer (MHAT) 7-endo-trig cycloisomerization─the first of its kind─to form the serratene core, and a tandem Fe-mediated reductive olefin coupling/enolate alkylation cascade─also unprecedented─to forge the [4.3.1] propellane motif of cyclodammaranes with complete diastereocontrol over three contiguous quaternary centers. These routes, completed in 5–9 steps, maximize skeletal bond-forming efficiency, feature unique radical cascades, and highlight the advantages of radical-based disconnections in terpenoid synthesis.

Electrogenerated bases (EGBs) are emerging as powerful and sustainable tools in synthetic chemistry, offering cleaner and more efficient alternatives to traditional stoichiometric bases. This Review outlines the fundamental principles of EGB formation and explores their expanding role in enabling diverse and selective organic transformations, including alkylations, trifluoromethylations, Stevens rearrangements, Wittig reactions, esterifications, additions, anionic chain reactions, macrolide formation, polymerizations, C–H deprotonations and functionalizations, condensation reactions, and electrocarboxylation. EGBs efficiently activate substrates bearing labile protons, facilitating the generation of reactive intermediates for key bond-forming steps. These methods enable access to heterocycles, fluorinated compounds, and valuable intermediates relevant to pharmaceuticals and materials science. Beyond expanding synthetic scope, EGBs enhance regio- and stereoselectivity, contributing to greater reaction precision. While batch electrolysis has been widely used, advances in flow electrochemistry offer improved control, safety, and scalability. Innovations such as “ex-cell” reactor designs, where oxidation and reduction steps are spatially separated, further improve efficiency and minimize side reactions. The use of environmentally benign materials—such as electrodes (e.g., magnesium), green solvents, and sustainable electrolytes—significantly influences both performance and sustainability. Despite these advantages, challenges remain, including limited substrate tolerance, sensitivity to reaction conditions, and the requirement for specialized electrochemical equipment.

The construction of C(sp³)–P bonds is of fundamental importance given the prevalence of organophosphorus scaffolds in multiple fields. However, direct access to -phosphorylated amines remains challenging, as traditional approaches often require prefunctionalized substrates, stoichiometric oxidants, or substrate-specific photocatalytic conditions. Here, we report an electrochemical strategy for the direct and generalized phosphorylation spanning from feedstock amines to peptides. The reaction proceeds via anodic oxidation to generate alpha-amino radical and cationic intermediates, which are efficiently coupled with secondary phosphine oxide-based nucleophiles under convenient conditions. Overall, this platform with its redox-neutral features, wide substrate scope, tolerance, and scalability, enables the synthesis of diverse alpha-phosphorylated amines in a streamlined manner. The integration of electrochemical activation with phosphorus chemistry offers a sustainable and general solution to C–P bond construction, allowing new opportunities in the design of bioactive molecules and organophosphorus ligands.

After decades of research into metal alkylidyne complexes and their extensive use as catalysts for alkyne metathesis, one might think that there is nothing fundamentally new to be discovered in this field. The present study into formally d⁴-configured Ru alkylidynes shows that this notion is incorrect: not only is a novel and convenient entry route disclosed but also an entirely unprecedented stepwise pathway for [2 + 2] cycloaddition reactions is uncovered.

Abstract

A new entry into square-planar, formally d⁴-configured ruthenium alkylidyne complexes is disclosed, using p-tolyl(trimethylsilyl)diazomethane as a convenient and safe alkylidyne synthon. The method furnished complex 12 supported by an electron-rich PNP-pincer ligand, which undergoes remarkably facile [2 + 2] cycloaddition with electron-rich, electron-deficient, and strained alkynes; these reactions represent the first examples of metallacyclobutadiene formation by a d⁴-configured transition metal alkylidyne complex. Strikingly, however, the cycloadditions proceed by a stepwise mechanism, which stands in marked contrast to the concerted pathway entertained by all prototypical d⁰ and d² Schrock-type alkylidynes, including the molybdenum, tungsten, and rhenium complexes that currently dominate the field of alkyne metathesis. In essence, it is the non-bonding lone pair forming the largely metal-centered HOMO of significant d_z2 character that accounts for this unorthodox behavior. The newly gained insight into this key reactivity determinant also allows the few other known reactions of formally d⁴-configured alkylidene complexes previously described in the literature to be explained and will empower further explorations of their chemistry.

An electrolytic-Ni-catalyzed general synthesis of ketones was reported, utilizing radicals and carbon monoxide as partners. The radical sorting effect was proposed within an outer sphere addition mechanism of alkyl radicals to Ni-stabilized ketyl radicals, thereby facilitating selectivity among different radicals. This protocol allows for a broad range of alkyl combinations, including numerous ¹³C-labeled amino acids and steroids.

Abstract

The construction of ketones with bulky units is a long-standing challenge for established nucleophilic addition or transition-metal-catalyzed cross coupling. In this work, a different route is reported to build bulky ketones ab initio that exploits the radical sorting effect in three-component cross coupling with electrolytic Ni catalysis. The sorting effect enables the selective construction of ketones, including all possible combinations of primary, secondary, and tertiary alkyl groups. In particular, the radical sorting pathway allows for efficient CO utilization and the synthesis of ¹³C-labeled ketones with a minimum amount of ¹³CO. In addition, square wave voltammetry was adopted as a quick tool to identify the catalyst driving both electron transfer and bond formation.

It is introduced in this report a unified toolbox comprising of 15 sulfonyl hydrazide reagents that enable the redox-neutral radical cross-coupling of 14 distinct C(sp³)-rich small fragments onto (hetero)arenes, providing a modular, efficient, and operationally simple platform for installing diverse small fragments. The platform has the potential to accelerate medicinal chemistry campaigns, enables late-stage modifications, and positions it as a useful resource for drug discovery.

Abstract

The hit-to-lead phase of drug discovery is frequently bottlenecked by the time-consuming, iterative synthesis of analogs, especially when incorporating small C(sp³)-rich fragments such as methyl, cyclopropyl, or oxetanyl groups—moieties known to improve drug solubility, bioactivity, and metabolic stability. Conventional approaches like Suzuki or Negishi couplings make use of unstable reagents, high costs, and harsh reaction conditions, while many modern radical-based methods rely on exogenous redox agents or costly metal catalysts. To overcome these limitations, a toolbox of 15 sulfonyl hydrazide reagents is disclosed to facilitate redox-neutral, nickel-catalyzed radical cross-coupling of 14 distinct small fragments onto (hetero)arenes under mild conditions. These crystalline, bench-stable reagents are straightforward to synthesize from accessible precursors and require no additional oxidants, reductants, or precious metals, offering a modular and operationally simple platform. Demonstrated across a diverse set of over 60 (hetero)aryl halides, the method exhibits exceptional substrate scope and functional group tolerance, accommodating complex, medicinally relevant scaffolds. Comparative studies with existing techniques underscore its advantages, including a 51% yield for trideuteromethylation of a MET kinase inhibitor precursor (versus a precedented 14% via Kumada coupling) and a streamlined one-step cyclobutylation of an NLRP3 inhibitor intermediate at 41% yield (versus a known < 5% over a four-step sequence).