Finn Moeller

A binary organic–inorganic acid cooperative catalytic system has been developed to achieve highly enantioselective electrochemical oxidative rearrangement of indoles. The use of electricity as an oxidant in this case showed several advantages including environmental benignity and improved enantiocontrol. A biphasic electrolysis system contributes to the general substrate scope by physically separating the chiral organic acids from the achiral inorganic acids.

Abstract

Disclosed here is the first catalytic enantioselective electrochemical oxidative rearrangement of indoles for the efficient synthesis of highly enantioenriched spirooxindoles. The in-situ generated HBr from substrate oxidation, known to be detrimental to the reaction itself, was perfectly consumed by cathode reduction. Challenges of this process include the difficulty in maintaining the synergy between substrate oxidation and cathode reduction as well as the general incompatibility of a hydrogen bonding catalytic system with the aqueous acidic media. A monophasic system was initially developed, but with little substrate generality. Further analysis of the mechanism and careful optimization allowed the development of a much more general and robust biphasic system that exhibited multiple advantages over chemical oxidation, including broader scope, less waste, milder conditions, and better enantioselectivity. It is also the first demonstration of chiral phosphoric acid catalysis in cooperation with H₃PO₄ in acidic aqueous media.

Herein, we report the use of bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane (DABAl-Me₃) as practical source of radicals for the introduction of valuable methyl groups to aryl bromides via a Nickel/metallaphotocatalytic cross coupling strategy.

Abstract

We report a metallaphotocatalytic strategy for the selective methylation of (hetero)aryl bromides via nickel-catalyzed cross-coupling with bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane (DABAl-Me₃), as a commercially available, air-stable, and non-pyrophoric aluminum-based reagent. The method enables a fast, robust, and scalable methylation protocol that broadly accommodates various functional groups while preventing protodehalogenation. Mechanistic studies confirm the unprecedented generation of methyl radicals from an organo-aluminum precursor under photoredox conditions, bypassing the limitations of conventional two-electron pathways. This work expands the toolbox of practical radical precursors and provides a streamlined approach for selective C(sp²)─CH₃ bond formation.

Nature Chemistry, Published online: 05 June 2025; doi:10.1038/s41557-025-01824-w

An intramolecular Pd-catalyzed spirocyclization enables the synthesis of chiral spirocyclic γ-lactams in up to 97% yield and 96% ee. The utility of this transformation has been demonstrated across 14 examples, including compounds bearing polyheterocyclic motifs and handles for further derivatization. Preliminary mechanistic investigations implicate the formation of catalytically relevant higher-order species.

Abstract

An enantioselective cyclization of Pd-enolates and isocyanates to form spirocyclic γ-lactams is reported. This reaction proceeds under mild reaction conditions and utilizes a novel Meldrum's acid derivative to achieve catalyst turnover, delivering enantioenriched products in up to 97% yield and 96% ee. Preliminary mechanistic investigations suggest that the reaction may proceed via the formation of higher-order species.

A regiospecific synthesis of 2,3-dialkylindoles via a 1,2-alkylpalladium migration to an in situ-generated aldimine intermediate. The unprecedented 1,2-alkylpalladium migration process is supported by density functional theory (DFT) calculations and control experiments, providing robust evidence for its mechanistic feasibility.

Abstract

2,3-Dialkylindoles play crucial roles in natural products and pharmaceuticals, but the step-efficient and regioselective construction of such privileged structures remains a long-standing challenge. Here, we report a regiospecific non-Fischer indole synthesis through chemoselective 1,2-migratory addition of alkylpalladium to an aldimine intermediate, formed in situ through a palladium hydride-triggered sequential isocyanide and intramolecular olefin insertion. This unprecedented 1,2-migratory addition leads to formal C═C bond cleavage and isocyano carbon insertion between the two sp² carbons, offering a novel approach to specific 2,3-dialkyl substituted N─H free indoles from readily available alkyl substituted 1-isocyano-2-vinylbenzenes.

Nature, Published online: 28 May 2025; doi:10.1038/s41586-025-09178-6

This study presents the first remote hydrogermylation of alkenes, utilizing a rare base-catalyzed strategy in the absence of transition metal catalysts. The methodology is operationally simple and highly versatile, enabling up to 8-carbon chain walks. This advance expands the scope of remote functionalization for modifying traditionally unactivated sites.

Abstract

Although remote functionalization has emerged as a powerful strategy for modifying unactivated sites that are traditionally challenging to functionalize, there has been no remote hydrogermylation known to date. This work reports the first remote hydrogermylation of alkenes, achieved through a rare base-catalyzed approach-completely free of added transition metal catalysts. The methodology is operationally simple, versatile, and capable of achieving up to 8-carbon chain walks, overcoming the previous two-carbon limit of base-mediated processes.

A biomimetic approach harnessing reactive species enabled the enantioselective synthesis of the complex meroterpenoid psiguadial A through an enolate–ortho-quinone methide (oQM) umpolung strategy and late-stage cationic ring closure. The final fully decorated aromatic core was successfully synthesized by adaptation of modern aryl methyl ether deprotection and formylation methodologies, establishing efficient access to this class of natural products.

Abstract

The first enantioselective total synthesis of the antiproliferative natural product (–)-psiguadial A is reported. This approach features the enantioselective synthesis of a complex tricyclic terpenoid precursor, the union of that precursor with a polyketide component by an enolate-ortho-quinone methide coupling reaction to form a highly congested carbon─carbon bond, and an acid-mediated intramolecular hydration ring-closure leveraging a fully substituted alkene to generate the unique oxepane core structure of the natural product.

Nature, Published online: 21 May 2025; doi:10.1038/s41586-025-09019-6