Finn Moeller

A novel skeletal remodeling strategy allows for the transformation of pyridine into aniline, which serves as a multifunctional synthetic intermediate. By utilizing Lewis acid catalysis, the process enhances nucleophilic addition and nitrogen atom transposition, facilitating the rapid synthesis of diverse bioactive compounds. Mechanistic investigations through DFT calculations provide insights into the underlying processes, highlighting the potential of this strategy in pharmaceutical applications.

Abstract

Heterocyclic replacements are crucial tools in medicinal chemistry, enhancing the physicochemical properties of lead compounds. Pyridine, a core structural motif in numerous drug candidates, often serves as a key heterocyclic scaffold. Nonetheless, a universally applicable synthetic strategy for the direct conversion of pyridines into a diverse array of other heterocycles has yet to be established. In this study, we present a skeletal remodeling strategy that enables the transformation of pyridines into corresponding anilines via Lewis acid-catalyzed nitrogen atom transposition. These anilines can subsequently serve as versatile intermediates for accessing a variety of heterocyclic structures, thereby facilitating the rapid synthesis of novel bioactive analogs. DFT calculations indicate that the Lewis acid catalyst not only aids in the formation of pyridinium salts, enhances nucleophilic addition and nitrogen release. This methodology demonstrates considerable utility across a range of complex pyridine derivatives and several commercially available drugs, highlighting its potential for pharmaceutical diversification.

We report a multicomponent reaction involving an aryl halide, an aldehyde, and a silane derivative, facilitated by low-valent bismuth redox catalysis under mild conditions. The protocol represents an unprecedented example of four elementary organometallic steps at a Bi center within the catalytic cycle. Experimental and computational studies indicate the involvement of intermediate species that supports a Bi(I)/Bi(III) cycle.

Abstract

Herein, we report a catalytic defluorinative arylation of aldehydes with (per) A fluoroarenes facilitated by a pincer-based PheBox-Bi(I) under mild conditions. The protocol features various novel aspects in bismuth redox catalysis; namely, (1) a catalytic 1,2-aryl migratory insertion to forge a C─C bond, (2) an unprecedented example of multicomponent reaction through four elementary organometallic steps at a Bi center, (3) an unusual strategy for Bi(I) compounds regeneration via O─Si reductive elimination. Experimental and computational studies aided in dissecting the various mechanistic aspects of the bismuth redox cycle.

Nature, Published online: 01 August 2025; doi:10.1038/d41586-025-02364-6

A triple C─C cascade approach to the synthesis of heteroaryl cyclopropanes is described. The reaction is metal-free, uses simple starting materials, and presents a new retrosynthetic approach for heteroaryl cyclopropane synthesis. A change of substituent creates a new route to sultines, under-explored motifs in medicinal chemistry.

Abstract

We describe a triple C─C bond cascade process for heteroaryl cyclopropane synthesis, through the reaction of vinyl sulfonium salts and sulfones under mild conditions. An initial conjugate addition (C─C bond 1) sets up a Smiles–Truce rearrangement (C─C bond 2), with a final 3-exo-tet ring closure (C─C bond 3) affording cyclopropanes. Serendipitously, we uncovered a novel reaction variant that affords sultines, an under-explored heterocycle with potential application as a bioisostere in medicinal chemistry.

Cooperative N-heterocyclic carbene and photoredox catalysis for C─H benzoylation and esterification of allenes is presented. This reaction proceeds through the cross-coupling of in situ generated ketyl and allyl radicals.

Abstract

This study demonstrates the use of cooperative photoredox and N-heterocyclic carbene (NHC) catalysis for sp² C─H acylation of allenes. The cascade comprises oxidative generation of an allene radical cation from an allene, its nucleophilic trapping to the corresponding allyl radical and highly regioselective cross coupling by a concomitantly reductively generated NHC-derived ketyl type radical. Ionic fragmentation of both the NHC and nucleophile ultimately yields the desired substituted allene. The organic photocatalyst, 4CzIPN, is highly effective in promoting both oxidative and reductive electron transfer steps. Tri- and tetra-substituted allenes can be obtained in good yields through such a cascade. Mechanistic studies—including radical trapping, acylazolium reactions, and Stern–Volmer quenching—support the proposed mechanism. Moreover, follow-up chemistry is conducted to demonstrate the synthetic value of the cascade products.

Natural alcohol and sugar dehydrogenases that utilize the redox cofactor pyrroloquinoline quinone (PQQ) can be repurposed for enantioselective photoredox catalysis. Upon blue-light irradiation, redox-neutral radical cyclizations are catalyzed. This work adds a new class of enzymes to the toolbox of photobiocatalysis.

Abstract

Photoenzymatic catalysis facilitates stereoselective new-to-nature chemistry under mild conditions. In addition to the rational design of artificial photoenzymes, naturally occurring redox enzymes can be repurposed to promote photoredox catalysis in the chiral protein environment. Here, we show that enzymes utilizing the pyrroloquinoline quinone (PQQ) cofactor expand the toolbox of photobiocatalysis. PQQ absorbs visible light and is capable of single-electron transfer. It thus exhibits mechanistic similarities to flavin cofactors, which are widely used for photoenzymatic approaches. First, we established the trimethyl ester PQQMe₃ as a stand-alone photoredox catalyst in pure organic solvent. Upon excitation, PQQMe₃ enables the redox-neutral radical cyclization of an N-(bromoalkyl)-substituted indole. We then tested a panel of PQQ-dependent sugar and alcohol dehydrogenases for photoenzymatic catalysis in aqueous buffer, focusing on a redox-neutral radical reaction to form oxindoles. Under optimized reaction conditions, we obtained a 69% yield and an 82:18 enantiomeric ratio. Our work thus demonstrates that PQQ enzymes are capable of stereoselective photoredox catalysis. Future enzyme engineering efforts based on computational modeling and directed evolution will fully unlock their synthetic potential.

A two-step formal C─H/C─H coupling of arylacetamides with sulfoxides proceeds via the formation and rearrangement of little-known α-amido sulfonium salts and provides an alternative to transition metal-catalyzed C─H activation. The protocol is showcased in a short synthesis of a dopamine D1 receptor allosteric modulator.

Abstract

Arylacetamides are important structural motifs found in many bioactive compound classes. Given their significance, the selective decoration of arylacetamides by transition metal-catalyzed C─H activation has attracted considerable attention. Here, we report a two-step transition metal-free formal C─H/C─H coupling of arylacetamides with sulfoxides that proceeds via the formation and rearrangement of little-known α-amido sulfonium salts; the amide motif “catches” the sulfoxide partner prior to its delivery to the ortho-position of the aromatic ring by rearrangement of a sulfur ylide intermediate. The approach delivers alkylated arylacetamides bearing sulfide functional handles that can be exploited in downstream manipulations. This protocol has allowed the synthesis of a dopamine D1 receptor allosteric modulator without recourse to the use of transition metals.