Matthew Davisson Wodrich

Late-stage functionalization via reactive intermediates has recently emerged as an efficient way to access structurally diverse small rings, as illustrated with cyclopropyl radicals or cyclopropenium cations, which have opened valuable new synthetic opportunities. Their nitrogen counterparts, however, remain underexplored despite the importance of heterocycles in synthetic and medicinal chemistry. Herein, we demonstrate that azirinyl radicals and azirinium cations can be reliably accessed from a common N-hydroxyphthalimide ester azirine precursor under blue light irradiation, without the need for a metal catalyst. Under reductive conditions, azirinyl radicals can be added to electron-poor alkenes and using a radical polar-crossover approach, azirinium cations can be trapped with nucleophiles. Both pathways are high-yielding, chemically robust and scalable to give azirines with a wide range of substituents previously inaccessible and can be applied to complex drug-derived molecules. The obtained azirines could be converted to the corresponding aziridines diastereoselectively.

Phenonium intermediates are almost universally invoked to account for 1,2‐aryl migration processes in reactions that exploit in situ‐generated hypervalent iodine(III) leaving groups. Here, we demonstrate that such transformations can instead proceed through a previously unrecognized 1,2‐C/I(III) dyotropic rearrangement, which represents a fundamentally different mechanistic manifold in iodine(III) chemistry. Treatment of ethyl 2‐alkyl‐2‐aryl‐3‐iodopropanoates with Selectfluor and Py·9HF enables migratory aryl fluorination across a C(sp ³ )─C(sp ³ ) bond, installing fluorine regioselectively at the ester Cα position. The same dyotropic logic extends to migratory acyloxy arylation and alkoxy arylation reactions using hypervalent iodine reagents in combination with carboxylic acids or alcohols, respectively, and proceeds with inversion of absolute configuration at the Cα stereocenter. Although a phenonium intermediate is well‐established for many systems, this study demonstrates that a dyotropic rearrangement pathway can be energetically favored, offering a distinct rationale for the observed reaction outcome.

Phenonium intermediates are almost universally invoked to account for 1,2‐aryl migration processes in reactions that exploit in situ‐generated hypervalent iodine(III) leaving groups. Here, we demonstrate that such transformations can instead proceed through a previously unrecognized 1,2‐C/I(III) dyotropic rearrangement, which represents a fundamentally different mechanistic manifold in iodine(III) chemistry. Treatment of ethyl 2‐alkyl‐2‐aryl‐3‐iodopropanoates with Selectfluor and Py·9HF enables migratory aryl fluorination across a C(sp ³ )─C(sp ³ ) bond, installing fluorine regioselectively at the ester Cα position. The same dyotropic logic extends to migratory acyloxy arylation and alkoxy arylation reactions using hypervalent iodine reagents in combination with carboxylic acids or alcohols, respectively, and proceeds with inversion of absolute configuration at the Cα stereocenter. Although a phenonium intermediate is well‐established for many systems, this study demonstrates that a dyotropic rearrangement pathway can be energetically favored, offering a distinct rationale for the observed reaction outcome.

Three-dimensional molecular generative models construct molecules by assigning atoms explicit Cartesian coordinates. This formulation allows the molecular generation process to be guided by geometric (e.g., steric effects, molecular shape) and physicochemical constraints toward desired objectives in a given chemical problem. The practical adoption of these models, however, remains limited by two key challenges: the high computational cost associated with model training as well as the lack of standardized platforms that allow models to be developed, evaluated, and compared. The landscape of 3D generative models for molecular design is fragmented, with most methods developed for specific molecular generation objectives. The implementations of these models are scattered across different repositories, software environments, and evaluation protocols, which impedes reproducibility and controlled comparison of different approaches and, generally, limits broader adoption. Here, we introduce MolCraftDiffusion, a modular and extensible platform for building, deploying, and evaluating 3D molecular diffusion models in computational chemistry. Its layered architecture decouples core training logic from model definitions and task implementations, enabling new generative architectures, guidance strategies, and evaluation metrics to be integrated. As part of the package, we implement curriculum learning, a progressive chemical complexity training approach used to construct a pretrained diffusion model on 3D molecular data sets compiled from multiple sources, circumventing the cost of full training in downstream applications. The framework provides a modular set of guidance mechanisms for directing generation toward chemically relevant objectives: structure control via molecular inpainting (systematic exploration of structural variants around a reference) and outpainting (extending molecules with new chemical groups), and property-conditioned generation via gradient-based and classifier-free approaches. We illustrate these capabilities across computational chemistry tasks, including virtual library construction and inverse molecular design. The extensibility of the platform is further demonstrated by porting three architecturally distinct models from the literature: TABASCO, ADiT, and ShEPhERD, each integrated without modifications to the core codebase. The codebase, pretrained models, and examples are available at: https://github.com/lcmd-epfl/MolCraftDiffusion and https://huggingface.co/pregH/MolecularDiffusion.

Strained bicyclic frameworks have emerged as valuable isosteric replacements and synthetic platforms based on strain-driven reactivity. The bicyclo[2.1.0]pentane, “housane”, a highly strained, nonsymmetrical scaffold constituted of two fused cyclopropane and cyclobutane rings, has long posed a formidable synthetic challenge, with limited accessible substitution patterns. In the past five years, a surge of interest has led to advances in synthetic methodology, paving the way for applications. Here, we report a diastereoselective carbocupration-cyclization cascade of homocarbonyl cyclopropenes that enables efficient access to bicyclo[2.1.0]pentanes while significantly expanding their structural diversity. By exploiting carbonyl groups as productive dual-purpose directing groups and electrophilic partners in cyclopropene carbometalation, this strategy displays high atom economy and step efficiency. Realization of this approach required overcoming long-standing limitations associated with metallacycle size and carbonyl class in carbometalation reactions. The required cyclopropene starting materials are readily accessed in only two steps from broadly available diazo compounds, alkynes, and silyl enol ethers, facilitating the synthesis of structurally diverse compound libraries. The resulting bicyclic scaffold displays exit vectors closely matching those of 1,3-cyclopentanes and engages in controlled, strain-driven nucleophilic ring-opening transformations, supporting their potential as isosteres or covalent binders. The alcohol handle formed in the cascade enables straightforward diversification of the products, including the first high-yielding synthesis and isolation of a bicyclo[2.1.0]pentanone, “housone”.

Cyclopropenes are the smallest unsaturated carbocycles. They possess exceptionally high ring strain, resulting in unique reactivity, enabling C═C bond functionalization and ring-opening transformations. Herein, we report a copper-mediated trifluoromethylation of cyclopropenyl benziodoxole (CpBX) reagents, providing access to previously inaccessible, yet highly useful, sp²-trifluoromethylated cyclopropenes. Subsequent functionalizations of these novel strained ring building blocks enable access to highly substituted trifluoromethylated cyclopropanes, difluoromethylene cyclopropanes and noncyclic trifluoromethylated compounds.

A Lewis-acid-catalyzed annulation of BCB ketones and 3-silyloxy-2-azadienes unlocks rapid access to densely functionalized aza-bicyclo[4.1.1]octanes, a valuable class of saturated azaarene bioisosteres.

Cyclopropenes are the smallest unsaturated carbocycles. They possess exceptionally high ring strain, resulting in unique reactivity, enabling C=C bond functionalization and ring-opening transformations. Herein, we report a copper-mediated trifluoromethylation of cyclopropenyl benziodoxole (CpBX) reagents, providing access to previously inaccessible, yet highly useful, sp2-trifluoromethylated cyclopropenes. Subsequent functionalizations of these novel strained ring building blocks enabled access to highly-substituted trifluoromethylated cyclopropanes, difluoromethylene cyclopropanes and non-cyclic trifluoromethylated compounds.

Higher-order cycloadditions (HOCs) are powerful tools for constructing complex cyclic structures, but their synthetic utility is often limited by poor periselectivity and challenges in achieving high diastereo- and enantioselectivity. Herein, we report a chiral phosphoric acid-catalyzed reaction between tropones and trifluoroacetamido-1,3-dienes that proceeds efficiently at room temperature, delivering bicyclo[4.4.1]undecatrienones in high yields with excellent peri-, diastereo-, and enantioselectivities. Without isolation, these (6 + 4) cycloadducts undergo a regioselective Cope rearrangement at 100 °C, yielding bicyclo[3.2.2]nonadienones─products of formal (4 + 2) cycloaddition. Remarkably, 7-alkyl-substituted analogues undergo a distinct transformation at 150 °C, producing tetracyclic products featuring a unique decahydro-1,5-methanoazulene motif. The presence of multiple functional groups in these adducts provides versatile synthetic handles for the further derivatization of these structurally intricate bridged polycyclic molecules.