Fabio Pesciaioli

Enantiodivergence, the formation of opposite enantiomers from the same chiral catalyst, remains a largely empirical phenomenon in asymmetric catalysis, with limited mechanistic understanding. We report a remarkable case of enantiodivergence in the asymmetric transfer hydrogenation of α,β-unsaturated aldehydes, catalyzed by nitrogen-doped carbon dots (NCDs) and a fixed-handedness chiral phosphoric acid (CPA) under asymmetric counteranion-directed catalysis (ACDC) conditions. The stereochemical outcome is strongly influenced by minimal structural changes to the Hantzsch ester (HE) used as hydride donor. A synergistic investigation combining experimental results with extensive Molecular Dynamics (MD) simulations reveals the origin of this counterintuitive stereochemical switch. Our analysis show that the reversal in enantioinduction originates from differences in the reactive complex preorganization involving iminium ion, CPA, and HE. The simulations reveals that, under the experimental conditions, the preferred preorganization involves the CPA selectively coordinating to the iminium ion derived from the NCD–aldehyde adduct. This supramolecular assembly is steered by a delicate balance of weak London dispersion forces, which modulate the conformational ensemble of the catalytic system in solution and dictate the preferred face of hydride attack. This work provides a compelling rationalization for a complex phenomenon and underscores the critical role of subtle non-covalent interactions in controlling asymmetric reactions.

An industrially applicable and enantioselective total synthesis of (S)-autumnaline, a key biosynthetic precursor to the colchicine alkaloids, is reported. The strategy relies on a Bischler-Napieralski cyclization–asymmetric imine reduction sequence to construct the chiral isoquinoline core. Significant process innovations include a cyanide-free homologation using a Darzens reaction and a chromatography-free purification strategy via D-tartrate salt formation. The absolute configuration was definitively confirmed through a combination of circular dichroism (CD) spectroscopy and computational modelling. This developed process affords (S)-autumnaline in 11 steps (9-step longest linear sequence) with a 14% overall yield.

Carbazole serves as a prominent framework in the design of synthetic receptors, being a valuable scaffold for supramolecular chemistry, thanks to its planarity, fluorescence and versatility. This review provides a comprehensive analysis of notable examples of carbazole‐based receptors, highlighting the impact of structural modifications on binding affinity and selectivity toward different guests.

A new heterogeneous polymeric disulfonimide was very easily synthesized from simple commercially available reagents. The new cost-effective catalytic material exhibited a tremendously enhanced reactivity in a benchmark Mukaiyama aldol reaction via silicon Lewis acid activation when compared with common acidic resins. Moreover, the reported polymeric disulfonimide exhibits outstanding robustness, as confirmed by its good thermal stability and excellent recyclability.

The catalytic application of chiral phosphoric acids (CPAs) from 2004 to date represents a true milestone for asymmetric organocatalysis. However, not only the free acids can be conveniently employed in numerous different asymmetric synthetic methodologies, thus being strictly compliant to the concept of “organocatalysis”, but also their metal salts. This review focuses on asymmetric reactions in which the catalyst is a chiral alkali or alkaline‐earth metal phosphate.

A Piers–Rubinsztajn reaction was key to enable a mild deprotection and a concise synthesis of 7-hydroxy cannabidiol from commercially available cannabidiol, in 31% overall yield.

Asymmetric organocatalyzed multicomponent reactions represent an important toolbox in the field of organic synthesis to build complex scaffolds starting from simple starting materials. The Enders three-component cascade reaction was a cornerstone in the field and a plethora of organocatalyzed cascade reactions followed. However, acetaldehyde was not shown as a successful reaction partner, probably because of its high reactivity. Herein, we report the Enders-type cascade reaction using acetaldehyde dimethyl acetal, as a masked form of acetaldehyde. This strategy directly converts acetaldehyde, nitroalkenes and enals into stereochemically dense cyclohexenals in good yield and excellent enantioselectivity.

Dibenzosuberone (DBS) is a key intermediate for the synthesis of relevant active pharmaceutical ingredients (APIs) for the treatment of several diseases related to the central nervous system. Herein, the design and development of a milder and greener approach to improve the well‐established methodology for the synthesis of DBS limiting waste production via the use of immobilized catalysts are presented.

The development of micellar catalysis offers a sustainable alternative to organic solvents, and represents an environmental milestone in organic synthesis. Here, the first Michael addition of masked acetaldehyde under neutral, cationic and anionic micellar catalysis is reported, affording the products in high yields and enantiomeric excess, despite the use of water as solvent.

The straightforward, continuous-flow synthesis of cyclopropyl carbaldehydes and ketones has been developed starting from 2-hydroxycyclobutanones and aryl thiols. This acid-catalyzed mediated procedure allows access to the multigram and easily scalable synthesis of cyclopropyl adducts under mild conditions, using reusable Amberlyst-35 as a catalyst. The resins, suitably ground and used for filling steel columns, have been characterized via TGA, ATR, SEM and BET analyses to describe the physical–chemical properties of the packed bed and the continuous-flow system in detail. To highlight the synthetic versatility of the arylthiocyclopropyl carbonyl compounds, a series of selective oxidation reactions have been performed to access sulfoxide and sulfone carbaldehyde cyclopropanes, oxiranes and carboxylic acid derivatives.