Enrico Marcantonio

An enantioselective eliminative inverse electron-demand Diels–Alder reaction of α-branched aldehydes, providing hydrindanone scaffolds in high yields and enantioselectivities, enabled by a cinchona alkaloid-based primary amine catalyst is reported.

Hetero-cycloaddition reactions are powerful, atom-economical strategies for the rapid construction of heterocyclic frameworks from readily available building blocks. Over the past two decades, advances in photochemistry, photocatalysis, and modern excitation strategies have driven remarkable developments in the field. By accessing electronically excited states, light enables cycloaddition pathways inaccessible under classical thermal conditions, providing access to reactive radical, ionic, or excited-state intermediates under mild conditions. Technological advances in light sources and photocatalyst design have improved reaction efficiency, site-, regio-, and stereoselectivity, while considerably expanding the accessible chemical space. Beyond established hetero-[2 + 2], hetero-(3 + 2), and hetero-[4 + 2] processes, new reaction classes, including π–σ hetero-cycloadditions exploiting strained small-ring systems, have emerged as powerful approaches to structurally complex saturated scaffolds of increasing relevance in medicinal chemistry. In this Review, we critically examine the evolution of photochemical hetero-cycloadditions from 2000 to 2026, discussing fundamental concepts and terminology, cycloaddition classes, heterocyclic targets, and activation mechanisms. We highlight the conceptual advances that have shaped modern photochemical hetero-cycloaddition chemistry and conclude by discussing current limitations and future directions for the field.

A new chapter starts now . Since its discovery in 2005, the diarylprolinol silyl ether catalytic concept has emerged as a general and reliable aminocatalytic tool for the synthesis of enantioenriched molecules. Recently its combination with emerging technologies, as well as its application in more complex molecular systems has opened new avenues for novel enantioenriched scaffolds. In this review, we will highlight these recent developments, unfolding five primary categories that define new horizons in the use of diarylprolinol silyl ethers: Photochemical‐, electrochemical‐, dual‐catalytic transformations, higher‐order cycloadditions and applications in total synthesis of complex natural products.

A new chapter starts now . Since its discovery in 2005, the diarylprolinol silyl ether catalytic concept has emerged as a general and reliable aminocatalytic tool for the synthesis of enantioenriched molecules. Recently its combination with emerging technologies, as well as its application in more complex molecular systems has opened new avenues for novel enantioenriched scaffolds. In this review, we will highlight these recent developments, unfolding five primary categories that define new horizons in the use of diarylprolinol silyl ethers: Photochemical‐, electrochemical‐, dual‐catalytic transformations, higher‐order cycloadditions and applications in total synthesis of complex natural products.

γ‐Butenolides are widespread structural motifs found in many natural and unnatural products which display an impressive range of biological activities. Among them, ε‐keto‐γ‐butenolides represent underestimated butenolide frameworks, which could serve as valuable platforms to build complex structures, for example, heterobicyclic derivatives. Quite unexpectedly, despite the apparent simplicity of their structures, efficient synthetic methodologies enabling the construction of chiral, ε‐keto‐γ‐butenolide architectures are quite underdeveloped. In this context, herein we present a novel, photoinduced regio‐ and chemoselective γ‐alkylation of 2‐silyloxyfurans with 2‐bromoketones providing a practical access to ε‐ketobutenolide scaffolds in racemic format, in one single step and high yields. The usefulness of these products as starting materials to build chiral, fused‐heterobicycle lactone derivatives was demonstrated by the implementation of a two‐step strategy which successfully delivered unprecedented phenyltetrahydrofuro[3,2‐ b ]furan‐2(3 H )‐one and tetrahydrofuro[3,2‐ c ]pyridazin‐6(1 H )‐one chemotypes.

The enantioselective [4 + 4] cycloaddition for the construction of cyclooctanoids is a challenging transformation in organic chemistry. Herein, we present the first organocatalytic enantioselective [4 + 4] cycloaddition of furan ortho‐quinodimethanes, activated by dearomatization of the heteroaromatic compound, which thereby allows for the cycloaddition with dienes. The [4 + 4] cycloaddition is catalyzed by a quinine‐derived primary amine in combination with a chiral phosphoric acid and a carboxylic acid affording cyclooctanoids isolated as a single diastereoisomer in good yields and with up to 94% ee. This reaction concept allows for the formation of cyclooctanoids without benzofusion, as demonstrated by oxidative opening of the furan ring. Computational studies of the reaction mechanism for the [4 + 4] cycloaddition point to a stepwise process. Surprisingly, the stereochemical outcome of the reaction is attributed to protonation of the two organocatalyst‐bound cyclooctanoid intermediates leading to a preferred set‐up for catalyst elimination to account for the absolute configuration of the cyclooctanoid.

The enantioselective [4 + 4] cycloaddition for the construction of cyclooctanoids is a challenging transformation in organic chemistry. Herein, we present the first organocatalytic enantioselective [4 + 4] cycloaddition of furan ortho‐quinodimethanes, activated by dearomatization of the heteroaromatic compound, which thereby allows for the cycloaddition with dienes. The [4 + 4] cycloaddition is catalyzed by a quinine‐derived primary amine in combination with a chiral phosphoric acid and a carboxylic acid affording cyclooctanoids isolated as a single diastereoisomer in good yields and with up to 94% ee. This reaction concept allows for the formation of cyclooctanoids without benzofusion, as demonstrated by oxidative opening of the furan ring. Computational studies of the reaction mechanism for the [4 + 4] cycloaddition point to a stepwise process. Surprisingly, the stereochemical outcome of the reaction is attributed to protonation of the two organocatalyst‐bound cyclooctanoid intermediates leading to a preferred set‐up for catalyst elimination to account for the absolute configuration of the cyclooctanoid.

Bicyclo[1.1.0]butanes have opened a new area of chemical space for construction of bicyclo[2.1.1]hexanes – a scaffold showing promise as ortho- and meta-aryl bioisosteres. Herein, we present the first aminocatalytic concept that enables the enantioselective [2 + 2] cycloaddition of bicyclo[1.1.0]butanes with α,β-unsaturated aldehydes. The reaction is general for α,β-unsaturated aldehydes, substituted at the γ-position with aromatic functionalities, esters and ketones, by applying a secondary aminocatalyst and Yb(OTf)₃ as a Lewis acid to activate the bicyclo[1.1.0]butane. For cinnamaldehydes, bicyclo[2.1.1]hexane cycloadducts are obtained in moderate to good yields, and up to 96.5 : 3.5 e.r. Pleasingly, α,β-unsaturated aldehydes containing ester and ketone functionalities in the γ-position provided high yields and enantioselectivities up to 98.5 : 1.5 e.r. For all three classes of [2 + 2] cycloadditions, a range of α,β-unsaturated aldehydes and bicyclo[1.1.0]butanes were successfully tolerated. Several transformations adding further complexity to the bicyclo[2.1.1]hexane scaffolds are disclosed. Finally, a reaction mechanism is proposed.

Polycyclic compounds bearing a complex heterocyclic core such as an aromatic heterocycle “fused” with one or more functionalized rings, are widespread leading molecules in the domain of synthetic organic chemistry and pharmaceuticals. Although many synthetic methodologies have been devised to access achiral, fused heteroaromatic scaffolds, or related chiral variants adorned with out‐of‐cycle stereogenic elements, equally efficient strategies to afford chiral heterocycles featuring in‐cycle stereocenters, exist to a lesser extent and presently represent a growing field of investigation. The mild, organocatalytic generation of elusive ortho‐quinodimethane intermediates (oQDMs), derived from suitable heteroaromatic carbonyl‐ or carbonyl‐like pronucleophiles has recently proved successful in the synthesis of such peculiar chiral architectures via stereoselective [4+2] cycloadditions. This review provides an overview of the most important advances attained in this field over the last decade.

Organocatalytic asymmetric transformation of common aromatic heterocycles via in situ formation of highly reactive dearomatized ortho‐quinodimethane diene species and subsequent [4+2] cycloaddition with suitable dienophiles has become a powerful tool to enter cyclohexane‐fused heterocycles. Most of these reactions were previously applied to benzo‐fused heterocycles or poorly aromatic rings. Herein, we disclose how previously intractable aromatic imidazole rings, equipped with removable methylidene malononitrile activating handle, could be involved as competent cycloaddends with β‐aryl enals in efficient eliminative [4+2] cycloadditions under mild organocatalytic conditions. This method allowed the efficient and direct preparation of scantly represented 6,7‐dihydrobenzo[d]imidazoles with optimal enantio‐ and regioselectivities. Post‐cycloaddition chemical editing provided imidazole‐based ring systems with diverse oxidation state and functional groups.