Light-Driven Synthesis and Functionalization of Bicycloalkanes, Cubanes and Related Bioisosteres.

Bicycloalkanes, cubanes and their structural analogues have emerged as bioisosteres of (hetero)arenes. To meet increasing demand, the chemical community has developed a plethora of novel synthetic methods. In this review, we assess the progress made in the field of light-driven construction and functionalization of such relevant molecules. We have focused on diverse structural targets, as well as on reaction processes giving access to: (i) [1.1.1]-bicyclopentanes (BCPs); (ii) [2.2.1]-bicyclohexanes (BCHs); (iii) [3.1.1]-bicycloheptanes (BCHeps); and (iv) cubanes; as well as other structurally related scaffolds. Finally, future perspectives dealing with the identification of novel reaction manifolds to access new functionalized bioisosteric units are discussed.

A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2-BCA) Hybrid Bioisosteres.

Here, we report a general approach to the synthesis of the difluoroalkyl bicycloalkanes (CF2 -BCAs), as structural surrogates of aryl ketones and ethers. The chemistry is driven by a dihydrobenzoacridine photocatalyst, that engages in a catalytic electron-donor acceptor (EDA) complex, or directly reduces the fluorinated substrate. These two convergent manifolds lead to the generation of the R-CF2 radical, that reacts with the [1.1.1]- or [3.1.1.]-propellane. The method is extremely general, and extendable to complex bioactive molecules (30 examples, up to 87 % yield). The structural features of the CF2 -BCP hybrid bioisostere were investigated by single crystal X-ray. Finally, we synthesised a CF2 -BCP analogue of a Leukotriene A4 hydrolase inhibitor, replacing the original aryl ether motif. In silico docking studies indicated that this new analogue maintains the same arrangement within the enzyme pocket, profiling the use of the CF2 -BCA hybrid bioisostere in medicinal chemistry settings.

Modern Photocatalytic Strategies in Natural Product Synthesis.

Modern photocatalysis has proven its generality for the development and functionalization of native functionalities. To date, the field has found broad applications in diverse research areas, including the total synthesis of natural products. This contribution covers recent reports of total syntheses involving as a key step a photocatalytic reaction. Among the selected examples, the photocatalytic processes proceed in a highly chemo-, regio-, and stereoselective manner, thereby allowing the rapid access to structurally complex architectures under light-driven conditions.

Mechanisms and Synthetic Strategies in Visible Light-Driven [2+2]-Heterocycloadditions.

The synthesis of four membered heterocycles usually requires multi-step procedures and prefunctionalized reactants. A straightforward alternative is the photochemical [2+2]-heterocycloaddition between an alkene and a carbonyl derivative, conventionally based on the photoexcitation of this latter. However, this approach is limited by the absorption profile of the carbonyl, requiring in most of the cases the use of high-energy UV-light, that often results in undesired side reactions and/or the degradation of the reaction components. The development of new and milder visible light-driven [2+2]-heterocycloadditions is, therefore, highly desirable. In this Review, we highlight the most relevant achievements in the development of [2+2]-heterocycloadditions promoted by visible light, with a particular emphasis on the involved reaction mechanisms. The open challenges will also be discussed, suggesting new possible evolutions, and stimulating new methodological developments in the field.

The Photochemical Activity of a Halogen-Bonded Complex Enables the Microfluidic Light-Driven Alkylation of Phenols.

A mild light-driven protocol for the direct alkylation of phenols is reported. The process is driven by the photochemical activity of a halogen-bonded complex formed upon complexation of the in situ generated electron-rich phenolate anion with the α-iodosulfone. The reaction proceeds rapidly (10 min) under microfluidic conditions, delivering a wide variety of ortho-alkylated products (27 examples, up to 97% yield, >20:1 regioselectivity, on a gram scale), including densely functionalized bioactive phenol derivatives.

The advent and development of organophotoredox catalysis.

In the last decade, photoredox catalysis has unlocked unprecedented reactivities in synthetic organic chemistry. Seminal advancements in the field have involved the use of well-studied metal complexes as photoredox catalysts (PCs). More recently, the synthetic community, looking for more sustainable approaches, has been moving towards the use of purely organic molecules. Organic PCs are generally cheaper and less toxic, while allowing their rational modification to an increased generality. Furthermore, organic PCs have allowed reactivities that are inaccessible by using common metal complexes. Likewise, in synthetic catalysis, the field of photocatalysis is now experiencing a green evolution moving from metal catalysis to organocatalysis. In this feature article, we discuss and critically comment on the scientific reasons for this ongoing evolution in the field of photoredox catalysis, showing how and when organic PCs can efficiently replace their metal counterparts.

A visible-light mediated three-component radical process using dithiocarbamate anion catalysis.

We report a photoinduced three-component radical process, which couples readily available alkyl chlorides, maleimides, and heteroaromatic fragments to rapidly generate complex chiral products with high diastereocontrol. This method generates radicals via an SN2-based photochemical catalytic mechanism, which is not reliant on the redox properties of the precursors. It therefore grants access to open-shell intermediates from substrates that would be incompatible with or inert to classical radical-generating strategies. The redox-neutral conditions of this process make it tolerant of redox-sensitive substrates and allow the installation of multiple biologically relevant heterocycles within the cascade products.

Forging Fluorine-Containing Quaternary Stereocenters by a Light-Driven Organocatalytic Aldol Desymmetrization Process.

Reported herein is a light-triggered organocatalytic strategy for the desymmetrization of achiral 2-fluoro-substituted cyclopentane-1,3-diketones. The chemistry is based on an intermolecular aldol reaction of photochemically generated hydroxy-o-quinodimethanes and simultaneously forges two adjacent fully substituted carbon stereocenters, with one bearing a stereogenic carbon-fluorine unit. The method uses readily available substrates, a simple chiral organocatalyst, and mild reaction conditions to afford an array of highly functionalized chiral 2-fluoro-3-hydroxycyclopentanones.

Enantioselective Organocatalytic Diels-Alder Trapping of Photochemically Generated Hydroxy-o-Quinodimethanes.

The photoenolization/Diels-Alder strategy offers straightforward access to synthetically valuable benzannulated carbocyclic products. This historical light-triggered process has never before succumbed to efforts to develop an enantioselective catalytic approach. Herein, we demonstrate how asymmetric organocatalysis provides simple yet effective catalytic tools to intercept photochemically generated hydroxy-o-quinodimethanes with high stereoselectivity. We used a chiral organic catalyst, derived from natural cinchona alkaloids, to activate maleimides toward highly stereoselective Diels-Alder reactions. An unconventional mechanism of stereocontrol is operative, wherein the organocatalyst is actively involved in both the photochemical pathway, by leveraging the formation of the reactive photoenol, and the stereoselectivity-defining event.