Challenges and Future Perspectives in Photocatalysis: Conclusions from an Interdisciplinary Workshop.

Photocatalysis is a versatile and rapidly developing field with applications spanning artificial photosynthesis, photo-biocatalysis, photoredox catalysis in solution or supramolecular structures, utilization of abundant metals and organocatalysts, sustainable synthesis, and plastic degradation. In this Perspective, we summarize conclusions from an interdisciplinary workshop of young principal investigators held at the Lorentz Center in Leiden in March 2023. We explore how diverse fields within photocatalysis can benefit from one another.

Facilitating [2+2] Photocycloadditions by Promoting Oxygen Tolerance and Substrate Activation in Water.

Micellar photocatalysis has been used to overcome oxygen quenching and enable a [2+2] photocycloaddition through triplet-energy transfer in water under aerobic conditions. The cheap and commercially available self-assembling sodium dodecyl sulfate (SDS) micelles were found to increase the oxygen tolerance of a typically oxygen-sensitive reaction. Furthermore, the use of the micellar solution was found to activate α,β-unsaturated carbonyl compounds to energy transfer and allow [2+2] photocycloadditions to take place.

Concise Total Synthesis of Agarozizanol B via a Strained Photocascade Intermediate.

The prezizane-type sesquiterpene agarozizanol B was synthesized employing a photochemical cascade reaction as the key step. Starting from a readily available 1-indanone with a tethered olefin, a strained tetracyclic skeleton was assembled which contained all carbon atoms of the sesquiterpene with the correct relative configuration. The conversion into the tricyclic prezizane skeleton was accomplished by a strategic cyclopropane bond cleavage.

Stereoselective Oxidative Bioconjugation of Amino Acids and Oligopeptides to Aldehydes.

The first stereoselective, near-equimolar, and metal-free oxidative bioconjugation of amino acids and oligopeptides to aldehydes is presented. Based on a newly developed organocatalytic oxidative concept, the C-terminal and side-chain carboxylic acid functionalities of amino acids and oligopeptides are shown to couple in a stereoselective manner to α-branched aldehydes catalyzed by a chiral primary amine and a quinone as oxidizing agent. The oxidative coupling generally proceeds in high yield.

Complex Carbocyclic Skeletons from Aryl Ketones through a Three-Photon Cascade Reaction.

Starting from readily available 7-substituted 1-indanones, products with a tetracyclo[5.3.1.

Oxidative organocatalysed enantioselective coupling of indoles with aldehydes that forms quaternary carbon stereocentres.

The first organocatalysed, metal-free cross-nucleophile coupling of indoles with α-branched aldehydes forming acyclic stereoselective quaternary carbon centres is presented. Applying an amino acid-derived catalyst with suitable organic oxidants affords the desired enantioenriched indole functionalised products with moderate to excellent yield and enantioselectivity. Two metal-free oxidative protocols employing either DDQ or a sequential approach that uses two organocatalysts to facilitate the use of O as the terminal oxidant are disclosed.

Enantioselective Oxidative Coupling of Carboxylic Acids to α-Branched Aldehydes.

A new reactivity in organocatalysis is proposed to account for the coupling of carboxylic acids to α-branched aldehydes by combining primary amine catalysis and an oxidant. The developed methodology is an enantioselective α-coupling of aromatic and aliphatic carboxylic acids to α-branched aldehydes and proceeds in high yields (up to 97%) and for most examples good enantioselectivities (up to 92% ee). On the basis of experimental and mechanistic observations, the role of the primary amine catalyst is discussed.

Direct Enantio- and Diastereoselective Oxidative Homocoupling of Aldehydes.

A novel strategy for the direct enantioselective oxidative homocoupling of α-branched aldehydes is presented. The methodology employs open-shell intermediates for the construction of chiral 1,4-dialdehydes by forming a carbon-carbon bond connecting two quaternary stereogenic centers in good yields and excellent stereoselectivities for electron-rich aromatic aldehydes. The 1,4-dialdehydes were transformed into synthetically valuable chiral pyrrolidines.

Catalytic Asymmetric Oxidative γ-Coupling of α,β-Unsaturated Aldehydes with Air as the Terminal Oxidant.

A novel concept for catalytic asymmetric coupling reactions is presented. Merging organocatalysis with single-electron oxidation by using a catalytic amount of a copper(II) salt and air as the terminal oxidant, we have developed a highly stereoselective carbon-carbon oxidative coupling reaction of α,β-unsaturated aldehydes. The concept relies on the generation of a dienamine intermediate, which is oxidized to an open-shell activated species that undergoes highly selective γ-homo- and γ-heterocoupling reactions.

Synergistic Catalysis for the Asymmetric [3+2] Cycloaddition of Vinyl Aziridines with α,β-Unsaturated Aldehydes.

The first asymmetric [3+2] cycloaddition of vinyl aziridines with α,β-unsaturated aldehydes, based on synergistic catalysis, is disclosed. This methodology allows the formation of attractive pyrrolidine structures in good yields (up to 84 %), moderate diastereoselectivity, and high enantioselectivity values (up to >99 % ee). Additionally, a tricyclic pyrrolidine core structure found in biologically active molecules was synthesized in a one-pot fashion by using the presented reaction concept.

Enantioselective Organocatalytic Cascade Approach to Different Classes of Benzofused Acetals.

A novel enantioselective organocatalytic strategy is presented for the synthesis of tetrahydrofurobenzofuran and methanobenzodioxepine natural product core structures. The strategy is based on a pair of divergent reaction pathways in which hydroxyarenes react with γ-keto-α,β-unsaturated aldehydes, catalyzed by a chiral secondary amine. One reaction pathway, which leads to chiral 5,5-fused acetals with two stereocenters-the tetrahydrofurobenzofuran scaffolds-proceeds in moderate yields and up to 96 % ee.

Asymmetric [3 + 2] Cycloaddition of Vinylcyclopropanes and α,β-Unsaturated Aldehydes by Synergistic Palladium and Organocatalysis.

The stereoselective [3 + 2] cycloaddition between vinylcyclopropanes and α,β-unsaturated aldehydes promoted by combined palladium and organocatalysis is disclosed. The unique synergistic catalytic system allows for the stereoselective formation of highly substituted cyclopentanes with up to four stereocenters in high yields and selectivities. Vinylcyclopropanes with two different geminal substituents facilitate the formation of cyclopentanes containing a quaternary stereocenter.

Asymmetric γ-Allylation of α,β-Unsaturated Aldehydes by Combined Organocatalysis and Transition-Metal Catalysis.

The first asymmetric regio- and diastereodivergent γ-allylation of cyclic α,β-unsaturated aldehydes based on combined organocatalysis and transition-metal catalysis is disclosed. By combining an aminocatalyst with an iridium catalyst, both diastereomers of branched allylated products can be achieved in moderate to good yields and excellent regio- and stereoselectivities. Furthermore, by replacing the iridium catalyst with a palladium catalyst, the linear allylated products are formed in good yields and excellent regio- and enantioselectivities.

An organocatalytic one-pot cascade incorporating the Achmatowicz reaction affording 3-pyrone derivatives.

The development of an organocatalytic one-pot cascade for the annulation of simple starting materials: α,β-unsaturated aldehydes, hydrogen peroxide, β-carbonyl compounds and NBS to furnish optically active 3-pyrones in good yield and with excellent enantioselectivity is presented. Further diversification of the obtained products is demonstrated by selective reductive transformations.