Eosin, blue LEDs and DIPEA are employed in a simple synthesis of (poly)cyclic O,O- and N,O-acetals.

A simple procedure for the synthesis of (poly)cyclic O,O- and N,O-acetals from various enol ethers, N-acyl enamines or Boc-protected enamines has been developed. The key step is a photocatalytic Stork-Ueno-type cylization using the very simple metal-free conditions of catalytic eosin, diisopropylamine in the green solvent ethanol with blue LED irradition.

The Rapid Synthesis of Colibactin Warhead Model Compounds Using New Metal-Free Photocatalytic Cyclopropanation Reactions Facilitates the Investigation of Biological Mechanisms.

Herein, we report the synthesis of a series of colibactin warhead model compounds using two newly developed metal-free photocatalytic cyclopropanation reactions. These mild cyclopropanations expand the known applications of eosin within synthesis. A halogen atom transfer reaction mode has been harnessed so that dihalides can be used as the cyclopropanating agents. The colibactin warhead models were then used to provide new insight into two key mechanisms in colibactin chemistry. An explanation is provided for why the colibactin warhead sometimes undergoes a ring expansion-addition reaction to give fused cyclobutyl products while at other times nucleophiles add directly to the cyclopropyl unit (as when DNA adds to colibactin). Finally, we provide some evidence that Cu(II) chelated to colibactin may catalyze an important oxidation of the colibactin-DNA adduct. The Cu(I) generated as a result could then also play a role in inducing double strand breaks in DNA.

Multiphotocatalyst Cascades: From Furans to Fused Butyrolactones and Substituted Cyclopentanones.

High value oxygenated polycycles have been rapidly and efficiently accessed from simple precursors in one pot processes. The reported methodology relies on a new and mild method for butenolide synthesis mediated by thiols. The initial photooxygenation and butenolide synthesis have been merged with subsequent photoredox reactions to achieve rare dual-photocatalyst cascades affording various fused butyrolactones. Ground state Lewis acid activity for methylene blue has been unveiled and then exploited in the synthesis of substituted cyclopentanones.

Access to high value sp3-rich frameworks using photocatalyzed [2 + 2]-cycloadditions of γ-alkylidene-γ-lactams.

By harnessing an energy transfer process, new photocatalyzed [2 + 2]-cycloadditions occurring between γ-alkylidene-γ-lactams and unsaturated substrates have been developed. The reaction mode is particularly powerful because it leads to the formation of different high value sp3-rich frameworks and further diversity can be introduced through cascade sequences wherein strain releasing opening of the cyclobutane intermediates gives access to complex polycyclic alkaloid frameworks.

Sequential Visible Light-Induced Reactions Using Different Photocatalysts: Transformation of Furans into 2-Pyridones via γ-Lactams Using a New Ring Expansion Reaction.

A new photocatalytic ring expansion reaction that transforms γ-lactams into 2-pyridones is described. The reaction is radical-triggered and was inspired by a late-stage oxidation commonly observed in fungal metabolism. The reaction is particularly powerful because it can be included in a one pot process which converts readily accessible furans directly into 2-pyridones through sequential photo-induced reactions (energy transfer and electron transfer). The study also unveiled unprecedented reactivity for the mild and metal-free photocatalyst eosin, wherein it is used to cleave a C-I bond activated only by an electron donor on the neighbouring carbon.

5-Hydroxy-pyrrolone based building blocks as maleimide alternatives for protein bioconjugation and single-site multi-functionalization.

Recent dramatic expansion in potential uses of protein conjugates has fueled the development of a wide range of protein modification methods; however, the desirable single-site multi-functionalization of proteins has remained a particularly intransigent challenge. Herein, we present the application of 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones (5HP2Os) as advantageous alternatives to widely used maleimides for the chemo- and site-selective labeling of cysteine residues within proteins. A variety of 5HP2O building blocks have been synthesized using a one-pot photooxidation reaction starting from simple and readily accessible furans and using visible light and oxygen. These novel reagents display excellent cysteine selectivity and also yield thiol conjugates with superior stability. 5HP2O building blocks offer a unique opportunity to introduce multiple new functionalities into a protein at a single site and in a single step, thus, significantly enhancing the resultant conjugate's properties.

One-Pot Transformation of Furans into 1-Azaspirocyclic Alkaloid Frameworks Induced by Visible Light.

High-value 1-azaspirocyclic scaffolds have been made from simple and readily accessible furan precursors in a single operation. The protocol is a one-pot sequence using highly sustainable conditions (oxygen, visible light, and a favored green solvent) that leads to a dramatic increase in molecular complexity. The initial substrates can include functionalities that are suitable for further elaboration; in this way, the pruned polycyclic skeletons of the stemonamine, cylindricine, and lepadiformine natural products were rapidly accessed.

Eosin: a versatile organic dye whose synthetic uses keep expanding.

Organic dyes, which absorb light in the visible region of the electromagnetic spectrum, offer a lower cost, greener alternative to precious metals in photocatalysis. In this context, the organic dye eosin's uses are currently expanding at a significant rate. For a long time, its action as an energy transfer agent dominated, more recently, however, there has been a growing interest in its potential as an electron transfer agent. In this short review, we highlight some recent (from 2016 onwards) contributions to the field with a focus on the breadth of the reactions eosin can catalyse.

Multi-Photocatalyst Cascades: Merging Singlet Oxygen Photooxygenations with Photoredox Catalysis for the Synthesis of Alkaloid Frameworks.

The development of photocascades that rapidly transform simple and readily accessible furan substrates into polycyclic alkaloid frameworks or erythrina natural products is described. Each of the sequences developed makes use of photocatalyzed energy transfer processes, which generate singlet oxygen, to set up the substrates for the second photocatalyzed reaction, wherein electron transfer generates carbon-centered radicals for the cyclizations that give the final complex frameworks. A chemical switch has been developed that can "switch off" one photocatalyst; thus, allowing a second photocatalyst to take over control of the sequence. As a corollary, this strategy represents the first time it has been possible to use multiple photocatalysts in photocascades, and, as such, it expands significantly the reactions that can be included in such cascades and the order in which they can be initiated.

Merging singlet-oxygen induced furan oxidations with organocatalysis: synthesis of enantiopure cyclopentanones and hydrindanes.

A new methodology is described herein which converts simple and readily accesible furan substrates into complex enantio-enriched carbocyclic skeletons through the implementation of a simple one-pot procedure. Singlet oxygen furan photoxygenation affords an enedione which then participates in an organocatalysed double-Michael reaction with an enal to furnish a cyclopentanone structure with up to four new contiguous stereogenic centres. The enantioselectivity and diastereoselectivity of this process are both excellent. If desired, further aldol-annulation steps can be appended to the cascade reaction sequence to afford key enantiopure hydrindane motifs.

The reticent tautomer: exploiting the interesting multisite and multitype reactivity of 4-pyrrolin-2-ones.

4-Pyrrolin-2-ones are a lesser known tautomeric relative of the 3-pyrrolin-2-ones. Despite their infrequent appearance in the literature, they are very interesting and useful compounds. They have highly controllable, multisite and multitype reactivities which are covered in this review. The applications of these transformations show how the 4-pyrrolin-2-ones make excellent intermediates en-route to a range of key alkaloids. Innovative, fast and adaptable syntheses of the 4-pyrrolin-2-ones and their onward use via cascade reaction sequences are also presented to complete the case for commending these compounds as highly versatile and valuable synthetic building blocks.

Singlet-Oxygen-Mediated Synthesis of Pandanusine A and Pandalizine C and Structural Revision of Pandanusine B.

The first synthesis of racemic pandanusines A and B and pandalizine C, isolated from Pandanus amaryllifolius, is reported. The key synthetic step is an efficient tandem reaction sequence initiated by the photooxidation of an easily prepared furylalkylamine precursor. In this reaction sequence, methylene blue plays a dual catalytic role of photosensitizer and redox catalyst, first in generating singlet oxygen and second in facilitating a triplet oxygen reaction. Through the synthesis of pandanusine B, the proposed structure has been revised.

Vinylogous Reactivity of Cyclic 2-Enones: Organocatalysed Asymmetric Addition to 2-Enals to Synthesize Fused Carbocycles.

A method for asymmetric and site selective annulations at the γ and γ' positions of cyclic 2-enones with α,ß-unsaturated aldehydes has been developed. The organocatalysed [3+3]-annulations proceed with high levels of regio-, diastereo-, and enantioselectivity, affording a series of high value fused carbocycles. Further elaboration gave key lactones (both bridged and fused).

One-Pot Synthesis of Diverse γ-Lactam Scaffolds Facilitated by a Nebulizer-Based Continuous Flow Photoreactor.

The use of a modified prototype continuous flow reactor (CFR) as a pivotal part of a number of versatile singlet oxygen-mediated reaction sequences is presented herein. These sequences target rapid access to structural complexity and diversity. The prototype reactor achieves high conversions and productivities by attaining large specific surface areas for these biphasic reactions. In the reactor, the reaction solution is nebulized (using either oxygen or air) and the resulting aerosol is irradiated by an LED jacket that surrounds the Pyrex reaction chamber. The one pot procedures developed herein are, according to many different criteria, both highly efficient and green. The key common intermediates and the source of both the complexity and variety of the final products are N-acyl imminium ions (NAI; protonated N-acyl enamines). The initial substrates are simple and readily accessible furans and the diverse array of products is composed of different complex γ-lactams. Many of the products are of particular interest due to their close relationships to known biologically active molecules.

The Power of Triplet and Singlet Oxygen in Synthesis: 2-Oxindoles, 3-Hydroxy-2-oxindoles, and Isatins from Furans.

A straightforward synthesis of substituted 2-oxindoles, 3-hydroxy-2-oxindoles, and isatins has been developed. Easily accessible furans were transformed into tetrahydropyranopyrrolones by a singlet oxygen initiated cascade reaction sequence. An acid-catalyzed rearrangement, followed by aromatization, gave access to a variety of 2-oxindole motifs, which were oxidized to 3-hydroxy-2-oxindoles or isatins using methylene blue as a radical initiator and molecular oxygen as a terminal oxidant.

Asymmetric and Site-Selective [3 + 2]-Annulations for the Synthesis of High-Value Bicyclic Lactams.

Asymmetric and site-selective formal [3 + 2]-annulations of γ-alkyl-ß,γ-unsaturated γ-lactams with α,ß-unsaturated aldehydes have been developed. These organocatalysed transformations yield high value enantioenriched bicyclic γ-lactams with up to four new stereocenters (sometimes including a quarternary carbon). The overall transformation starts from simple and readily accessible furans and oversees a rapid, controlled, and dramatic enhancement in 3D complexity.

Synthesis of cyclopent-2-enones from furans using a nebulizer-based continuous flow photoreactor.

A series of hydroxycyclopent-2-enones and methoxycyclopent-2-enones have been synthesized in a single operation from simple furan substrates using an innovative continuous flow nebulizer system (NebPhotOX). Photooxygenation of the furan substrates takes place in an aerosol within the NebPhotOX system.

One-Pot Transformation of Simple Furans into Octahydroindole Scaffolds.

A highly efficient and general singlet-oxygen-initiated one-pot transformation of readily accessible furans into octahydroindole scaffolds has been developed.

Total Synthesis and Structural Revision of (+)-Yaoshanenolide B.

(+)-Yaoshanenolide B was synthesized employing as a key step an endo- and face-selective Diels-Alder reaction between natural R-(-)-α-phellandrene and the exocyclic double bond of a 5-methylene-2(5H)-furanone. The dienophile furanone was prepared by photooxygenation of a suitably substituted 2-thiophenylfuran followed by dehydration of the resulting γ-hydroxybutenolide. Through this synthesis, the initially proposed structure for (+)-yaoshanenolide B has been revised to the 1R,2S,4R,7R,1″S diastereomer.

Regiocontrolled Synthesis of γ-Hydroxybutenolides via Singlet Oxygen-Mediated Oxidation of 2-Thiophenyl Furans.

Photooxygenation of 2-thiophenyl-substituted furans in ethanol leads to the rapid, regiocontrolled, and quantitative synthesis of γ-hydroxybutenolides. The carbonyl group in butenolide holds the position of thiophenyl moiety in reacting furans. Decomposition of the initially formed [4 + 2] endoperoxide into products through a radical chain mechanism is proposed, as the fate of thiophenyl moiety is its transformation into ethyl phenylsulfenate (PhS-OEt) and diphenyldisulfide. Under the reaction conditions, the sulfenate is fast oxidized into the corresponding sulfinate.