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.

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.

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.

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).

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.

Singlet Oxygen-Induced Furan Oxidation for Site-Specific and Chemoselective Peptide Ligation.

A novel chemoselective ligation methodology has been developed for the facile construction of peptide-based fluorescent probes. Furan-containing peptides were activated by singlet oxygen and covalently engaged by nitrogen nucleophiles to yield stable conjugates. Singlet oxygen was compatible with sensitive amino acid residues within the peptides and a range of fluorophores, bearing different functionalities, were successfully incorporated, illustrating the broad scope of the developed strategy.

Photooxygenation of Furylalkylamines: Easy Access to Pyrrolizidine and Indolizidine Scaffolds.

A highly adaptable method targeting the ubiquitous and very important pyrrolizidine and indolizidine scaffolds is presented. The general synthetic utility of the method is underscored by its application to the rapid and easy synthesis of five natural products starting from readily accessible alkylfuran precursors. These unprotected primary furylalkylamines are subjected to photooxygenation conditions, which initiate a complex cascade reaction sequence concluding with the production of high value motifs. This sequence can be tailored to need by varying the choice of both photosensitizer and base additive.

Methylene Blue as a Photosensitizer and Redox Agent: Synthesis of 5-Hydroxy-1H-pyrrol-2(5H)-ones from Furans.

A highly efficient and general singlet-oxygen-initiated one-pot transformation of readily accessible furans into 5-hydroxy-1H-pyrrol-2(5H)-ones has been developed. The methodology was extended to the synthesis of other high-value α,ß-unsaturated γ-lactams. This useful set of transformations relies not only on the photosensitizing ability of methylene blue, but also on its redox properties: properties that have until now been virtually ignored in a synthetic context.

One-pot transformation of simple furans into 4-hydroxy-2-cyclopentenones in water.

A highly efficient one-pot transformation of readily accessible furans into 4-hydroxy-2-cyclopentenones in H2O, using singlet oxygen as oxidant, has been developed.

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.

From simple furans to complex nitrogen-bearing aromatic polycycles by means of a flexible and general reaction sequence initiated by singlet oxygen.

All-in-one: A new and general one-pot reaction sequence initiated by singlet oxygen that transforms simple furan substrates into complex nitrogen-bearing aromatic polycycles having all the structural features of a number of important natural products (for example, the erythrina alkaloids; see scheme, RB = rose Bengal) is reported. The reaction sequence itself uses mild conditions and has wide functional group tolerance.

Oxone-mediated oxidative cleavage of ß-keto esters and 1,3-diketones to α-keto esters and 1,2-diketones in aqueous medium.

A versatile and highly efficient method for the direct synthesis of α-keto esters and 1,2-diketones has been developed. This approach utilizes the oxidative cleavage of a variety of ß-keto esters and 1,3-diketones mediated by an Oxone/aluminum trichloride system. The simple one-step oxidation reaction proceeded selectively in aqueous media to afford products in high yields, short reaction times, and environmentally benign conditions.

Using singlet oxygen to synthesise the CDE-ring system of the pectenotoxins.

A non-classical route to the key CDE-ring fragment of the pectenotoxins has been developed which showcases a remarkable singlet oxygen-mediated cascade reaction sequence to install the complete DE ring system.

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.

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.