The impact of UV light on synthetic photochemistry and photocatalysis.

During the past 15 years, an increasing number of research groups have embraced visible-light-mediated synthetic transformations as a powerful strategy for the construction and functionalization of organic molecules. This trend has followed the advent and development of photocatalysis, which often operates under mild visible-light irradiation. Nowadays, the general perception of UV-light photochemistry is often as an out-of-fashion approach that is difficult to perform and leads to unselective reaction pathways. Here we wish to propose an alternative and more realistic point of view to the scientific community. First, we will provide an overview of the use of UV light in modern photochemistry, highlighting the pivotal role it still plays in the development of new, efficient synthetic methods. We will then show how the high levels of mechanistic understanding reached for UV-light-driven processes have been key in the implementation of the related visible-light-driven transformations.

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.

Self-assembly of benzophenone-diphenylalanine conjugate into a nanostructured photocatalyst.

The conjugation of photoactive benzophenone with diphenylalanine yielded a self-assembling photocatalyst that was probed in the E → Z photoisomerisation of stilbene derivatives.

A Proton-Coupled Electron Transfer Strategy to the Redox-Neutral Photocatalytic CO2 Fixation.

Herein, we report our study on the design and development of a novel photocarboxylation method. We have used an organic photoredox catalyst (PC, 4CzIPN) and differently substituted dihydropyridines (DHPs) in combination with an organic base (1,5,7-triazabicyclodec-5-ene, TBD) to access a proton-coupled electron transfer (PCET) based manifold. In depth mechanistic investigations merging experimental analysis (NMR, IR, cyclic voltammetry) and density-functional theory (DFT) calculations reveal the key activity of a H-bonding complex between the DHP and the base. The thermodynamic and kinetic benefits of the PCET mechanism allowed the implementation of a redox-neutral fixation process leading to synthetically relevant carboxylic acids (18 examples with isolated yields up to 75%) under very mild reaction conditions. Finally, diverse product manipulations were performed to demonstrate the synthetic versatility of the obtained products.

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.

Chemo-Enzymatic Synthesis of S. mansoni O-Glycans and Their Evaluation as Ligands for C-Type Lectin Receptors MGL, DC-SIGN, and DC-SIGNR.

Due to their interactions with C-type lectin receptors (CLRs), glycans from the helminth Schistosoma mansoni represent promising leads for treatment of autoimmune diseases, allergies or cancer. We chemo-enzymatically synthesized nine O-glycans based on the two predominant O-glycan cores observed in the infectious stages of schistosomiasis, the mucin core 2 and the S. mansoni core. The O-glycans were fucosylated next to a selection of N-glycans directly on a microarray slide using a recombinant fucosyltransferase and GDP-fucose or GDP-6-azidofucose as donor. Binding assays with fluorescently labelled human CLRs DC-SIGN, DC-SIGNR and MGL revealed the novel O-glycan O8 as the best ligand for MGL from our panel. Significant binding to DC-SIGN was also found for azido-fucosylated glycans. Contrasting binding specificities were observed between the monovalent carbohydrate recognition domain (CRD) and the tetravalent extracellular domain (ECD) of DC-SIGNR.

A Photochemical Organocatalytic Strategy for the α-Alkylation of Ketones by using Radicals.

Reported herein is a visible-light-mediated radical approach to the α-alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon SN 2-based activation of alkyl halides and blue light irradiation. The resulting open-shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two-electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox-neutral nature of this process makes it compatible with a cinchona-based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α-alkylation of ketones.

Stereocontrolled Synthesis of 1,4-Dicarbonyl Compounds by Photochemical Organocatalytic Acyl Radical Addition to Enals.

We report a visible-light-mediated organocatalytic strategy for the enantioselective acyl radical conjugate addition to enals, leading to valuable 1,4-dicarbonyl compounds. The process capitalizes upon the excited-state reactivity of 4-acyl-1,4-dihydropyridines that, upon visible-light absorption, can trigger the generation of acyl radicals. By means of a chiral amine catalyst, iminium ion activation of enals ensures a stereoselective radical trap. We also demonstrate how the combination of this acylation process with a second catalyst-controlled bond-forming event allows to selectively access the full matrix of all possible stereoisomers of the resulting 2,3-substituted 1,4-dicarbonyl products.

A New Surface Plasmon Resonance Assay for In Vitro Screening of Mannose-Binding Lectin Inhibitors.

Mannose-binding lectin (MBL) is a circulating protein that acts as a soluble pattern recognition molecule of the innate immunity. It binds to carbohydrate patterns on the surface of pathogens or of altered self-cells, with activation of the lectin pathway of the complement system. Recent evidence indicates that MBL contributes to the pathophysiology of ischemia-reperfusion injury and other conditions. Thus, MBL inhibitors offer promising therapeutic strategies, since they prevent the interaction of MBL with its target sugar arrays. We developed and characterized a novel assay based on surface plasmon resonance for in vitro screening of these compounds, which may be useful before the more expensive and time-consuming in vivo studies. The assay measures the inhibitor's ability to interfere with the binding of murine MBL-A or MBL-C, or of human recombinant MBL, to mannose residues immobilized on the sensor chip surface. We have applied the assay to measure the IC50 of synthetic glycodendrimers, two of them with neuroprotective properties in animal models of MBL-mediated injuries.

Scaffold Optimisation of Tetravalent Antagonists of the Mannose Binding Lectin.

Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C.

Synthesis of vinylogous amides by gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines.

The gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines, prepared by the Sonogashira coupling of lactam-derived enol triflates or phosphates, provides vinylogous amides, which are useful intermediates in the synthesis of natural compounds. The Au(I)-catalyzed reaction is carried out with Ph3PAuOTf as a catalyst and proceeds via a 6-endo-dig cyclization to form a vinylgold species that after protodeauration generates a cyclic carbamate intermediate. This intermediate is in most cases not isolated, but the addition of a base to the reaction mixture rapidly and quantitatively delivers the target vinylogous amide. The first synthesis of a natural compound from Sonneratia hainanensis has been accomplished by this approach.