Quaternary Carbon as a Locus for Skeletal Disconnection. Total Synthesis of (±)-Tubingensin A Featuring Assembly of the Backbone Stereotriad Using a -Prins/-Nazarov Cascade.

The first successful fragment coupling/cationic cascade approach for the synthesis of a complex indoloditerpenoid tubingensin A is described. The synthesis is the first example of a novel disconnection strategy targeting a central quaternary carbon locus. A -Prins/-Nazarov cationic cascade sequence enabled the rapid preparation of a complex intermediate as a single diastereomer, containing the vicinal quaternary centers found in the backbone stereotriad.

Photo-amygdalin: light-dependent control over hydrogen cyanide release and cytotoxicity.

Amygdalin is a natural glycosidic compound found in bitter almonds and apricot seeds. After enzymatic hydrolysis, amygdalin forms a cyanohydrin which spontaneously decays to release toxic hydrogen cyanide in a process called cyanogenesis. Due to this capacity to release cyanide, it has a long and controversial history of use as an anticancer therapeutic in alternative medicine.

Diastereoselective C(sp)-H acetoxylation of phosphoramidites.

Chiral phosphines are important ligands in asymmetric catalysis, yet their potential as directing groups for asymmetric C-H activation remains unexplored due to the oxidative nature of these reactions. We present a Pd-catalysed, P(III)-directed diastereoselective acetoxylation of phosphoramidites, with DFT calculations elucidating their unique reactivity and supporting the proposed reaction mechanism.

Photocleavable Protecting Groups Using a Sulfite Self-Immolative Linker for High Uncaging Quantum Yield and Aqueous Solubility.

Using light as an external stimulus to control (bio)chemical processes offers many distinct advantages. Most importantly, it allows for spatiotemporal control simply through operating the light source. Photocleavable protecting groups (PPGs) are a cornerstone class of compounds that are used to achieve photocontrol over (bio)chemical processes.

The fate of the contact ion pair determines the photochemistry of coumarin-based photocleavable protecting groups.

Photocleavable protecting groups (PPGs) enable the precise spatiotemporal control over the release of a payload of interest, in particular a bioactive substance, through light irradiation. A crucial parameter that determines the practical applicability of PPGs is the efficiency of payload release, largely governed by the quantum yield of photolysis (QY). Understanding which parameters determine the QY will prove crucial for engineering improved PPGs and their effective future applications, especially in the emerging field of photopharmacology.

Cation delocalization and photo-isomerization enhance the uncaging quantum yield of a photocleavable protecting group.

Photocleavable protecting groups (PPGs) enable the light-induced, spatiotemporal control over the release of a payload of interest. Two fundamental challenges in the design of new, effective PPGs are increasing the quantum yield (QY) of photolysis and red-shifting the absorption spectrum. Here we describe the combination of two photochemical strategies for PPG optimization in one molecule, resulting in significant improvements in both these crucial parameters.

Electron-Poor Butenolides: The Missing Link between Acrylates and Maleic Anhydride in Radical Polymerization.

Butenolides are a class of 5-membered lactones that hold great potential as bio-based monomers to replace oil-derived acrylates, of which they are cyclic analogues. Despite this structural resemblance, the reactivity of the unsaturated ester moiety of electron-poor butenolides leans toward that of maleic anhydride, another essential monomer that does not homopolymerize but copolymerizes in a highly alternating fashion with polarized electron-rich comonomers. By studying the reactivity of 5-methoxy and 5-acyloxy butenolides through a combination of kinetics and density functional theory (DFT) experiments, we explain why electron-poor butenolides constitute a missing link between acrylates and maleic anhydride in radical polymerization.

Visible light activated BINOL-derived chiroptical switches based on boron integrated hydrazone complexes.

Chiral optical switches, which use light to control chirality in a reversible manner, offer unique properties and fascinating prospects in the areas of molecular switching and responsive systems, new photochromic materials and molecular data processing and storage. Herein, we report visible light responsive chiroptical switches based on tetrahedral boron coordination towards an easily accessible hydrazone ligand and optically pure BINOL. Upon instalment of a non-planar dibenzo[,]-cycloheptene moiety in the hydrazone ligand's lower half, the enantiopure boron complex shows major chiroptical changes in the CD read-out after visible light irradiation.

Strategy for Engineering High Photolysis Efficiency of Photocleavable Protecting Groups through Cation Stabilization.

Photolabile protecting groups (PPGs) enable the precise activation of molecular function with light in many research areas, such as photopharmacology, where remote spatiotemporal control over the release of a molecule is needed. The design and application of PPGs in recent years have particularly focused on the development of molecules with high molar absorptivity at long irradiation wavelengths. However, a crucial parameter, which is pivotal to the efficiency of uncaging and which has until now proven highly challenging to improve, is the photolysis quantum yield (QY).

Computational Design, Synthesis, and Photochemistry of Cy7-PPG, an Efficient NIR-Activated Photolabile Protecting Group for Therapeutic Applications.

Photolabile Protecting Groups (PPGs) are molecular tools used, for example, in photopharmacology for the activation of drugs with light, enabling spatiotemporal control over their potency. Yet, red-shifting of PPG activation wavelengths into the NIR range, which penetrates the deepest in tissue, has often yielded inefficient or insoluble molecules, hindering the use of PPGs in the clinic. To solve this problem, we report herein a novel concept in PPG design, by transforming clinically-applied NIR-dyes with suitable molecular orbital configurations into new NIR-PPGs using computational approaches.

One-Pot Double-Annulation Strategy for the Synthesis of Unusual Fused Bis-Heterocycles.

A novel metal-free double-annulation cascade for the construction of unusual fused heterocyclic systems is described. This simple protocol enables the sequential assembly of two rings in one pot from two simple precursors. Acidic conditions promote the condensation and the intramolecular alkynyl Prins reaction of an enyne or arenyne alcohol with a cyclic hemiaminal to form a five-, six-, or seven-membered oxacycle followed by a seven- or eight-membered azacycle.

Stereochemical Relay through a Cationic Intermediate: Helical Preorganization Dictates Direction of Conrotation in the -Nazarov Cyclization.

A stereocontrolled -Prins/-Nazarov cyclization protocol is reported, where chiral information from a secondary alcohol is relayed through several intermediates yielding halocyclopentene products diastereoselectively. An enantiopure product is obtained when a nonracemic secondary alcohol is used. Experimental and computational studies are described, enabling the design and synthesis of systems that ionize and cyclize with >95% chirality transfer through a mechanism involving the creation and preservation of transient helical chirality in a pentadienyl cation intermediate.

Tuning Mechanism through Buffer Dependence of Hydrogen Evolution Catalyzed by a Cobalt Mini-enzyme.

Cobalt-mimochrome VI*a (CoMC6*a) is a synthetic mini-protein that catalyzes aqueous proton reduction to hydrogen (H). In buffered water, there are multiple possible proton donors, complicating the elucidation of the mechanism. We have found that the buffer p and sterics have significant effects on activity, evaluated via cyclic voltammetry (CV).

Leveraging the Halo-Nazarov Cyclization for the Chemodivergent Assembly of Functionalized Haloindenes and Indanones.

In this report, we describe a halo-Prins/aryl halo-Nazarov cyclization strategy that employs readily available starting materials, inexpensive reagents, and convenient reaction procedures to generate functionalized haloindenes and indanones. The scope and limitations of the method are outlined, demonstrating that aromatic systems readily react under mild, catalytic conditions when this strategy is implemented. Furthermore, we present both experimental and computational data supporting the notion that cyclizations of 3-halopentadienyl cationic intermediates are more kinetically accessible, as well as more thermodynamically favorable, than cyclizations of the analogous 3-oxypentadienyl cationic systems.

Cationic Cascade for Building Complex Polycyclic Molecules from Simple Precursors: Diastereoselective Installation of Three Contiguous Stereogenic Centers in a One-Pot Process.

An expedient strategy for the synthesis of polycyclic small molecules is described. The method first joins together two achiral building blocks (an enyne and an aldehyde or a ketone) using an alkynyl halo-Prins protocol. Then, in the same reaction vessel, acidic conditions initiate a cationic cascade that includes a stereospecific halo-Nazarov electrocyclization and a diastereoselective Friedel-Crafts allylation.

Development of a Cannabinoid-Based Photoaffinity Probe to Determine the Δ-Tetrahydrocannabinol Protein Interaction Landscape in Neuroblastoma Cells.

Δ-Tetrahydrocannabinol (THC), the principle psychoactive ingredient in , is widely used for its therapeutic effects in a large variety of diseases, but it also has numerous neurological side effects. The cannabinoid receptors (CBRs) are responsible to a large extent for these, but not all biological responses are mediated via the CBRs. The identification of additional target proteins of THC to enable a better understanding of the (adverse) physiological effects of THC.

Diastereoselective Construction of Densely Functionalized 1-Halocyclopentenes Using an Alkynyl Halo-Prins/Halo-Nazarov Cyclization Strategy.

A diastereoselective two-step strategy for the synthesis of densely functionalized 1-halocyclopentenes with several chiral centers has been developed. In the first step, a multicomponent alkynyl halo-Prins reaction joins an enyne, a carbonyl derivative, and either a chloride, bromide, or iodide to produce a cyclic ether intermediate. In the subsequent step, the intermediate is ionized to generate a halopentadienyl cation, which undergoes an interrupted halo-Nazarov cyclization.

Cannabinoid CB receptor ligand profiling reveals biased signalling and off-target activity.

The cannabinoid CB receptor (CBR) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CBR, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CBR ligands to date.

Synthesis and evaluation of N-substituted 2-amino-4,5-diarylpyrimidines as selective adenosine A receptor antagonists.

We report the synthesis and biological evaluation of new 2-amino-4,5-diarylpyrimidines as selective antagonists at the adenosine A receptor. The scaffold they are based upon is a deaza variation of a previously reported collection of 3-amino-5,6-diaryl-1,2,4-triazines, members of which had a subnanomolar affinity but limited selectivity over the A subtype. Initially, similar structure-affinity relationships at the 5-aryl ring were established, and then emphasis was put on increasing selectivity at the hAAR by introducing substituents on the N-position, all the while maintaining a nanomolar affinity.