PyrAtes: Modular Organic Salts with Large Stokes Shifts for Fluo-rescence Microscopy.

The deployment of small-molecule fluorescent agents plays an ever-growing role in medicine and drug development. Herein, we complement the portfolio of powerful fluorophores, reporting the serendipitous discovery and development of a novel class with an imidazo[1,2-a]pyridinium triflate core, which we term PyrAtes. These fluorophores are synthesized in a single step from readily available materials (>60 examples) and display Stokes shifts as large as 240 nm, while also reaching NIR-I emissions at λmax as long as 720 nm. Computational studies allow the development of a platform for the prediction of λmax and λEm. Furthermore, we demonstrate the compatibility of these novel fluorophores with live cell imaging in HEK293 cells, suggesting PyrAtes as potent intracellular markers.

A Photochemical Strategy for the Conversion of Nitroarenes into Rigidified Pyrrolidine Analogues.

Bicyclic amines are important motifs for the preparation of bioactive materials. These species have well-defined exit vectors that enable accurate disposition of substituents toward specific areas of chemical space. Of all possible skeletons, the 2-azabicyclo[3.2.0]heptane framework is virtually absent from MedChem libraries due to a paucity of synthetic methods for its preparation. Here, we report a modular synthetic strategy that utilizes nitroarenes as flat and easy-to-functionalize feedstocks for the assembly of these sp3-rich materials. Mechanistically, this approach exploits two concomitant photochemical processes that sequentially ring-expand the nitroarene into an azepine and then fold it into a rigid bicycle pyrroline by means of singlet nitrene-mediated nitrogen insertion and excited-state-4π electrocyclization. A following hydrogenolysis provides, with full diastereocontrol, the desired bicyclic amine derivatives whereby the aromatic substitution pattern has been translated into the one of the three-dimensional heterocycle. These molecules can be considered rigid pyrrolidine analogues with a well-defined orientation of their substituents. Furthermore, unsupervised clustering of an expansive virtual database of saturated N-heterocycles revealed these derivatives as effective isosteres of rigidified piperidines. Overall, this platform enables the conversion of nitroarene feedstocks into complex sp3-rich heterocycles of potential interest to drug development.

Gold-Catalyzed Cycloisomerization of Sulfur Ylides to Dihydrobenzothiepines.

The metal-promoted nucleophilic addition of sulfur ylides to π-systems is a well-established reactivity. However, the driving force of such transformations, elimination of a sulfide moiety, entails stoichiometric byproducts making them unfavorable in terms of atom economy. In this work, a new take on sulfur ylide chemistry is reported, an atom-economical gold(I)-catalyzed synthesis of dihydrobenzo[b]thiepines. The reaction proceeds under mild conditions at room temperature.

Unconventional Macrocyclizations in Natural Product Synthesis.

Over the past several decades, macrocyclic compounds have emerged as increasingly significant therapeutic candidates in drug discovery. Their pharmacological activity hinges on their rotationally restricted three-dimensional orientation, resulting in a unique conformational preorganization and a high enthalpic gain as a consequence of high-affinity macrocycle-protein binding interactions. Synthetic access to macrocyclic drug candidates is therefore crucial. From a synthetic point of view, the efficiency of macrocyclization events commonly suffers from entropic penalties as well as undesired intermolecular couplings (oligomerization). Although over the past several decades ring-closing metathesis, macrolactonization, or macrolactamization have become strategies of choice, the toolbox of organic synthesis provides a great number of versatile transformations beyond the aforementioned. This Outlook focuses on a selection of examples employing what we term unconventional macrocyclizations toward the synthesis of natural products or analogues.

Cycloisomerization of Conjugated Allenones into Furans under Mild Conditions Catalyzed by Ligandless Au Nanoparticles.

Au nanoparticles supported on TiO2 (1 mol %) catalyze the quantitative cycloisomerization of conjugated allenones into furans under very mild conditions. The reaction rate is accelerated by adding acetic acid (1 equiv), but the acid does not participate in the protodeauration step as in the corresponding Au(III)-catalyzed transformation. The process is purely heterogeneous, allowing thus the recycling and reuse of the catalyst effectively in several runs.

Towards a Scalable Synthesis of 2-Oxabicyclo[2.2.0]hex-5-en-3-one Using Flow Photochemistry.

Cyclobutene lactones hold great potential as synthetic building blocks, yet their preparation by photochemical rearrangement in batch can often be a bottleneck in synthetic studies. We report the use of flow photochemistry as a tool to enable a higher-throughput approach to the synthesis of 2-oxabicyclo[2.2.0]hex-5-en-3-one, which reduces reaction times from 24 h to 10 min. Accordingly, a significantly improved throughput of 144 mg/h (vs 14-21 mg/h in batch) was achieved. Scale-out experiments showed problematic reactor fouling and steps were taken to explore and minimize this effect.