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Molecular switches have received major attention to enable the reversible modulation of various molecular properties and have been extensively used as trigger elements in diverse fields, including molecular machines, responsive materials, and photopharmacology. Antiaromaticity is a fascinating property that has attracted not only significant fundamental interest but is also increasingly relevant in different applications, in particular organic (opto)electronics. However, designing systems in which (anti)aromaticity can be judiciously and reversibly switched ON and OFF remains challenging. Herein, we report a helicene featuring an indenofluorene-bridged bisthioxanthylidene as a novel switch wherein a simultaneous two-electron (electro)chemical redox process allows highly reversible modulation of its (anti)aromatic character. Specifically, the two thioxanthylidene rotors, attached to the initially aromatic indenofluorene scaffold via overcrowded alkenes, adopt an anti-folded structure, which upon oxidation convert to singly bonded, twisted conformations. This is not only associated with significant (chir)optical changes but importantly also results in formation of the fully conjugated, formally antiaromatic as-indacene motif in the helical core of the switch. This process proceeds without the buildup of radical cation intermediates and thus enables highly reversible switching of molecular geometry, aromaticity, absorbance, and chiral expression under ambient conditions, as evidenced by NMR, UV–vis, CD, and (spectro)electrochemical analyses, supported by DFT calculations. We expect this concept to be extendable to a wide range of robust antiaromatic–aromatic switches and to provide a basis for modulation of the structure and properties of these fascinating inherently chiral polycyclic π-scaffolds.

A process using an engineered phenylalanine ammonia lyase (PAL) enzyme was developed as part of an alternative route to a key intermediate of olodanrigan (EMA401). In the first part of this report, the detailed results from a screening for the optimal reaction conditions are presented, followed by a discussion of several workup strategies investigated. In the PAL-catalyzed reaction, 70–80% conversion of a cinnamic acid derivative to the corresponding phenylalanine derivative could be achieved. The phenylalanine derivative was subsequently telescoped to a Pictet–Spengler reaction with formaldehyde, and the corresponding tetrahydroisoquinoline derivative was isolated in 60–70% yield with >99.9:0.1 er. On the basis of our screenings, carbonate/carbamate-buffered ammonia at an NH3concentration of 9–10 M and pH 9.5–10.5 was found to be optimal. Enzyme loadings down to 2.5 wt % (E:S = 1:40 w/w) could be achieved, and substrate concentrations between 3–9 v/w (1.17–0.39 M) were found to be compatible with the reaction conditions. A temperature gradient was applied in the final process: a pre-equilibrium was established at 45 °C, before making use of the temperature dependence of the entropy term with subsequent cooling to 20 °C to achieve maximum conversion. This temperature gradient also allowed balancing of the enzyme stability (low at 45 °C, high at 20 °C) with the activity (high at 45 °C, low at 20 °C) in order to achieve optimal conversion (low at 45 °C, high at 20 °C). From the various workup operations investigated, a sequence consisting of denaturation of the enzyme, NH3/CO2removal by distillation, acidification, and telescoping to the subsequent Pictet–Spengler cyclization was our preferred approach. The process presented in this study is a more sustainable, shorter, and more cost-effective alternative to the previous process.

During route scouting for EMA401 (1), an angiotensin II type 2 antagonist, we identified the synthesis of key amino acid intermediate 2viaits cinnamic acid derivative 3as a streamlined option. In general, cinnamic acids can be synthesized from the corresponding aldehydes by a Knoevenagel–Doebner condensation in pyridine with piperidine as an organocatalyst. We aimed to replace both of these reagents and found novel conditions involving toluene as the solvent and morpholine as the organocatalyst. Scale-up of the process allowed the production of 25 kg of cinnamic acid 3that was of the quality required for process development of the subsequent phenylalanine ammonia lyase-catalyzed step. The modified conditions were found to be widely applicable to alternative aldehydes and thus are of relevance to practitioners of chemical scale-up.