An enabling synthesis of tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-amine was developed starting from p-phenylenediacetic acid. The readily available p-phenylenediacetic acid was first converted in four steps to 1,4-dibromo-2,5-bis(2-bromoethyl)benzene, which was then subjected to Parham cyclization conditions. The mechanistic analysis of the Parham cyclization revealed that controlling the temperature and solvent environment was crucial. Process analytical technology (PAT) was used in the optimization of this intramolecular cyclization to identify the optimal temperature range for the halogen–metal exchange and intramolecular cyclization steps by means of a single kinetic experiment with increasing temperatures. A set of these small-scale experiments were conducted to fine-tune the reaction parameters and ensure scalability. Additionally, THF/n-hexane mixtures were utilized to balance solvent effects and solubility of the reactants, thereby minimizing competitive E2 elimination and affording the desired product in >60% assay yields. To complete the synthesis of tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-amine, tricyclo[6.2.0.03,6]deca-1,3(6),7-triene was iodinated using N-iodosuccinimide and subsequently subjected to direct C–N coupling conditions.

Enhancement of the cyclization of membrane lipids GDGTs (glycerol dialkyl glycerol tetraethers) is a critical strategy for archaea to adapt to vari...

Brennan et al. integrate chemical peptide cyclization with live-cell screening, expanding the functional chemical space accessible to intracellular genetically encoded peptide libraries. The approach delivers functional cyclic peptide inhibitors of the oncogenic transcription factor CREB1, illustrating a general strategy for targeting transcription factor-DNA interactions previously considered “undruggable.”

Brennan et al. integrate chemical peptide cyclization with live-cell screening, expanding the functional chemical space accessible to intracellular genetically encoded peptide libraries. The approach delivers functional cyclic peptide inhibitors of the oncogenic transcription factor CREB1, illustrating a general strategy for targeting transcription factor-DNA interactions previously considered “undruggable.”

A cascade photochemical cyclization strategy enables peripheral N-doped nanographenes with programmable monolayer and bilayer architectures. The bilayer assembly undergoes solvent-responsive dissociation in hydrogen-bond-accepting solvents. ABSTRACT Nitrogen-doped nanographenes (NGs) with precise structures are attractive because of their tunable electronic structures and supramolecular assembly behaviors. However, the synthesis of structurally diverse architectures, especially discrete bilayer systems, remains challenging. Herein, we report a cascade photo-induced radical cyclization (PIRC) strategy for the programmable synthesis of a series of peripheral nitrogen-doped NGs with tunable monolayer and bilayer architectures. Starting from nitrogen-doped nanographene 1 as a versatile structural platform, π-extension affords the larger monolayer nanographene 2, whereas modulation of the peripheral steric substituents enables the formation of a discrete bilayer assembly, (3)2. Single-crystal x-ray diffraction confirmed the monolayer structures of 1 and 2, while NMR spectroscopy, MALDI-TOF mass spectrometry, and DFT calculations revealed that (3)2 adopts a bilayer configuration. Compared with the monolayer analogues, the bilayer assembly shows broadened and blue-shifted absorption features characteristic of H-type coupling. More importantly, peripheral N─H functionalities enable solvent-responsive dissociation of the bilayer through hydrogen bonding with oxygen-containing solvents, leading to a solvent-switchable transformation between bilayer and monolayer states. The aggregation behavior of (3)2 is governed by the orthogonality between π–π interactions and hydrogen bonding, giving rise to a unique solvent-dependent yet concentration-independent structural transformation.