Regio- and diastereoselective synthesis of cyclobutylated phenothiazines via [2 + 2] photocycloaddition: demonstrating wavelength-gated cycloreversion inside live cells

Abstract

Herein, we unveiled a regio- and diastereoselective synthesis of cyclobutylated phenothiazines, a unique class of structural congeners of phenothiazines via visible-light-irradiated intermolecular [2 + 2]-cycloaddition reaction, from readily available naphthoquinones, 2-aminothiophenols, and styrenes, either in a two-step or three-component coupling process. By varying substitutions in all three coupling partners, a library of cyclobutylated phenothiazines, including late-stage derivatization with five commercial drugs, has been realized with up to 97% isolated yield. In contrast to the reported pathways, the developed [2 + 2]-photocycloaddition seems to proceed via a ‘photoinduced-electron-transfer’ (PET) mechanism, which is well corroborated with the experimental observations, Rehm–Weller equation, and computation studies. Delightfully, a wavelength-gated reversibility of the [2 + 2]-photocycloaddition reaction has been accomplished on the synthesized cyclobutylated phenothiazines. By monitoring the rate of the cycloreversion reactions for different derivatives, a structure–activity relationship has also been achieved. Interestingly, this phenomenon was further replicated inside living cells, which leads to turn-on emission and is applied for photoresponsive cell imaging. This marks the first report of a light-triggered [2 + 2]-cycloreversion phenomenon occurring inside a live cell, leading to cell imaging. Moreover, the synthesized drug derivatives were utilized for synchronous cell imaging as well as drug delivery through the developed [2 + 2]-photocycloreversion process, which demonstrated the potential applicability of this class of molecules.