Strategies towards Redshifted Hemithioindigo Photoswitches & Development of a Semi-Automated Photochemical Screening Platform

Mikkel Krell-Jørgensen

Research output: Book/ReportPh.D. thesis

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Abstract

Light has found numerous uses as an external stimulus to trigger or control events in photochemical applications, such as the spatial geometry and properties of molecular photoswitches in addition to mediating chemistry in drug discovery as exemplified in this thesis.
Molecular photoswitches comprise a class of photochromic molecules able to interconvert reversibly between a stable and metastable isomer upon absorption of incident light, which can be exploited similar to an “ON”/”OFF” switch to control biological functions, or as a system to store solar thermal energy. A limitation with current molecular photoswitches is the need for low-wavelength UV light to initiate the switching process, as the associated energy is sufficiently high to cause photodegradation of the switch itself, but also of the surrounding material, which for biological applications is less favourable. Redshifting the wavelengths of absorption towards the low-energy red part of the visible electromagnetic spectrum through molecular tailoring serves as a viable strategy in developing new and improved systems. In this context, it enabled the development of hemithioindigo photoswitches with improved photophysical properties in which the absorption was substantially redshifted to facilitate switching with near-infrared light, which is of great value for future applications in photopharmacology.
Light may also be employed to conveniently mediate chemistry, and in connection to this, multiple microfluidic photoreactors were designed and fabricated employing 3D printing technology to allow photochemical transformations in flow. However, despite the many advantageous of performing photo-chemistry in flow, it cannot provide the same throughput in terms of screening many reaction conditions in parallel as other systems might offer.
Therefore, a simple and inexpensive semi-automated photochemical screening platform was developed and applied to expedite the discovery of new photochemical transformations. It enabled parallel screening of reactions in 96-well microtitre plates to discover the most optimal reaction conditions facilitating product formation. This high-throughput experimentation approach far outcompetes the discovery capabilities of the classical one-at-a-time batch approach used as a standard for chemical synthesis when comparing rates of output. In this context, the platform was exploited to discover a new triplet-sensitized photochemical [2+2] cycloaddition reaction that will later set up the synthesis of an alkaloid-inspired natural product-like compound library, with potential applications in drug discovery.
Original languageEnglish
PublisherDTU Chemistry
Number of pages236
Publication statusPublished - 2022

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