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Intramolecular thiomaleimide [2+2] photocycloadditions: stereoselective control for disulfide stapling and observation of excited state intermediates by transient absorption spectroscopy

Malde, Roshni; Parkes, Michael A; Staniforth, Michael; Woolley, Jack M; Stavros, Vasilios G; Chudasama, Vijay; Fielding, Helen H; (2022) Intramolecular thiomaleimide [2+2] photocycloadditions: stereoselective control for disulfide stapling and observation of excited state intermediates by transient absorption spectroscopy. Chemical Science 10.1039/d1sc06804k. (In press). Green open access

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Abstract

Thiomaleimides undergo efficient intermolecular [2 + 2] photocycloaddition reactions and offer applications from photochemical peptide stapling to polymer crosslinking; however, the reactions are limited to the formation of the exo head-to-head isomers. Herein, we present an intramolecular variation which completely reverses the stereochemical outcome of this photoreaction, quantitatively generating endo adducts which minimise the structural disturbance of the disulfide staple and afford a 10-fold increase in quantum yield. We demonstrate the application of this reaction on a protein scaffold, using light to confer thiol stability to an antibody fragment conjugate. To understand more about this intriguing class of [2 + 2] photocycloadditions, we have used transient absorption spectroscopy (electronic and vibrational) to study the excited states involved. The initially formed S2 (π1π*) excited state is observed to decay to the S1 (n1π*) state before intersystem crossing to a triplet state. An accelerated intramolecular C–C bond formation provides evidence to explain the increased efficiency of the reaction, and the impact of the various excited states on the carbonyl vibrational modes is discussed.

Type: Article
Title: Intramolecular thiomaleimide [2+2] photocycloadditions: stereoselective control for disulfide stapling and observation of excited state intermediates by transient absorption spectroscopy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1039/d1sc06804k
Publisher version: https://doi.org/10.1039/d1sc06804k
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology, Physical Sciences, Chemistry, Multidisciplinary, Chemistry, LASER FLASH-PHOTOLYSIS, TETRAHYDROPHTHALIC ANHYDRIDE, PHOTOCHEMICAL-REACTIONS, CROSS-LINKING, MALEIMIDE, CHEMISTRY, FLUORESCENCE, CONJUGATION, EFFICIENT, ALKENOLS
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10143113
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