Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 219 Multicomponent Reactions in 11 C / 12 C Chemistry – Targeting the Angiotensin II Subtype 2 Receptor MARC STEVENS

Stevens, M. 2016. Multicomponent Reactions in C/C Chemistry. – Targeting the Angiotensin II Subtype 2 Receptor. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 219. 93 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9636-4. Section 1 of this thesis contains an introduction to method development in organic synthesis, multicomponent reactions, sulfonyl azides, tracer development in C chemistry and the biological target. Section 2 describes the use of sulfonyl azides in carbonylative chemistry. Paper I covers development of a diazotransfer protocol. In total, 30 arylsulfonyl azides were synthesised from primary sulfonamides (20–90% yield). N mechanistic studies were carried out and in Paper II, the products were converted into sulfonamides, sulfonylureas and sulfonyl carbamates (19– 90% yield). For ureas and carbamates, a two-chamber protocol was employed to release CO from Mo(CO)6. N mechanistic studies showed that the sulfonamides were formed by direct displacement of azide. Section 3 covers imaging and biological studies of the angiotensin II receptor subtype 2 (AT2R). In Paper III, 12 C-sulfonyl carbamates were prepared in isolated radiochemical yields of 3–51% via Rh(I)-mediated carbonylation. The first non-peptide AT2R agonist, C21, was labelled (isolated RCY 24±10%, SA 34–51 GBq/μmol). C21 was tested in a prostate cancer assay, followed by biodistribution and small-animal PET studies. In Paper IV, a C-labelled AT2R ligand prepared via Pd(0)-mediated aminocarbonylation was used for autoradiography, biodistribution and small-animal PET studies. Section 4 describes the development of a multicomponent method for the synthesis of 3,4dihydroquinazolinones (Paper V). 31 3,4-dihydroquinazolinones were synthesized via a cyclic iminium ion.