Palladium(0)-Catalyzed Spirocyclization and Carbonylation Reactions: Ligands Targeting the Angiotensin II Type 2 Receptor

Palladium(0)-catalyzed chemistry represents one of the most important methods for the construction of carbon-carbon bonds, which are ubiquitous in organic compounds. The first part of this thesis describes the palladium(0)-catalyzed diastereoselective Mizoroki-Heck reaction of Vince lactam-derived precursors for the formation of spiroindolines ( paper I ) and spirooxindoles, which are scaffolds present in several natural products with interesting biological activity. The scope of the spiroindoline synthesis was investigated by varying the substitution on the cyclopentenyl-tethered aniline spirocyclization precursor. The mechanistic reasons behind the high diastereoselectivity of the spirocyclization reaction was also investigated through density functional theory (DFT) calculations. Functionalization of the N-terminal amino acid of therapeutic peptides is a strategy that has been employed for the improvement of metabolic stability. In paper II , a palladium(0)-catalyzed carbonylation method employing ex situ carbon monoxide generation from Mo(CO) 6 in a two-chamber system is used for the N-capping of amino acids using various aryl bromides and triflates. The second part of the thesis describes the synthesis and biological evaluation of angiotensin II type 2 receptor (AT 2 R) ligands. The AT 2 R is a G-protein coupled receptor belonging to the renin-angiotensin-aldosterone system (RAAS), which is most commonly associated with the hypertensive disorder caused by an exaggerated activation of the angiotensin II type 1 receptor (AT 1 R). However, activation of AT 2 R exerts different and sometimes completely opposing effects to AT 1 R and has been implicated in processes related to neuropathic pain, where the AT 2 R antagonist EMA401 has been in clinical trials for this indication. In papers III and IV , the AT 2 R antagonist C38 developed in our laboratory, is used as a model compound for the synthesis of analogs with the aim of expanding our knowledge regarding the structure-activity relationship of the C38 scaffold. Three general strategies were used; functionalization of the C38 phenyl ring, replacement of the benzyl imidazole of C38 with bicyclic amides and extension of the linker between the phenyl ring and imidazole by the inclusion of a carbonyl. Through these approaches, compounds with improved affinity towards AT 2 R and increased metabolic stability were identified, which might serve as tools for the continued study of the AT 2 R.