Final Report Summary - ASADO-CH (Development and application of Artificial Systems for Activation of DiOxygen and C-H bonds) We have developed an interesting ligand platform to develop new catalysts for the transformation of alkanes into alcohols. We aim to address this problematic catalysis with the potential to change the retrosynthetic planning of complex molecules. Inspired by iron metallo-proteins we are developing artificial systems that can address this need using new ligand designs taking lessons on the most active artificial catalysts currently available. Our approach to minimize deactivation is based on an unusual dinuclear design that we pioneered with our first publication (Angew. Chem. Int. Ed. 2015, 14094). This design surpasses in activity previously known privileged ligands in the most challenging oxidations on inactivated alkanes. The desired second-generation pyrrolidine ligand that was required to synthesize our catalyst was challenging. It was difficult to devise a feasible route to prepare this pyrrolidine scaffold using simple starting materials, and this objective has driven our activity on the second period of this project. The use of simple, accessible sources to generate complex catalysts have always been a fundamental objective of this project. In collaboration with our partners at AstraZeneca and Bayer Pharma, we have recently put forward the concept of using "ligand total synthesis" as a source of inspiration for development of organic chemistry (Synlett 2016, 1753). As such, we decided to tackle the fundamental problem associated with the synthesis pyrrolidines decorated with nitrogen-heterocycles suitable because of the higher basicity of the pyramidalized nitrogen in pyrrolidine ligands. In addition to the application in our program in catalysis, streamlined synthetic methods to access densely functionalized and stereodefined pyrrolidines is of general importance in medicinal chemistry.Some years ago, we introduced a new approach to the synthesis of piperazines, which was based on simple starting materials (aldehydes and amines), an aluminum promoter and visible-light, and allowed access to densely functionalized piperazines in one-step, high-yield and scalable fashion (reference above). To our delight, our hypothesis on the deactivation of iron catalysts was also been preliminarily demonstrated. We have deeply reviewed the state-of-the-art in [3+2] cycloadditions between imines and unactivated alkenes, which would produce aliphatic pyrrolidine cores with basic heterocycles required for robust assembly of ligands and catalysts (Synthesis 2017, 802). In this contribution we also put forward a hypothesis on the fundamental step required to address the challenge of engaging unactivated olefins in this context. We have verified the suitability of electron-rich organoaluminum promoters to address this need (Angew. Chem. Int. Ed. 2017, 12962) in a thermal reaction that allowed to transform commercial olefins into complex ligands in one-step.These developments inspired the development of an organometallic equivalent of the Pummerer reaction for the synthesis of functionalized thioether products (Angew. Chem. Int. Ed. 2017, 16042). This reaction makes use of Grignard nucleophiles to overcome the fundamental difficulties of Pummerer reactions with carbon nucleophiles, which were limited to soft nucleophiles with limited connectivity patterns. We have also extended the utility of this reaction and introduced the concept of the iterative assembly of thioether products through telescoped S-oxidation / C-C coupling iterations (Synlett 2018, DOI: 10.1055/s-0036-1591864).The results of our collaborative work, that was introduced in the medium-term report, in the elucidation of the mechanism and the origin of the enantioselecitivity of a palladium-catalyzed borylation process has recently been published (Chem. Eur. J. 2018, 2433). This work showcase the integration within the department and the active collaboration with the groups of Prof. Himo and Prof. Bäckvall.During the period of the Marie Curie Career Integration Grant, my independent research career has been stablished in Sweden with an original line of research. The concepts that have been introduced in synthesis and catalysis have been received with excitement by the synthetic community and have allowed us to award prestigious grants such as the ERC Starting Grant and the Wallenberg Academy Fellows award. This has facilitated the promotion of the activity in my laboratories and the expansion of my research group, and the promotion to the Professor status already planned.Website: www.organ.su.se/am/
