Periodic Reporting for period 2 - TECHNOTRAIN (Enabling TECHNOlogies-driven chemistry: a tailored TRAINing research program for batch and flow synthesis of chiral amino derivatives) Reporting period: 2020-11-01 to 2022-10-31 Summary of the context and overall objectives of the project The main aim of “TECHNOTRAIN” proposal (Enabling TECHNOlogies-driven chemistry: a tailored TRAINing research program for batch and flow synthesis of chiral amino derivatives) is to create a training platform for young European researchers, based on the creativity, flexibility and accuracy characteristic of an academic working environment, but with an industrial focus. “TECHNOTRAIN” has the specific objective to develop general, reproducible and also profitable, stereoselective, catalytic synthetic methods applicable for industrial production of enantiomerically pure, functionalized amino derivatives featuring a quaternary stereocenter. Target molecules will be chiral pharmaceutically active ingredients, or immediate precursors, including nonproteogenic alfa-disubstituted-amino acids. The combination of two modern, catalytic strategies (photocatalysis and organocatalysis) with safe and environmental friendly technologies (flow chem and 3D-printed devices) is a key step towards the development of a more efficient and sustainable chemistry. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far 1. Explanation of the work carried out by the beneficiaries and Overview of the progress The action officially started on November 1, 2018.Three students, namely Patricia Camarero Gonzalez (Spain), Fabian Herbrik (Germany), Milena Krstic (Serbia) were selected for the three PhD positions and they have been officially enrolled in the Doctorate School of Industrial Chemistry at the Università degli Studi di Milano- Prof. Dr. Maurizio Benaglia (University of Milano) will act as Tutor (Supervisor) and Dr. Miguel Sanz (Taros Chemicals) as co-Tutor (co-Supervisor) of all three students.They started their own research activities and PhD programme on June 1 2019.General progress of the actionFor the scientific WPs, the following activities done by the ESRs can be summarizedESR 1, MILENA KRSTIC In batch and in flow catalytic addition of C1 fragments to C=N bondsThe PhD student worked on the preparation of substrates for cyanide addition (imines) but not really on the synthesis of chiral catalysts for cyanide addition. One chiral catalyst only was prepared but more focus was given on the preliminary exploration of the biomimetic approach and ion pair concept (deliverable D1.6). Therefore, ESR1 worked on topics related to D1.6 and D1.5 and in parallel, she has started to study other chiral catalysts related to deliverable D1.2 iminophosphoranes, and started to work on the use of flow reactors to develop enantioselective phase transfer catalytic reactions for the preparation of chiral quaternary amino acids, that is the main goal of the project.ESR 2 – PATRICIA CAMARERO GONZALEZStereoselective reactions of nitroesters with different organocatalystsFirst times focused particularly on the synthesis of α,α-disubstitued-nitroacrylates, which have not been extensively studied before. After optimizing the synthesis of α-nitroacrylates, the enantioselective reduction was studied, using diethyl and tert-butyl Hantzsch ester and a thiourea-based catalyst. Enantioselectivities up to 70% were obtained. DFT Computational analysis on the reduction of the model compound has been performed. Future studies will focus on the determination of absolute configuration of the obtained products and study on the scope of the reaction.ESR 3 – FABIAN HERBRIKSupported, recyclable chiral catalysts, catalytic and 3D-printed reactors; flow chemistry.ESR3 has mainly explored the use of in-flow catalytic reactors, but he has also studied the development of a multistep telescoped synthesis of a chiral pharmaceutically relevant molecule.Continuous flow experiments showed a drastic increase of productivity, up to 100-fold, going from batch to flow chemistry. The proof of concept, i.e. the possibility to perform enantioselective organo-photoredox catalysis with immobilized catalysts, was demonstrated for the first time.In parallel, the investigation of in-flow photocatalytic reactions under homogeneous conditions was also performed. The light-catalysed alkylation of an aldehyde, promoted by a chiral imidazolidinone, followed by oxidation to carboxylic acid, its activation and condensation with an heterocyclic amine to afford an enantiomerically enriched active pharmaceutically relevant molecule, is the subject of the study of the last six months aimed to realize a multistep telescoped synthesis of a chiral molecule. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) 1.1 ObjectivesESR1: Specific objectives: - development of an efficient, reliable and profitable synthesis of quaternary aminoacids through a stereoselective catalytic addition of C1 fragments to C=N, exploring also photochemically generated in situ imines; it was decided to postpone the topic; major focus was given to other two objectives: study of Iminophosphoranes as catalyst and Use of flow chemistry.ESR2: Specific objectives: - Development of an efficient and profitable synthesis of quaternary aminoacids through stereoselective catalytic reactions of nitroesters, ESR has worked heavily on the synthesis of nitroacrilates as starting materials; she has developed a catalytic reduction protocol; reduction in alternative solvents has been studied (manuscript in preparation); and she is working on the second step, aimed to establish the formation of a second, quaternary stereocenter in the chiral moleculeESR3: Specific objectives: - Development of an efficient recyclable catalysts, catalytic reactors and 3d-printed mesoreactors for the synthesis of quaternary amino derivatives. ESR3 worked successfully on the first merging of solid supported organocatalysis with photoredox catalysis and the development of continuous flow processes.1.3 Impact Immediate benefits will be: - To carry out cutting-edge research within a stimulating scientific environment. - To spend the same amount of time at an academic and at an industrial site.- To carry out their research activity in a highly collaborative environment, learning the importance of team-work in tackling and solving scientific problems.- To receive a first-order experimental, scientific and complementary training.- To receive exposure to the concepts of economic and environmental sustainabilityLonger-term benefits:- The ESRs will become expert in asymmetric catalysis, especially in organocatalysis.- The ESRs will become aware of academic and industrial research approaches, pursued with an open and flexible scientific mentality. Their awareness of the demands of industry will offer excellent career prospects.- The ESRs will develop the attitude to collaboration and team-working. The intersectoral (industrial/academic) and “international” character of the projects will provide ESRs with the correct attitude to tackle the problems and solve them beyond the national boundaries and to establish useful scientific contacts - The researchers will become experienced in communicating with the scientific public (at network meetings and international conferences), as well as with the general audience. They will also become able to write scientific reports and papers.Working in an industrial site will be the occasion for the ESRs to develop entrepreneurial skills, and invaluable skills in development and management.