Periodic Reporting for period 4 - ANaPSyS (Artificial Natural Products System Synthesis) Reporting period: 2020-10-01 to 2021-12-31 Summary of the context and overall objectives of the project The search for novel drugs and new medicines strongly depends on the efficiency of synthetic processes. Especially in complex molecule synthesis the challenge to access a structure synthetically can be so huge and the effort so enormous, rendering the overall process inefficient.In the quest for new medicines natural products are very often used, since they intrinsically are biologically active and give the medicinal chemist a head start. But natural product typically display a challenging three-dimensional structure - and thus are laborious to synthesise.This has the consequence, that pharmaceutical companies stick to simple target molecules. The problem thereby is that simple structures only allow very crude design and thus the need for more selective and specific drugs cannot be met, since these properties most often are connected with a complex three-dimensional architecture. To overcome this process and make the quest for new bioactive compounds more efficient, we chose to develop a strategic approach called "artificial Natural product systems synthesis (ANaPSyS)". This concept aims to develop central building blocks that are structurally embedded in different natural products - so to say comprise a core structure - or as we like to call it "privileged intermediate". These building blocks are on the one hand advanced intermediates but at the same time can be flexibly used for different structure types of natural products. As a consequence such an intermediate is valuable not only for one specific target structure - as is normally the case in drug research - but can be used for multiple molecules with different biological activities. This inherently enhances synthetic efficiency and renders scale up process utmost important, since the privileged intermediate can be used multiple times, thus is needed in large quantities. We were able to put this concept into practice and showcase that this strategy is feasible by the synthesis of two different natural product family congeners with different biological activity (anti-jussive and hypotensive). The design of the privileged intermediate is thereby of utmost importance, and is developed with the help of intensive database search as was performed in our case. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Since the beginning of this project we have accomplished the total syntheses of 6 different sarpagine alkaloids and the stemona alkaloid parvineostemonine (Figure 1). Furthermore we have accessed 16 non-natural sarpagine derivatives which will be tested for their biological profile and submitted to SAR studies. The syntheses are outlined in schemes 1+2. In addition to that we have extended the scope of ANaPSyS beyond the original proposal by implementing a new milestone 6 -originally not included in the proposal. Thereby we were able to show that ANaPSyS is not limited to the special case of the 3 natural product families sarpagines stamina and macrolide alkaloids but can be extended based on structure pattern recognition of any other structurally and not necessarily biognetically related natural product. The increase of synthetic efficiency is dramatic and evidently showcased with the sarpagine alkaloids and their non-natural derivatives (altogether 16) which can further be extended on demand depending on SAR studies and their results as currently carried out. The synthetic access is at a minimum of only one additional transformation to test novel compounds. 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) The synthesis of a single natural product of this complexity (such as sarpagines and parvineostemonine) by conventional strategic approaches in total synthesis typically takes 3-4 years. The fact that we were so far able to access 17 compounds in 2.5 years clearly shows the success of our main objectives proposed in this project. Up to the end of the project we will now focus on two major objectives:1) The total synthesis of macroline alkaloids, which comprise the third group of natural products accessible by this strategy (Figure 2)2) Design non-natural congeners of the sarpagines synthesised so far based on the preliminary SAR studies which we are currently taking out in collaboration with the HZI in Braunschweig (Prof. M. Brönstrup)Another issue will be the development of a methodology for cyclohepta[b]indoles, which is already envisioned as an outlook in our original proposal. This method should enable us to extend the concept of ANaPSyS to novel classes of compounds. Scheme 2 Scheme 1 Figure 2 Figure 1
