With more than 30 drug candidates in clinical trials, fragment-based drug discovery (FBDD) has become a very successful strategy to identify bioactive molecules during the past 20 years.^[1] However, the success of FBDD is often dependent on the quality of the fragment library. It is therefore critical to access new and advanced fragments or building blocks. Reymond et. al. extensively enumerated the chemical space of small molecules with up to 17 heavy atoms in the chemical space project. This project lead to different chemical universe databases, GDB-11 (26.4 million molecules), GDB-13 (970 million molecules), and GDB-17 (166 billion molecules). The vast majority of the molecules in these databases have not been described in synthetic literature and are therefore a source of inspiration for novel fragments or building blocks.^[2-4] The use of GDB for drug discovery was exemplified with the successful identification of new Glutamate Transporter 1 (GLT-1) inhibitors. First, Aspartate and Glutamate were systematically diversified using GDB.  High-throughput virtual screening followed by synthesis of high-ranking molecules then yielded a new Norborane-type inhibitor. These Aspartate analogues showed not only good micromolar activity but also high selectivity towards GLT-1.^[5] Extensive analysis of molecules described in literature compared to molecules in GDB revealed that a large part of novelty resides in polycyclic compounds.^[6] In this work we focussed on the synthesis of conformationally restricted structures bearing one quaternary carbon. So here we present a new approach to the design of the synthesis of novel polycyclic molecules from GDB, displaying pharmacophoric features of interest for medicinal chemistry.

[1] D. A. Erlanson, S. W. Fesik, R. E. Hubbard, W. Jahnke, H. Jhoti, Nat. Rev. Drug Discov., 2016, 15, 605—619;
[2] L. C. Blum, J.-L. Reymond, J. Am. Chem. Soc., 2009, 131, 8732—8733;
[3] L. Ruddigkeit, R. van Deursen, L. C. Blum, J.-L. Reymond, J. Chem. Inf. Model., 2012, 52, 2864—2875;
[4] http://gdb.unibe.ch/tools/ (25.04.2019);
[5] E. Luethi, K. T. Nguyen, M. Bürzle, L. C. Blum, Y. Suzuko, M. Hediger, J.-L. Reymond, J. Med. Chem., 2010, 53, 7236—7250;
[6] R. Visini, J. Arús-Pous, M. Awale, J.-L. Reymond, J. Chem. Inf. Model., 2017, 57, 2707—2718