Listening to nature's hints : exploiting a natural product scaffold to simplify a complex chemical structure

Natural products are important sources of bioactive compounds. Their complex chemical structure is at the same time their main perk and the major problem involved in their use as therapeutic agents. Total synthesis is, in many cases, long and low yielding while relaying completely on extraction from natural sources could lead to environmental issues. An alternative to total synthesis may be the exploitation of a three-dimensional scaffold that guide the interaction of different functional group with their biological target. Prof. Quinn group at the Eskitis Institute recently identified 1 -azaspiroundecane as a highly conserved privileged scaffold embedded in many natural products extracted from different sources. This structure is present in Phoebegrandine D, an alkaloid found in Phoebe grandis leaves, whose extract owns a good antimalarial activity (IC50 < 8 µg/ml).(1) We present here the synthesis of 8-amino-1 -azaspiroundecane scaffold realized in six high yielding steps. The scaffold was used as a starting point for a series of compounds mimicking the aromatic systems present in Phoebegrandine D. This strategy led to a compound more active than the plant extract (IC50: 4.7 µg/ml), and could be used in the future to simplify other bioactive natural products, circumventing total synthesis.