Total synthesis and structure elucidation of the meridamycin family Maike Birkner 1 , Daniel Lohrberg 1 , Prof. Markus Kalesse 1,2 1 Institute for Organic Chemistry, Gottfried Wilhelm Leibniz Universität Hannover, Germany, 2 Centre for Biomolecular Drug Research (BMWZ), Gottfried Wilhelm Leibniz Universität Hannover, Germany In 1994 and 1995 the polyketide meridamycin was isolated independently by Merck [1] and Sandoz, [2] the latter patent also proposing the absolute stereoconfiguration of the natural product. Finally, 4-normeridamycin and meridamycinsA‑D could be added to this family of polyketides. [3] The macrocyclic members of this group, meridamycin and 4-normeridamycin, bare a pipecolonic acid moiety, which resembles the immunosuppressants FK506 and rapamycin. Both compounds were tested for similar activity, eventhough they lack immunosuppression, they still exhibit neuroprotection, making them a valuable target for the treatment of the degeneration of dopaminergic neurons. In 2013, Kalesse and Kitsche used an in-silico approach to calculate the absolute configuration of meridamycin based on the amino-acid sequence of the polyketide synthase (PKS). Their prediction proposed a different configuration at 8 positions compared to the structure published by Sandoz. [2,4] The goal of this project is to synthesize meridamycin D to assign absolute stereoconfiguration to the polyketidal backbone of the meridamycins and thus validate the in-silico method used to predict the outcome of different PKS. The synthesis could rely on two fragments, which would be connected via a stereoselective Paterson-aldol reaction. The ketone for this step could again be obtained from two Paterson-aldol reactions, while the aldehyde could be produced from a boron-mediated metallate rearrangement, followed by a Wittig olefination and a reduction and oxidation sequence. The in-silico assignment predicts two stereocenters with low probability, resulting in two routes towards the respective diastereoisomers of the ketone and aldehyde fragments. While the anti-syn ketone (Scheme 1) could be obtained from two Paterson aldol reactions, the syn-anti motif relies on two different retrosynthetic cuts and a Masamune-aldol reaction. The diastereoisomer of the TIB ester would be easily obtained from Myers alkylation.
Scheme 1: Retrosynthetic analysis of Meridamycin D. Marked stereocenters could only be predicted with low confidence and might be of different configuration. PG: protecting group, TIB: 2,4,6-triisopropylbenzoyl, pin: pinacoyl. References 1. Salituro, Tetrahedron Lett . 1995 , 36, 997–1000 2. Fehr, WO9418207A1, 1994
3. Shen, RSC Adv . 2016 , 6, 49792-497960 4. Kalesse, ChemBioChem . 2013 , 14, 851–861
P10
© The Author(s), 2023
Made with FlippingBook Learn more on our blog