TY - GEN A1 - Kiebist, Jan A1 - Holla, Wolfgang A1 - Heidrich, Johannes A1 - Poraj-Kobielska, Marzena A1 - Sandvoss, Martin A1 - Simonis, Reiner A1 - Gröbe, Glenn A1 - Atzrodt, Jens A1 - Hofrichter, Martin A1 - Scheibner, Katrin T1 - One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases T2 - Bioorganic & Medicinal Chemistry N2 - Unspecific peroxygenases (UPOs, EC 1.11.2.1) have proved to be stable oxygen-transferring biocatalysts for H2O2-dependent transformation of pharmaceuticals. We have applied UPOs in a drug development program and consider the enzymatic approach in parallel to a conventional chemical synthesis of the human metabolites of the bile acid reabsorption inhibitor SAR548304. Chemical preparation of N,N-di-desmethyl metabolite was realized by a seven-step synthesis starting from a late precursor of SAR548304 and included among others palladium catalysis and laborious chromatographic purification with an overall yield of 27%. The enzymatic approach revealed that the UPO of Marasmius rotula is particularly suitable for selective N-dealkylation of the drug and enabled us to prepare both human metabolites via one-pot conversion with an overall yield of 66% N,N-di-desmethyl metabolite and 49% of N-mono-desmethylated compound in two separated kinetic-controlled reactions. KW - Peroxgenase Y1 - 2017 UR - https://opus4.kobv.de/opus4-UBICO/frontdoor/index/index/docId/18616 UR - http://www.sciencedirect.com/science/article/pii/S0968089615005295 SN - 0968-0896 VL - 23 IS - 15 SP - 4324 EP - 4332 ER -