• DOI:10.1016/j.bmc.2015.06.035
• Corpus ID: 25092621

One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases.

@article{Kiebist2015OnepotSO,
  title={One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases.},
  author={Jan Kiebist and Wolfgang Dr. Holla and Johannes Heidrich and Marzena Poraj-Kobielska and Martin Sandvoss and Reiner Simonis and Glenn Gr{\"o}be and Jens Atzrodt and Martin Hofrichter and Katrin Scheibner},
  journal={Bioorganic \& medicinal chemistry},
  year={2015},
  volume={23 15},
  pages={
          4324-32
        }
}

• Jan Kiebist, W. Holla, +7 authors K. Scheibner
• Published 1 August 2015
• Chemistry, Medicine
• Bioorganic & medicinal chemistry

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.