Tetrapeptide-Catalyzed Dynamic Kinetic Resolution Grants Access to Helically Chiral Loratadine Analogues

Key words

peptide catalysis - asymmetric catalysis - dynamic kinetic resolution - loratadine - helical chirality

Significance

Miller and co-workers report a peptide-catalyzed dynamic kinetic resolution of analogues of the antihistamine loratadine to yield the corresponding helically chiral N-oxides with moderate yields and poor to excellent enantiomeric ratios. Notably, the challenging differentiation between the substrate’s pyridine ring and its adjacent alkene moiety could be achieved to favor N- over C-oxidation with moderate to high chemoselectivities. The resulting products were found to be configurationally stable at physiological temperatures.

 

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Comment

Building upon their initial investigations (J. Am. Chem. Soc. 2019, 141, 18624), the authors expanded their work to include challenging loratadine-type substrates. The resulting conformationally rigidified enantioenriched products had significantly different antagonist activities toward the human histamine H₁ receptor, which binds preferentially to the (–)-enantiomer of the compounds. The identified configuration–bioactivity correlation paves the way for the development of more-efficient therapeutics.

 

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Publikationsverlauf

Artikel online veröffentlicht:
17. September 2020