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.

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.

Publication History

Article published online:
17 September 2020