Synfacts 2020; 16(10): 1211
DOI: 10.1055/s-0040-1707375
Organo- and Biocatalysis

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

Rezensent(en):
Benjamin List
,
Sebastian Brunen
Stone EA, Cutrona KJ, Miller SJ. * Yale University, New Haven, USA
Asymmetric Catalysis upon Helically Chiral Loratadine Analogues Unveils Enantiomer-Dependent Antihistamine Activity.

J. Am. Chem. Soc. 2020;
42: 12690-12698
 

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.




Publikationsverlauf

Artikel online veröffentlicht:
17. September 2020

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