Zhang R,
Yu T,
Dong G.
*
University of Chicago, USA
Rhodium Catalyzed Tunable Amide Homologation through a Hook-and-Slide Strategy.
Science 2023;
382: 951-957
DOI:
10.1126/science.adk1001
Key words
amide homologation - carboxylic acid homologation - skeletal editing
Significance
Functional group homologation represents a powerful strategy in medicinal chemistry,
enabling late-stage access to drug homologs with potentially significantly different
bioactivities to the parent compound. Given the prevalence of amides in medicinal
chemistry and dearth of available methods, new methods for amide homologation are
particularly needed. In this work, Dong and co-workers present a ‘hook-and-slide’
strategy for amide homologation involving α-alkylation, amidine formation, rhodium-catalyzed
branched-to-linear isomerization, and directing group removal.
Comment
The hook-and-slide strategy, while requiring an aromatic substituent in the α-position
of the amide, is amenable to a variety of homologation lengths and substituents on
the amide nitrogen. Incorporating an amidation step in the sequence and altering the
conditions for the directing group removal allowed for the homologation of carboxylic
acids as well. This strategy was utilized for creation of homologs of the anti-inflammatory
drug isoxepac and the GPR120 agonist TUG-891.
