An improved aldehyde linker for the solid phase synthesis of hindered amides.
A novel aldehyde dual-linker system has been developed for the solid phase synthesis of sterically hindered amides. The linker [5-(4-formyl-3-hydroxyphenoxy)pentanoic acid] exploits an intramolecular oxygen-nitrogen acyl transfer mechanism to prepare compounds that are unattainable with current commercially available linkers. A dual linker system, exploiting the hyper-acid labile Sieber amide linker as part of the construct, enabled the initial reductive alkylation reactions of hindered amines and their subsequent acylation with a range of carboxylic acids with varying stereoelectronic properties to be monitored. Simple acylation conditions (HBTU/HOBt/NMM) sufficed to provide near quantitative reaction of test acids with support-bound hindered amines, reaction conditions which failed when commercial linkers were used.
Liley
Mark J
MJ
Medivir UK Ltd., Chesterford Research Park, Little Chesterford, Essex C10 1XL, United Kingdom. mark.liley@medivir.com
Johnson
Tony
T
Gibson
Susan E
SE