Solid-Phase Synthesis of Hindered Amides

Significance

The solid-phase synthesis of hindered amides was demonstrated using the aldehyde dual-linker [5-(4-formyl-3-hydroxyphenoxy)-pentanoic acid and Sieber amide] system. Thus, the secondary amine 2 was prepared by reductive alkylation of valine-OMe with Sieber amide resin-bound aldehyde 1 using NaBH₃CN followed by deprotection of the allyl group with Pd(PPh₃)₄ and PhSiH₃. Acylation of the secondary amine with Z-Leu-OH was performed via O to N acyl transfer using HBTU, HOBt, and N-methylmorpholine (NMM), and the subsequent cleavage from the resin by TFA gave sterically hindered amide 3. The conversion was determined by HPLC analysis to be 95%.