Potent HIV-1 Protease Inhibitors: Stereoselective Synthesis of a Dipeptide Mimic

The synthesis of a differentially protected dipeptide mimic 10 in enantiomerically pure form is described. The key step involves the epimerization of the C-2 center of the lactone 4, hydrolysis and protection of the resulting hydroxy acid, followed by Curtius rearrangement to introduce the urethane functionality. The scope and versatility of this isostere has been demonstrated by its conversion to potent HIV-1 protease inhibitors with nanomolar potencies. Also, established through the synthesis of compound 13 and 14, the 3S hydroxyl configuration of the dipeptide isostere 1 is the preferred configuration for its potency. The present synthesis is efficient and provides an access to other dipeptide mimics with a great deal of structural diversity.