Stereoselective synthesis of Xaaψ[CH2CH(OH)]Yaa dipeptidomimetics and their inclusion in HIV-1 protease inhibitors

Two stereoselective syntheses of a new pseudodipeptide isostere, the right-hand hydroxyethylene dipeptido-mimetic (Xaaψ[CH2CH(OH)]Yaa), are presented. In one method readily available amino acids are used as starting materials for Evans chiral aldol condensation chemistry. The second method relies on the synthesis of an anti-aldol product for the hydroxyethylene isostere via an E-selective ethyl hydrocinnamate enolization, and thus allows for the synthesis of isosteres having side chains other than those available from amino acids. Both methods are illustrated by the chiral synthesis of Boc-Pheψ[CH2CH(OH)]Phe. Two diastereomers, (S,S,R)and (S,R,R) are incorporated into an HIV-1 protease inhibitor template which yields potent inhibitors of HIV-1 protease when the pseudodipeptide isostere is Pheψ[CH(OH)CH2]Phe or Pheψ[CH(OH)CH(OH)]Phe. The resulting Pheψ[CH2CH(OH)]Phe-containing inhibitors possess modest potency. © Munksgaard 1995.