Synthesis of hydroxyethylene isosteres of the transition state of the HIV protease-catalyzed Phe-Pro hydrolysis: reaction of 2-[(Boc)amino]-1-(2'-oxocyclopentyl)-3-phenylpropanols with diethyl phosphorocyanidate and lithium cyanide followed by samarium iodide

Abstract

Reaction of cyclopentanone enolate (7) with Boc-L-phenylalaninal (6) afforded a mixture of four aldol products 5a-d in a 3:3:1:1 ratio. Reaction of 5a with diethyl phosphorocyanidate followed by samarium iodide reduction afforded lactone 13a and phosphate 12. The structure of 12 was confirmed by X-ray crystallography. Deprotection of 13a gave (1R,1'S,2S,2'S)-2-(2'-amino-1'-hydroxy-3'-phenylpropyl)cyclopentanecarboxylic acid lactone (14a), which was transformed to a crystalline lactam 15a under basic conditions. The structure of 15a was also confirmed by X-ray analysis