Puromycin Analogs. Studies on Ribosomal Binding with Diastereomeric Carbocyclic Puromycin Analogs

A direct and convenient route to the antimicrobial carbocyclic puromycin analog, 6-dimethylamino-9-[(n)-[(2n)- hydroxy-(3P)-(p-methoxyphenyl-L-alanylamino)]cyclopentyl]purine (la), is described. Epoxidation of 3-acetamidocyclopentene (3) gave exclusively cis-3-acetamido-1,2-epoxycyclopentane (4). Opening of the epoxide with NaN₃, followed by reduction of the resulting azido alcohol 5, gave a high yield of 2α-acetamido-5β-aminocyclopentan-la-ol (6). This amine was easily resolved via tartrate formation. Introduction of the purine moiety by standard methods gave the enantiomeric carbocyclic aminonucleosides (-)- and (+)-2α-acetamido-5β-(6-dimethylamino-9-purinyl)- cyclopentan-la-ol (10a and 10b). Resolution at an early point allows for the conversion of 10a and 10b to a wide variety of diastereomeric aminoacyl derivatives. Studies on protein synthesis inhibition with diastereomeric carbocyclic puromycin analogs indicate that two distinct types of protein synthesis inhibitors may have been developed— series a which are peptidyl transferase substrates, and series b which are peptidyl transferase inhibitors.