Diversity-oriented synthesis of a drug-like system displaying the distinctive N-->C=O interaction

This study describes the syntheses and characterization of two hydrazino ureas. These fold into a six-membered ring by virtue of the infrequently observed (delta+)N-->C=O (delta-) interaction when solvated by polar protic media. The highly polar functional group resulting from this interaction is hypothesized to especially reproduce electronic but also steric features of the transition states of peptide hydrolysis. The urea moiety constitutes an additional key element of modern HIV-1 protease (HIV PR) inhibitors and is meant to interact with the enzyme flaps. We have developed an efficient, convergent synthetic route to enantiopure compounds that uses CDI to couple two independent building blocks, one derived from amino acids and the other one from easily accessible hydrazines. It is thus amenable to rapid generation of diversity in order to screen for novel HIV PR inhibitors. A complete study using one- and two-dimensional NMR as well as UV spectroscopy confirmed the sole existence of the cyclic constitution of target compounds 7 and 8 in methanol. Total reversal to the linear aldehydic form is observed upon passage to apolar media.