Synthesis of [d4U]-Spacer-[HI-236] Bifunctional HIV-1 Reverse Transcriptase Inhibitors

This book describes the design and synthesis of bifunctional drugs combining a nucleoside (d4U) and non-nucleoside (HI-236) reverse transcriptase inhibitor linked via different spacers between C-5 of the NRTI and O-1 of the NNRTI. Three targets were successfully synthesized in a divergent manner from uridine in 13 steps for the butyne target and 19 steps for targets bearing PEG-propyne units using Sonogashira coupling as a key step. The most challenging step of the synthesis involved Boc deprotection and thiourea condensation in the final step, which suffered from anomeric cleavage with loss of the sugar moiety. As a result, the target with a three-carbon propynyl spacer could not be accessed. Progress towards the synthesis of a bifunctional system bearing a saturated and more flexible tether is highlighted in Chapter 4. The key reactions included Sonogashira coupling of iodo nucleosides, 2',3'-dideoxygenation of the vicinol diol, phenolic alkylation and condensation of amine with thiourea reagent. The synthesis surmounted several challenges, with chemoselective distinction of unsaturation via late introduction of the d4U double bond using Corey-Winter methodology.