Synthesis of Antiviral Imino-C-Nucleoside Analogues

Abstract

Nucleoside analogues are a diverse class of synthetic drugs that exhibit broad antiviral and anti infective activity. Critically, nucleoside analogues serve as first-line therapeutic agents to treat viral infections of pandemic potential. Despite various clinical successes, nucleoside drug discovery has been hampered by inefficient access to unnatural nucleoside frameworks, such as the iminoribitol scaffold observed in the adenosine analogue, galidesivir (29). With the overall goal of streamlining the synthesis of nucleosides, the modular assembly of imino-C-nucleosides was devised, featuring use of a cycloaddition reaction as the key heterocycle-forming step. The first part of this work involved identification of an appropriate alkyne-bearing intermediate that would be compatible with the proposed cycloaddition reaction and downstream transformations to effect nucleoside synthesis. To this end, divergent access to both imino-C-nucleoside anomers was established from protected D-serine 112. Hemiaminal 130, when subjected to a telescoped cycloaddition and pyrrolidine formation sequence, showed preference for α-nucleoside formation. On the other hand, the analogous cycloaddition and deprotection using alkynyl pyrrolidine 148 led to the exclusive formation of the desired β-nucleoside 139·HCl. The second part of this work elaborated on the cycloaddition strategy as a rapid method to introduce diversity in medicinal chemistry campaigns. To maximise the efficiency of triazole construction, a one-pot method was developed for the in-situ generation of aryl or heteroaromatic azides from the corresponding boronic acids using Chan-Lam-type conditions, that were then captured for concomitant Copper-catalysed Azide Alkyne Cycloaddition (CuAAC). Copper-cyclodextrin complex was identified as the superior catalyst for this transformation. After extensive optimisation, 24 analogues were prepared from advanced alkyne 200 using the developed protocol. Synthetic efforts were supported by structural analysis and antiviral assessment of the flex-imino-C-nucleosides, a subclass of nucleoside analogues characterised by a split arene ring motif. This work provides insight for the continued development of nucleoside analogues, whereby use of a cycloaddition strategy could be broadly implemented for the convenient access to C-nucleosides bearing unique heterocyclic nucleobase surrogates in future diversity oriented syntheses.