LaCl3-Enabled Synthesis of 2′- C -Substituted Galidesivir Analogues
James M. Wood, Rinu Shrestha, Ashley Nutsford, Blake Sullivan-Hill, Scott A. Cameron, Hong Wang, Gary B. Evans, Justin Julander, Natalie E. Netzler, Lawrence D. HarrisAbstract
The first synthesis of 2′-C-ethynylgalidesivir is reported. Access to this highly congested imino-C-nucleoside required development of a LaCl3·2LiCl-enabled addition of a 9-deazaadenine-derived Grignard reagent to 2′-C-substituted cyclic nitrones. The reaction proceeds with high β selectivity and enables the synthesis of galidesivir, 2′-C-methylgalidesivir, and 2′-C-ethynylgalidesivir. The respective syntheses required 6, 11, and 11 steps from known intermediates and proceeded in 54%, 22% and 17% overall yield. NMR titration and order-of-addition studies suggested that LaCl3·2LiCl perturbs both the nitrone substrate and Grignard speciation. Antiviral evaluation of the ethynyl analogue and its phosphoramidate prodrug revealed only weak activity at high concentration.