Question 6: Scientists around the world are conducting more than 300 clinical trials to
investigate treatments to help patients infected with the novel coronavirus. Early results
show that remdesivir, an antiviral drug originally developed by Gilead Sciences to treat
Ebola, may be a promising treatment for COVID-19. Consider the structure of remdesivir:
a) One of the steps in the synthesis of remdesivir involves the protection of a primary
amine prior to the formation of an organolithium reagent, which acts as a carbanion in
a subsequent synthetic step. The reagent used to protect the primary amine is
trimethylsilyl chloride (TMS-CI), as shown below:
1. 2 TMS-CI, THE
2. 4 n-BuLi
Draw a multistep arrow-pushing mechanism to show how the primary amine is
protected using TMS-CI. Assume that the CI leaving group acts as the base.
b) In the next step of the reaction sequence, a reaction with a lactone results in the
formation of a following tricyclic product. Note that the TMS protecting group is
removed using acid after the coupling reaction is complete.
Based on the above reaction, what competing reaction could have occurred if the
primary amine was not protected using TMS-CI? (2 points)
c) When designing a synthetic scheme, what is more advantageous to try to include: a
chemoselective reaction or a protecting group strategy? Explain your reasoning.