Remdesivir, an inhibitor of RNA-dependent
RNA polymerase developed
by Gilead Sciences, has been used for the treatment of COVID-19. The
synthesis of remdesivir is, however, challenging, and the overall
cost is relatively high. Particularly, the stereoselective assembly
of the P-chirogenic center requires recrystallization of a 1:1 isomeric p-nitrophenylphosphoramidate mixture several times to obtain
the desired diastereoisomer (39%) for further coupling with the d-ribose-derived 5-alcohol. To address this problem, a variety
of chiral bicyclic imidazoles were synthesized as organocatalysts
for stereoselective (S)-P-phosphoramidation employing
a 1:1 diastereomeric mixture of phosphoramidoyl chloridates as the
coupling reagent to avoid a waste of the other diastereomer. Through
a systematic study of different catalysts at different temperatures
and concentrations, a mixture of the (S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9
ratio when 20 mol % of the chiral imidazole-cinnamaldehyde-derived
carbamate was utilized in the reaction at −20 °C. A 10-g
scale one-pot synthesis via a combination of (S)-P-phosphoramidation
and protecting group removal followed by one-step recrystallization
gave remdesivir in 70% yield and 99.3/0.7 d.r. The organocatalyst
was recovered in 83% yield for reuse, and similar results were obtained.
This one-pot process offers an excellent opportunity for industrial
production of remdesivir.
Hitherto unknown catalytic enantioselective transformation of p-quinone diimides is achieved using chiral bifunctional organic molecules. Bifunctional thiourea compounds catalyze the Michael addition of cyanoacetates with excellent yields and enantioselectivities. The initially formed Michael adducts undergo cyclization to yield functionally rich, fused cyclic imidines bearing a quaternary benzylic chiral center. Density functional theory calculations of the competing transition states (TSs) were carried out to explain the observed stereochemical outcome.
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