Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication

Linlin Zhang; Daizong Lin; Yuri Kusov; Yong Nian; Qingjun Ma; Jiang Wang; Albrecht von Brunn; Pieter Leyssen; Kristina Lanko; Johan Neyts; Adriaan de Wilde; Eric J. Snijder; Hong Liu; Rolf Hilgenfeld

Synthesis (Scheme 1) started with the dianionic alkylation of N-Boc glutamic acid dimethyl ester with bromoacetonitrile. As expected, this alkylation occurred in a highly stereoselective manner, giving 1 as the exclusive product. In the following step, the cyano group of 1 was subjected to hydrogenation. The in-situ cyclization of the resulting intermediate afforded the lactam 2. The lactam derivative 3 was generated by removal of the protecting group of 2. On the other hand, the amidation of acyl chloride and a-amino acid methyl ester afforded the intermediates 4, which gave rise to the acids 5 via alkaline hydrolysis. The key intermediates 6 were obtained via the condensation of the lactam derivative 3 and the N-capped amino acids 5. The ester group of compounds 6 was then reduced to the corresponding alcohol. Oxidation of the alcohol products 7 by Dess-Martin periodinane generated the aldehydes 8, which followed by nucleophilic addition with isocyanides gave rise to compounds 9 under acidic conditions. Then, the a-hydroxyamides 10 were prepared by removing the acetyl group of compounds 9. In the final step, the oxidation of the exposed alcohol group in compounds 10 generated our target a-ketoamides 11.