ABSTRACT
We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the development of a concise and efficient scale-up process to Ensitrelvir. In this process, introducing a meta-cresolyl moiety successfully enhanced the stability of intermediates. Compared to the initial route at the early research and development stage, the overall yield of the longest linear sequence (6 steps) was improved by approximately 7-fold. Furthermore, 9 out of the 12 isolated intermediates were crystallized directly from each reaction mixture without any extractive workup (direct isolation). This led to an efficient and environmentally friendly manufacturing process that minimizes waste of organic solvents, reagents, and processing time. This practical process for manufacturing Ensitrelvir should contribute to protection against COVID-19.
ABSTRACT
NW-G01, a cyclic hexapeptide antibiotic, and 34-epi-NW-G01 were synthesized by the highly stereoselective convergent approach for the first time, thereby unambiguously determining the absolute structure of NW-G01.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Depsipeptides/chemical synthesis , Anti-Bacterial Agents/chemistry , Depsipeptides/chemistry , Molecular Conformation , StereoisomerismABSTRACT
A general methodology applicable for the synthesis of the phoslactomycin family of antibiotics, potent and selective protein phosphatase inhibitors, has been developed starting from a beta-isocupreidine-catalyzed asymmetric Baylis-Hillman reaction of 3-(4-methoxybenzyloxy)propanal with hexafluoroisopropyl acrylate, and thereby formal syntheses of (+)-fostriecin and (+)-phoslactomycin B have been accomplished.
Subject(s)
Alkenes/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pyrones/chemical synthesis , Alkenes/chemistry , Anti-Bacterial Agents/chemistry , Catalysis , Enzyme Inhibitors/chemistry , Hydroxyquinolines/chemistry , Lactones/chemical synthesis , Lactones/chemistry , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/chemistry , Polyenes , Protein Phosphatase 1/antagonists & inhibitors , Protein Phosphatase 1/metabolism , Pyrones/chemistry , Quinuclidines/chemistry , StereoisomerismABSTRACT
(+)-Phoslactomycin B was synthesized by a highly enantio- and stereoselective approach involving asymmetric pentenylation, Suzuki-Miyaura coupling, ring-closing metathesis, asymmetric dihydroxylation, and Stille coupling. The synthetic method developed enables us to synthesize three other isomers concerning the C11-OH and Delta12-double bond.
