A straightforward trifluoromethylation at the C6 position of morphinane alkaloids, their modification and evaluation of inhibition of the SARS-CoV-2 main protease

• Published in: Journal of fluorine chemistry Vol. 271; pp. 110189 - 110198
• Main Authors: Finke, Anastasija O., Krasnov, Vyacheslav I., Rybalova, Tatyana V., Chirkova, Varvara Yu, Belenkaya, Svetlana V., Volosnikova, Ekaterina A., Shcherbakov, Dmitry N., Shults, Elvira E.
• Format: Journal Article
• Language: English
• Published: LAUSANNE Elsevier B.V 01.10.2023; Elsevier
• Subjects: Carbonylation-cross-coupling reaction; Chemistry; Chemistry, Inorganic & Nuclear; Chemistry, Organic; Hydroxycodeinone; Main viral protease 3CLpro; Physical Sciences; Ruppert–Prakash reagent; SARS-CoV-2; Science & Technology; Sinomenine; Trifluoromethylation; SARS-CoV-2; Trifluoromethylation; Main viral protease 3CLpro; Hydroxycodeinone; Ruppert–Prakash reagent; Carbonylation-cross-coupling reaction; Sinomenine; SUBSTITUTION; Ruppert-Prakash reagent; TRIFLUOROMETHYLTRIMETHYLSILANE; OPIOIDS; SINOMENINE DERIVATIVES; AGONIST
• ISSN: 0022-1139; 1873-3328
• DOI: 10.1016/j.jfluchem.2023.110189

•A methodology for trifluoromethylation of stereoisomeric 6-ketomorphinans using Ruppert–Prakash reagent.•Selective synthesis of (9α,13α,14α)-8β‑chloro-6,7-didehydro-6-(trifluoromethyl)-3,4,7-trimethoxy-N-methylmorphinane.•(9α,13α,14α)-7,8-Didehydro-1-iodo-6α-(trifluoromethyl)-6β-(hydroxy)-3,4,7-trimethoxy-N-methylmorphinan hor the synthesis of novel 6α-(trifluoromethyl)sinomenin-6β-ol – pyrimidine hybrid compounds.•8β‑chloro-6,7-didehydro-6-(trifluoromethyl)-3,4,7-trimethoxy-N-methylmorphinane shown inhibition of the main viral protease (3CLpro) of SARS-CoV-2. A catalytic trifluoromethylation of stereoisomeric 6-ketomorphinans using Ruppert–Prakash reagent and tetrabutylammonium fluoride (TBAF) was studied. 14β-Hydroxycodeinone, 4-O-methylsinomenine and 1-iodo-4-O-methylsinomenine provided good to excellent yields of the corresponding 6-trifluoromethylated compounds. The new morphinan derivative (6-deoxo-1-iodo-6α-(trifluoromethyl)-4-O-methylsinomenin-6β-ol) was involved in some catalytic transformations for introduction of additional substituent on C-1 position of the morphinan core. The palladium-catalyzed carbonylation–cross coupling reaction of 1-iodo-derivative with phenylacetylene in the presence of PdCl2-(1-Ad)2PBn catalytic system and Mo(CO)6 as a source of carbon monoxide in MeCN proceeds with high selectivity with the formation of alkynyl ketone as the main product. The cyclocondensation with acetamidine hydrochloride afforded the arylpyrimidine – 6α-(trifluoromethyl)-4-O-methylsinomenin-6β-ol hybrid compound. The action of the dehydration system (SOCl2-Py-DMAP) on 6-deoxo-6α-(trifluoromethyl)-4-O-methylsinomenin-6β-ol have led to the formation оf 8β‑chloro-6,7-didehydro-6-(trifluoromethyl)morphinan which showed inhibition the main viral protease (3CLpro) of SARS-CoV-2 at IC50 value of 25 μM. [Display omitted]