TY - JOUR

T1 - A straightforward trifluoromethylation at the C6 position of morphinane alkaloids, their modification and evaluation of inhibition of the SARS-CoV-2 main protease

AU - Finke, Anastasija O.

AU - Krasnov, Vyacheslav I.

AU - Rybalova, Tatyana V.

AU - Chirkova, Varvara Yu

AU - Belenkaya, Svetlana V.

AU - Volosnikova, Ekaterina A.

AU - Shcherbakov, Dmitry N.

AU - Shults, Elvira E.

N1 - We gratefully acknowledge financial support from the Russian Science Foundation (grant No. 23-73-00077 ). We thank the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements.

PY - 2023/10

Y1 - 2023/10

N2 - 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.

AB - 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.

KW - Carbonylation-cross-coupling reaction

KW - Hydroxycodeinone

KW - Main viral protease 3CLpro

KW - Ruppert–Prakash reagent

KW - SARS-CoV-2

KW - Sinomenine

KW - Trifluoromethylation

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85171743860&origin=inward&txGid=1017b9fd72f7a55f3c30c5b93c3532ca

UR - https://www.mendeley.com/catalogue/d6be1e7a-7be3-3f15-ab88-5fa01e6d2b4e/

U2 - 10.1016/j.jfluchem.2023.110189

DO - 10.1016/j.jfluchem.2023.110189

M3 - Article

VL - 271

JO - Journal of Fluorine Chemistry

JF - Journal of Fluorine Chemistry

SN - 0022-1139

M1 - 110189

ER -