Palladium-Catalyzed C-H Arylation and Azetidination of Pentacyclic Triterpenoids
ACS Omega 2025
Vladislavs Kroškins, Jevgeņija Lugiņina, Rihards Lācis, Dinesh Kumar, Viktors Kumpiņš, Vitālijs Rjabovs, Anatoly Mishnev, Māris Turks

Synthetic protocols for site-selective palladium-catalyzed C-H arylation and azetidination of pentacyclic triterpenoids have been developed. Betulin, oleanolic, and ursolic acids were converted into primary amines C(28)-NH2 that were further transformed into the corresponding picolinamides. The latter was found to be a suitable directing group for triterpenoid C(sp3)-H (het)arylation with iodo(het)arenes in the presence of Pd(OAc)2/CuBr2/CsOAc system. C(sp3)-H (het)arylation provided yields from 29 to 83%, and the C(22)/C(16) selectivity from 9:1 in the lupane (betulin) series to 19:1 in the oleane and ursane series. The highest isolated yields of C(sp3)-H arylated products were achieved with iodoarenes bearing electron-donating groups, but the use of electron-deficient iodoarenes gave a significant proportion of N-picolinoyl azetidine side product. The latter were obtained with good selectivity as major products when 1-iodo-4-nitrobenzene was used as an additive. C(sp3)-H arylation revealed C(22)-selectivity in all tested triterpenoid series; however, the azetidination occurred at C(22) in lupane (betulin) series and at C(16) in oleane series. C(sp3)-H (het)arylation and azetidination is a new entry in the derivatization of natural triterpenoids and can be regarded as a useful tool for further exploration in terms of medicinal chemistry.


Keywords
C-H activation; triterpene; betulin; oleanolic acid; ursolic acid
DOI
10.1021/acsomega.5c01632

Kroškins, V., Lugiņina, J., Lācis, R., Kumar, D., Kumpiņš, V., Rjabovs, V., Mishnev, A., Turks, M. Palladium-Catalyzed C-H Arylation and Azetidination of Pentacyclic Triterpenoids. ACS Omega, 2025, Vol. 10, No. 26, pp.27992-28019. Available from: doi:10.1021/acsomega.5c01632

Publication language
English (en)
The Scientific Library of the Riga Technical University.
E-mail: uzzinas@rtu.lv; Phone: +371 28399196