Palladium-Catalyzed C–H Arylation and Azetidination of Pentacyclic Triterpenoids

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.