Kroškins Vladislavs, Lugiṇina Jevgeṇija, La̅cis Rihards, Kumar Dinesh, Kumpiṇš Viktors, Rjabovs Vita̅lijs, Mishnev Anatoly, Turks Ma̅ris
Institute of Chemistry and Chemical Technology, Faculty of Natural Sciences and Technology, Riga Technical University, P. Valdena Str. 3, LV-1048 Riga, Latvia.
Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, LV-1006 Riga, Latvia.
ACS Omega. 2025 Jun 26;10(26):27992-28019. doi: 10.1021/acsomega.5c01632. eCollection 2025 Jul 8.
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)-NH that were further transformed into the corresponding picolinamides. The latter was found to be a suitable directing group for triterpenoid C-( )-H (het)-arylation with iodo-(het)-arenes in the presence of Pd-(OAc)/CuBr/CsOAc system. C-( )-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-( )-H arylated products were achieved with iodoarenes bearing electron-donating groups, but the use of electron-deficient iodoarenes gave a significant proportion of -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-( )-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-( )-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.
已开发出用于五环三萜类化合物的位点选择性钯催化C-H芳基化和氮杂环丁烷化的合成方案。桦木酸、齐墩果酸和熊果酸被转化为伯胺C(28)-NH，其进一步转化为相应的吡啶甲酰胺。发现后者是在Pd-(OAc)/CuBr/CsOAc体系存在下，用于三萜类化合物C-( )-H（杂）-芳基化与碘代（杂）芳烃反应的合适导向基团。C-( )-H（杂）-芳基化反应的产率为29%至83%，C(22)/C(16)选择性从羽扇豆烷（桦木酸）系列中的9:1到齐墩果烷和乌苏烷系列中的19:1。带有供电子基团的碘芳烃实现了C-( )-H芳基化产物的最高分离产率，但使用缺电子碘芳烃会产生相当比例的 -吡啶甲酰氮杂环丁烷副产物。当使用1-碘-4-硝基苯作为添加剂时，后者以良好的选择性作为主要产物获得。C-( )-H芳基化在所有测试的三萜类化合物系列中均显示出C(22)选择性；然而，氮杂环丁烷化反应在羽扇豆烷（桦木酸）系列的C(22)位和齐墩果烷系列的C(16)位发生。C-( )-H（杂）-芳基化和氮杂环丁烷化是天然三萜类化合物衍生化的新方法，可被视为药物化学进一步探索的有用工具。
