Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jun 26;10(26):27992-28019.
doi: 10.1021/acsomega.5c01632. eCollection 2025 Jul 8.

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

Vladislavs Kroškins  1 , Jevgeṇija Lugiṇina  1 , Rihards La̅cis  1 , Dinesh Kumar  1 , Viktors Kumpiṇš  1 , Vita̅lijs Rjabovs  1 , Anatoly Mishnev  2 , Ma̅ris Turks  1
Affiliations

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

Vladislavs Kroškins et al. ACS Omega. .

Abstract

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-(sp 3)-H (het)-arylation with iodo-(het)-arenes in the presence of Pd-(OAc)2/CuBr2/CsOAc system. C-(sp 3)-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-(sp 3)-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-(sp 3)-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-(sp 3)-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.

PubMed Disclaimer

Figures

1
1
Previously reported C–H functionalized PCT.
2
2
Triterpenic 8-aminoquinolinamides 2a–d and picolinamides 3a–d.
1
1. Synthesis of Picolinic Amides 3a,b
2
2. Synthesis of Picolinamides 3c,d
3
3
Single crystal X-ray diffraction analysis of 6a and 6b.
3
3. C­(sp 3)-H Hetarylation of Picolinamide 3a
4
4. C­(sp 3)-H Arylation and Azetidination of Lupane-Derived Picolinamide 3b
5
5. Synthesis of Unprotected Azetidines 12 and 13
6
6. C­(sp 3)-H Arylation of Oleanolic and Ursolic Amides 3c,d
7
7. Azetidine 17 Formation from Oleanolic Amide 3c
8
8. C–H Deuteration of Picolinamides 3a,c at Different Times
9
9. Plausible Pd-Catalyzed C­(sp 3)-H Arylation and Azetidination Mechanism
10
10. Arylation Attempts of Compounds 6a, 7a, and Extended Amide 23
11
11. Synthesis of Amine 24 and Amino Acid 26
See this image and copyright information in PMC

References

    1. Sheng H., Sun H.. Synthesis, biology and clinical significance of pentacyclic triterpenes: a multi-target approach to prevention and treatment of metabolic and vascular diseases. Nat. Prod. Rep. 2011;28:543–593. doi: 10.1039/c0np00059k. - DOI - PubMed
    1. Ren Y. L., Kinghorn A. D.. Natural product triterpenoids and their semisynthetic derivatives with potential anticancer activity. Planta Med. 2019;85:802–814. doi: 10.1055/a-0832-2383. - DOI - PMC - PubMed
    1. Teodoro T., Zhang L., Alexander T., Yue J., Vranic M., Volchuk A.. Oleanolic acid enhances insulin secretion in pancreatic b-cells. FEBS Lett. 2008;582:1375–1380. doi: 10.1016/j.febslet.2008.03.026. - DOI - PubMed
    1. Jang S. M., Yee S. T., Choi J., Choi M. S., Do G. M., Jeon S. M., Yeo J., Kim M. J., Seo K. I., Lee M. K.. Ursolic acid enhances the cellular immune system and pancreatic beta-cell function in streptozotocin-induced diabetic mice fed a high-fat diet. Int. Immunopharmacol. 2009;9:113–1194. doi: 10.1016/j.intimp.2008.10.013. - DOI - PubMed
    1. Genet C., Strehle A., Schmidt C., Boudjelal G., Lobstein A., Schoonjans K., Souchet M., Auwerx J., Saladin R., Wagner A.. Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes. J. Med. Chem. 2010;53:178–190. doi: 10.1021/jm900872z. - DOI - PubMed

LinkOut - more resources