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ACS Omega. 2018 Mar 31;3(3):2661-2672. doi: 10.1021/acsomega.8b00179. Epub 2018 Mar 6.

Synthesis of TMPA Derivatives through Sequential Ir(III)-Catalyzed C-H Alkylation and Their Antidiabetic Evaluation.

Author information

1
School of Pharmacy, Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea.
2
College of Pharmacy, Catholic University of Daegu, Hayang-ro, Hayang-eup, Gyeongsan 38430, Republic of Korea.
3
Department of Chemistry, Sookmyung Women's University, Cheongpa-ro, Yongsan-gu, Seoul 04310, Republic of Korea.

Abstract

The synthesis and antidiabetic evaluation of ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA) and its structural analogs are described. The construction of TMPA derivatives has been successfully achieved in only two steps, which involve the iridium(III)-catalyzed α-alkylation of acetophenones with alcohols and the ketone-directed iridium(III)- or rhodium(III)-catalyzed redox-neutral C-H alkylation of α-alkylated acetophenones using Meldrum's diazo compounds. This synthetic protocol efficiently provides a range of TMPA derivatives with site selectivity and functional group compatibility. In addition, the site-selective demethylation of TMPA derivative affords the naturally occurring phomopsin C in good yield. Moreover, all synthetic compounds were screened for in vitro adenosine 5'-monophosphate-activated protein kinase (AMPK) activation using HepG2 cells. Furthermore, TMPA (5ac) and 5cd showing the most potent AMPK activation were treated for the in vivo antidiabetic experiment. Notably, our synthetic compound 5cd was found to display the powerful antidiabetic effect, stronger than that of metformin and TMPA (5ac).

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