Utilizing a copper-free Sonogashira reaction in the synthesis of the leukotriene a4 hydrolase modulator batatasin IV

• Published in: Tetrahedron letters 2020-11, Vol.61 (47), p.152547, Article 152547
• Main Authors: Petruncio, Greg, Girgis, Michael, Moummi, Sanae, Jayatilake, Meth, Lee, Kyung Hyeon, Paige, Mikell
• Format: Article
• Language: English
• Subjects: Aminopeptidase; Batatasin IV; Enzymology; Sonogashira; Total synthesis
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2020.152547

[Display omitted] •A copper-free Sonogashira proceeds at room temperature through aid of SPhos.•The substrate scope shows tolerance of aldehydes, alcohols, and nitro groups.•The Sonogashira was implemented in a shortened total synthesis of batatasin IV.•Batatasin IV was found to be a modest inhibitor of the LTA4H aminopeptidase activity. Batatasin IV is a dihydrostilbenoid isolated from Chinese yams which was shown to have inhibitory activities against plant growth. Later studies showed that this compound may exhibit anti-inflammatory properties by inhibiting the epoxide hydrolase activity of the leukotriene A4 hydrolase enzyme. To access the dihydrostilbenoid skeleton, a copper-free SPhos-mediated Sonogashira reaction was conceived and the substrate scope was explored. Our results indicate that the reaction can tolerate the presence of free alcohols, aldehydes, nitro groups, and anilinyl groups. However, a substituent with an acidic phenol or carboxylic acid group gave significantly lower yields. Next, a total synthesis of batatasin IV was accomplished in 16% overall yield incorporating the reported copper-free Sonogashira reaction. Finally, we show that batatasin IV inhibits the hydrolysis of alanine p-nitroanilide by leukotriene A4 hydrolase with an IC50 of 91.4 µM.