作者: Muzzio, Miguel ; Pasion, Edward ; Chen, Hui ; Hewitt, Bradley D. ; Tseng, Nai-Wen ; Gao, Qi ; Sullivan, Ryan ; Fevig, Thomas L. ; Karnes, Harold A. ; Crouch, Ian T. ; D’Ambrosio, Stephen ; Phillip Cox, D. ; Thompson, Andrew S. ; Barbut, Denise ; D′Ambrosio, Stephen ; Jones, Stephen R. ; Kinney, William A. ; Wade, Peter ; Zasloff, Michael A. ; Rosner, Thorsten ; Beale, Thomas ; Hessler, Edward J.
ENT-03 was predicted to be the mammalian equivalent of trodusquemine, based on knowledge of the bile acids produced in mammals, such as 7-HOCA.The individual C-25 isomers of ENT-03 were prepared and both isomers were detected in neonatal mouse brain and liver.Trodusquemine and ENT-03 have both demonstrated dramatic effects in obesity and insulin resistance. (25S)-ENT-03 was selected for development for the treatment of diabetes and obesity.In this paper the first synthesis of this putative natural product is described.Starting with a stereo-defined steroidal intermediate 2, the semi-synthesis involves three stereoselective steps: Horner-Emmons olefination, hydrogenation, and reductive amination.Asym. hydrogenation using a ruthenium coordinated Mandyphos ligand was found to be effective in controlling the C25-stereochem. of both isomers.The syntheses of the ENT-03 isomers and a deuterated reference standard facilitated identification and quantification of this natural product in mouse tissues, and exploration of its therapeutic potential.
