Asymmetric synthesis of ENT-03, the predicted mammalian ortholog of the dog fish shark aminosterol trodusquemine (MSI-1436)

[Display omitted] 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 EN...

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Bibliographic Details
Published in:	Tetrahedron letters Vol. 148; p. 155220
Main Authors:	Kinney, William A., Phillip Cox, D., Jones, Stephen R., Hessler, Edward J., Karnes, Harold A., Fevig, Thomas L., Hewitt, Bradley D., Sullivan, Ryan, Tseng, Nai-Wen, Pasion, Edward, Beale, Thomas, Rosner, Thorsten, Crouch, Ian T., D’Ambrosio, Stephen, Wade, Peter, Chen, Hui, Gao, Qi, Thompson, Andrew S., Muzzio, Miguel, Barbut, Denise, Zasloff, Michael A.
Format:	Journal Article
Language:	English
Published:	Elsevier Ltd 19-09-2024
Subjects:	7-HOCA Asymmetric hydrogenation Diabetes Mandyphos Metabolic activity Obesity Trodusquemine Obesity Metabolic activity Asymmetric hydrogenation Trodusquemine Diabetes Mandyphos 7-HOCA
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Summary:	[Display omitted] 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. Asymmetric hydrogenation using a ruthenium coordinated Mandyphos ligand was found to be effective in controlling the C25-stereochemistry 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.
ISSN:	0040-4039
DOI:	10.1016/j.tetlet.2024.155220