Three‐Component, One‐Pot Tandem Sonogashira/Suzuki‐Miyaura Coupling Reactions for the Synthesis of a Library of Ceramide‐Transport Protein Inhibitors Designed In Silico

We have developed a one-pot, tandem Sonogashira/Suzuki–Miyaura coupling reaction, which is unknown synthetically, and applied it for the synthesis of a library of potential natural ligand nonmimetic inhibitors of the lipid-transfer protein, ceramide-transport protein (CERT). The characteristic feature of this reaction is that the two-step coupling reaction proceeds smoothly with only 5 mol% of palladium catalyst. Furthermore, the location of the formed carbon–carbon bond would be strictly defined because of the difference in reactivity. Therefore, many derivatives could be synthesized in high yields without the formation of regioisomeric byproducts by the same procedure. We also performed a semi-gram scale synthesis of several derivatives to provide the bioactive assey. After synthesizing as many as 113 derivatives, we identified a nonnatural mimetic inhibitor with activity comparable to that of the known inhibitor (1R,3S)-HPA-12.

This is the peer reviewed version of the following article: M. Ueno, N. Miyoshi, K. Hanada, S. Kobayashi, Asian J. Org. Chem. 2020, 9, 267., which has been published in final form at https://doi.org/10.1002/ajoc.201900689. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.