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

Abstract

We have developed a one‐pot, tandem Sonogashira/Suzuki‐Miyaura coupling reaction, which was 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 assay. After synthesizing as many as 113 derivatives, we identified a non‐natural mimetic inhibitor with activity comparable to that of the known inhibitor (1R,3S)‐HPA‐12.

Recent Progress in Pd-Catalyzed Tandem Processes

“…Palladium is known as a catalyst for the cross-coupling processes [33,34]. Both sequential and iterative Pd-catalyzed reactions can be carried out in tandem cross-coupling reactions, and the order of C-C bond forms can be regulated by either the attenuated leaving groups of the multireactive substrate or certain catalyst/ligand combinations [35][36][37][38]. Both the nucleophilic and electrophilic sites may be coupled in a specific manner.…”

Natural Ligand-Mimetic and Nonmimetic Inhibitors of the Ceramide Transport Protein CERT

“…To improve this situation, CERT inhibitors with no apparent structural similarity to ceramides have recently been developed using a structure-based drug design strategy [28,86]. In the first step, a seed compound with no ceramide-like structure but with the ability to form a hydrogen-bonding network in the ceramide-binding START domain of CERT was obtained, following the virtual screening of approximately 3 × 10 6 compounds.…”

One‐Pot Tandem Coupling Method for the Short‐Step Formal Synthesis of Riccardin C

“…Moreover, since many methods utilize multiple coupling reactions using metal catalysts such as palladium, the number of metal catalysts used increases as the number of reaction steps increases. Therefore, to synthesize such polyaryl compounds, we developed a one‐pot tandem coupling method, in which substituents with different reactivities are arranged in each unit, and the desired coupling reactions are sequentially achieved using readily available metal catalysts [10] . This method is beneficial for library construction based on combinatorial chemistry approaches.…”

“…Therefore, to synthesize such polyaryl compounds, we developed a one-pot tandem coupling method, in which substituents with different reactivities are arranged in each unit, and the desired coupling reactions are sequentially achieved using readily available metal catalysts. [10] This method is beneficial for library construction based on combinatorial chemistry approaches. In fact, more than 100 analogs of in silico designed non-ceramide mimetic ceramide transport protein (CERT) inhibitors have been successfully synthesized, resulting in the development of a novel, highly potent compound, HPCB-5.…”