Optimization of three- and four-component reactions for polysubstituted piperidines: application to the synthesis and preliminary biological screening of a prototype library |
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Authors: | Ulaczyk-Lesanko Agnieszka Pelletier Eric Lee Maria Prinz Heino Waldmann Herbert Hall Dennis G |
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Institution: | Department of Chemistry, University of Alberta, Edmonton, Alberta, T6H 3L7, Canada. |
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Abstract: | Several solid- and solution-phase strategies were evaluated for the preparation of libraries of polysubstituted piperidines of type 7 using the tandem aza4+2]cycloaddition/allylboration multicomponent reaction between 1-aza-4-boronobutadienes, maleimides, and aldehydes. A novel four-component variant of this chemistry was developed in solution phase, and it circumvents the need for pre-forming the azabutadiene component. A parallel synthesis coupled with compound purification by HPLC with mass-based fraction collection allowed the preparation of a library of 944 polysubstituted piperidines in a high degree of purity suitable for biological screening. A representative subset of 244 compounds was screened against a panel of phosphatase enzymes, and despite the modest levels of activity obtained, this study demonstrated that piperidines of type 7 display the right physical properties (e.g., solubility) to be assayed effectively in high-throughput enzymatic tests. |
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