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Synthesis and bioactivity of (±)-tetrahydrohaliclonacyclamine A |
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| Authors: | Brian J Smith Matthew Mulder Craig W Lindsley Gary A Sulikowski |
| Institution: | a Departments of Chemistry, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 77842-3012, USA b Departments of Pharmacology, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 77842-3012, USA c Departments of Biochemistry, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 77842-3012, USA d Departments of Chemistry, Texas A&M University, College Station, Texas 77482, USA |
| Abstract: | The total synthesis of tetrahydrohaliclonacyclamine A (5) is described. A key step involves the hydrogenation of an unsaturated bis-piperidine incorporated into a 17-membered macrocycle to provide the cis-syn-cis stereochemistry common to haliclonacyclamines A-D. The hydrogenation product is advanced to the title compound following a five-step reaction sequence. Tetrahydrohaliclonacyclamine A is shown to bind to a variety of ion channels/GPCRs and act as a muscarinic M1 antagonist. |
| Keywords: | Marine alkaloid Ring-closing metathesis Stereoselective hydrogenation Stille cross-coupling Muscarinic M1 antagonist |
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