Absolute stereochemistries and total synthesis of (+)-arisugacins A and B, potent, orally bioactive and selective inhibitors of acetylcholinesterase |
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Authors: | Toshiaki Sunazuka Masaki Handa Tatsuya Shirahata Kazuhiko Otoguro Satoshi ōmura |
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Institution: | a Kitasato Institute for Life Sciences, Kitasato University, and CREST, Shirokane, Minato-ku, Tokyo 108-8641, Japan b The Kitasato Institute, Shirokane, Minato-ku, Tokyo 108-8641, Japan c School of Pharmaceutical Sciences, Kitasato University, Shirokane, Minato-ku, Tokyo 108-8641, Japan |
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Abstract: | In the current studies, we used the Kakisawa-Kashman modification of the Mosher NMR method to determine the complete absolute stereochemistry of arisugacins. We also report the convergent total synthesis of (+)-arisugacins A and B by a sequence including (i) ruthenium complex-catalyzed asymmetric reduction of the cyclohexenone derivative; (ii) stereoselective construction of the arisugacin skeleton by a Knoevenagel-type reaction of an α,β-unsaturated aldehyde derivative with production of a 4-hydroxy-2-pyrone derivative as a key reaction; and (iii) stereoselective dihydroxylation to give the diol derivative, followed by deoxygenation. Accordingly, we defined the absolute structures of arisugacins A and B as 4a-(R),6a-(R),12a-(R), and 12b-(S). Finally, we characterized the bioactivities of the synthetic intermediates to understand the structure-activity relationships of the arisugacins. |
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Keywords: | α-Pyrone Meroterpenoid AChE inhibitor 6π-Electron electrocyclic ring closure Inversion of stereochemistry Stereoselective dihydroxylation |
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