Synthesis of ent-Nanolobatolide†
Dr. Hau Man Cheng
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Search for more papers by this authorDr. Weiwei Tian
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Search for more papers by this authorDr. Philippe A. Peixoto
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Search for more papers by this authorDr. Bhartesh Dhudshia
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Search for more papers by this authorCorresponding Author
Prof. Dr. David Y.-K. Chen
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869Search for more papers by this authorDr. Hau Man Cheng
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Search for more papers by this authorDr. Weiwei Tian
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Search for more papers by this authorDr. Philippe A. Peixoto
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Search for more papers by this authorDr. Bhartesh Dhudshia
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Search for more papers by this authorCorresponding Author
Prof. Dr. David Y.-K. Chen
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667 (Singapore), Fax: (+65) 6874-5869Search for more papers by this authorWe thank Doris Tan (ICES) for assistance with high-resolution mass spectrometry (HRMS). Financial support for this work was provided by A*STAR, Singapore.
Graphical Abstract
Effizient und anpassbar: Die Schlüsselschritte bei der Totalsynthese von ent-Nanolobatolid, dem Enantiomer des neuartigen und wirksamen neuroprotektiven Stoffes, sind eine oxidative Ringerweiterung von (−)-Menthon, eine Nazarov-Cyclisierung, eine intermolekulare Diels-Alder-Reaktion und eine intramolekulare Epoxidöffnung (siehe Schema). Die beiden letzten Schritte stützen den vermuteten Biosyntheseweg.
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- 8Attempts to install the C5–C6 olefin from ketone 16 through the corresponding enol triflate, enol phosphate, vinyl halide, and hydrazone all proved unsuccessful, leading to either recovery or extensive decomposition of the starting material 16.
- 9Attempts to eliminate alcohol 17 through its corresponding triflate, selenide, halide, xanthate, or under Mitsunobu, Martin’s sulfurane, Burgess reagent, and POCl3/SOCl2–pyridine conditions all proved ineffective for this process.
- 10Notably, although (+)-menthone, which would lead to the naturally occurring form of (+)-nanolobatolide (1) in accordance to our synthetic strategy, is less readily available and more expensive than (−)-menthone, both enantiomeric forms of menthol are readily available, and this compound can be easily oxidized to give (+) and (−)-menthone.
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