Synthesis of (±)‐Spongiolactone Enabling Discovery of a More Potent Derivative |
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| Authors: | Natalie L. Harvey Dr. Joanna Krysiak Dr. Supakarn Chamni Dr. Sung Wook Cho Prof. Dr. Stephan A. Sieber Prof. Dr. Daniel Romo |
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| Affiliation: | 1. Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, TX 77842 (USA) http://www.chem.tamu.edu/rgroup/romo/index.html;2. Department of Chemistry, TU München Lichtenbergstra?e 4, D‐85748 Garching (Germany);3. Present address: Department of Pharmacognosy and Pharmaceutical Botany, Chulalongkorn University, Bangkok (Thailand);4. Present address: Dow Chemical Co., Hwaseong, Gyeonggi‐do (Korea) |
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| Abstract: | An eleven‐step synthesis of (±)‐spongiolactone from 1,3‐cyclohexanedione is reported that relies on a diastereoselective, nucleophile‐catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated β‐lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure–activity studies that revealed a regio‐ and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested. |
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| Keywords: | allyl zinc reagent beta‐lactone cytotoxicity spongiane diterpenoid total synthesis |
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