Illicium Sesquiterpenes: Divergent Synthetic Strategy and Neurotrophic Activity Studies |
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Authors: | Dr Lynnie Trzoss Dr Jing Xu Michelle H Lacoske Prof Dr William C Mobley Prof Dr Emmanuel A Theodorakis |
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Institution: | 1. Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093‐0358 (USA), Fax: (+1)?858‐822‐0386;2. Department of Neurosciences, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093‐0752 (USA) |
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Abstract: | Majucin‐type sesquiterpenes from Illicium sp., such as jiadifenolide ( 2 ), jiadifenin ( 3 ), and (1R,10S)‐2‐oxo‐3,4‐dehydroxyneomajucin ( 4 , ODNM), possess a complex caged chemical architecture and remarkable neurotrophic activities. As such, they represent attractive small‐molecule leads against various neurodegenerative diseases. We present an efficient, enantioselective, and unified synthesis of 2 , 3 , and 4 and designed analogues that diverge from tetracyclic key intermediate 7 . The synthesis of 7 is highlighted by the use of an enantioselective Robinson annulation reaction (construction of the AB rings), a Pd‐mediated carbomethoxylation reaction (construction of the C ring), and a one‐pot oxidative reaction cascade (construction of the D ring). Evaluation of the neurotrophic activity of these compounds led to the identification of several highly potent small molecules that significantly enhanced the activity of nerve growth factor (NGF) in PC‐12 cells. Moreover, efforts to define the common pharmacophoric motif suggest that substitution at the C‐10 center significantly affects bioactivity, while the hemiketal moiety of 2 and 3 and the C‐1 substitution might not be critical to the neurotrophic activity. |
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Keywords: | cascade reactions natural products oxidation sesquiterpene total synthesis |
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