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Structure Assignment, Total Synthesis, and Evaluation of the Phosphatase Modulating Activity of Glucolipsin A

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Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Ruiz-Caro,  Juliana
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Fürstner, A., Ruiz-Caro, J., Prinz, H., & Waldmann, H. (2004). Structure Assignment, Total Synthesis, and Evaluation of the Phosphatase Modulating Activity of Glucolipsin A. The Journal of Organic Chemistry, 69(2), 459-467. doi:10.1021/jo035079f.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000F-96A7-C
Abstract
The previously unknown stereostructure of glucolipsin A (1), a complex glycolipid endowed with glucokinase-activating properties, was unambiguously elucidated as (2R,2‘R,3S,3‘S) by comparison of its spectroscopic and analytical data with those of all conceivable C2-symmetric stereoisomers. This set of macrodiolides was prepared by a sequence comprising auxiliary guided aldol reactions, glycosidation of the resulting β-hydroxy acid derivatives with trichloroacetimidate 7, followed by hydrolytic cleavage of the auxiliaries used. The hydroxy acids thus formed were subjected to a macrodilactonization reaction mediated by 2-chloro-1,3-dimethylimidazolinium chloride (22) as the activating agent; this transformation is highly productive only in the presence of admixed potassium cations which likely serve as templates to preorganize two substrate molecules in a favorable head-to-tail arrangement. Glucolipsin and analogues were subjected to enzymatic assays that revealed that glycoconjugates of this type effectively inhibit the activity of the dual specific phosphatase Cdc25A with IC50 values in the low micromolar range, while being hardly active against the tyrosine phosphatase PTP1B in vitro. This activity profile was compared to that of other glycolipids previously prepared in this laboratory, including cycloviracin B1 (2), caloporoside (38), woodrosin I (39), sophorolipid lactone (40), and tricolorin G (41).