Abstract |
The stereoselective syntheses of 7,8,9-trideoxypeloruside A (4) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety (3) are described. The syntheses proceeded through the PMB- ether of an ω-hydroxy β-keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3-syn and -anti diols by stereoselective Duthaler-Hafner allylations and subsequent 1,3-syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high-yielding Prins reaction, to provide the precursor for bicyclic analogue 4. Downstream steps for both syntheses included the substrate-controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring-closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi-type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub-micromolar IC50 values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.
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Authors | Christoph W Wullschleger, Jürg Gertsch, Karl-Heinz Altmann |
Journal | Chemistry (Weinheim an der Bergstrasse, Germany)
(Chemistry)
Vol. 19
Issue 39
Pg. 13105-11
(Sep 23 2013)
ISSN: 1521-3765 [Electronic] Germany |
PMID | 24038407
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Chemical References |
- Antineoplastic Agents
- Biological Factors
- Bridged Bicyclo Compounds, Heterocyclic
- Lactones
- peloruside A
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Topics |
- Antineoplastic Agents
(chemical synthesis, chemistry, metabolism, pharmacology)
- Biological Factors
(chemistry, metabolism)
- Bridged Bicyclo Compounds, Heterocyclic
(chemical synthesis, chemistry, metabolism, pharmacology)
- Cell Line, Tumor
- Cell Proliferation
- Cyclization
- Humans
- Inhibitory Concentration 50
- Lactones
(chemical synthesis, chemistry, metabolism, pharmacology)
- Stereoisomerism
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