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- Title
Synthesis and Biological Activity of 7,8,9-Trideoxy- and 7 R DesTHP-Peloruside A.
- Authors
Wullschleger, Christoph W.; Gertsch, Jürg; Altmann, Karl‐Heinz
- 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 n M biological activity.
- Subjects
TETRAHYDROPYRANYL compounds; DIASTEREOISOMERISM; ISOMERS; DIMERS; STEREOSELECTIVE reactions; CHEMICAL synthesis
- Publication
Chemistry - A European Journal, 2013, Vol 19, Issue 39, p13105
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201301796