| Autor: |
Zurwerra, Didier, Glaus, Florian, Betschart, Leo, Schuster, Julia, Gertsch, Jürg, Ganci, Walter, Altmann, Karl-Heinz |
| Zdroj: |
Chemistry - A European Journal; Dec2012, Vol. 18 Issue 52, p16868-16883, 16p |
| Abstrakt: |
A new total synthesis of the marine macrolide (−)-zampanolide ( 1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide ( 2), that is, ent- 2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent- 2. The β-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ω-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent- 2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene- ent- 2 as well as the monocyclic desTHP derivatives of 1 and ent- 2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with n M IC50 values, while ent- 2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene- ent- 2 as well as the reduced versions of ent- 2 and 13-desmethylene- ent- 2 all showed similar cellular activity as ent- 2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent- 2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only μ M antiproliferative activity, thus being several hundred-fold less potent than 1. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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